Introduction

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

*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

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