Diabetes mellitus

Diabetes mellitus is defined by the World Health Organization as "a chronic disease that occurs when the pancreas does not produce enough insulin, or alternatively, when the body cannot effectively use the insulin it produces."

A conservative analysis estimated that in the year 2000, 2.8% of the global population had diabetes mellitus and this was projected to rise to 4.4% in 2030. It is expected that by 2030 at least 366 million people will have diabetes; that is one in every 23 people. Diabetes is the fourth leading cause of global death by disease and at least 50% of all people with diabetes are unaware of their condition. In some countries, this figure may reach 80%.

The disease is characterised by increased levels of glucose (a form of sugar) in the blood.

Regulation of blood glucose

Main article blood glucose regulation

A healthy individual maintains blood glucose levels between 3.5 – 8 mmol/L (63-144 mg/dL) despite wide fluctuations in both glucose intake from meals and glucose utilisation to meet energy demands. When blood glucose levels are outside this range, the body experiences adverse effects.

If blood glucose levels are low (hypoglycaemia), the brain is unable to function correctly. This is because oxidation of glucose provides the energy for brain cell activity. As the brain cannot store glucose, it requires a constant supply of glucose in its blood supply.

A persistently high glucose level (hyperglycaemia) is the main indicator of diabetes mellitus.

Diabetes mellitus:imbalance between insulin secretion and insulin resistance

Main articles: Insulin

The hormone, insulin is the key regulator of blood glucose levels. It is released from the beta cells of the pancreas in response to a range of neural, nutrient, hormonal and chemical stimuli. Insulin secretion is increased by high blood glucose levels and inhibited by falling glucose levels. The actions of insulin lower blood glucose levels.

Insulin’s actions include:

• Stimulation of:
  • Glucose uptake by fat and muscle cells,
  • Glucose oxidation within cells to release energy, cellular respiration,
  • Glucose storage as glycogen in liver and muscle cells, glycogenesis,
  • Manufacture of triglycerides by fat cells using glucose as a substrate, and
• Inhibition of glucose production from the intermediaries of fat and protein metabolism, gluconeogenesis.

Maintaining normal blood glucose levels therefore requires a balance between the secretion of insulin and the sensitivity of liver, muscle, fat and other cells to the action of insulin. The sensitivity of these cells to the action of insulin is impaired by obesity, genetic, hormonal and a range of other factors. This impaired sensitivity is termed insulin resistance.

Normally insulin resistance can be compensated for by increased insulin secretion. The elevated blood glucose levels that are characteristic of diabetes mellitus result from either absolute insulin deficiency or insulin resistance accompanied by impaired ability to compensate by increased insulin secretion.

Other hormones influencing blood glucose levels

The hormone glucagon opposes many of the actions of insulin. In particular, it stimulates the release of glucose stored as glycogen in the liver and if these stores are depleted, promotes gluconeogenesis.

Other hormones influencing blood glucose levels include adrenalin (epinephrine), corticosteroids, growth hormone and thyroid hormones.

Classification of diabetes mellitus

The classification of diabetes mellitus is still evolving. The terms “Juvenile Diabetes”, “Maturity-onset Diabetes” “Insulin Dependent Diabetes Mellitus (IDDM)” and “Non-Insulin Dependent Diabetes Mellitus (NIDDM)” have been abandoned and replaced by classifications based on the underlying physiological changes. As understanding of the causes of diabetes improves, it is likely that classification will evolve further.

Current classification of diabetes mellitus includes:

• Diabetes Mellitus type 1
• Diabetes Mellitus type 2
• Gestational Diabetes
• Other types

Diabetes mellitus type 1

Main article: Diabetes mellitus type 1

Type 1 diabetes is caused by selective destruction of the insulin-producing beta cells of the pancreas eventually resulting in absolute insulin deficiency. It does not include diabetes caused by general destruction of pancreatic tissue such as by pancreatitis or pancreatic cancer.

In approximately 90% of type 1 diabetes, destruction of beta cells is caused by an auto-immune response, triggered by an interaction of genes and environmental factors. This is termed diabetes type 1A.

Type 1 diabetes usually occurs before the age of 30 years with a peak age of onset between 10 and 14 years. There is a prolonged prodromal phase preceding the onset of symptoms, but when they do occur, onset is usually abrupt. Blood sugar rises rapidly with associated thirst, hunger, excessive urination, weight loss and fatigue. Insulin therapy is required for survival.

The cause has not yet been determined for the remaining 10% of type 1 diabetes (diabetes type 1B).

Diabetes mellitus type 2

Main article: Diabetes mellitus type 2

People with type 2 diabetes have insulin resistance combined with an impaired ability to compensate by increasing insulin secretion. It is the most frequently occurring form of diabetes mellitus and the rate of onset increases with increasing age. Although type 2 diabetes is predominantly a disease of older people, it is increasingly occurring in young obese people.

Onset of symptoms is usually gradual and the majority of people with undiagnosed diabetes have type 2 diabetes. Type 2 diabetes is often present for several years before diagnosis and complications of the disorder may already be present.

The development of type 2 diabetes is influenced by genetic and lifestyle factors. People who have two parents with type 2 diabetes have an approximately 40% risk of developing it themselves. Risk of developing type 2 diabetes is increased by obesity and physical inactivity.

Gestational diabetes mellitus

Main article: Gestational diabetes

Gestational diabetes is caused by the development of insulin resistance during late pregnancy related to the metabolic changes that occur. Gestational diabetes usually settles after the baby has been born but women who have experienced gestational diabetes are left with an approximately 50% chance of developing diabetes mellitus.

Other specific types of diabetes mellitus

There are other less common types of diabetes mellitus.

These are associated with:

• Genetic beta-cell secretory defects;
• Genetic defects in insulin action;
• Diseases of the pancreas, such as pancreatitis or pancreatic cancer;
• Endocrine disorders, such as Cushing syndrome, acromegaly and phaeochromocytoma;
• Drugs or chemicals, such as corticosteroids and thiazide diuretics;
• Infections, such as rubella and cytomegalovirus;
• Uncommon forms of immune-related diabetes, such as the type associated with insulin-receptor antibodies;
• Genetic syndromes associated with diabetes, such as Klinefelter syndrome and Down syndrome.

Diagnosis of diabetes mellitus

Diagnosis of diabetes mellitus is crucial to reduce the associated high rates of death and disability.

Fasting blood glucose

A diagnosis of diabetes mellitus is made when venous plasma glucose samples on two separate occasions are ≥ 7.0mmol/l (126mg/dl). The diagnosis can be made on a single sample, when the fasting blood glucose level is unequivocally elevated, for example above 11mmol/L (200mg/dl), and the person has symptoms of diabetes mellitus.

There has been much debate about this threshold level. There is no clear cut-off blood sugar level under which the risks of the complications of diabetes mellitus disappear. For example a recent study of diabetic eye disease (retinopathy) found the “current cutoff of 7.0 mmol/L used to diagnose diabetes did not accurately identify people with and without retinopathy."

Clearly, although the criteria for a fasting glucose is > 7mmol/L, this is not the threshold level below which results can be considered normal. There is no worldwide agreement on the level of fasting glucose that is considered normal.

In 1997, the term Impaired Fasting Glucose (IFG) was introduced to describe the range between ‘normal’ fasting glucose and diabetes mellitus. This was thought to be analogous to a previously introduced category called Impaired Glucose Tolerance (IGT), which describe a state of glucose regulation between ‘normal’ and diabetes mellitus. However, this has not turned out to be the case.

People with Impaired Fasting Glucose or Impaired Glucose Tolerance have an increase risk of developing diabetes and already have some increase in the risks associated with it but the majority do not progress to develop diabetes mellitus. There is strong evidence that lifestyle changes and some medications can reduce the risk of progression to diabetes for people with Impaired Glucose Tolerance. The evidence is less clear-cut for people with Impaired Fasting Glucose, although it does seem likely.

Although there is no absolute worldwide agreement on the figures involved, the following is a practical application of current knowledge:

Perform immediate plasma glucose testing on people who are ill and hyperglycaemia is suspected.

Perform fasting plasma glucose testing on venous blood for people with:

• Risk factors for diabetes mellitus,
• Symptoms suggestive of diabetes mellitus, or
• Other illnesses, which are known to occur as complications of diabetes.

Respond to the results as follows:

Fasting Glucose Result	<5.5	5.5 - 6.0	6.1 - 6.9	> 7.0
Interpretation	Normal Result	Borderline Result	Impaired Fasting Glucose	Diabetes mellitus
Action	Retest in five years or three years for those at risk	OGTT* for those at increased risk	Confirm results on second sample

• OGGT = a 75 g Oral Glucose Tolerance Test

Oral Glucose Tolerance Test

An 75g oral glucose tolerance test consists of a fasting venous plasma glucose test, following which the person is given 75g of oral glucose. A further venous plasma glucose test is taken two hours later. The results can be interpreted as follows.

	Fasting result		2-hour result
Normal	<5.5	and	<7.8
IFG	6.1 - 6.9	and	<7.8
IGT	<7	and	7.8 - 11.0
Diabetes mellitus	>7.0	and/or	>11.0

Urinary Glucose testing – not suitable for diagnostic test

Although glucose spills over to the urine when blood glucose levels are high, the finding of glucose in urine is not a reliable test of diabetes. Approximately 1% of the population have glucose in their urine even when blood glucose levels are normal and urinary glucose is not a consistent finding in people with diabetes mellitus.

Glycosylated haemoglobin - not yet suitable for diagnostic test

Changes in HbA1c levels provide the best practical estimation for monitoring control of blood glucose levels in people with diabetes mellitus. However, it is not suitable as a diagnostic test for diabetes as there is, as yet, no demonstrated direct correlation between HbA1c and blood glucose levels.

Adverse effects of Diabetes Mellitus

Diabetes has a wide range of adverse effects ranging from mild fatigue to increased risk of renal failure, blindness, heart attack and stroke. The life expectancy of people with diabetes is reduced by an average of five to 10 years, mainly because of an increased risk of cardiovascular disease but also because of complications specific to diabetes.

Polyuria, Polydipsia and weight loss

The classic triad for the presentation of diabetes mellitus is frequent urination (polyuria), thirst (polydipsia) and weight loss. This is often accompanied by fatigue.

The frequency of urination is caused by the presence of glucose in the urine taking excess water with it by osmotic attraction. The loss of excess fluid results in thirst and weight loss. Impaired glucose utilisation leads to break down of triglycerides (types of fats) and amino acids (from proteins) further adding to weight loss.

Diabetic ketoacidosis

Diabetic ketoacidosis is a life threatening acute complication of diabetes mellitus that usually occurs in type 1 diabetes but can occur in type 2 diabetes especially in children. It is usually the result of absolute deficiency in insulin production.

In the absence of insulin, cells cannot utilise glucose to produce energy and triglycerides are broken down instead. This results in the production of ketones, which add to the frequent urination already experienced and cause acidosis, a reduction in pH. The net result is dehydration, vomiting or changes in the mental state. This is often accompanied by rapid deep breathing, Kussmaul respirations, which exhale excessive carbon dioxide in an attempt to correct the acidosis.

People with diabetic acidosis require immediate care to correct dehydration, acidosis and insulin deficiency and to replace electrolytes, which have been lost from damaged cells.

Diabetic ketoacidosis may be the initial sign of type 1 diabetes and may be mistakenly overlooked.

Increased risk of cardiovascular disease

Main article: Cardiovascular disease

All age groups of people with diabetes mellitus have an increased risk of developing cardiovascular disease, such as myocardial infarction (heart attack), stroke and peripheral arterial disease (usually causing impaired blood supply to the legs). It is the main cause of death for people with type 1 or type 2 diabetes.

One mechanism for this increased risk is that impaired glucose metabolism leads to increased use of free fatty acids, levels of which rise in the circulation. This stimulates the production of lipoproteins including Very Low Density Lipoproteins (VLDL), which are known to promote the formation, development and rupture of plaques on the inner lining of arteries. Other mechanisms include increased risk of clot formation within arteries due to increased platelet reactivity and augmented activity of the coagulation system along with impaired ability to break down clots that have formed.

The strongest risk factors for developing cardiovascular disease for people with diabetes are genetic influences, smoking, raised blood pressure, raised blood lipid levels and the presence of albumen in the urine.

The increase risk of cardiovascular disease in people with diabetes is often termed the macrovascular complications of diabetes in contradistinction to the microvascular complications of diabetes, which are specific to diabetes and are due to damage to small blood vessels.

Microvascular complications of diabetes mellitus

Microvascular complications of diabetes mellitus are caused by damage to small blood vessels throughout the body. This is particularly dangerous in the eyes, kidneys and nerve sheaths where they cause:

• Diabetic retinopathy,
• Diabetic nephropathy, and
• Diabetic neuropathy.

The strongest risk factors for the development of microvascular complications in people with diabetes are genetic influences, duration of diabetes, poor control of blood glucose levels, and raised blood pressure.

Diabetic retinopathy

Main article: Diabetic retinopathy

Diabetic retinopathy causes approximately 5% of blindness worldwide. Almost everyone with diabetes has some degree of retinopathy after 20 years with the disease. Approximately 20-50% develop sight-threatening disease. Screening for diabetic retinopathy must start immediately type 2 diabetes is diagnosed, as people may have had diabetes for many years prior to diagnosis. The initial screening is less urgent for people diagnosed with type 1 diabetes.

Diabetic nephropathy

Main article: Diabetic nephropathy

Diabetic nephropathy, renal disease caused by diabetes, can progress to renal failure and increases the risk of cardiovascular disease. Approximately 20-50% of people with renal failure requiring renal dialysis have diabetes.

Microalbuminuria is an early marker for renal disease. It is an estimation of urinary albumin excretion between 30 and 300 mg per day. Approximately 2-4% of people with diabetes will develop microalbuminuria each year. Of these: approximately one third will revert to normal albumin excretion, one third will continue to demonstrate microalbuminuria and one third will progress to frank proteinuria, which is albumin excretion above 300mg per day.

Almost all people with diabetes and proteinuria will progress to end stage renal disease or die prematurely from cardiovascular disease.

Diabetic neuropathy

Main article: Diabetic neuropathy

Diabetic neuropathy is damage to the nerves caused by diabetes. It will affect approximately 30-50% of people with diabetes. The commonest forms cause reduced sensation with or without burning pain in the legs or erectile dysfunction. Several other forms of peripheral and autonomic neuropathies are associated with diabetes mellitus.

Non alcoholic fatty liver disease

Main article: Non alcoholic fatty liver disease

Non-alcoholic fatty liver disease is the accumulation of triglycerides in liver cells without excess alcohol intake. It is most commonly associated with insulin resistant states such as in diabetes mellitus and obesity. It is the commonest cause of abnormal Liver Function Tests (LFTs) in type 2 diabetes, the most frequent being mild to moderate elevation of serum aminotransferases.

The disorder ranges from simple fatty liver with normal liver function tests, through minor abnormalities of liver function testing to progressive fibrosis and cirrhosis of the liver. Although non-alcoholic liver disease is common, people with simple fatty liver have a low risk of progression to fibrotic liver disease.

Increased risk of infection

People with persistently elevated blood glucose levels due to poorly controlled diabetes mellitus are at increased risk of some infections because high glucose levels impair the action of neutrophils.

People with poorly controlled diabetes are at increased risk of the following infections:

• Staphylococcal skin infections
• Candidal infections
• Urinary tract infections
• Some forms of pneumonia
• Tuberculosis

Conversely, when people with diabetes get infections, it can lead to loss of control of the diabetes and may trigger ketoacidosis. People on insulin therapy are at particular risk and often need to adjust their insulin dose when they have infections.

Management of diabetes mellitus

Although diabetes mellitus can be devastating illness, much can be done to improve outcomes for people who have it. Management of diabetes mellitus focuses on improving quality of life for people at risk of or with diabetes mellitus by:

• Prevention
• Early detection
• Control of blood glucose levels
• Management of other risk factors contributing to adverse effects
• Early recognition and management of adverse effects

Prevention of diabetes mellitus

There is no clearly established means of preventing diabetes mellitus type 1. It is an autoimmune disease caused by a combination of genetic susceptibility and environmental triggers. Although a great deal of progress has been made in the prediction of Type 1 diabetes by the discovery of autoantibodies to beta cells, this has not yet led to the an effective intervention that prevents progression of the disease.

A strategy to prevent type 1 diabetes would be for genetically susceptible people to avoid the environmental factors that trigger the autoimmune response. However, there is a long list of plausible environmental triggers and of these, only prenatal rubella infection has direct evidence of causation. Countries with universal rubella immunisation have abolished this cause of diabetes mellitus type 1.

Major preventable factors contributing to the worldwide increase in type 2 diabetes are obesity and lack of physical exercise. Both these factors are associated with insulin resistance, type 2 diabetes, fatty liver, cardiovascular disease, high blood pressure, adverse blood lipid levels and a wide range of musculoskeletal, respiratory and other conditions. Although the exact biological relationship between these conditions, physical activity and obesity is not yet fully elucidated, there is no doubt that reducing the prevalence of obesity, especially central obesity, and increasing levels of physical activity would significantly reduce the prevalence of type 2 diabetes.

Early detection of diabetes mellitus

Diabetes can be detected by performing blood sugar testing on people with:

• Symptoms suggestive of diabetes
• Increased risk of diabetes
• Health conditions associated with diabetes

Symptoms suggestive of diabetes

Type 1 diabetes is usually diagnosed when there is acute onset of symptoms related to high blood sugar levels.

Type 2 diabetes is often present for many years before the development of the classical symptoms of excess urination, thirst and weight loss.

Increased risk for diabetes

Because type 2 diabetes is often present for many years prior to the onset of symptoms, it is useful to screen people at increased risk of the disease. Risk factors for type 2 diabetes have not been quantified and they need to be interpreted within the context in which they are being applied. The risk factors can be grouped into five categories:

• Genetic
• Lifestyle
• Ethnicity
• Insulin resistance phenotype
• Some Medications

Genetic

The genetic factors, which confer susceptibility to type 2 diabetes are still being identified but there is good evidence that susceptibility is inherited. Studies of twins show a concordance rate of over 50% in monozygotic twins but only 37% in dizygotic twins.

People with a first degree relative with type 2 diabetes have a 40% chance of developing the disease.

Lifestyle

Lifestyle factors, which lead to increase adiposity and decreased physical activity, are responsible for the worldwide explosion in prevalence of type 2 diabetes.

Although we do not have a practical clinical measure of adiposity, the BMI and waist measurements are useful surrogates for it.

Ethnicity

There is generally a preponderance of type 2 diabetes in a country’s ethnic minorities. For example the high rates of type 2 diabetes in Native Americans, Mexican Americans and African Americans in the United States and in Māori and Pacific peoples in New Zealand. Ethnicity encompasses cultural, behavioural and social traits.

People identifying with these ethnicities are at increased risk of type 2 diabetes.

Insulin resistance phenotype

As insulin resistance is a major factor in the development of type 2 diabetes, conditions in which insulin resistance is a feature carry increased risk of type 2 diabetes. These include:

• Polycystic Ovary Syndrome
• Metabolic Syndrome
• Acanthosis Nigrans
• Increasing age
• Puberty
• History of gestational diabetes or having a baby over 4Kg in weight
• Impaired glucose tolerance
• Hypertension
• Adverse lipid profile
• Abnormal liver function tests

People with any of these conditions are at increased risk of type 2 diabetes.

Medications

Some medications such as some anti-psychotics, beta blockers are associated with increased risk of diabetes mellitus.

Test people with conditions associated with diabetes

Because people with type 2 diabetes may develop adverse effects before the disease becomes symptomatic, a major adverse effect such as heart attack or stroke may present the first opportunity to test for the disease.

Controlling blood glucose levels in diabetes mellitus

Controlling blood glucose levels significantly reduces the risks of adverse effects in all types of diabetes mellitus. The degree of control achieved is assessed by measurement of the Glycosylated Haemoglobin.

Assessed with glycosylated haemoglobin (HbA1C )

Main article: glycosylated haemoglobin

Glycosylated haemoglobin (HbA1C) is formed by a bond between a glucose molecule and the beta chain of the haemoglobin molecule. The percentage of normal haemoglobin, which has been glycosylated in this way, is the HbA1C measurement. It is normally between approximately 4 and 8%.

Measurement of HbA1c gives an indication of the average glucose levels over the life of a haemoglobin molecule , approximately six weeks. The rate at which glycosylation occurs depends on the concentration of glucose in the blood over this time. At higher concentrations, more haemoglobin becomes glycosylated.

Any lowering of HbA1C levels is beneficial down to at least 5.5%. Many people with diabetes mellitus cannot achieve this low level and people on insulin therapy often cannot achieve this level without significant risk of hypoglycaemia.

HbA1C levels are unreliable for someone who has a haemoglobinopathy or has a high turnover of red blood cells.

Advantages of controlling blood glucose levels

Controlling blood glucose levels, glycaemic control, decreases the risk of most adverse effects associated with diabetes mellitus. People with diabetes mellitus who achieve near normal blood glucose levels can expect to abolish the thirst, excessive urination, weight loss and increased risk of infection associated with the disease.

There is convincing evidence that reducing HbA1C levels significantly reduces the risks of microvascular disease, such as diabetic neuropathy, retinopathy and neuropathy. For example reducing HbA1C levels from a mean of 9% to a mean of 7.2% reduces the risk of developing the early stages of diabetic nephropathy by one third.

Good evidence is emerging that reducing HbA1C also reduces the increased risk of cardiovascular disease associated with diabetes mellitus. A 1% reduction of HbA1C results in a 14% reduction in cardiovascular risk.

Lifestyle changes to control blood glucose levels

Physical exercise and dietary changes, which reduce energy intake and promote weight loss improve glycaemic control for people with diabetes mellitus. These lifestyle interventions also decrease the risk of progression to diabetes mellitus for people with impaired glucose tolerance. However, many people find it difficult to persist with these changes and require ongoing support and encouragement.

Lifestyle modification alone provides adequate control of blood glucose levels for only a minority of people with diabetes mellitus and then for only a short period after diagnosis.

Medication to reduce control blood glucose levels

A wide range of glucose lowering pharmaceutical therapies are available for use in diabetes mellitus, these are sometimes referred to as hypoglycaemic agents. These include a number of oral agents and insulin injections.

Metformin reduces insulin resistance and therefore increases the glucose uptake in peripheral tissues and decreases hepatic glucose production. It requires the presence of insulin in the circulation to be effective. It is normally the first-line glucose lowering agent for people with type 2 diabetes, especially those who are overweight, as unlike other agents its use is not associated with weight gain and there is good evidence that it reduces risk for people with diabetes.

In overweight people, its use is associated with a relative risk reduction of: 32% for any diabetes related endpoint 42% for diabetes related death, and 36% for all cause mortality.

It should not be used for people who have poor renal function. Its use is associated with the rare, but of fatal, complication of lactic acidosis.

Sulfonylureas are insulin secretagogues, they stimulate beta cells to release insulin and therefore require the presence of functioning beta cells to be effective. There are several sulfonylureas available. Unlike metformin, they are associated with weight gain and the risk of hypoglycaemia. A sulfonylurea is usually added to metformin in type 2 diabetes when it has not been effective used alone or for people who cannot tolerate metformin. A sulfonylurea may be used as first-line glucose lowering therapy for people with diabetes who are not overweight.

Thiozolidinediones, often referred to as glitazones, reduce blood glucose by increasing glucose uptake by muscles, inhibiting the break down of fat and reducing glucose production in the liver. Although they have been shown to reduce blood glucose levels there is, as yet, limited evidence on their ability to reduce the adverse effect of diabetes. They have been associated with oedema, anaemia, weight gain and liver damage.

Acarbose is an alpha-glucosidase inhibitor and inhibits the digestion of carbohydrates resulting in less glucose being available for absorption. This may result in gastrointestinal effects such as flatulence and bloating but in general it appears to be a safe drug.

Insulin replacement insulin therapy is essential for all people with type 1 diabetes and is often beneficial for people with type 2 diabetes not well controlled on oral therapy. Insulin cannot be given by mouth and is usually given by injection. Insulin therapy has a significant risk of hypoglycaemia and self-monitoring of blood glucose levels is usually recommended.