• Hyperosmolar hyperglycaemic state (HHS) was formerly known as HyperOsmolar Non-Ketotic coma (HONK).
• HHS is a condition that occurs in patients who suffer from type 2 diabetes mellitus and have very high blood sugars (over 33.3mmol/L).
• The condition can have an insidious onset, worsening over several days or weeks before the patient presents to a health care provider.
• HHS is often caused by a combination of illness (i.e. infection) and dehydration.
• HHS is an emergency with a high associated-mortality and therefore requires specialist treatment, usually in a high-dependency setting.

Aetiology

• In type 1 diabetes, an absolute lack of insulin can cause high blood sugars and lead to the production of ketones which results in Diabetic Ketoacidosis (DKA)- see related article here.
• In type 2 diabetes, however, patients usually retain some usable insulin and the body will not need to resort to ketone production. Therefore someone with type 2 diabetes can have extraordinarily high blood sugar levels without a clinically significant rise in ketones.
  • In HHS, the pancreas is still able to produce small amounts of insulin and this is enough to suppress lipolysis and therefore prevent ketogenesis which would lead to DKA but not enough to lower blood glucose levels to a safe level.
• Importantly, patients with type 2 diabetes who are insulin dependent may develop DKA rather than HHS (as they do not have any usable insulin).
• HHS can be the first presentation of type 2 diabetes.[1]

Epidemiology

• There are fewer hospital admissions for HHS than there are for DKA.
• Sources report HHS accounts for less than 1% of all primary diabetic admissions.
• However, the mortality rate for HHS is 10-20% which is about 10x higher than that of DKA[2].
• Poor outcomes with HHS occur in:
  • Patients at the extremes of age (very young or very old)
  • Those who present with coma and
  • Those with profound hypotension.

Pathology

• While DKA and HHS are separate emergencies, they represent 2 points along the same spectrum of metabolic derangement caused by a lack of insulin.
• Roughly 1 in 3 patients who present with a hyperglycaemic crisis will actually have a mixed picture of DKA and HHS[3].
• As patient’s blood glucose levels gradually rise they will have increasing polyuria due to the osmotic diuresis effect of glucose in urine and this will cause polydipsia.
• As the patient loses more and more fluid through their urine they will develop profound dehydration and electrolyte imbalances.
• The urine will become hyperosmolar.
• Osmolality is calculated from the formula:
  • Osmolality = 2 Na +urea +glucose.
    • NB The equation doubles the value for sodium as it presumes that the body will maintain a balance of anions and cations

Clinical presentation

• Patients with HHS often present with symptoms of:
  • Increased thirst
  • Recent weight loss
  • Urinary frequency
  • Nausea
  • Vomiting
  • Disorientation, drowsiness, reduced GCS, coma
• It is also important to consider the cause for their deterioration i.e. a chest infection or a urinary infection and a patient may present with symptoms associated with the underlying cause.

Clinical features

• On examination of a patient with HHS you will notice signs of volume depletion:
  • Dry mucus membranes (dry mouth)
  • Reduced skin turgor
  • Reduced urine output
  • Cold, clammy peripheries
  • Mottled skin (sign of circulatory collapse secondary to hypovolaemia).
  • Physiological responses to hypovolaemia: tachycardia, hypotension

Diagnosing HHS

• An important step in the management of HHS is recognising it as a potential differential!
• HHS should be a differential for anyone presenting with altered mental status, especially if they have a history of type 2 diabetes (although, as mentioned above this could be their first presentation of diabetes).

• HHS is characterised by:
  • Profound hyperglycaemia (glucose >33.3mmol/L)
  • Hyperosmolality (serum osmolality >320mmol/kg)
  • Volume depletion in the absence of ketoacidosis (pH>7.3 and HCO3>15mmol/L)

Acute management of HHS

Treatment of HHS requires consideration of 5 different goals:

1. Replace fluid and electrolyte losses.
   • These patients are profoundly dehydrated and require careful and considered fluid resuscitation.
   • A Cochrane review has recommended the use of crystalloid rather than colloid fluids[2].
   • Replacing fluids too quickly might lead to cerebral oedema or cerebral pontine myelinosis as it causes fluid shifts and further electrolyte imbalances.
   • Replacing fluids too slowly would be futile and the patient would likely remain hypotensive and hypoperfused.
2. Normalise blood glucose levels
   • Fluid replacement will start to bring down blood glucose levels. Once fluid replacement alone stops bringing the plasma glucose down an insulin infusion can be started.
   • A fixed rate intravenous insulin infusion should be started at a very low dose to prevent bringing the glucose down too quickly.
   • A rapid decrease in glucose might cause the patient to become hypoglycaemic.
3. Normalise osmolality.
   • Rapid changes in osmolality can also be harmful.
   • Fluid replacement alone (without insulin) will lower blood glucose which will reduce osmolality causing a shift of water into the intracellular space. This will cause a rise in serum sodium (a fall in blood glucose of 5.5 mmol/L will result in a 2.4 mmol/L rise in sodium).
   • Rising sodium is only worrying if the osmolality is not declining at the same time.
   • To prevent cerebral pontine myelinosis sodium can only be safely reduced at a rate of 4-6 mmol/hr.
   • Patients with HHS are potassium deplete and require potassium replacement.
4. Treat pre-disposing cause
   • Consider the predisposing cause (i.e. infection, MI, stroke) and treat accordingly.
5. Prevention of complications including:
   1. Arterial or venous thrombosis
      • Hypernatraemia and increasing ADH levels, which both occur in HHS, can lead to a hypercoagulable state.
      • All patients will require low-molecular weight heparin to reduce their risk of developing an arterial or venous thromboembolism.

Cerebral oedema.

• • See above for careful management of fluids, glucose and electrolytes.

Foot ulcers

• • Daily foot checks.

Patients with HHS will need to be treated in a high dependency setting.

Further management

• Correcting blood glucose, electrolyte imbalances and increased osmolality will be done carefully as rapid correction is harmful.
• These patients do best when they are cared for with an MDT approach:
  • Mobility: Early mobilisation is essential for recovery.
  • Nutrition: dietician involvement to assess nutritional status and give advice regarding re-feeding once well enough to avoid re-feeding syndrome.
• Diabetes management:
  • IV insulin can be discontinued once the patient is eating and drinking and SC insulin therapy can recommence.
  • All people with HHS should be referred to the specialist diabetes team.
  • Education! All patients will receive education to reduce the chance of reoccurrence and long-term complications.

References

1. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001;24:131-153
2. Diabetic ketoacidosis and hyperosmolar hyperglycaemic state – UpToDate
3. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med. 1991;6:495-502
4. Diabetes UK (2012). The management of the hyperosmolar hyperglycaemic state (HHS) in adults with diabetes
5. Perel, P. and Roberts, J. (2011). Colloids vs crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systemic Reviews. Issue 3.

Read more about our sources

The post Hyperosmolar Hyperglycaemic State (HHS) appeared first on almostadoctor.

• Type I diabetes is a disorder that results from the destruction of the beta cells of the pancreas, which produce insulin
• It accounts for about 10% of cases of diabetes mellitus, the other 90% are type 2 diabetes
• It occurs in genetically susceptible individuals with environmental trigger factors, although the exact aetiology is not well understood
• The development of the disease probably occurs over months or years, during which time, the patient is asymptomatic
• It can cause the acute presentation diabetic ketoacidosis (DKA) which is life-threatening if untreated, although with the correct treatment, it often improves rapidly
• Patients require life-long insulin therapy
• The pathology differs from type 2 diabetes, where decreased insulin production, and increase insulin resistance in the peripheral tissues are the main factors

Aetiology

• It is not strictly genetically determined, but a given individual may have an increased risk due to their genetic make-up. Monozygous twins show a concordance rate of 30-50%.
• The risk is highest in those with a close family member with type 1 diabetes
• Certain human leucocyte antigen (HLA) variants are correlated with the disease
• Having a father with type 1 puts you at greater risk (3-8%) than having a mother with type 1 diabetes (1-4%)
• It is often associated with other autoimmune diseases, particularly auto-immune thyroid disease, celiac disease and pernicious anaemia.
• Proposed environmental triggers include viral infection, and early exposure to cow’s milk in childhood. Particularly suspected are enteroviruses such as coxsackie, Epstein-Barr, rubella, mumps. It is thought that this risk is greatest if an individual was exposed wither very early in life, or before they were born, via the mother (in utero).
• Also suspected but not proven is a ‘clean environment’ during childhood. This means less exposure to pathogens, and thus the immune system is not stimulated as much as normal in a child. This is known as the hygiene hypothesis and it is a hypothesis for all autoimmune diseases.
• Bovine serum albumin (BSA) has also been implicated. This is found in cow’s milk. This link has been proposed because type 1 diabetes is more common in those who were not breast fed. BSA can cross the neonatal gut and enter the blood stream. Its structure is similar to a heat-shock protein that is expressed on the surface of beta cells, and thus the child may develop antibodies to BSA, which it is then suggested may cause an immune reaction against beta-cells.
• Nitrousamides – these are found in smoked and cured meats and some have also suggested these may be implicated.
• Islet cell autoantibodies (ICAs) have been identified in up to 85% of individuals with type I diabetes, although it is likely there are several antibodies involved, including anti-insulin antibodies
  • Testing for antibodies can help to confirm the type of diabetes present (T1 vs T2)
  • Anti-insulin, anti-islet cell antibodies and GAD (glutamic acid decarboxylase) can all be tested
  • They are not totally specific. up to 10% of T2DM patients will show antibodies, and they are absent in about 10% of T1DM patients
  • If the diagnosis remains uncertain, consider referral to an endocrinologist

Epidemiology

• It is a disease that usually shows itself in childhood. There are two incidence peaks, one around age six, and one around the time of puberty (age 10-14).
• Incidence shows strong geographical variation. In the USA, in white children, the incidence is about 15 per 100,000, and lower in children of other racial backgrounds
• The incidence of type-1 diabetes is on the increase, particularly in children under 5. The annual increase in Europe is about 3-4%.
• There is no gender difference in incidence, despite the fact that autoimmune diseases are usually more common in women

Pathology

• It is a T-cell mediated autoimmune disease that results in destruction of beta cells of the pancreas. It is quite slowly progressing. It can be caused by other pathologies, and so technically speaking the type caused by T-cell mediated autoimmunity is type 1A, however, the other causes are very rare.
• High glucose levels, lead to high osmolality of blood, and thus the patient become ‘dehydrated’ and has to drink lots. They will also secret lots and lots of aldosterone.
• Age of onset is typically around puberty.
• Investigations have shown that the first islet antibodies appear in the blood during the first few years of life. This shows that the disease is very slow to progress, and also opens up the possibility of screening and prevention programs. However, there has yet to be a preventative method that has proven effective.
• In the short term, cyclosporin as an immunosuppressive agent has been shown to reduce beta cell degeneration.

Clinical presentation

• These people will usually have a normal BMI
• Patients will present when beta-cell destruction is such that the remaining beta-cells can no longer secrete enough insulin. High glucose levels may actually induce beta-cell death, thus speeding up the progression of the disease in later stages.
• Weight loss is a major symptom, and this will fail to correct itself when diet is altered. There will also be ketourea, hyperglycemia, and the presence of autoimmune products. Note that these are only present in 90% of newly presenting patients.
• The majority of patients present with the classicla presentation of hyperglycaemia, without ketoacidosis. They have symptoms such as polyuria, polydipsia and weight loss. The mean duration of symptoms before presentation is about 10 days.
• Diabetic Ketoacidosis (DKA)– is an acute life-threatening medical presentation, less common but more serious than the classical presentation.. It is a result of lack of insulin. In normal function, the liver produces keto acids from deamination of amino acids (this is how the liver gets most of its energy). Keto acids are also produced through metabolism of fatty acids. In diabetes, there is a massive perceived lack of glucose by the body (because little or no glucose can be taken up by cells), and so the body resorts to metabolism of fatty acids, and thus production of ketone bodies as its main source of energy. The body produces two ketoacids in this process, one of which is called acetoacetic acid. This spontaneously breaks down to form acetone which is the smell (of nail polish / varnish) that can be smelt on a person’s breath who is suffering from type one diabetes
• Ketoacidosis can also occur in alcoholism. Alcohol blocks the first step in gluconeogenesis, and thus the body has to break down fatty acids to get its energy.
• Ketoacidosis is also significant because it causes a generalised acidosis.
• It principally occurs in those with type 1 diabetes, because most people with type two can still utilise enough glucose to prevent this from occurring.
• It is a medical emergency and a major cause of morbidity. Many type 1 patients present in this state, but it can also occur in those that have been diagnosed and are undergoing treatment.
• In established diabetes there will usually be a precipitating event for DKA (although one isn’t always found). This is commonly illness, most usually infection. It occurs because during this episode, patients will lose their appetite, and thus reduce their levels of insulin in a mistaken belief that they no longer need it.
• During illness, patients need up to 25% extra insulin to help them fight the infection – the immune system’s effectiveness is reduced as a result of diabetes!
• The mortality rate from ketoacidosis is 5-10% in developed countries. This increases with age.
• It is estimated that 25% of cases of this could be prevented through better communication to the patient- they should be instructed never to stop taking their insulin!
• The three key features of DKA are:
  • Hyperglycaemia – this has a profound effect on osmosis, and causes osmotic diuresis, leading to dehydration and electrolyte loss.  However, the level of hyperglycaemia is not necessarily related to the level of ketoacidosis. In some cases, only a small hyperglycaemia can cause ketoacidosis, whilst in other patients, there may be massive hyperglycaemia but little or no ketoacidosis.
  • Hyperketonaemia – this occurs as a result of very little circulating insulin. The effect is exaggerated by stress proteins, such as those present during illness. This results in the utilization (by the liver via ketogenesis) of loads of free fatty acids for metabolism. The mitochondira of cells will then utilise these for metabolism, producing excess ketones as a result. This results in metabolic acidosis.
  • Metabolic acidosis- When the number of free ketones in the blood exceeds those that can be metabolised, ketoacidosis occurs. This will then force H+ into cells, where it will replace potassium. The potassium will go into the blood, where it may induce vomiting. Otherwise, the potassium ions are lost in the urine. (Thus two possible signs and symptoms of ketoacidosis are high potassium levels in the urine, and vomiting (also containing large amounts of potassium).
  • Only a slight elevation in insulin level is enough to prevent ketogenesis in the liver, and thus reverse or prevent this state.
  • The real danger in this condition is reduced perfusion of the kidneys as a result of fluid and electrolyte depletion. This will result in an inability to excrete the excess hydrogen and ketones, and the patient will die. This process is due to a COMBINATION of high levels of both glucose and ketones. The ketones cause the damage, but the glucose is responsible for much of the fluid and electrolyte depletion.
  • Respiratory compensation for the acidosis will occur, leading to hyperventilation (Kussmaul respiration).

• Water – 6L
• Sodium – 500mmol
• Chloride – 400mmol
• Potassium – 350mmol

Clinical features

• Polyuria, thirst
• Weight loss
• Weakness
• Nausea / vomiting
• Leg cramps
• Blurred vision
• Abdominal pain
• Kussmaul breathing
• Dehydration
• Hypotension
• Cold extremities / peripheral cyanosis
• Tachycardia
• Hypothermia
• Smell of acetone
• Confusion / drowsiness / coma

Management of DKA

Based on Joint British Diabetes Societies Inpatient Care Group guidelines, September 2013 

DKA is a serious and potentially life-threatening presentation. It is a combination of acidosis, hyperglycaemia, and ketonuria. It may be the first presentation of type I diabetes in a child or young adult, but is also a common presentation in type I diabetics with poor insulin compliance. Treatment should be initiated promptly, and needs regular monitoring with (hourly) blood ketone (and glucose) levels, or, if not available, bicarbonate levels on venous blood gas.

You should involve a specialist as soon as possible (ideally within 24 hours), as this has been shown to reduce morbidity and mortality.

Severe DKA is characterised by:

• Blood ketones >6 mmol/L
• Bicarb <5 mmol/L
• pH <7.0
• Hypokalaemia (k+ <3.5)
• GCS <12
• O2 <92% on room air
• Systolic BP <90
• HR >100 or <60
• Raised anion gap

• Insulin dose should be based on weight. Sliding scales should not be used, as they can be inaccurate in overweight and pregnant patients
• The type of insulin regimen is often referred to as a Fixed rate Intravenous Insulin Infusion, or FRIII
• Check the effectivesness of the FRIII using blood ketones and revise the dose if it is not effective
• If bedside blood ketone testing is not available, venous blood gasses can be used to asses bicarbonate level, but only for the first 6 hours, as this becomes inaccurate after infusion of large amount of normal saline.

• Use IV 0.9% sodium chloride (normal saline)
• If hypotensive (systolic BP <90mmHg) give a bolus of 500mls normal saline. If still hypotensive, seek senior help. Consider discussion with ICU, and think about other possible causes of hypotension.
• Once hypotension is resolved, or if it is not present at presentation, patient will still require large amounts of IV fluid. A typical regimen might be 1L normal saline in the first hour, then 1L over 2 hours, then 1L over 4 hours etc, but be wary of a ‘one size fits all’ regimen
• Monitor electrolytes, particularly potassium  closely. You will likely need to replace potassium, which can be done by adding KCl to the bags of normal saline. Be careful not to infuse potassium too quickly.

Potassium
DKA patients are at risk of both hypokalaemia, and hyperkalaemia. Initially they are often hyperkalaemic, but their total body potassium is low. This is because potassium is taken up into cells with insulin, so with a lack of insulin, extra cellular potassium rises, and the intracellular level falls.
Titrate potassium replacement to the potassium level, as measured on hourly venous blood gasses.

• K+ >5.5mmol/L – dont replace
• K+ 3.5 – 5.5 mmol/L – replace by using 40mmol/L in infused solution
• K+ <3.5 – seek senior help – additional potassium replacement may be require

Approach
DKA patients are often very sick. As with any sick patient, it is useful to have a systematic approach. Do the basics first:

• A – Airway
  • ​Are they maintaining their own airway?
  • Do you need urgent airway assistance? Consider ICU / anaesthetic input
• B – Breathing
  • ​What are the O2 saturations?
  • What is the respiratory rate?
  • Do they need oxygen?
• C – Circulation
  • ​Get IV access
  • Send regular bloods (FBC, U+Es, CRP, formal glucose level, blood cultures)
  • Blood ketone and glucose (bedside testing)
  • Venous blood gas
• D – Disability (/conscious level)
  • Assess GCS – helps to assess severity of DKA
  • Consider causes for DKA (e.g. infection – send off cultures, check temperature)
• Start IV fluids – as described above
• Replace Potassium – as described above
• Start Fixed Rate Intravenous Insulin Infusion – as described above

Monitoring

• Re-assess hourly, including bedside ketones and glucose, venous blood gas (VBG) and clinical assessment and examination.
• The aim is to reduce the ketone level, and stop ketogenesis.
• Aim for reduction of ketone level of >0.5mmol/L/hr
  • If unable to measure blood ketones, use VBG instead, and aim for bicarbonate rise of >3.0mmol/L/hr, and blood glucose fall of 3.0mmol/L/hr
• Maintain serum potassium of 3.5 – 5 mmol/L (see above for potassium management)
• Avoid hypoglycaemia. It may be necessary to use 10% dextrose IV
• Consider urinary catheter if anuric
• Consider NG tube if persistent vomiting or obtunded

Resolution of DKA

• Defined as blood ketones <0.6 mmol/L and venous pH >7.3
• After 6 hours, bicarbonate level should not be used as a measure of progress, as hyperchloraemia may exist secondary to saline infusion. Hyperchloaraemic acidosis can lower bicarb.
• Continue to treat precipitating factors
• If patient is eating and drinking, start subcutaneous insulin. If not, can start a sliding sclae (VRIII – variable rate intravenous insulin infusion)
• Most cases resolve within 24 hours. If not resolving, seek specialist / senior support urgently.

Long Term Management

Patients will require life-long insulin therapy

References

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Type 2 diabetes mellitus (T2DM) is a largely preventable, common metabolic disorder, of increasing incidence and increasing significance, particularly in developed countries. In 2014, about 3% of the population had a diagnosis of T2DM. It is estimated that by 2025, this could be as high as 10%. The incidence is thought to be growing due to the increasing prevalence of obesity, as well as lifestyle and dietary changes, and an ageing population.

Uncontrolled type 2 diabetes can lead to an increased risk of cardiovascular disease – including MI and stroke, as well as renal failure, blindness, and limb amputation – secondary to peripheral neuropathy.

It is caused by a progressive defect in the secretion of insulin, secondary to insulin resistance.

It is a huge topic. If you are just starting out learning about diabetes, you might find it useful to read the article an Introduction to Diabetes.

Most cases are managed by GPs in primary care, but more complex and resistant cases may require an endocrinologist. Patients should regularly have eye checks, see a podiatrist for management of complications of peripheral neuropathy, and have regular blood tests for HbA1c, urea and electrolytes, and urine testing for the effects of renal disease.

The general principles of management are the same in most developed countries. The author of this article is a British Doctor, trained in the UK, now practising in Australia. I have tried to cover management recommendations from both countries (based on NICE Guidelines for Type 2 diabetes for the the UK, and the RACGP guidelines on the management of type 2 diabetes for Australia), and where differences arise I have detailed these separately.

Aetiology

• The four main determining factors are; age, obesity, family history and ethnicity.
  • Under-activity, overeating and obesity are all factors in the formation of this disease.
• It is thought that the presence of excess triglyceride within the cell has some effect in causing the insulin resistance.
• The genetic link in type 2 diabetes is stronger than that in type 1 – monozygotic twins have a greater than 50% chance of developing the disease (compared to 30-50% in type 1).
• MODY – maturity onset diabetes of the young – this is a rare type of type 2 diabetes. It will present in young people who have a family history of type 2 diabetes. It is dominantly inherited.
• There is evidence to suggest that low birth weight and low weight at 12 years of age predisposes to type 2 diabetes, as well as to cardiovascular disease and hypertension. The theory is that low weight is related to malnutrition, and poor nutrition can impair beta cell development, thus putting you at greater risk of type 2 diabetes later in life.
• There is no evidence that type 2 diabetes is related to autoimmunity. However, there is some evidence that inflammatory markers (CRP) and cytokines are raised in obesity, and as a result some people believe this plays a role in the development of diabetes.
• Whether or not a person will develop type 2 diabetes is generally due to genetic factors. When it occurs can be influenced by lifestyle factors.
• Diabetes diagnosed in a man aged 40-59 will cause a reduction in life expectancy of 5-10 years. Therefore, preventing the onset of type 2 diabetes can have a significant impact on life expectancy. Diabetes diagnosed after the age of 70 has little effect on life expectancy.
• Age – particularly age over 40
• Weight gain is thought to be the main aetiological factor. However, it is not as simple as “energy in vs energy out”. It is true that people in modern western societies eat more energy dense foods and do less exercise, but there are thought to be other factors implicated in weight gain too:
  • Reduced sleep – we sleep less than previous generations. This is linked to weight gain
  • People tend to become heavier as they get older – and now populations are living longer
  • Efficient heating and air conditioning reduce the body’s energy expenditure during heating and cooling

Epidemiology

• The overall prevalence of this disease in the UK is about 5%. This rises to 10% by the age of 70.
  • Excepted to double by 2030
• The disease is relatively common in all populations enjoying an affluent lifestyle.
• ‘In poor countries, diabetes in a disease of the rich, but in rich countries, diabetes is a disease of the poor’
• The disease may be present in a subclinical form for many years before it is detected.
• The onset of the disease can be accelerated by stress, pregnancy, illness or certain drugs.
• In western societies, adults of the age 25-55 gain about 1 gram of weight a day. This is due to an excess of just 90 calories a day (one chocolate coated digestive biscuit!). Due to a combination of excess calorie intake and sedentary lifestyle.
• The insulin resistant state associated with type two diabetes often presents with other risk factors that put someone at greater risk of cardiovascular disease. These include things like;
  • Hypertension, obesity, hypertriglyceridaemia, decreased HDL cholesterol and acanthosis nigricans; 
• The insulin resistant state, often combined with the symptoms above has been called metabolic syndrome, syndrome X or insulin resistance syndrome.  The syndrome is a product of genetic susceptibility combined with a sedentary lifestyle, and obesity. It is not strictly a true syndrome, as alterations in the above factors can remove the aetiology, and thus mean you are no longer a sufferer of metabolic syndrome.  Metabolic syndrome is a state which puts you at much greater risk of cardiovascular disease and diabetes (i.e. you are on the road to developing these diseases), but by modifying lifestyle and body weight, you can ‘revert’ to normal levels of risk
• About 1/3 of the adult population have some of these symptoms, not necessarily associated with type 2 diabetes.
  • Do not confuse this with ‘Cardiac syndrome X’.

Pathology

Progressive – involves a combination of initial insulin resistance and later followed by relative secretory failure of insulin.

• Initially insulin is still released normally, and will still bind to insulin receptors, but it will not cause the normal physiological changes inside the cell. This occurs in genetically susceptible individuals due to modifiable lifestyle related factors. This is known as insulin resistance
• Type-2 diabetes results when a person cannot secrete enough insulin to overcome this ‘resistance’.
• Muscle cells in particular show increased insulin resistance and decreased glucose uptake
  • Exercise is very effective at reducing this resistance in muscle cells
• The secretory failure of insulin occurs when there is increase Beta-islet cell apoptosis, and the remaining cells fail to respond to insulin signalling
• Increased lipolysis with elevated free fatty acids
• Alpha-cell dysfunction  – elevated glucagon levels
• Increased glucose reabsorption by the kidneys
• Altered cerebral responses to insulin and apetite

• Elevated glucose production by the liver in response to insulin resistance – not only does a high blood glucose occur because normal digested glucose cant be taken up by cells, but it has a secondary effect on the liver; there is less glucose entering liver cells, and so the liver reacts as if blood glucose were low, and begins glycogenolysis, and raises blood glucose even more.
• Patients will have up to 50% of their beta cell mass at diagnosis. However, this destruction of beta cells is nowhere near as extensive as in type 1 diabetes. Most patients will also show amyloid deposition around the islets at autopsy. Amylin is a product secreted with insulin by the beta cells. It is not known if the amylin is a cause or a consequence of beta cell failure.

• Most studies show the the complications of diabetes can be prevented with an HbA1c of <7% – slightly higher than the cut off required for diagnosis

• The RACGP [Australia] recommends that patients with an HbA1c of between 5.5 – 6.9 mmol/L undergo oral glucose tolerance testing to confirm the diagnosis

Glucose Tolerance Test and Impaired Fasting Glucose

Diagnosing diabetes by glucose levels

 

• IGT – within 5 years, 25% of these patients will develop type 2 diabetes. 25% will also revert to normal glucose levels. Patients with IGT are not likely to suffer microvascular complications but can still suffer from cardiovascular disease secondary to IGT (macrovascular disease). These patients must be followed up due to their risk of developing macrovascular disease. So basically, the difference between diabetes and IGT is diabetes has microvascular complications, and IGT does not. However, there is the same high risk of macrovascular complications.
• You should monitor these patients levels of glucose tolerance via an oral test.
• Weight loss, increased physical activity, and a low fat diet have all been shown to reduce the risk of progression to type 2 diabetes. Currently, antihyperglycaemic drugs (e.g. metformin) are being evaluated for use in this group of patients.
• IFG – almost identically to IGT, 25% of these patients will progress to type 2 diabetes within 5 years, and again, microvascular risks are thought to be negligible. However the cardiovascular risks are not as high as IGT or diabetes, but they are still increased over those of the general population.

Screening

Everyone over the age of 40 should be screened regularly. Those deemed at higher risk by ethnic background should be screened from a younger age. Screening involves the use of a questionnaire scoring system to stratify the risk, and those at high risk should have HbA1c testing every 1-5 years (depending on other risk factors).

UK and Australian guidelines differ slightly, as outlined below.

UK (NICE Guidelines)

• Screen everyone over 40
  • Consider screening anyone over 25 if likely high risk – e.g. high risk ethnic group (South Asian, Chinese, African-Caribbean, Black African origin)
• Use a verified screening assessment tool – for example the Diabetes Risk Assessment Tool – I use AUSDRISK (because I work in Australia), but NICE don’t specify a specific tool.
  • If low or intermediate risk, screen every 5 years
  • If high risk, perform HbA1c or fasting glucose

Australia (RACGP Guidelines)

• Screen everyone over 40 every three years – using AUSDRISK scoring tool
  • Screening should start at age 18 in patients of Aboriginal or Torres Straight Islander origin
• Anyone with an AUSDRISK score of >12 (high risk), OR history of previous cardiovascular event, gestational diabetes, PCOS, on antipsychotic drugs;
  • Should have HbA1c testing every 3 years
• Anyone with a high risk AUSDRISK score AND a previously elevated fasting blood glucose or impaired glucose tolerance test should have HbA1c testing every year

Clinical presentation

Acute presentation – Patients who are acutely unwell are typically those with type 1 diabetes, although not always. The classic triad of the acute diabetic presentation includes:

• Polyuria – due to osmotic diuresis that occurs when blood glucose levels exceed the renal threshold. (the renal threshold is the concentration in the blood of a substance at which the kidneys will begin to remove it from the blood).
• Thirst – due to the resulting loss of fluid and electrolytes
• Weight loss – due to fluid depletion and the accelerated breakdown of fat and protein reserves as a result of insulin deficiency.
• Ketonuria may also be present, and in severe cases it may progress to ketoacidosis.

• Acanthosis nigricans – dark coloured skin, often with a velvet-like texture. Typically around the neck and in the axxilae
• Skin tags
• Central obesity
• Hirsutism – excess male pattern hair growth – most notable in women

If accurate information is not supplied, then misinformation from friends and family may take its place.
Patients should be encouraged to learn how to manage their condition themselves, with guidance from clinicians.

• 20-30% of patients can be managed by diet alone
• About 1/3 of patients will be managed by oral treatments
• About 1/3 will be managed with insulin

Summary of goals

• Weight – aim for BMI in the health range (18.5 – 24.9). This may be unrealistic for many patients – in which case – aim for weight loss of 5-10%
  • Surgery should be recommended for those with BMI >40, or BMI >35 with poor glycemic control
• Physical activity
  • Children – 60 minutes a day, including 3 days of muscle strengthening activities
  • Adults – 30 minutes per day (150 minutes per week) of moderate intensity activity, including 2-3 days (at least 60 minutes) of strengthening exercise
• Cigarette consumption – Zero
• Alcohol – <2 standard drinks a day, and two alcohol free days per week (same recommendations as general population
• Blood glucose levels and monitoring
  • Aim for fasting level of 4-7 mmol/L
  • Post prandial (2hrs) – 5-10mmol/L
  • Regular blood glucose monitoring is only routinely recommended for those on insulin. Those on other diabetes medications should have an individualised plan – especially when monitoring changes to medications
• HbA1c – aim for <7%
• BP – <140/90, or if any evidence of renal disease <130/80
• Urine ACR – <2.5mg/mmol for men, <3.5 mg/mmol for women
• Vaccinations – annual influenza, pneumococcus, diphtheria, tetanus and pertussis

Step wise approach

• Lifestyle
• Lifestyle + metformin
• Lifestyle + metformin + secondary drug agent << start here if HbA1c >8.5% at diagnosis
• Lifestyle + metformin + secondary drug agent + insulin (+/- third line agent – most commonly GLP-1 agonists)

When we talk about weight, we are particularly concerned with intra-abdominal weight as insulin resistance in closely linked to abdominal obesity. Measuring waist circumference is particularly important in identifying at risk populations. Weight is the most important factor for determining diabetes risk – the fatter you are, the greater the risk – the risk rises exponentially!
 

Diet modifications

Dietary and lifestyle modifications can have a massive positive impact on insulin sensitivity.

Dietary habit changes are often slow and incremental.

Contrary to popular belief, the diet for somebody suffering from diabetes should be no different from a normal healthy diet. There is no ‘special’ diabetes diet. A sensible healthy diet should include:

• A low sugar diet
• High starch carbohydrate (especially foods with a low glycaemic index). Carbohydrate should account for 40-60 of total energy intake.
  • Three servings of whole grains daily is recommended
  • Confectionary foods (cakes, biscuits etc) should account for no more than 10% of energy intake
• Starchy carbohydrates are absorbed slowly and thus prevent rapid swings in circulating glucose. For example, the peak of circulating glucose is much lower when eating brown rice than that seen when eating white potato.
• High in fibre. Soluble fibre can be absorbed by the gut and has beneficial effects on metabolism. Insoluble fibre cannot be absorbed and so does not affect metabolism, however it is good for GI motility and increases feeling of satiety.
• Low in fat (particularly saturated fat). Fat should not account for more than 35% of the energy intake
• Low protein – this should account for no more than 10% of energy intake. Eating oily fish once or twice a week is recommended.
• Consuming at least 1.5 servings of dairy foods per day is associated with a decreased risk of developing T2DM
• Vitamins and minerals – there is no evidence that supplements are beneficial, therefore these should be obtained through the mixed intake of fruit and vegetables in a well rounded diet.
• Less than 6g salt a day. This should be even less in those with hypertension.
• Alcohol is not forbidden but should be taken in moderation. Don’t forget its calorific value, and also remember that it can cause hypoglycaemia in those treated with insulin.
• Overweight patients should be strongly encouraged to lose weight through dietary and lifestyle modification.

Generally, people find it very difficult to alter their diet. Patients should be encouraged to set targets for achievable modifications. All newly diagnosed patients should be referred to a dietician and diabetes educator. Changes to food intake should make as little impact on lifestyle as possible.

Exercise

30 minutes of moderate intensity exercise daily, for a total of at least 150 minutes per week, including strengthening exercises on at least 2 days a week totalling at least 60 minutes.

Exercise has multiple, independent benefits:

• Improves insulin sensitivity
• Reduces cardiovascular risk
• May help with weight loss
• Reduces BP
• Improves lipid profile
• Improves mood
• Increases energy expenditure

These benefits are independent – i.e. regular exercise will improve insulin sensitivity and reduce cardiovascular risk, regardless of whether or not it reduces weight.

Patients on medication that carry risk of hypoglycaemia (sulphonylureas and insulin) should be aware of the effects of exercise on blood sugar – in particular – delayed hypoglycaemia – which can occur 6-12 hours after the activity. Advise patients to check their blood sugar level (BSL) before, during and after exercise. If the pre-exercise BSL is <5 mmol/L, there is a risk of hypoglycaemia during the activity. Patients should carry a rapid glucose source with them at all time when doing physical activity. Also advise patients to be vigilant to check their feet after any physical activity.

Recommendations

Patients should have an independently tailored exercise plan. The generalised advice below may not be suitable for all. When discussing this with patients it is important to set specific goals. Setting short term, gradually increasing goals may improve compliance and assist in achieving goals.

• 30 minutes of exercise on at least 5 days per week
• At least 150 minutes per week of “moderate intensity” exercise
• Including both aerobic exercise and resistance / strength training (on at least 2 days totalling at least 60 minutes)
• No more than two consecutive days without exercising
• Exercise has been proven to have a similar effect to metformin or sulphonylurea – on average will lower HbA1c by about 0.7% compared to 0.9% for medication
• Regular exercise also reduces the risk of developing type 2 diabetes
• Encourage a reduction in sedentary behaviours
• Suggest that sitting be interrupted every 30 minutes
• Consider flexibility and balance exercises 2-3x per week for patients aged >60

Moderate intensity

• Defined as 55-69% of maximum heart rate
• Max HR = 208 – (0.7 x age in years)
• In layman’s terms – this roughly equates to a brisk walk or any other activity that increases the rate of breathing, but where you are still able to talk in full sentences
• Many fitness gadgets – e.g. fitbit, garmin or apple watch include wrist based heart rate monitors and will automatically perform this calculation and display the information on the device and within the accompanying app. If patients are keen to engage in lifestyle modifications it may be worthwhile explaining how to keep track of this with a fitness device [authors opinion].

Patients should be advised to stop the activity if they feel unwell (e.g. symptoms of hypoglycaemia, claudication or cardiovascular disease – i.e. angina) and to follow up with their GP before performing any more exercise.

Weight

Patients who are overweight or obese should be encouraged to lose weight. A healthy weight should be assessed using the Body Mass Index scale (BMI). It is also important to do a waist measurement – abdominal obesity (larger waist) is more strongly correlated to disease risk than weight alone. A waist measurement of >80cm for women and >94cm for men is considered significant.

5-10% weight loss is associated with reduced cardiovascular risk, better glycaemic control and delayed progression of complication of diabetes. It is associated with about a 0.6% reduction in HbA1c. Aiming for a ‘healthy weight’ id often a much larger weight reduction than 5-10%. This is often not achievable and discourages patients from even attempting to lose weight.

• Healthy weight – BMI 18.5 – 24.9
• Overweight – BMI 25 – 29.9
• Obese – BMI – 30+

In general, patients with a BMI of >40, or >35 with any co-morbidities (including diabetes) should be offered the option of bariatric surgery.

Excess weight usually results from a prolonged period of “energy imbalance”. This balance is the sum of calorie intake (diet) and energy expenditure (exercise). However, it is more complicated than this. There are a wide range of genetic, environmental, social and physiological adaptive factors that influence weight gain and weight maintenance.

Other lifestyle factors

• Advised patients to stop smoking. Smoking is associated with worse outcomes in type 2 diabetes in both men and women
• Advised patients about safe drinking limits. Alcohol interferes with the action of insulin and increases the risk of hypoglycaemia.

Medical Management

There are many medical agents. Patients should usually start on metformin first (unless contraindicated). Monitor the effectiveness of treatment with 3-monthly HbA1c, and increase the dose if required. If this is ineffective add a second agent. Usually the second agent is a sulphonylurea. 

• Both NICE [UK] and RACGP [Australia] recommend that other agents (i.e. other than metformin or syulphonylurea) should be reserved for instances where metformin or a sulphonylurea cannot be tolerated, or have been ineffective.
• This is due to insufficient long-term evidence for the benefits (i.e. reduction in microvascular and macrovascular complications) of many of these other agents (e.g. DPP-4i, SGLT-2i, TZD, GLP-1 drugs)

Monitor HbA1c again, and a third agent can be added as necessary.

Summary Table of Glucose Lowering Medications

Medication	Weight	Hypo Risk	Reduced Renal Function	Other Info
Metformin		Low	Reduce dose – eGFR 30-60 Contraindicated – eGFR <30	First Line Agent
Sulphonylurea	May ­↑*	Yes	Increased risk of hypo
DPP-4i	May ↓	Low	Reduce dose	Contraindicated with GLP-1
SGLT2i	↓	Low	Contraindicated – eGFR <30	Associated with modest reduction in BP, and increased risk of UTI
GLP-1	↓	Low	Contraindicated – eGFR <30 Reduce dose in more mild renal impairment	Contraindicated with DPP-4i Can be given once weekly
TZD	↑­­	Low	Avoid	Many side effects – weight gain, fluid retention, bladder cancer, osteoporosis
Acarbose	May ↓	Low	Contraindicated	Case GI side effects – such as increased flatulence and diarrhoea
Insulin	↑­­	Yes	Increased risk of hypo

*Gliclazide thought to have a neutral effect. Other sulphonylureas associated with weight gain

Biguanides (Metformin)

Metformin is the only biguanide in clinical use.

• e.g. Metformin 500mg BD, increasing to 1000mg BD as required

Metformin in the first line medical agent in type 2 diabetes – unless contraindicated.
It increases insulin sensitivity – particularly in peripheral muscle tissue. The actual mechanism is unclear, but it reduces gluconeogenesis, and thus reduces glucose output from the liver, and so insulin sensitivity is increased.
This is generally preferred to sulphonylureas because it cannot cause hypoglycaemia, and is not associated with weight gain. Therefore this is normally first line treatment.

There is good evidence that it reduces both the macrovascular and microvascular complications of diabetes.

Starting dose is typically 500mg, and can be titrated up to a maximum of 3,000mg daily.

Side effects include ; epigastric pain, anorexia, diarrhoea, bloating, flatulence.

• Many unnecessary colonoscopies have been ordered, when stopping metformin would have stopped the symptoms!
• Taking metformin with food can minimise the GI side effects
• About 5% of patients are unable to tolerate the side effects despite a reduction in dose
• Side effects are more common with underlying gastrointestinal disease (e.g. coeliac disease, inflammatory bowel disease, irritable bowel syndrome)

Contraindications

• Severe liver or kidney disease as lactic acidosis has been known to occur
  • Reduce dose if eGFR 30 – 60
  • Contraindicated if eGFR <30
• Not able to tolerate side effects
• Very low BMI, patients may be given sulphonylureas as first line (as these encourage weight gain)

Sulphonylureas

(e.g. tolbutamide, gliclazide, glipizide, glimeperide)

• e.g. gliclazide 40mg OD or BD, increasing to maximum of 160mg BD

Sulphonylureas stimulate insulin secretion in response to glucose and other secretagogues.

They are proven to reduce the microvascualr complications, but often cause weight gain, and evidence for the risk of risk of macrovascualr complications (i.e. cardiovascular disease) is unclear.
They work by closing the K+ channels in the beta cell membrane thus causing opening of voltage controlled calcium channels, and allowing influx of calcium, which sets of second messenger cascades that result in the release of insulin by exocytosis.

• They require a certain mass of functional beta cells, otherwise they are ineffective. As a result they are not much use in ketotic patients. 
• They cause the beta cells of the pancreas to produce insulin regardless of blood sugar levels
• They should be avoided during pregnancy.
• They should also be avoided in those with liver conditions Some sulphonureas are removed primarily by the liver, whilst others are mainly removed by the kidney. Those with renal impairment should be placed on one which is primarily metabolised by the liver.
• They encourage weight gain – and therefore should not be first line treatment in obese patients. The mechanism of weight gain is not well understood. It is thought to be due to a combination of:
  • Reduction of glycosuria as diabetes is brought under control – and thus this previously “lost” glucose is now retained
  • Induction of hypoglycaemia – which may result in secondary over-eating
• They interact with warfarin
• They bind to albumin, and thus may be affected by other competitively binding drugs such as sulphonamides
• Hypoglycaemia is a common side effect. It is also quite dangerous, because the effects of some of these drugs can last over 24 hours. In some cases this can mean hospitalisation is necessary.
  • More common with longer acting agents – e.g. glimepiride, and slow-release gliclazide)
  • Patients with renal impairment are more likely to have hypoglycaemia and should be prescribed a reduced dose

Tolbutamide

• This is the drug of choice in the elderly due to its short half-life. However, it is also less effective than other sulphureas.
• It is largely metabolised by the liver, and can thus be used in cases of renal impairment

Glibencamide, glipizide, glimepiride

• These are not suitable for use in renal impairment
• They have a very long half-life and active metabolites

Gliclazide

• Has a long half-life
• Metabolised by the liver and thus can be used in renal impairment

Chlorpropamide

• Very long half-life
• Not suitable in renal impairment
• very expensive (so not used in developing countries)
• can cause a facial flush when used with alcohol
• 1-2% will develop ADH like syndrome.

Other drugs

• There are a wide range of other classes of medications used to treat diabetes – as outlined below
• These are not as widely used and tend to be used where there are contraindications to the main two types – metformin and sulphonylureas
• Occasionally one of these drugs might be added as a third line agent to the above two drugs before insulin is used
• In many cases, once maximal doses of metformin and a sulphonylurea are reached, if diabetes remains uncontrolled, insulin is initiated
• SGLT-2 inhibitors, DPP-4 inhibitors and GLP-1 analogues are becoming more widely used. The other agents are less widest used

SGLT-2 Inihibitors

aka Gliflozins

(e.g. dapagliflozin, empagliflozin –  “Jardiance” – 10-25mg OD)

Cause the kidney to excrete glucose.

The sodium-glucose co-transporter-2 (SGLT-2) is found in the proximal renal tubule, and is responsible for reabsorption of glucose in the kidney. By inhibiting this co-transporter, the amount of reabsorbed glucose is reduced and the result is lower blood sugar, and an osmotic diuresis (increased urine output).

• Associated with weight loss – average of 1-2kg in the first six months, although some patients report up to 5kgs
• Less effective with reduced renal function
  • Generally not advised if eGFR <60
• Indicated as a single agent if metformin is contraindicated, or in combination with metformin if sulphonylurea is ineffective, or as a third line agent.
• May be particularly useful in patients whom struggle with dietary adherence
• Also, evidence is emerging that they are more effective than some of the other second line (after metformin) drugs use for diabetes – particularly in those patients with heart disease. Consider metformin + SGLT-2 inhibitors in patients with T2DM and heart disease.
• Side effects:
  • Increased risk of UTI and genital candidiasis – due to the glucose rich environment created by passing large amounts of sugar-filled urine
    • There are case reports of Fournier’s Gangrene in patients on SGLT-2 inhibitors
  • Can cause polyuria and increased thirst
  • Can affect other diuretic medications
  • Can cause euglycaemic Ketoacidosis – which can be a medical emergency. The risk of this is increased if the patient becomes dehydrated, during infection or if they are undergoing surgery – some guidelines suggest ceasing SGLT-2 inhibitors 3 days before surgery

There is limited long-term data supporting their use or their effectiveness at reducing macrovascular or microvascular complications.

DPP-4 Inhibitors (Gliptins)

e.g. sitagliptin, linagliptin

• e.g. sitagliptin 100mg OD PO
• e.g. linagliptin 5mg OD PO – unlike sitagliptin, Linagliptin does not need to be ceased in renal impairment

Dipeptidyl dipeptidase-4 inhibitors are involved with modifying the incretin effect. They bind to DPP-4 receptors and thus inhibit these receptors. This causes a raise in the amount of GLP-1. This stands for glucagon-like-peptide, thus these peptides cause an increase in secretion of insulin from the pancreas, and reduce the amount of gluconeogenesis in the liver. This peptide is released by the presence of food in the stomach, and inhibiting DPP-4 reduces the activity of enzymes that break down GLP-1.

Their effects are similar to GLP-1 analogues – because they act on the same pathway.

Dose should be reduced in renal impairment.

There is no long-term data supporting their use or their effectiveness at reducing macrovascular or microvascular complications.

• They appear to be less effective than both metformin and sulphonylureas at reducing HbA1c

Side effects

• Skin rash
• Constipation
• May cause increased risk of hypo when used with sulphonylurea or insulin

GLP-1 Analogues

(e.g. Exenatide – “Byetta”, Dulaglutide – “Trulicity”)

• e.g. dulaglutide 1.5 mg SC, once weekly
• e.g. exenatide 5mcg SC, twice daily before the morning and evening meals, increase to max 10mcg BD

Glucagon-like-peptide receptor activation causes an increase in glucose-dependent insulin secretion, impaired glucagon secretion and delayed gastric emptying. Clinically this causes a feeling of fullness and satiety.

• Usually injectable agents
• Taken once daily or in some cases once weekly
• Some are licensed for T2DM and some for obesity
• Increased insulin is glucose related so there is no risk of hypoglycaemia
• Can cause nausea and more rarely vomiting – this tends to improve within 2 weeks of initiating tretment
• Useful in patients who struggle with dietary adherence
• Associated with weight loss – typically 2-3kgs over 2 years
• Risk of pancreatitis – contraindicated if any previous episodes of pancreatitis
   

There is no long-term data supporting their use or their effectiveness at reducing macrovascular or microvascular complications.

Thiazolidinediones (Glitazones) 

e.g. troglitazone, rosiglitazone, pioglitazone

The mechanism of TZDs is not fully understood. They interact with a nuclear receptor PPR-gamma. This receptor is involved with genes that regulate lipid metabolism and insulin action. A popular theory as to how these work is that they lower the circulation of free fatty acids, and thus promote glucose utilisation by muscle cells.
These drugs will lower circulating insulin relative to glucose levels – i.e. they reduce insulin resistance – however, they will not return glucose levels to normal. As a result they tend to be used only in combination with other agents.
They are generally used in patients who cannot tolerate metformin or sulphonureas.

Their effect is slow. Re-checking HbA1c within 3 months is not likely to show their full benefit.

A single trail of high risk patients showed that pioglitazone reduced the risk of macrovascular complications, but compared to metformin and sulphonylureas, their evidence is poor.

They have a substantial risk of side effects:

• Weight gain
• Salt and fluid retention leading to peripheral oedema – can worsen heart failure
• It is important to monitor liver biochemistry
• Increased risk of bladder cancer
• Reduced Bone density

Meglitinides 

e.g. repaglinide, nateglinide

• These are very similar to the sulphonureas, and act by the same mechanism – as insulin secretagogues
• Their receptor binding abilities are different to those of sulphonamides, and as a result they are very short acting and tend to promote insulin release around meal times – thus reducing the risk of hypoglycaemia.
• They are more expensive than sulphonureas and their effectiveness as opposed to short acting sulphonureas has never been clinically assessed
• They are rarely used in clinical practice

Intestinal enzyme inhibitors (Acarbose)

Acarbose inhibits the action of alpha-glucosidases – enzymes that break down carbohydrates.  This is a novel way to treating overweight type 2 diabetes patients. Acarbose is a ‘fake’ sugar that will competitively bind alpha-glucosidase in the brush border. The result of this is that dietary carbohydrate is poorly absorbed and thus blood glucose levels do not rise as much as they would otherwise after ingestion of carbohydrate.

This also means that undigested carbohydrate then carries on through the intestine, where it will be fermented, resulting in abdominal discomfort, flatulence and diarrhoea. These side effects can be minimised and even avoided through careful dosage management, and tend to be worse in patients with poor dietary adherence.

It is mostly excreted in the gut, and not absorbed, but it is contra-indicated in renal impairment.

Need to be taken regularly and thus the dosing regimen can result in poor compliance. Maximum dose equates to 2 tablets, three times a day.

There is no long-term data supporting their use or their effectiveness at reducing macrovascular or microvascular complications.

Orlistat also may have a role in weight management in diabetes. In inhibits intestinal lipase, and thus reduces fat absorption. It also induces steatorrhea which may have the secondary effect of reducing fat intake by the patient because the steatorrhea is unpleasant.

Insulin

Once insulin secretion has declined sufficiently, then exogenous insulin is indicated. This is typically associated with new onset symptoms such as:

• Increased lethargy
• Increasing blood sugars despite other medical management
• Rising HbA1c in an otherwise previously stable patient
  • Rule out recent changes in diet and exercise that may account for these symptoms before starting insulin
• Weight loss – may be mistaken for good dietary habits and exercise!

Insulin is found in all vertebrates. There is very little variation in the molecule between species, and what variations there are only affect the antigenicity of the molecule, and do not affect its function in any way.

Patients on insulin should regularly monitor their blood sugar levels, aiming for:

• Fasting glucose – 4-7mmol/L
• Post-prandial glucose (2hrs) – 5-10mmol/L

Short acting insulins
In the past, animal-derived insulins were used, however in most countries these have now been replaced by synthetically produced varieties. These are produced by genetically modifying yeast or bacteria to produce insulin.
Short acting insulins are the standard treatment for many patients. They are also used whenever continuous intravenous infusion may be needed, and in medical emergencies.

• Normal insulin – is not very clinically useful in the short term. It tends to clog together in ‘hexamers’ which are 6 insulin molecules around a core of zinc. These will form soon after infusion, and prevent the insulin from ‘dissolving’ away from the initial injection site. This means that blood insulin levels don’t peak until 60-90 minutes after injection, and that their effect persists for too long and can result in hypoglycaemia. Thus, insulins have been developed that have been slightly modified to prevent this effect. These are known as short acting insulin analogues. 
• Analogues such as insulin lispro and insulin aspart allow the insulin to dissociate from the hexamers much more quickly, meaning it can diffuse away into the blood more easily, and also be removed from circulation more easily.

Long-acting insulins
To create this, you can add protamine or zinc to insulin, which makes it form crystals. Insulin prepared in this manner will be cloudy in appearance. You can alter the length of action of the insulin by:

• Protamine – mixing protamine insulin with normal insulin – changing the ratio
• Zinc – altering the size of the crystals formed.

You can also create longer acting insulin by making long-acting analogues that have had their structure altered.

Bi-phasic insulins
These can be made by mixing normal insulin and long-acting insulin together. This will give you a short burst of insulin to help you digest your meal, as well as giving you the benefits of long-acting insulins.

Inhaled insulin has recently been successful in clinical trials and is a very real alternative for the future. However, only short-acting insulins can be administered in this manner. With these preparations, only 10% of the inhaled insulin reaches circulation, and this may have cost implications.

Administering insulin
This is done subcutaneously –  usually with a small needle. Often the injection is painless, but understandably patients are apprehensive. The injection is normally given via a pen device into subcutaneous fat in the abdomen, thighs or arms. The needle should be inserted to its full length.
The injection site should be changed regularly to avoid lipohypertrophy
The rate of absorption of insulin into the blood depends on the site of injection, exercise, and warmth. It can also be speeded up by massaging the area. Absorption is most rapid from the abdomen, and slowest from the thigh.

• In normal individuals, there is a sharp rise of insulin just after meals, superimposed on a background level of insulinsecretion. In insulin treatment, we try to mimic this pattern. However, totally normal insulin levels are virtually impossible to achieve because;
• Insulin secreted in the normal individual enters the portal circulation- and about 50% of it is cleared by the liver. Insulin given by subcutaneous injection is delivered to the systemic circulation.
• Subcutaneous insulin takes up to 90 minutes to act – so its onset of action is too slow
• Absorption of insulin is variable
• It is very hard to achieve a basal rate of insulin secretion – the levels are constantly falling and rising in people who have to inject insulin, thus metabolic activity is altered from normal.

Multiple insulin regimens, with a longer-acting insulin before bed-time are recommended in younger patients. The provides great flexibility for meal times, and meal sizes – as the insulin peaks roughly with food intake.
In type 1 diabetes there may be a ‘honeymoon period’ after insulin treatment is started, whereby endogenous insulin secretion returns, and thus insulin injections may have to be reduced or even stopped. However, this will only be a short respite. Strict control in type-1 patients will help prolong beta-cell life, and reduce the risk of hypoglycaemia.
Twice-daily injections require a stricter lifestyle. Mealtimes have to be fixed, and meal sizes also have to be roughly the same. These patients should aim for blood glucose of 4-7mmol/L before meals, and 4-10mmol/L after meals. This is seen in example A above.

In patients where hypoglycaemia is a problem, long-acting insulin analogues may be used. These are particularly useful in nocturnal hypoglycaemia. In normal insulin treatments, short-acting analogues are not used that often, as normal insulin is good enough in most cases.

Insulin pumps are also available -these deliver a constant trickle of subcutaneous insulin all day. A meal-sized dose can be delivered when the patient presses a button on the side of the device. They allow tailoring of insulin doses to meet a particular patient’s needs, e.g. they are good at preventing nocturnal hypoglycaemia. These have been extremely useful for some patients, but they are expensive, and many people will not like the fact they have to be constantly attached to a device. They are also a risk for infection. They are typically used in T1DM and there is no evidence for their use in T2DM.

Complications of insulin therapy
At the injection site – if the patient makes the injection too shallow, they can end up with a painful lesion, and there may even be scarring. Very rarely, abscesses form at the injection site.

• Local allergic responses also occur at the injection site for some patients in early therapy. These tend to spontaneously resolve
• Lipohypertrophy – little fatty lumps – these may occur if one injection site is overused
• Weight gain – particularly with short acting insulins

Insulin resistance – mild insulin resistance will cause obesity. In more sever cases, large doses of insulin may be needed. Some patients (those who poorly adhere) may require very large doses irregularly. Insulin resistance has been associated with antibodies against insulin receptors in patients with acanthosis nigricans.

Weight gain – many patients will experience this. The effect will be particularly apparent in patients who have had their dosage inappropriately increased – insulin makes you feel hungry! Generally it is the patients with the worst control who gain the most weight.

Dosing Insulin

More of an art than a science. Start with low doses of long acting insulins, ideally given at night. Increase doses slowly.

• e.g. glargine or isophane insulin once daily
• e.g. 0.2 units / Kg (max 30 units) initially – at the same time each day. Increase as required. Theoretically no maximum dose – but be cautious about hypoglycaemia – I have seen patients on hundreds of units per day in divided doses!

Measure progress with HbA1c. If HbA1c is elevated ask patient to keep a diary of blood sugars before and after meals to assess if obvious hyperglycaemia is present frequently. This is usually the cause of poor control. Options to manage this include:

• Reducing portion size of meal composition
• Increase activity after meals
• Add an oral agent (if not already on one)
• Add in a ‘prandial’ (short acting) insulin
• Switch to a “mixed” insulin (combined short and long-acting)

Managing IGT and IFG

This also includes patients with an HbA1c of 6.0-6.4% who do not otherwise have a diagnosis of IGT, IFG or T2DM.

• Recommend a 7% reduction in weight
• Recommend at least 150 minutes of moderate intensity exercise per week

Experimental therapies

These tend to involve the pancreas. Whole pancreas transplantation has been attempted in patients who require kidney transplant – because they will already require immunosuppressive therapy; however, prognosis is not that great, and the immunosuppressive therapy is expensive and has many side-effects.
Another method has been to harvest beta-cells from cadavers, and inject them into the patient. These will adhere to the liver, and will function, however again these require immunosuppressive therapy.

The Management Process

Patients should have annual review for

• Eye assesment – for retinopathy – by optometrist
• Foot / peripheral nerves assessment – for peripheral neuropathy. Typically by a podiatrist, can be done by GP with a 10g monofilament, and a 128Hz tuning fork to assess vibration sensation on the dorm of the big toe
• Bloods (HbA1c, urea and electrolytes and eGFR, lipid profile)
  • Those with HbA1c >7% should have more frequent HbA1c (i.e. every 3 months) to assess effectiveness of management changes
• Urinalysis, including urine microalbumin
• Weight, BMI and waist circumferences
• Blood Pressure
• Physical activity
• Smoking
• Alcohol Intake
• Diet review (+/- with dietician)
• Calculation of cardiovascular disease risk score

All patients with early onset T2DM should be referred to an endocrinologist.

Hypoglycaemia

Hypoglycaemia is defined as blood glucose of <3.5mmol/L. It occurs as a result of treatment and not as a result of diabetes itself. It usually occurs on those taking insulin, although it can occur in those taking sulphonylureas, and rarely in those taking metformin.
Hypoglycaemia can sometimes occur in non-diabetic patients, in which case it is called spontaneous hypoglycaemia.
Symptoms of hypoglycaemia vary widely and differ with age. Sometimes they can be vague, such as tiredness, irritability (possibly anger) and general behavioural changes (particularly in children).
Common symptoms include:

Autonomic:

• Sweating
• Trembling
• Pounding heart
• Hunger
• Anxiety

Neuroglycopenic (due to lack of glucose to the brain)

• Confusion
• Drowsyness
• Speech difficulties
• Inability to concentrate
• Inco-ordination

Non-specific

• Nausea
• Tiredness
• Headache

In many cases of hypoglycaemia, the patient can recognise the symptoms and take appropriate action. If they are asleep, lying down, or distracted by another activity, they may not recognise the event as easily. However, there are also two more important factors that affect recognition of hypoglycaemia:
Impaired perception of hypoglycaemia – in people without diabetes, symptoms of glycaemia will be present if blood glucose drops below 2.5-3.0mmol/L. in diabetic patients who are chronically hyperglycaemic, the same effect may be seen with higher levels of blood glucose. However, the real problems are in people with ‘very well controlled diabetes’ partciulalry those on insulin. They may be so used to low blood sugar levels, that symptoms do not really show themselves, even well below the 2.5mmol/L level. However, the effects of hypoglycaemia are still present, even if the symptoms are not – i.e. they are more likely to slip into a coma without realising they are having a hypo. Patients are 6x a likely to have ‘a hypo’ in this situation.

• In insulin treated patients, this effect is irreversible once it has occurred. After 20 years of insulin treatment, almost 50% of type 1 diabetes sufferers are affected.
• In therapy treated patients, the effect is thought to be reversible.

Therefore it is important to note the importance of controlling glucose levels within certain limits – not just trying to get it down as low as possible.
Deficient counter-regulatory mechanisms – in an individual without diabetes, when the blood glucose beings to drop, glucagon and adrenaline may be released. These are the two most powerful hormones at keeping blood glucose up.
Within 5 years of type 1 diabetes developing, the hypoglycaemia – glucagon action will be impaired in most patients. After several years, many may also develop impaired adrenaline response in relation to glucose.
Both mechanisms described above often happen in conjunction, suggesting a similar pathological mechanism in the brain that accounts for both.
 
Causes

• Missed, delayed or inadequate meal
• Alcohol
• Exercise
• Breastfeeding by diabetic mother
• Poor adherence
• Badly designed insulin regimen

Risk Factors – many of these will be obvious if you have read above!

• Sleep
• Previous hypoglycaemia
• Age (very old and very young)
• Strict control of diabetes
• Duration of diabetes
• Renal impairment

Hypoglycaemia is serious! Severe hypoglycaemia (which is any glycaemia that requires another person to help the individual recover) has a mortality of 2-4%.
Occasionally, death whilst asleep can occur in otherwise well diabetes type 1 patients. It often occurs in the young, and is known as ‘dead in bed syndrome’. It is though this is caused by a hypoglycaemia induced cardiac arrhythmia, or respiratory arrest.
During the night, the level of blood glucose fluctuates naturally. During the early hours of the morning it is quite low, but then rises by about 4am. This means that many patients on insulin wake with a high blood glucose. This can be reduced by taking more insulin before bed, however, this increases the risk of hypoglycaemia during the early hours of the morning. Patients are therefore recommended to take a higher amount of insulin, and also have a bedtime snack.

Monitoring Blood Glucose

Routine self-monitoring of blood glucose is only recommended for those who are using insulin. Those on sulphonylureas may also benefit. It is not recommended for patients who are using only lifestyle modifications, or taking other oral agents, not including sulphonylureas.

Long-term diabetic control is assessed with HbA1c.

Managing Hypoglycaemia

Mild attack – patients should always carry readily absorbed carbohydrate in the form of glucose or sweets. In more severe cases, liquid carbohydrate (such as non-sugar-free soft drink, or fruit juice) is more effective. Patients and close relatives need appropriate training about hypoglycaemia. Patients should not take more carbohydrate than necessary, as this increases the risk of rebound hyperglycaemia. Patients should also be warned about alcohol excess and the dangers of driving.

If patients are feeling symptomatic, it is recommended they check their blood glucose, and in the event that it is <4mmol/L, they should take 15g of carbohydrate, in the form of one of the following:

• Half a can of soft drink or fruit juice
• 6 jellybeans
• 3 glucose tablets
• 3 teaspoons of sugar or honey

Severe attack – this is where severely impaired consciousness or even coma occurs. Often the diagnosis is quite simple and can be made clinically. This may be aided by a blood test if you are unsure. The diagnosis may also be aided if the patient carries a card or wears a bracelet stating that they are a diabetic. Patients should be given intramuscular glucagon or intravenous glucose (this will be 50% dextrose, and give 25-50ml). The intravenous glucose should always be followed by a saline flush, as dextrose causes sclerosis of veins. Glucagon acts almost as rapidly as glucose in increasing the blood level of glucose – however, remember that it will not work after a prolonged fast, and once the patient is revived, you should give glucose anyway to replace glycogen reserves.

• Often many patient carry a glucagon pen with them, and can administer it themselves or have a relative do it in the case of a severe attack.
• Oral glucose is always the first option – further treatments should only be considered if this is not possible (i.e. the patient is not able to swallow due to impaired consciousness).

Following recovery it is important to try and identify a cause, and make adjustments to the insulin regimen to reduce the risk of further hypoglycaemia. The general rule is to reduce the next dose of insulin by 10-20% until medical advice can be obtained.
Exercise can also induce hypoglycaemia – due to fact that during exercise, your body would normally naturally reduce the amount of insulin secreted – but in insulin controlled patients, this doesn’t happen. If patients anticipate they are going to be involved in strenuous activities, they should decrease their insulin dose, and increase carbohydrate. They should make doubly sure there is a supply of glucose ready incase of hypo.

Nocturnal hypoglycaemia
This often goes undetected, and thus actual figures for how prevalent it is are difficult to obtain. Some symptoms of this may be ; poor quality of sleep, morning headaches (‘hangover feeling’), chronic fatigue, and vivid dreams or nightmares. There may also be profuse sweating.

Hypoglycaemia is linked to a reduced risk of complications. The better your control (of diabetes) the more likely you are to have hypo’s, however, the less likely you are to suffer complications. Thus, you can say that more frequent hypo’s means fewer complications.

Complications of Diabetes

The complications of diabetes are considered in a separate article – Monitoring and Complications of Diabetes

Flashcard

References

• Shaw J, Tanamas S, editors. Diabetes: the silent pandemic and its impact on Australia. Melbourne: Baker IDI Heart and Diabetes Institute, 2012. Search PubMed
• Use of HbA1c in diagnosing diabetes and identifying individuals at a high risk of diabetes
• General practice management of type 2 diabetes (RACGP) [Australia]
• Type 2 diabetes in Adults
• Glucose lowering medications for type 2 diabetes

Read more about our sources

The post Type 2 Diabetes – T2DM appeared first on almostadoctor.

Epidemiology

• Diabetes affects 2% of the British population, i.e. over 1 million people, and takes up 5-10% of the health budget.
• The prevalence is increasing rapidly in Western World
• More than 90% of diabetic patients have type 2 diabetes; less than 10% have type 1.

Rare Causes

Clinical presentation

• Polyuria
• Thirst
• Weight loss
• Ketonuria which may progress to ketoacidosis

• Lack of energy
• Blurred vision

Such cases may also present with complications such as…

• Staphylococcal skin infections
• Retinopathy
• Polyneuropathy
• Erectile dysfunction
• Arterial disease
• Inflammation of genitals  – due to Candida infection

Diagnosis

• HbA1c >6.5% (48 mmol/mol)
• OR Fasting glucose > 7 mmol/L and a glucose tolerance test
• OR random glucose > 11mmol/L (usually on 2 separate occasions)

Management

• Insulin and dietary modification

• Lifestyle modification (>>+ metformin >>+ further drugs>> + insulin)

Basic principles of monitoring

• Weight – can have significant impact on insulin sensitivity
• Blood glucose – self-monitoring for those taking insulin
• Urine glucose –is an alternative for those who do not want blood glucose methods, but it is imprecise
• Haemoglobin A1c (HbA1c) – for long term management/risk assessment; should keep the value <7% to minimise complications
• Maintaining other parameters within ideal range in order to minimise risk of complications, including blood pressure (<130/80 mmHg), total cholesterol (<4.5 mmol/L), LDL (<2.6), HDL (>1.1) and triglycerides (<1.7)

Type 1 Diabetes

Epidemiology

• Usually becomes apparent in childhood, with a peak incidence around puberty.
• Incidence of type 1 diabetes is on the increase, particularly in children < 5.

Aetiology

• NOT genetically determined; monozygous twins show concordance rate of 30-50%.
• Often associated with other autoimmune diseases, e.g. autoimmune thyroid disease

Pathology

• A T-cell mediated autoimmune disease resulting in the destruction of pancreatic beta cells.
• The first islet antibodies appear in the blood during the first few years of life; therefore disease is very slow to progress.

1. ↓anabolism → hyperglycaemia (fatigue) → glycosuria → osmotic diuresis (polyuria, polydypsia)→ salt and water depletion (↑HR, ↓BP) → death
2. ↑catabolism → ↑glycogenolysis, ↑gluconeogenesis (wasting), ↑lipolysis (↓ weight)  → hyperketonaemia → acidosis (↑RR, ↓BP, ↓T) → diabetic ketoacidosis → death
3. ↑secretion of glucagon, cortisol, GH and catecholamines

Acute Presentations

• Diabetic ketoacidosis (DKA) characterised by hyperglycaemia, hyperketonaemia and metabolic acidosis
• Thromoembolic episodes
• Non-ketoic hyperosmolar diabetic coma

• Polyuria, thirst
• Weight loss and weakness
• Nausea/vomiting
• Leg cramps
• Blurred vision
• Abdominal pain
• Kussmaul breathing
• Dehydration
• Hypotension
• Cold extremities / peripheral cyanosis
• Tachycardia
• Hypothermia
• Smell of acetone on breath
• Confusion / drowsiness / coma

Management of DKA

Based on Joint British Diabetes Societies Inpatient Care Group guidelines, September 2013 

DKA is a serious and potentially life-threatening presentation. It is a combination of acidosis, hyperglycaemia, and ketonuria. It may be the first presentation of type I diabetes in a child or young adult, but is also a common presentation in type I diabetics with poor insulin compliance. Treatment should be initiated promptly, and needs regular monitoring with (hourly) blood ketone (and glucose) levels, or, if not available, bicarbonate levels on venous blood gas.

You should involve a specialist as soon as possible (ideally within 24 hours), as this has been shown to reduce morbidity and mortality.

Severe DKA is characterised by:

• Blood ketones >6 mmol/L
• Bicarb <5 mmol/L
• pH <7.0
• Hypokalaemia (k+ <3.5)
• GCS <12
• O2 <92% on room air
• Systolic BP <90
• HR >100 or <60
• Raised anion gap

• Insulin dose should be based on weight. Sliding scales should not be used, as they can be inaccurate in overweight and pregnant patients
• The type of insulin regimen is often referred to as a Fixed rate Intravenous Insulin Infusion, or FRIII
• Check the effectivesness of the FRIII using blood ketones and revise the dose if it is not effective
• If bedside blood ketone testing is not available, venous blood gasses can be used to asses bicarbonate level, but only for the first 6 hours, as this becomes inaccurate after infusion of large amount of normal saline.

• Use IV 0.9% sodium chloride (normal saline)
• If hypotensive (systolic BP <90mmHg) give a bolus of 500mls normal saline. If still hypotensive, seek senior help. Consider discussion with ICU, and think about other possible causes of hypotension.
• Once hypotension is resolved, or if it is not present at presentation, patient will still require large amounts of IV fluid. A typical regimen might be 1L normal saline in the first hour, then 1L over 2 hours, then 1L over 4 hours etc, but be wary of a ‘one size fits all’ regimen
• Monitor electrolytes, particularly potassium  closely. You will likely need to replace potassium, which can be done by adding KCl to the bags of normal saline. Be careful not to infuse potassium too quickly.

Potassium
DKA patients are at risk of both hypokalaemia, and hyperkalaemia. Initially they are often hyperkalaemic, but their total body potassium is low. This is because potassium is taken up into cells with insulin, so with a lack of insulin, extra cellular potassium rises, and the intracellular level falls.
Titrate potassium replacement to the potassium level, as measured on hourly venous blood gasses.

• K+ >5.5mmol/L – dont replace
• K+ 3.5 – 5.5 mmol/L – replace by using 40mmol/L in infused solution
• K+ <3.5 – seek senior help – additional potassium replacement may be required

Approach
DKA patients are often very sick. As with any sick patient, it is useful to have a systematic approach. Do the basics first:

• A – Airway
  • ​Are they maintaining their own airway?
  • Do you need urgent airway assistance? Consider ICU / anaesthetic input
• B – Breathing
  • ​What are the O2 saturations?
  • What is the respiratory rate?
  • Do they need oxygen?
• C – Circulation
  • ​Get IV access
  • Send regular bloods (FBC, U+Es, CRP, formal glucose level, blood cultures)
  • Blood ketone and glucose (bedside testing)
  • Venous blood gas
• D – Disability (/conscious level)
  • Assess GCS – helps to assess severity of DKA
  • Consider causes for DKA (e.g. infection – send off cultures, check temperature)
• Start IV fluids – as described above
• Replace Potassium – as described above
• Start Fixed Rate Intravenous Insulin Infusion – as described above

Monitoring

• Re-assess hourly, including bedside ketones and glucose, venous blood gas (VBG) and clinical assessment and examination.
• The aim is to reduce the ketone level, and stop ketogenesis.
• Aim for reduction of ketone level of >0.5mmol/L/hr
  • If unable to measure blood ketones, use VBG instead, and aim for bicarbonate rise of >3.0mmol/L/hr, and blood glucose fall of 3.0mmol/L/hr
• Maintain serum potassium of 3.5 – 5 mmol/L (see above for potassium management)
• Avoid hypoglycaemia. It may be necessary to use 10% dextrose IV
• Consider urinary catheter if anuric
• Consider NG tube if persistent vomiting or obtunded

Resolution of DKA

• Defined as blood ketones <0.6 mmol/L and venous pH >7.3
• After 6 hours, bicarbonate level should not be used as a measure of progress, as hyperchloraemia may exist secondary to saline infusion. Hyperchloaraemic acidosis can lower bicarb.
• Continue to treat precipitating factors
• If patient is eating and drinking, start subcutaneous insulin. If not, can start a sliding sclae (VRIII – variable rate intravenous insulin infusion)
• Most cases resolve within 24 hours. If not resolving, seek specialist / senior support urgently.

Type 2 Diabetes

Epidemiology

• Four main determining factors are age, obesity, family history and ethnicity.
• Overall prevalence of this disease in the UK is about 2%, rising to 10% by age 70.
• Relatively common in all populations enjoying an affluent lifestyle.
• Onset can be accelerated by stress, pregnancy, illness or certain drugs.
• Insulin resistant state often presents with other risk factors that put someone at greater risk of cardiovascular disease, including hypertension, obesity, hypertriglyceridaemia, decreased HDL cholesterol and acanthosis nigricans.

Aetiology

• Under activity, over-eating and obesity are all factors in the formation of this disease.
• Presence of excess triglyceride within the cell has some effect in causing the insulin resistance.
• The genetic link is type 2 diabetes is stronger than that in type 1 – monozygotic twins have a greater than 50% chance of developing the disease.
• Low birth weight and low weight at 12 years of age predisposes to type 2 diabetes.
• Inflammatory markers, i.e. CRP, and cytokines are raised in obesity, and may play a role in the development of diabetes.

Pathology

• Insulin resistance and relative secretory failure of insulin occur for unknown reasons resulting in hyperglycaemia.
• Hyperglycaemia has a secondary effect on the liver, promoting glycogenolysis, raising blood glucose levels even further.
• Patients will have up to 50% of their beta cell mass at diagnosis, however, this destruction of beta cells is nowhere near as extensive as in type 1 diabetes.

Management

Complications of diabetes

• Cardiovascular disease (70%)
• Renal failure (10%)
• Infection (6%)
• Other causes (14%)

• Non-enzymatic glycosylation (glycation) – this leads to accumulation of AGE’s, leading to direct cellular damage and inflammation.
• Polyol pathway – when intracellular levels of glucose are elevated, glucose that can’t be metabolised via the TCA cycle, will enter this pathway, where aldose reductase reduces glucose to sorbitol, which is further reduced to fructose.
• This mechanism causes diabetic complications as cells of the retina, kidney and nerves DO NOT REQUIRE INSULIN for intracellular glucose uptake. Therefore these cells receive a high intra-cellular concentration of glucose when glucose levels are raised in the blood.
• Sorbitol cannot cross the cell membrane,thus water is drawn into the cell via osmosis. Fructose has a similar effect, modifying cell permeability to various ions and compounds, therefore altering normal cell functioning.
• The sorbitol pathway also produces reactive oxygen species which directly causes cell damage.
• Abndormal microvascular blood flow – this impairs the supply of nutrients and oxygen.
• Other factors – excess growth factors, particularly VEGF (vascular endothelial growth factor), are produced by ischaemic tissues in diabetics which cause endothelial cells to proliferate, exaggerating and accelerating microvascular damage.
• Activation of protein kinase C

• Stroke – 2x as likely
• MI – 3-5x as likely – women also lose their pre-menopausal protection
• Amputation of a foot due to gangrene is 50x as likely.

• Hypertension – treatment by at least 2 drugs concomitantly.
• Smoking
• Lipid abnormalities – virtually all diabetics are on statins.
• Low dose aspirin
• ACE inhibitors – also greatly reduce the risk of nephropathy.

• Non-proliferative/background retinopathy
• Diabetic maculopathy
• Pre-proliferative retinopathy
• Proliferative retinopathy
• Cataracts

• Glomerular damage
• Ischemia caused by damage to efferent and afferent arterioles.
• Ascending infection – remember that the immune system of diabetic patients is often compromised, thus resulting in a greater risk of UTI.

• Renal hypertrophy – indicated by a raised GFR often presenting soon after diagnosis.
• Albuminurea – this is the first detectable marker of diabetic nephropathy.
• Transient nephrotic syndrome – may exist, inducing oedema and hypoalbuminurea.

• Symmetrical mainly sensory neuropathy – “stocking and glove” distribution.
• Acute painful neuropathy – often felt in shins and feet, worse at night.
• Mononeuropathy and mononeuritis multiplex – most commonly in CN III and VI, and carpal tunnel syndrome.
• Diabetic amyotrophy – this is progressive wasting of muscle tissues.
• Autonomic neuropathy = CV and bladder problems; silent MI; erectile dysfunction

References

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So it is important to monitor that treatment is effective, and to closely watch for any of the effects of the complications of diabetes.

Targets for the lifestyle factors, blood pressure control and lipids should be set for patients and monitored. Of note, is that the recommended BP for all diabetic patients – 130/80 is lower than for non-diabetic patients – 140/90.

The main complications of diabetes can be divided into macrovascular complications and microvascular complications:

Microvascular complications

Damage to the larger (macro) blood vessels

• Cardiovascular disease
  • Increased risk of stroke and myocardial infarction

Microvascular complications

Damage to the smaller (micro) blood vessels

• Peripheral neuropathy
  • Occurs in about 10% of patients with diabetes
• Diabetic retinopathy
• Diabetic nephropathy
  • Occurs in 3% of men and 11% of women with diabetes

Monitoring diabetic control

• Wellbeing and weight
• Urine glucose
  • Imprecise, but useful as a ‘traffic light’
• Blood glucose
  • For self regulation. However, its only really people on insulin who can benefit from this.
• Haemoglobin A1c (HbA1c)
  • For risk assessment. Everyone with diabetes should have this measured at least twice a year!
• Blood glucose monitoring – this can be done quickly and easily by measuring a tiny amount of blood. It is an essential skill for all involved in diabetic care, and for many diabetic patients themselves. The testing equipment contains glucose oxidase which catalyses the reaction of glucose to gluconic acid, and a detection system that detects the products of this reaction. The detection is either done electrochemically, or colorimetrically (using dyes). Then this signal is either read electrically or by a reflective material, and this signal converted to a number corresponding to glucose concentration. Some more basic tests may involve a colour strip that changes colour.
  • The sample is obtained by pricking the sides of the finger (not the pad – which is more sensitive)
  • Blood must cover the whole of the test area, and the result must be taken after an exact amount of time – many modern kits do this by themselves now – however in cases where they don’t inaccurate readings are common.
  • These tests are accurate enough for the purposes of self monitoring, but are not accurate enough for diagnosis.
• Urinary (micro)albumin:creatinine ratio (ACR)
• eGFR
  • Both of these tests screen for the presence of nephropathy
• Cholesterol profile
  • This should be treated aggressively to reduce the risk of cardiovascular disease

Monitoring schedules

• Patients should be encouraged to record their glucose levels, as this makes it easier to spot any abnormalities. They should also be encouraged to check their glucose frequently when they feel unwell.
• Patients on insulin are encouraged to alter their own regimen from their glucose level results, although a clinician should always be available via telephone for advice.
• These home testing kits also require that the patient has been taught how to use them properly!

HbA1c and fructose amide

• When this process occurs via an enzymatic pathway, as part of a deliberate physiological process, we call it glycosylation. Some medical textbooks fail to make this distinction and refer to HbA1c as “glycosylated” rather than “glycated” which is technically incorrect.

• Once a haemoglobin is glycated it stays like that forever.
• Therefore, this method of monitoring shows us the level of glucose in the blood over the last 4-12 weeks. Many experts believe that the value is weighted towards glucose levels of the last 2-4 weeks.
• A good target rate is 4-7%. This percentage value is a percentage of the total amount of Hb. The levels in a normal individual are 4-6.5%.
• The value can be misleading if there is thalassaemia, or reduced red cell lifespan, or something affecting haemoglobin.

• Anaemia
• Haemoglobinopathy
• Pregnancy – when the turnover of RBC’s is variable.

AGEs – advanced glycation end products. Some AGE’s are benign whilst the production of some others can predispose to certain conditions such as;

• cardiovascular diseases (fibrinogen, collagen and endotherlium are all damaged by AGE’s). Collagen will be stiffened and weakened. This results in increased blood pressure (due to stiffening) and increased risk of aneurysms (due to weakening). These aneurysms can result in stroke. Glycation products can also be the basis of the formation of atherosclerotic plaques.
• Alzheimer’s disease (amyloid plaques are side products in the production of AGE’s)
• cancer (acylamide and other AGE side products are released)
• peripheral neuropathy (myelin is affected), blindness (due to microvascular damage to the retina).

Monitoring urine glucose and ketones

Therefore in patients where this is used as the main monitoring method, consistent negative results, and no symptoms of hypoglycaemia will usually confirm that the disease is being well controlled.

Monitoring risk factors

Managing Hypertension

First line therapy for management of hypertension in diabetic patients should involve the use of an ACE-inhibitor or angiotensin-receptor blocker (ARB). If this is insufficient, add a calcium channel blocker.

he use of ACE-i or ARB is associated with decreased rate of progression to albuminurea in T2DM. 

• ACE-i and ARBs should not be used in combination

Managing Lipids

This is much the same as lipid lowering therapy for non-diabetic patients. Statins are the first line treatment.

The use of other cholesterol lowering medication can be controversial. There is not good evidence that any other medications (except perhaps for Ezetemibe) used to lower cholesterol actually reduce the risk of cardiovascular disease (despite lowering cholesterol).

Fibrates (e.g. fenofibrate), nicotinic acid and bile-acid resins are all treatemnts that have been show to lower cholesterol, but their cardiovascular disease benefit is doubtful.

Complications of diabetes

The duration and degree of hyperglycaemia is directly related to the severity of the disease.
Good diabetic control can directly reduce the risk of complications; in studies when the HbA1c was kept below 7%, the risk of developing complications was reduced by 60% over 9 years.
Treated patients still have a lower life-expectancy than non diabetic patients. In the case of insulin dependent diabetes, death is usually due to :

• Cardiovascular disease (70%)
• Renal failure (10%)
• Infection (6%)
• Other (14%)

i.e. 86% of insulin treated patients die as a result of their diabetes

Generally complications cannot be reversed by good control after they have taken hold, however, some patients in the very early stages of complications may benefit from early treatment. Therefore, for microvascular damage in particular it appears there is a threshold level for damage, and when this is reached, the damage is irreversible.
 
There are also problems in controlling diabetes. The better your control, the more likely you are to suffer episodes of hypoglycaemia and to gain weight, however the less likely you are to suffer from the microvascular complications of diabetes. So you have to have a balance. Obviously gaining weight increases your risk of macrovascular complications.
Thus in those patients:

• Who are at very high risk of cardiovascular complications (e.g. family history of MI, obese)
• Are very young or very old

Then the best method for managing their disease is NOT to have the strictest possible control. However, in all other cases, strict control will yield better long term outcome.

The mechanisms leading to the following complications are not well understood. They may involve some of the following consequences of hyperglycaemia:
Non-enzymatic glycosylation (glycation) – this leads to accumulation of AGE’s all over the body. Not only can these cause direct damage (as described above in section on HbA1c), but they can also set off the inflammatory reaction.
Polyol pathway – (akak sorbitol aldose reductase pathway) – this becomes active when intracellular levels of glucose are elevated. Glucose that can’t be metabolised in the normal way (TCA cycle), will enter the polyol pathway. Aldose reductase will reduce glucose to sorbitol, and then sorbitol to fructose.

• This mechanism is favoured as a cause of diabetic complications because most cells require insulin for glucose to enter, however, cells of the retina, kidney and nerves DO NOT REQUIRE INSULIN for glucose to enter the cell. Thus these cells can get a high intra-cellular concentration of glucose, when glucose levels are raised in the blood. Any glucose that cannot be utilised in the normal way will enter the polyol pathway, and produce sorbitol.
• Sorbitol cannot cross the cell membrane and thus water is drawn into the cell via osmosis. Fructose also has a similar effect. This then alters cell permeability to various other ions and compounds, and thus may alter cell functioning
• The sorbitol pathway also produces reactive oxygen species. These can directly lead to cell damage.
• There is research that has been conducted in animals that shows that by giving them modified aldose reductase enzymes, that don’t produce the same products as those in the normal pathway, many microvascular complications are prevented. Thus this mechanism of damage is probably the most important.

Abndormal microvascular blood flow – this impairs the supply of nutrients and oxygen. Microvascular occlusion is due to release of vasoconstrictors, such as endothelins and thrombogenesis, and over a prolonged period of time this can cause permanent endothelial damage.

• Other factors – excess growth factors, particularly things like VEGF (vascular endothelial growth factor) are produced by ischaemic tissues in diabetics. This will cause endothelial cells to proliferate, and thus exaggerate and accelerate the microvascular damage.
• Activation of protein kinase C.

Macrovascular complications

Diabetes is a risk factor in atherosclerosis. This risk is in relation to the background population. For example, Japanese diabetics are more likely to suffer MI than non-diabetic Japanese, however their risk is far lower than diabetic Europeans. Generally, the risks are:

• Stroke – 2x as likely
• MI – 3-5x as likely- women also lose their pre-menopausal protection
• Amputation of a foot due to gangrene is 50x as likely.

Cardiovascular risks are barely affected even by aggressive treatment – thus they remain very high. Therefore, when treating diabetes it is very important to tackle the cardiovascular risk factors individually, and not just focus on the blood glucose.
The sort of risks that need to be aggressively tackled are:

• Hypertension – this will probably need treatment by at least 2 drugs in conjunction. 1/3 of diabetics will need treatment by 3 or more drugs.
• Smoking
• Lipid abnormalities – there is no safe cut-off point, and so you should try and get the lipid concentration down as low as possible! In practice this means virtually all diabetics are on a statin.
• Low dose aspirin – this will lower cardiovascular risk, but is obvious associated with GI bleeding. The cardiovascular benefits outweigh the risk of bleeding when the cardiovascular 10 year risk is >30%. This risk level is present in:
• People under 45, with 3+ strong additional risk factors
• People 45-54, with 3 additional risk factors
• People 55-64, with 2 additional risk factors
• People 65+, with 1 additional risk factor
• ACE inhibitors – treating people with diabetes with at least one additional cardiovascular risk factor with ACE inhibitors reduces the risk of cardiovascular complications by 25-35%. They also greatly reduce the risk of nephropathy.

So we can see that people with diabetes require a lot of basic treatments!

Microvascular complications

These are specific to diabetes – which is in contrast to macrovascular disease, which is prevalent in the west in general.
Small blood vessels throughout the body are in danger, however, there are 3 sites at particular risk; the retina, the kidney and the nerve sheaths.
These side effects will manifest about 10-20 years after initial diagnosis. They will present sooner in older patients, probably because these patients have gone longer before having their diabetes diagnosed.
Genetic factors seem also to be involved. Siblings of those with diabetic microvascular complications have 3-5x greater chance of developing the complications than those with diabetes but without sibling involvement.
Nephropathy is also more common in certain races, including Hispanic, and black.

Diabetic eye complications

Diabetes is the most common cause of blindness under the age of 65. Diabetes can effect the eyes in many ways, but diabetic retinopathy is the most common mechanism. Young patients with diabetes have a 1/3 chance of developing some form of this.
5% of diabetic patients can become blind as a result of retinopathy.

Other types of diabetic eye damage include:

• Lens damage – this can be due to reversible osmotic changes in patients with acute hyperglycaemia. It may also be due to cataracts.
• New vessel formation – this can occur in the iris is late stage diabetes. It can result in glaucoma
• External ocular palsies – these commonly occur in the 6^th cranial nerve and effects motor movements of the eye.

 
Pathology of retinopathy
Diabetes causes thickening of the basement membrane and increased permeability of retinal arteries. This can result in two types of damage – occlusion, or aneurysm formation. The increased permeability of cells results in the formation of exudates. Flourescin angiography is the best way of detecting these changes early (see below).

• After 20 years of type I diabetes, almost all patients will have some type of retinopathy, and 60% will progress to sight threatening proliferative retinopathy. Without treatment, 50% of cases of proliferative retinopathy will become blind within 5 years.
• After 20 years of type 2 diabetes, 58% of patients will have some form of retinopathy.

Non-proliferative / background retinopathy
The first abnormality visible through the ophthalmoscope is ‘dot haemorrhage’. These are not actually haemorrhages, but are in fact, small aneurysms. Fluid may leak from these into deeper parts of the retina causing blot haemorrhages. These are also responsible for the formation of hard exudates. These will usually be present in patients 10-20 years after diagnosis. They are rarely present in young patients. This type of damage does not itself impair vision, however it can progress to maculopathy or proliferative retinopathy.
 
Diabetic maculopathy This can lead to blindness, even in the absence of proliferation. It tends to affect older patients with type 2 diabetes.
Macular oedema is the first sign of this, and this in itself can cause permanent damage if not treated quickly enough.
The main symptom of this is decreasing visual acuity. You need to look at the retina (photography of ophthalmoscopy) to be able to diagnose this. This is why it is essential to regularly test the visual acuity of all diabetics.
The later stages of this disease will result in hard exudates being deposited on the macular area.

Pre-proliferative retinopathy
This is a stage inbetween background retinopathy and proliferative retinopathy. Many patients will not progress to this stage. The earliest sign of this is cotton wool spots. Sometimes people use the term ‘soft exudates’ to refer to cotton wool spots, but its use is gradually being discouraged. Hypertensive retinopathy may also cause cotton wool spots. Unlike the appearance of exudates, these have a matt finish, and the boarders tend to be less well defined. They are larger and more white in colour than hard exudates.
There may also be venous bleeding, and the appearance of venous loops on the retina.

Proliferative retinopathy
This involves the proliferation of new blood vessels. Hypoxia is though to be the signal for the proliferation of new blood vessels. These lie superficially, and will grow forwards into the vitreous. They resemble bundles of seaweed! They are very fragile and bleed eaily, as they lack supporting connective tissue. Haemorrhages can be either in the retina or sometimes even into the vitreous.

• The haemorrhage will be notices as a possible loss of vision in one eye, or less severely, as a floating shadow effecting the field of vision. Generally, partial or even full recovery of vision will be seen as the blood is reabsorbed, but rebleeds tend to occur often.
• Loss of vision can also occur from fibrous proliferation that is associated with the proliferation in blood vessels. This can form traction bands which will contract over the course of time, and can result in retinal detachment.

Cataracts
Senile cataracts tend to develop 10-15 years earlier in diabetic patients than in the general population. As well as this, there are two further types of lens problem associated with diabetes:

• Juvenile (‘snowflake’) cataracts – these are rare, but develop very quickly in ssome people with poorly controlled diabetes.
• Cloudyness in the lens is a feature of the hyperosmolar state, but this will correct itself with time.

Treatment is most effective when given early – usually when the patient is symptomless. This means that you have to constantly monitor the patients for any signs of eye problems and initiate treatment immediately as soon as you recognize any. This involves regularly checking the retina (fundus). There are several ways of doing this.

Examinations
Visual acuity should be tested, along with a good view of the retina. To obtain a good view of the retina, you need to dilate the pupil; and this can be achieved within 15-30minutes by the drug tropicamide.
You need to be careful because dilating drugs shouldn’t be used in patients with a history of glaucoma.
It is important to sketch or photograph any abnormalities you find in the notes for future reference.
Fluorescein angiography – a fluorescent dye is injected into a vein in the arm. You can then view and photograph this as it flows through the arteries in the patient’s retina.
 
Using a retinoscope – When examining the fundus you should look for:
Exudates – these are very common in diabetes and are also seen sometimes in hypertension. They are little white dots on the retina. They are caused by blood plasma leaking out of blood vessels. They coincide with areas of retinal damage – and thus are useful to show where the damage is occurring. They are most common in the perimacular area. If they are close to the macula they are far more dangerous. To measure how close to the macula they are, we say they are ‘within one disc diameter’ referring to the diameter of the optic disc as a reference for size. Another measurement would be ‘within the arcades’ – this means ‘within the two main arcing blood vessels’ that arc around the macula.
Exudates are actually collections of lipid that gloop together from the leaking blood plasma.  

Fatty deposits can sometimes look like exudates. They are generally a big bigger and more yellow than exudates. The main cause of these is diet. Food known to stave these off are blackberries and spinach.

Management
There is no specific treatment for background retinopathy, but smoking and hypertension worsen the prognosis. All patients with retinopathy need to be examined regularly by a diabetologist or ophthalmologist.
In severe non-proliferative and proliferative retinopathy, photocoagulation is the treatment of choice. In this treatment, a laser is used to clot blood vessels. It is used in many different eye diseases. In diabetic retinopathy, this treatment will be used to:

• Destroy areas of ischaemic tissue – as it is thought that these play a vital role in neovascularisation.
• Seal microanearysms and thus reduce oedema

The procedure carries very little risk and can be done under local anaesthetic. It reduces visual loss by up to 90% – this is only 50% of patients with maculopathy.
Patients have to be regularly monitored to check for new growths, and may require repeat treatment. Extensive bilateral photocoagulation can reduce the visual field, and affect driving and night vision.

Diabetic nephropathy

The kidney can by damaged by three mechanisms in diabetes:

• Glomerular damage
• Ischemia caused by damage to efferent and afferent arterioles.
• Ascending infection – remember that the immune system of diabetic patients if often compromised, thus resulting in a greater risk of UTI.

Kidney damage in diabetes is a very important cause of morbidity and mortality. It is also one of the most common causes of end-stage renal failure (ESRF) in developed countries.
As with a lot of things to do with diabetes, management is difficult, and thus prevention is very beneficial.
 
Epidemiology
Nephropathy usually presents as a result of glomerular damage about 15-25 years after diagnosis.
It affects 25-35% of patients diagnosed before the age of 30
It is primarily a disease of younger diabetics, and the incidence is lower in older patients.
Incidence if type 1 diabetes has been falling, and it is thought this can be attributed to good diabetic control. However, it is expected that diabetic nephropathy will rise as more and more younger people become affected by type 2 diabetes.

Pathology
There are several different effects that diabetes can exert on the kidney:

Renal hypertrophy
The first pathological abnormality will be renal hypertrophy. This is associated with a raised GFR. This often presents soon after diagnosis, and is a direct result of hyperglycaemia. The mechanism for this is as follows. The afferent arteriole will become more dilated than the efferent arteriole. This results in an increased intraglomerular filtration pressure, and this will further damage glomerular capillaries. The shearing forces that occur locally will also contribute to mesangial cell hypertrophy, and will cause mesangial cells to secrete more extracellular matrix. This eventually leads to glomerular sclerosis. There is thickening of the basement membrane, and disruptions in the linkages between cells – this ultimately means that larger molecules are allowed to be filtered that normally wouldn’t be so.

Albuminurea
This is the first detectable marker of diabetic nephropathy. Initially, only microalbuminurea is present – this means amounts of albumin that are so small they cannot be detected by normal dipstick, and special tests have to be performed. It not only is a sign that the kidney is heading towards nephropathy, but also (in type 2 diabetes) of increased cardiovascular risk.
Somewhere down the line, the pateint may enter the territory of persistent proteinurea. At this stage, plasma creatinine may be normal, but the patient may only be 5-10 years from end stage renal failure.
Transient nephrotic syndrome may also exists – which will induce oedema, and lead to hypoalbuminurea.
Patients with nephropathy tend to have a normocytic normochromic anaemia, and may also be hypertensive – which itself can further damage the kidney.
ESR will be raised.

Screening for microalbuminurea is an important marker in the development of kidney damage. Note also that if kidney damage does not present within 20 years of diagnosis, then the risk of developing it is very low (<1% per year)

• Type 1 diabetic patients annually from 5 years after diagnosis. In these patients, this test is pretty much diagnostic of microalbuminurea.
• Type 2 diabetic patients annually from diagnosis. In these patients, microalbuminurea may be contributed to by many other factors.

The risk of progression can be reduced by:

• Aggressively tacking cardiovascular risk factors (particularly hypertension)
• Giving ACE-inhibitor therapy
• Strictly controlling glucose.

Usually diabetic retinopathy is present with nephropathy. So if it is not, you may suspect another cause for the nephropathy.

Ischaemic lesions
These are similar to those that occur in hypertension and are a result of hypertrophy and hyalinization of blood vessels.

Infective lesions UTI’s are more common in women with diabetes, but not more common in men. Ascending infection can be a result of bladder stasis resulting from autonomic neuropathy. Infections can also become more easily established in damaged renal tissue. Autopsy shows that there is evidence of infective lesions in many diabetic patients – however these can often be difficult to determine from ischaemic lesions, and thus the true prevelance of pyelonephritis in diabetes is uncertain.

Management
Aside from the preventative measures, there is not much you can do. You need to avoid any diabetes treatments that involve excretion by the kidney (such as glibenclamide), and also a reduction in insulin therapy is probably useful, as insulin sensitivity tends to increase.
There is often an associated rapid progression with retinopathy once we reach the stage of nephropathy.
Management of end-stage disease is difficult due to the presence of other complications, such as blindness, cardiovascular disease and neuropathy. Haemodialysis is not that useful as shunts tend to calcify very quickly.
Renal transplant is an often, but is not as successful as in non-diabetic patients. Often this may be carried out in conjunction with a pancreatic transplant, that in many cases will give the patient freedom from insulin therapy for a year or so.

Diabetic neuropathy

It is directly related to the duration and degree of abnormal metabolic control.
It tends to occur relatively early on in the progression of the disease, although many patients will be symptomless.
The mechanism of this is not entirely clear, however it is though to be due to metabolic disturbances. One of the most common theories is that Schwann cells are affected. It is thought that accumulation of fructose and sorbitol in schwann cells leads to their degradation.

The first sign in diabetic neuropathy is delayed nerve signal transit time. This is a direct result of demyelination, as a result of damage to schwann cells. At this stage, the axon itself is still intact, and thus the potential for repair is still present. At a later stage, the axons become damaged, and here irreversible damage has occurred. There are several type of neuropathy in diabetes:

• Symmetrical, mainly sensory neuropathy in distal regions
• Acute painful neuropathy
• Mononeuropathy and mononeuritis multiplex. This can occur either to cranial nerves, or to individual peripheral nerves
• Diabetic amyotrophy – this is progressive wasting of muscle tissues
• Autonomic neuropathy

Symmetrical mainly sensory neuropathy
This is generally not recognised by the patient in the early stages. The first signs are loss of pain, temperature and vibration feelings. You lose the deep sensation before the superficial, and the first place this tends to happen is in the feet.
Later patients may begin to notice these sensations and often describe them as ‘walking on cotton wool’. They may lose their balance whilst washing the face, or walking in the dark due to reduced proprioception.

• Involvement of the hands does occur but it is much less common. Sensation is lost in a ‘stocking and glove’ pattern. When the hands are involved, there may be wasting of the muscles of the hand. However this is rare, and should be distinguished from carpal tunnel syndrome, which is common in diabetes.
• This is important due to complications – often patients will suffer from unrecognised trauma. The most common thing is that a patient will get a blister, and they won’t notice, and it will develop into a leg ulcer.
• Sequelae (consequence) of neuropathy – motor neurones to the interosseous muscles of the foot can also be involved. This leads to wasting of these muscles, and this then alters how other muscles act on the foot. This gives rise to a classic foot shape of a high arch and clawing toes. This alters the weight distribution on the foot, and can lead to calluses and ulcer formation.

Acute painful neuropathy
This is less common than the symptoms described above. Patients will describe this as a very strong burning or crawling pain often felt in the shins and feet. It is often worse at night, and the pressure from bed clothes may be unbearable. It often develops after sudden improvement in glycaemic control (i.e. the patient starts insulin). it often disappears, but will return within 3-12 months, even in the case of good control.
Late on in the disease a chronic form may develop which is virtually resistant to all therapies.
Muscle wasting is not usually present, and objective signs can be hard to find.
Sometimes, all patients need is reassurance and a good explanation of what is going on.
Gabapentin, carbamezipine and tricyclic antidepressants can reduce the pain, but often not as much as the patient would like.
TENS and acupuncture have been known to be beneficial.

Mononeuritis and mononeuritis multiplex
This can affect any nerve in the body at any stage of diabetes. The onset is often sudden and painful. The most common involvement is with the 3^rd and 6^th cranial nerves, thus resulting in reduced ocular movement. Most instances will have a full spontaneous recovery. Lesions are more common at sites that have external compression. Carpal tunnel syndrome is also more common in diabetes, and does not respond as well to decompression as carpel tunnel syndrome in the general population.

Diabetic amyotrophy
This tends to be seen in older men with diabetes. Presentation tends to be with painful wasting of the quadriceps muscles. The wasting can be very marked, and the knee reflexes are often absent. Amyotrophic events in diabetes are often associated with poor glycaemic control, and this condition may be present at diagnosis. The events tend to rectify themselves if a strict control regimen is adhered to.
 
Autonomic neuropathy
Asymptomatic neuropathy can be demonstrated in many diabetic patients, but it is rare to find it presenting with symptoms. It affects both the sympathetic and parasympathetic nervous systems, and can be disabling.

• Cardiovascular problems – vagal neuropathy can result in a tachycardia and loss of sinus arrhythmia. Postural hypotension may also occur. A warm foot with a bounding pulse is sometimes seen in polyneuropathy as a result of peripheral vasodilation.
• Silent MI– The patient has a heart attack, but doesn’t feel it. They just get a bit breathless. The heart attack is caused by the increased risk of macrovascular complications, but the important part is that you don’t feel the heart attack due to autonomic neuropathy of the vagus nerves.
• Gastrointestinal problems – vagal damage can also lead to gastroparesis. In many cases this is asymptomatic but in some cases it may cause intractable vomiting. Autonomic diarrhoea may also occur at night, and is accompanied by urgency and incontinence. Diarrhoea steatorrhea can also occur as a result of overgrowth of bacteria. This is treated with antibiotics.
• Bladder problems – autonomic damage of the nerves to the bladder can result in incomplete stasis and emptying. Not only does this predispose to infection, but also can lead to painless distended bladder.
• Erectile dysfunction – this is very common – the first manifestation is incomplete erection, which often progresses to total failure. There can be many causes, including; anxiety, depression, alcohol, drugs, primary or seconday gonadal failure, hypothyroidism, inadequate vascular supply. You should try to pick out a cause during history taking and examination.

You should take blood tests for LH, FSH, testosterone, prolactin and thyroid function.
Phosphodiesterare type-5 inhibitors will increase the effect of nitrous oxide on smooth muscle, and thus can increase penile blood flow, and can be given to patients who aren’t taking nitrates e.g. for angina.
If this therapy works, it is worth discontinuing it after a few months, as after this time, confidence returns, and patients may no longer require treatment.
Side effects include headaches, and a green tinge to vision the next day.
60% of diabetic patients will benefit from this therapy.
There are also several other treatments available, but these tend to have lower efficacy and worse side effects.

Diabetic Foot (peripheral neuropathy)

Educate patients about the principles of foot care. Older or high risk patients should visit a chiropodist / podiatrist regularly and may be advised not cut their own toe nails.

Foot pain is a major cause of morbidly amongst patients with peripheral neuropathy. Agents known to be effective against neuropathic pain include:

• Amitriptyline – a tricyclic antidepressant. Should be used first line
• Pregabalin (Lyrica®) – may be considered in cases resistant to amitriptyline
• Gabapentin

Once tissue damage has occurred, then the main aim is preservation of viable tissue.
There are four main threats to viable tissue:

1. Infection – this takes hold very quickly, and you need early antibiotic treatment. Treatment should be modified in the light of culture results. The organisms grown from the skin may not be the organisms causing deeper skin infection. Excisions of bone may be needed if the infection spreads this far. Regular x-rays of the foot are needed to check the progress of this.
2. Ischaemia – the blood flow to the foot should be assessed with Doppler ultrasound. Femoral angiography is sometimes used to locate areas of occlusion, and in very rare cases, the leg may need amputation. Sometimes surgery to treat occlusion may be necessary, however, the risks of this are high, and so this is not often performed.
3. Abnormal pressure – you need to keep pressure off an ulcerated area. You may need to rest the affected leg, and wear special shoes / insoles. Even after healing these special shoes and insoles are still recommended to prevent repeated damage to the affected area. In some cases a chiropodist should be involved, and this helps prevent calluses that can distort normal foot architecture, and can itself lead to wound damage.
4. Wound management- you need to keep the wound moist, remove exudates and protect from external factors. Also keeping pressure around the affected area can help reduce the risk of oedema. Many new types of dressing contain growth factors and other molecules designed to aid healing, however, these are often expensive, and their role in treatment is yet unclear.

 
Foot problems are the major cause of admission for diabetic patients. When arterial occlusion is present, it is often quicker and kinder to amputate the affected area than subject the patient to a successive sequence of conservative procedures.

Infection
There is actually no evidence that diabetic patients with good glycaemic control are subject to more infections that the general population.
However – there is evidence that patients with poor glycaemic control are at greater risk. The mechanism for this is not fully understood however, it is thought that high glucose concentrations impairs the production of superoxides by leucocytes, and thus chemotaxis and phagocytosis are reduced.

• In an exaggerating effect, infections can also lead to a loss of glycaemic control, and are a very common cause of ketoacidosis.
• Insulin patients should increase insulin dose by 25% during infection, and non-insulin treated patients may need insulin during their period of illness.
• Diabetic patients should have the flu vaccine, and pneumococcal vaccine.

Skin and joints
The skin of diabetic patients may be thickened, particularly on the back of the fingers. This condition is not progressive.
Also, diabetes in childhood can affect the joints. You can notice this if you ask the patient to put their hands together as if in prayer. The patient will not be able to oppose the interphalangeal joints or metacarpophalangeal joints.

Diabetes and Driving

It is necessary for all patients requiring tablet or insulin therapy to inform the DVLA. There is a risk of hypoglycaemia at the wheel – which could result in an RTA. However, they will not be prevented from driving. In many countries, the driver will have to go for assessment every few years to check they are fit to drive, and commercial driving is usually not allowed.
Blurred vision may also be an issue, but is not as dangerous

References

• General practice management of type 2 diabetes (RACGP) [Australia]
• Type 2 diabetes in Adults

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Introduction

Epidemiology and Aetiology

• Affects 2-10% of pregnancies
• Risk factors:
  • Previous GDM
  • >35 years
  • Obesity (BMI >25, especially BMI > 35)
    • Note that women with BMI >27 should be given advice on weight loss if planning pregnancy
  • PCOS
  • Smoking
  • Previous stillbirth
  • Previous ‘large’ baby (>4.5Kg)
  • FH of type 2 diabetes
  • More common in Asians, those from the middle east and Black Africans
  • 40% of women with GD have none of these risk factors!
• Regular exercise during pregnancy is protective against development of gestational diabetes

Pathology

• The hormone Human placental lactogen (aka Human Chorionic Somatomammotropin) is responsible for reduce insulin sensitivity. It also alters maternal fat metabolism, releasing fatty acids as an alternate energy source for the mother, freeing up glucose for the foetus.
• The normal physiological response to this increased insulin resistance is for the body to produce more insulin. However, in some women this does not occur, resulting in hyperglycaemia
• It is often genetic – and tends to occur more in those who have a genetic predisposition for T2DM

Clinical features and presentation

• The risk of baby’s problems is greatest when glycaemic control is poor around the time of conception.
• Fetal macrosomia – this means big baby! The excess maternal glucose the baby is exposed to results in the storage of more fat than normal. Definition – abdominal circumference >70^th percentile.
• The newborn may be hypoglycaemic, as they have been producing their own endogenous insulin during pregnancy to counteract they hyperglycaemia of the mother. This is usually self-limiting, but may require IV glucose.
• Increased risk of shoulder dystocia during delivery
• Increased risk of jaundice
• Increased risk (2x) of congenital defects: congenital heart disease, respiratory distress syndrome, NTD’s. the risk of defects is inversely related to level of control of the gestational diabetes.
  • The risk of congenital defect is highest in type II diabetes, and lowest in type I. the risk in gestational diabetes is moderate.
• Increased risk of type II diabetes in later life
• Increased risk of obesity in childhood
• Increased risk of stillbirth

Mother’s risks

• Increased risks of vaginal tears

Complications

Increased risk of type II diabetes in the mother

• 50% will develop type II diabetes within 15 years
• 50% of those requiring insulin will develop type II within 5 years
• Increased risk of cardiovascular disease – independent of T2DM

Increased risk of stillbirth – to reduce this risk, the many mother have a caesarean at 38-39 weeks (instead of the usual 40)

• Consider caesarean or induced birth after 38 full weeks.
• Those with proven macrosomia should be informed of the risks of vaginal birth.
• Some older guidelines recommend offering caesarian or induction to all GDM mothers, some newer guidelines suggest only to offer this if there is evidence of complications – such as macrosomia, polyhydramnos (increase amniotic fluid), very poor glycaemic control, or any other complications.

Increased risk of GD in subsequent births (30-85%) – particulary if pregnancy occurs within 1 year.
Type I diabetes – any women with type I diabetes who becomes unwell during pregnancy should have DKA excluded as a differential!

For the baby

• Increased risk of obesity
• Impaired intellectual achievement
• Birth injuries – shoulder dystocia, fractures, nerve palsies – these are all problems associated with macrosomia (large baby)

Classification

• Type A1 – abnormal OGTT, but normal glucose levels during fasting and two hours after meals
  • Can usually be controlled with diet and exercise
• Type A2 – abnormal OGTT and high levels of glucose during fasting and 2 hours after meals
  • More likely to require pharmacological intervention

Management

Exercise – low impact activities are encouraged – such as walking, swimming, yoga and pilates. Particularly important in those with BMI >27Kg. These women may also be instructed to restrict calorie intake.

• Aim for 30 minutes a day of “moderate intensity” exercise (“sufficient to induce slight breathlessness”). This is proven to reduce insulin resistance.
• Weight loss is not advised, but limiting weight gain may be appropriate

Meals – eat regular meals, focus on the quantity and quality of carbohydrates and control fat intake. Aim for 175g of carbohydrates daily. Recommend use of complex carbohydrates, which reduce high peaks of glucose, and are digested slowly (“low GI foods”). Also, peak glucose levels are associated with breakfast more than with other meals, so it may be necessary to restrict carbohydrate intake at breakfast.

• GI – foods are given a rating from 1- 100, e.g. glucose (100) and spaghetti (41). Foods below 55 are considered low GI.
• Salt – monitor salt intake
• Fruit + Veg – at least 5 portions a day!
• Oily fish, lean meat, and polyunsaturated fats are also recommended
• Consider referral to dietician
• Be wary of severe calorie restriction, which can cause ketonuria and is related to adverse pregnancy outcomes – such as small for gestational age baby

Advise patients to check blood sugar level daily at home:

• On waking, first thing in the morning, whilst still fasted – aim for <5.3 mmol/L
• 2 hours after each meal (i.e. 3x per day) – aim for <7mmol/L

Metformin +/- Insulin

Until 2008, it was recommended that type II diabetic mother considering pregnancy, and those with gestational diabetes should avoid oral medications, and go on to using insulin for the duration of the pregnancy. However a large study in Australia and NZ confirmed that oral treatments are as effective, and do not increase the risk of birth defects relative to insulin.

Metformin is thought to be particularly useful in obese women.

Indications for insulin

• Glucose not controlled with diet + exercise + metformin
• Patients with a fasting sugar >7.0 mmol/L at diagnosis
• Patients with evidence of complications (e.g. macrosomia, hydramnios) and a fasting BSL >6.0 mmol/L

Rapid acting insulins (aspart and lispro) are more effective than endogenous insulins for controlling diabetes during pregnancy.
Insulin pumps should be recommended to those whose diabetes is not adequately controlled by multiple daily manual injections.

• If insulin is used during pregnancy, the dose is usually increased by 50%
• Warn about the risk of hypoglycaemia, how to recognise it and how to treat it
• Women on insulin should always carry within them a rapid acting glucose – e.g. glucose-containing drinks or dextrose tablets
• Any woman who is on insulin and unwell should have ketones checked

Other oral agents

• Only metformin is usually recommended
• In circumstances where sugars are not controlled with metformin and lifestyle measures, and the patient declines insulin, the glibenclamide may be considered
• Other oral agents are not recommended

• Consider Insulin + dextrose infusion in those with type I, or poorly controlled diabetes.

The time of birth

• Patients should deliver no later than 40+6 weeks
• If they have not delivered by this stage, offer induction or caesarian section
• Consider earlier elective than this if there is any evidence of complications (e.g. macrosomia, polyhydramnios). GDM in itself without complication is not an indication for pre-term induction
• GDM alone is NOT a contraindication to vaginal birth in the context of previous caesarian section

• Treatment can be ceased immediately after birth in GDM
• In T1DM and T2DM, treatment should continue, but doses of medications may need to be altered
• Breastfeeding – glibemclamide and metformin are safe to take whilst breastfeeding. Other oral agents should be avoided.
  • Breastfeeding itself is thought to have advatanges to both the mother and the baby in reducing their risk of being overweight.

Treatment can usually be stopped after birth, as the insulin resistance returns to normal. NICE recommends a random glucose test at the 6 week checkup, and if this normal, treatment can be stopped. If this is not normal, then patients should undergo further investigation for T2DM – e.g. OGTT or HbA1c).

• In Australia, an OGTT is recommended at 6 weeks – but HbA1c is considered a suitable alternative. Fasting blood glucose is not recommended.

Follow-up

• Recommend ongoing diet and lifestyle advice after birth (the same as given during GDM in pregnancy)
• Patients have an increased risk of T2DM in the long term
  • Also have a 50% of GDM in any future pregnancy
• In UK, recommended to perform annual HbA1c annually to all patents with previous GDM
• In Australia – recommended to perform an OGTT at 6-12 weeks postpartum to screen for T2DM, and then a fasting blood sugar every 3 years

Diabetes in Pregnancy

The diabetes is under control before pregnancy to give them the greatest chance of keeping it under control during pregnancy. Control should be measured with HbA1c test (should be below 6.1 for those planning on / who are pregnant. Those with HbA1c >10 should be strongly advised to avoid pregnancy!
The need to take folic acid supplements – 5mg/day when planning pregnancy and for 3 months after.
In type II diabetic mothers – Increased risk of birth defects

• Advise to take 5mg folic acid supplements when planning to conceive and for the first 12 weeks of pregnancy
• Risks include:
  • Birth defects mentioned above
  • Increased risk of miscarriage
  • Increased risk of stillbirth and neonatal death
• Women with BMI >27 who are planning to become pregnant should be given advice on how to lose weight

Targets for control in pregnant diabetics:

• Fasting glcusoe – 3.5 – 5.9
• 1 hour post prandial <7.8

Investigations and screening

• Fetal USS – four chamber view of heart and outflow tracts at 18-20 weeks
• Routine monitoring of fetal wellbeing is not recommended, unless pregnancy continues past 39 weeks.

Control of diabetic complication risk factors

• Hypertension – ACE-i and angiotensin-II antagonists should not be used in pregnancy! Use alternative treatments if planning a pregnancy or as soon as pregnancy is known. Use
  • Methydopa
  • Methynifedipine
• Statins – should be discontinued if planning pregnancy or as soon as pregnancy is known
• Retinopathy – up to 20% will experience some retinopathy during pregnancy
• Nephropathy – may worsen during pregnancy, avoid pregnancy is severe (e.g. creatinine >100, urea >4.5).

Antenatal care in diabetes

Blood glucose monitoring – targets should be set, and reviewed every 2 weeks with a medical professional
Retinal digital screening

• As soon as pregnancy confirmed (if not screened for >12 months)
• Perform at first ante-natal appointment
  • Perform at 16-20 weeks if previous result positive
  • Perform at 28 weeks if previous result negative
• 20% of diabetic mothers will develop proliferative retinopathy during pregnancy

Renal screening

• At first appointment – dipstick for protein, albumin, creatinine. Refer to nephrologist if creatinine >120, or protein >2g/day
• Thromboprophylaxis should be given to all those with protein excretion >5g/day

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• HealthPathways – Gestational Diabetes
• Gestational Diabetes – Patient.info
• Gestational Diabetes Mellitus – afp

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Introduce yourself

Get good and proper consent. Say exactly what you are going to do.

Inspect

Look at the feet

• Are there any ulcers?
• Skin damage? Look for calluses, cracked skin, nail changes (e.g. ingrowing nail), skin discolouration
• How is the general foot hygiene (does this look like a patient who takes care of their feet)? Does the patient look comfortable?
• Ask them if they are experiencing any difficulty with their feet.  sensory nerve loss is the first change seen in diabetic neuropathy – so often patients can have damage to their feet without realising it. if they are experiencing pain / discomfort or tingling sensations, it is likely the irreversible changes are quite far advanced.

Palpate

• Feel for the posterior tibial and the dorsalis pedis arteries. Posterior tibial is on the inner aspect of the ankle, the dorsalis pedis is on top of the foot lateral to the tendon of the big toe. The dorsalis pedis can be particularly difficult to palpate. If you press too hard you will occlude it. If you are finding it hard to feel, you can start by pressing hard and gradually let off to see if you can feel it. You may also want to ask the patient to extend their big toe to exaggerate the tendon, making the landmark more prominent and thus making it easier to palpate in the right place.
• Feel how warm the feet are- checking peripheral perfusion. Note that on a cold day, this is not a particularly reliable sign!
• Press on the nail beds to test capillary return –press for 5 seconds, then release and watch as the nail returns from pale to pink/red. This time should be less than 3 seconds, but could also be longer if it is cold. Compare both feet.

Check nerve function

• Tell the patient it won’t hurt and show this on yourself. Using the soft touch first. Often care centres have a ‘pen’ tool specially designed for the diabetic foot check, with a soft touch microfilament at one end, and a pain receptor tester at the other. Do not drag the microfilament across the surface of the skin, just gently press it against the skin and aski the patient for a response. The purpose of the microfilament is to visibly show when you are applying to much pressure. The filament will bend if you press too hard.
• Demonstrate the soft touch on the back of the patient’s hand so they know what sensation to expect. Then test the feet. Start distally (sensation is lost here first) and move up the foot and then up the leg. Sensation is lost in a glove and stocking pattern consistent with all peripheral neuropathies.
• If light touch sensation is lost, then use the sharp (pain) receptor tester. Again, mark out the pattern of sensory loss.
• Use the tuning fork. A 128Hz tuning fork should be used for this (proprioception). Again demonstrate it on yourself, then try it on the hand or perhaps clavicle of the patient so they know what it feels like.  Again, start distally, and use bony prominences (usually the MTP joint (“knuckle”) of the big toe. vibration testing is more sensitive than touch.

Interpreting Results

• Action – advise patient to check their own feet regularly for any changes, and to make an appointment if they notice any ulcer, callouses, skin or nail changes, or any altered sensation. Review in 12 months, manage in primary care

Grade 1 – No ulcer, but one of the following: callus, ingrowing toe nail, absent pulse, loss of sensation

• Action – give foot care advice. Refer to podiatry if any deformity / nail changes. Assess glycaemia control. Review in 6 months, manage in primary care, unless claudication @ <200m walking distance.

Grade 2 – Grade 1 PLUS previous Hx of ulcer, skin changes, minor ongoing ulcer

• Action – refer to podiatry and to diabetologist/ specialist diabetic foot care. Consider refer to vascular care if claudication @ <200m walking distance. Cosndier use of shoe inner-soles / specialist shoes, encourage tighter glycaemic control. Review at 3 months

Grade 3 – ACTIVE ONGOING PROBLEM – including acute ischaemia / necrosis / gangrene, cellulitis / infection, large ulcer, foot pain

• Action – REFER IMMEDIATELY – to diabetologist / specialist diabetic foot care, plus referral to vascular care due to ischaemia. PLUS all of grade 2 actions.

References

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Pathology

The exact mechanism by which diabetes causes diabetic retinopathy is not well understood.

• Diabetic retinopathy is a type of microvascular complication of diabetes
  • Other examples include diabetic nephropathy
  • This is opposed to the microvascular complications such as the increased risk of heart attack, stroke and other cardiovascular disease.
• Development of diabetic retinopathy correlates to the time since diagnosis of diabetes – the longer the duration the higher the chance of diabetic retinopathy (80% have retinopathy after 20 years)
• Coexisting disease- especially hypertension
• Smoking
• Pregnancy– may accelerate retinopathy

• the development of microaneurysms which allow plasma leakage into the retina
• the development of ischaemic retina
• the development of AV shunts

Presentation

Most patient are asymptomatic. Even in those with visual declines, the onset may be so insidious (slow and variable) that symptoms may not beneficed by the patient.

Haemorrhages may cause acute onset dark spots (‘floaters’). Severe haemorrhage may cause visual loss. Haemorrhages are painless.

Examination

Slit-lamp / ophthalmoscope

• Assessment and diagnosis is very difficult without the use of a slit lamp and / or retinal photography.

Fluorescein angiography (FFA)- to assess damage

Optical coherence tomography (OCT)- to assess if there is any macular oedema

Features of diabetic retinopathy as seen on the retina include:

• Microanueysms – weaknesses in the capillary walls leads to small aneurysms
• Hard exudates – collections of proteins that congregate on the retinal surface
• Cotton wool spots – shite ‘fluffy’ patches on the retina
• Haemorrhages – from repute of weakened capillaries. Typically larger in appearance than micoaneurysms
• Neovascularisation – new blood vessel formation – an attempt by the retina to heal

The main differential for diabetic retinopathy is macular degeneration – which can have some similar exudates on the retina. Late stage diabetic retinopathy however should be easy to differentiate due to the larger number of signs.

Features

Non-proliferative retinopathy (background retinopathy)

• Microaneurysms
• Dot and blot haemorrhages
• Cotton wool spots
• Hard exudates

The vision is usually NORMAL

• Macular oedema- gradual reduction in vision
• New vessel growth (neovascularisation)
• Retinal haemorrhage
• Vitreous haemorrhage- sudden loss of vision

Treatment

Screening

Prevention

• Optimal Management of DM
  • Lifestyle factors – diet and exercise
  • Medication
  • Insulin
  • Aim or HbA1c <7%
• Optimal management of HTN
• Smoking cessation
• Encourage to go to screening

• Most common cause of blind registration in younger patients
• May be asymptomatic
• Annual Screening and prevention is key
• Laser and pan-retinal photocoagulation treatment is available in some circumstance

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Charcot’s Joint (aka Charcot’s osteoarthropathy or Charcot’s neuroarthropathy) is most commonly seen as a complication of diabetes, but is also sometimes seen with syphilis. It is the result of peripheral neuropathy.

It results in swelling, redness and pain, typically the ankle, and sometimes involving other joints of the feet.

It can cause gross structural deformities, skin ulceration and may result in lower limb amputation. The onset of often insidious, and diagnosis frequently missed. It may be mistaken for cellulitis, gout or DVT or any other cause of lower limb pain, welling and redness.

It was first described by French Physician Jean Martin Charcot in around 1880.

It is a medical emergency. Delay to diagnosis and misdiagnosis can significantly impact the outcome.

Epidemiology

• Estimates vary widely, from 0.1% – 13% of patients with diabetes
• Frequently misdiagnosed
  • Delay in diagnosis often leads to much worse prognosis

Presentation

• Usually a history of diabetes, with established peripheral neuropathy
• Pain (75%)
• Swelling of the foot
• Redness
• Increased skin temperature

It may be difficult to differentiate from osteomyelitis both clinically and radiologically.

Pathophysiology

• Monoarthritis
• This is a neuropathic arthropathy
• it is a progressive degeneration of a weight bearing joint – usually in the ankle. There is usually bone destruction, remodelling and resorption, with ultimately results in deformity
  • Initially acute inflammation, which subsequently leads to fracture of the bone, joint instability +/- dislocation, and ultimately causing large deformities
• Usually gradual slow onset
• Can also result in ulceration – usually due to severe deformity causing abrasions of the skin against footwear which develop into ulcers

It is believed that loss of proprioception due to peripheral neuropathy induces recurrent micro trauma at the affected joint. This damage is not noticed, due to another effect of peripheral neuropathy: loss of sensation. It is also believed that the microvascular effects of diabetes lead to alteration of blood flow to the damaged foot (increased blood flow: hyperaemia) which causes increased osteoclast activity, thus further weakening the bone and contributing to bony destruction.

In syphilis, the knee is atypical affected.

Staging

• Stage – 0
  • No x-ray changes, but signs of inflammation may be apparent on MRi or bone scan
• Fragmentation stage
  • Bony fragments are apparent on x-ray as bones break down
  • Often there is joint disruption with bony fragments around joints
• Coalescence
  • The bony fragments may coalesce and attempt to heal

Investigation

If the diagnosis is a possibility, consider:

• X-ray
  • May miss early disease
  • May show fractures or other bone deformities in later disease
• MRI
  • Can detect early disease
  • Often shows bone marrow oedema, as well as bone deformities
• Bone scan
  • Can also detect early disease
  • Shows up areas of rapid bone turnover (i.e. inflammation in this instance)

Management

• Treatment is limited; early identification allows for modifications to minimise deformity
  • If diagnosed in Stage 0 the risk of long-term deformity and future ulceration is very low
• Non-weight bearing
  • Usually for several weeks, with gradual introduction of weight bearing as the inflammation settles
• Strict diabetic control
• Total contact casting (TCC)
  • A type of cast that completely covers the foot and the lower leg
  • It redistributes weight from the foot into the leg, allowing the foot to heal
  • After a period of weight bearing, patients can mobilise with their TCC
  • It may take up to 9 months for symptoms to settle, the average healing time is about 2-3 months
• In the long term, after the inflammatory process has settled, any deformity may require the use of custom made footwear, to redistribute weight in a similar manner to the TCC
• Amputation may be required in severe cases where there is complete bony destruction of the foot and severe ulceration

References

• Charcot osteoarthropathy of the foot – RACGP
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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