Introduction

Type 2 diabetes mellitus (T2DM) is 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 bu 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 bloods 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

  • Underactivity, 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 two 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.

Epidemiology

  • The four main determining factors are; age, obesity, family history and ethnicity.
  • The overall prevalence of this disease in the UK is about 2%. This rises to 10% by the age of 70.
  • 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!), but is not due to overeating, more likely due to sedentary lifestyles.
  • 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; 
      • This is a condition where there is hyperpigmentation of the skin, particularly in the neck, axilla, groin and umbilicus. It results from excess insulin (which tends to be present in those with insulin resistance), which in turn causes excess growth of melanocytes. There are many causes of this, but the most common is type 2 diabetes.
  • The insulin resistant state, often combined with the symptoms above has been called syndrome X, metabolic syndrome, or insulin resistance syndrome.  The syndrome is basically a product of genetically 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 syndrome X.  Syndrome X 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 its receptor, 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’ factor.
  • Muscle cells in particular show increased insulin resistance and decreased glucose uptake
  • 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 is a high blood glucose 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.
Insulin changes over time - from normal insulin sensitivity on the right, through "insulin resistance" in the middle, and the states of insulin production and sensitivity in established T2DM on the right

Insulin changes over time – from normal insulin sensitivity on the left, through “insulin resistance” in the middle, and insulin production and insulin sensitivity levels in established T2DM on the right

Diagnosis and investigations

Diagnosis can be confirmed via one of three methods:

  • HbA1c >6.5% – on greater than two occasions
  • Fasting blood glucose (FBG) >7.0 mmol/L
    • OR – Random blood glucose >11.0 mmol.L, with subsequent elevated FBG on a separate day
  • Oral glucose tolerance test (OGTT)
    • Initial fasting blood sugar level (BSL) >7.0 mmol/L
    • End of test (after 75g of oral glucose, retested at 2 hours) >11.0 mmol/L
    • See below for fruther details

HbA1c

HbA1c has dramatically altered diabetes diagnosis and management targets in recent years.
HbA1c is a type of ‘glycated haemoglobin’ – essentially haemoglobin that has been altered due to the presence of glucose in the bloodstream.
The higher the glucose level, the greater the amount of glycated haemoglobin is produced – or HbA1c – in the blood. And, as red blood cells have a lifespan of about 90 days, the HbA1c value is in indicator of what glucose levels have been doing for the past 90 days.
The WHO now recommends that diabetes can be diagnosed with a single blood test for HbA1c. The test is positive if the value is  ≥ 6.5%.
  • 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
Diagnosing ‘impaired glucose tolerance’ with an HbA1c test alone is more difficult, although it probably corresponds to a value of between 5.5% and 6.4%.
  • 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
If presenting symptoms are obvious, then further investigation (beyond glucose level test) is not always necessary. For example – a patient with DKA, or iuncontrolled T2DM who turns up in the emergency department with a BSL (blood sugar level) of, for example>15.

Glucose Tolerance Test and Impaired Fasting Glucose

Using HbA1c is much simpler than the old methods of impaired glucose tolerance and impaired fasting glucose. However, there is still a role for glucose tolerance testing – for example in patient with a strong clinical suspicion, but who have an HbA1c <6.5%
This old-fashioned way of diagnosing diabetes, which may still be used in some centres, and is still used for diagnosing impaired glucose tolerance, sometimes called “pre-diabetes”.
Diagnosing impaired glucose tolerance (IGT) is still important because the risk of macrovascular complications (i.e. cardiovascular disease – as opposed to microvascular complications – i.e. peripheral neuropathy, renal disease and diabetic retinopathy) for those with IGT is the same as for those with diabetes.
But, higher glucose levels are associated with higher risk of microvascular complications.

IFG (impaired fasting glucose) is not as widely used as IGT. It also has a lower threshold for diagnosis, and thus more people fall into this category. Also, due to this lower threshold, the risk of macrovascular disease is not directly comparable to that of actual type 2 diabetes. Some people of course will fall into both IGT and IFG categories.

For every person diagnosed with diabetes, there is another somewhere out there in the population who is undiagnosed.
  • The OGTT – oral glucose tolerance test – the patient is fasted overnight (usually from midnight). In the morning they are given 75g glucose in 300ml water, and a blood sample is taken before and two hours after the administration of glucose.

Diagnosing diabetes by glucose levels

This graph shows the development of type two diabetes in relation to insulin secretion and sensitivity.
At first there will be compensatory secretion of insulin to counteract the reduced insulin sensitivity, however as the disease develops more, the amount of insulin secreted will also reduce.
 
 
Often the same patient will show IGT and IFG. These stages are important because they show the first signs of the disease, and these patients should be followed up.
  • 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

Australia (RACGP Guidelines)

  • Screen everyone over 40 every three years – using AUSDRISK scoring tool
    • 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.

 

Subacute presentation

Symptomatic type 2 diabetes tends to be more subtle and most commonly is asymptomatic and diagnosed on screening.
The clinical onset is often very gradual over months or years. It is particularly common in older patients, and the older the patient is often the more gradual the symptoms. Symptomatic presentation can include:
  • Lethargy / lack of energy
  • Polyuria, polydipsia
  • Visual blurring – as a result of glucose affecting refraction
  • Frequent fungal or bacterial infections  – often of the genitals (e.g. UTI, balanitis – inflammation of the glans penis in men, pruritis vulvae in females – due to candida infection)
    • This is thought to be secondary to the glucose in the urine causing a high glucose environment in the genital region – which encourages the growth of pathogens
  • Loss of sensation – e.g. touch, vibration or cold
  • Weight loss
Such cases may also present with complications:
  • Staphylococcal skin infections
  • Retinopathy – often noted during a visit to the optician
  • Polyneuropathy – causing tingling and numbness in the feet
  • Erectile dysfunction
  • Arterial disease – possibly resulting in MI, or gangrene.
Occasionally, hyperglycaemia or glycosuria may be detected incidentally (e.g. for insurance purposes). This is not diagnostic for diabetes. About 1% of people have glycosuria naturally, due to a low renal threshold for glucose.
Clinical Signs of insulin resistance
  • 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

Treatment

Education of patients is very important. This should take place soon after diagnosis. Patients should be informed of the benefits of good glycaemic control and how to stop signs of complications (such as diabetic foot complications). They should also be informed about reducing risk factors (e.g. stopping smoking!), and benefits of regular exercise

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

Step wise approach

  • Lifestyle
  • Lifestyle + metformin
  • Lifestyle + metformin + secondary drug agent
  • Lifestyle + metformin + secondary drug agent + insulin

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 (although not sugar free)
  • High starchy 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 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 serving 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 forgets 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

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
  • 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

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 gadget – 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].
Intensity Minutes of Exercise in diabetes management

Garmin Connect app showing “Intensity Minutes” view for a particular week

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+

Patients with a BMI of >40, of >35 with other co-morbidities 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 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. DDP-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

MedicationWeightHypo RiskReduced Renal FunctionOther Info
MetforminLowReduce dose – eGFR 30-60

Contraindicated – eGFR <30

First Line Agent
SulphonylureaMay ­↑*YesIncreased risk of hypo
DDP-4iMay LowReduce doseContraindicated with GLP-1
SGLT2iLowContraindicated – eGFR <30Associated with modest reduction in BP, and increased risk of UTI
GLP-1LowContraindicated – eGFR <30

Reduce dose in more mild renal impairment

Contraindicated with DDP-4i

Can be given once weekly

TZD­­LowAvoidMany side effects – weight gain, fluid retention, bladder cancer, osteoporosis
AcarboseMay LowContraindicatedCase GI side effects – such as increased flatulence and diarrhoea
Insulin­­YesIncreased 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.

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 and diarrhoeaMany unnecessary colonoscopies have been ordered, when stopping metformin would have stopped the symptoms!

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)
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 ketoic patients. 
  • 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.
  • 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.

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

SGLT-2 Inihibitors

(e.g. dapagliflozin, empagliflozin –  “Jardiance”)

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
  • Increased risk of UTI and genital candidiasis – due to the glucose rich environment created by passing large amounts of sugar-filled urine
  • Can affect other diuretic medications
  • Less effective with reduced renal function
    • Generally not advised if eGFR <60
  • Indicated as a single agent if metofrmin is contraindicated, or in combination with metformin if sulphonylurea is ineffective
  • May be particularly useful in patients whom struggle with dietary adherence

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

DPP-4 Inhibitors (Gliptins)

e.g. sitagliptin, linagliptin

Dipeptidyl dipeptidase-4 inhibitors are relatively new drugs. They 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.

Side effects

  • Skin rash

 

GLP-1 Analogues

(e.g. Exenatide – “Byetta”)

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.

  • 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.

Intestinal enzyme inhibitors (Acarbose)

(e.g. 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 no 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.

Short acting insulins
In some developing countries, synthetics insulins are still used, however in most developed countries these have now been replaced by synthetically produced varieties. It is 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 – This is not very 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 have been created, and with these, the insulin dissociates 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. Increase doses slowly.

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)

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
  • Foot / peripheral nerves assessment
  • Bloods (HbA1c, urea and electrolytes and eGFR, lipid profile)
  • 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

 

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

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%.
Occasional, 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 Lucozade) 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.
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

References

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