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 is caused by an 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
Action	Retest in five years or three years for those at risk	OGTT* for those at increased risk	OGTT*	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

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.

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.