Focus on Diabetes 2

Type 2 Diabetes: Background

What is type 2 diabetes?

Type 2 diabetes - formerly known as non insulin-dependent diabetes mellitus or NIDDM - is a metabolic disorder characterised by an inability to control blood glucose (sugar) levels.  The main hormone controlling blood glucose levels is insulin.  In people with type 2 diabetes, early phase insulin secretion (the phase of insulin secretion that occurs immediately following a meal) is reduced and the body's cells do not respond properly to insulin.  As a result, blood glucose levels are too high.

Blood glucose levels are usually expressed in terms of the glucose concentration in plasma (the liquid part of the blood that remains after removing the blood cells).  In healthy people, fasting plasma glucose levels (usually measured first thing in the morning) are less than 6.1mmol/l, and plasma glucose levels two hours after consuming 75g glucose are under 7.8mmol/l.  According to World Health Organisation criteria, type 2 diabetes is diagnosed if fasting plasma glucose levels are 7.0mmol/l or greater and/or plasma glucose levels two hours after consuming 75g glucose are 11.1mmol/l or greater.1

Impaired Glucose Metabolism

Before people develop type 2 diabetes, they often go through a phase in which their blood glucose is higher than normal, but not yet high enough to diagnose diabetes.

Impaired fasting glycaemia (IFG) is diagnosed when a person's fasting plasma glucose level is at least 6.1 mmol/l but less than 7.0mmol/l.1

Impaired glucose tolerance (IGT) is diagnosed when a person's plasma glucose level two hours after consuming 75g glucose is at least 7.8mmol/l but less than 11.1mmol/l.1

People who have IFG or IGT (or both) are said to have impaired glucose metabolism (IGM).  People with IGM are at increased risk of developing type 2 diabetes.

Prevalence of type 2 diabetes

Type 2 diabetes is one of the world's most common chronic diseases.

It is estimated that worldwide, there are 151 million people with diabetes.  Over 85% of these cases are type 2 diabetes.2

In Europe, approximately 22.5 million adults (5% of the adult population) have type 2 diabetes.2 Other parts of the world suffer even greater diabetes rates, e.g. over 8% in the USA and India and over 14% in Mexico.

Throughout the world, the prevalence of type 2 diabetes is rising at an alarming rate. This is believed to be due to increases in longevity, obesity and sedentary lifestyles. The World Health Organisation (WHO) estimates that by 2025, at least 300 million people worldwide will have type 2 diabetes.2 This implies an increase of nearly 6 million cases every year.  Type 2 diabetes is also affecting people at a younger and younger age, even in childhood and adolescence.3

What causes type 2 diabetes?

Type 2 diabetes is caused by a combination of impaired secretion of insulin (the main hormone controlling blood glucose) and reduced sensitivity of the body's cells to insulin (insulin resistance). 

Individuals with type 2 diabetes show a marked reduction in early insulin secretion i.e. the phase of insulin secretion that occurs prior to and immediately after eating. This is the result of malfunctioning of pancreatic ß-cells.  It is believed that by the time type 2 diabetes is diagnosed, ß-cell function may have been declining for up to 12 years. In the long-term, high blood glucose levels are toxic to ß-cells, leading to further deterioration in ß-cell function and worsening blood glucose control.

Insulin resistance means that liver, muscle and fat cells have ceased to be highly sensitive to insulin. This means that insulin released at mealtimes does not stimulate a sufficient increase in glucose uptake.  Insulin resistance is a common feature of individuals who are obese, particularly if they carry a lot of fat in the central (abdominal) region, are physically inactive, have hypertension or dyslipidaemia, or had a low birth-weight, indicating fetal undernutrition.  Genetic factors are also important. 

As people age, ß-cell function declines. There also tends to be a decrease in physical activity and an increase in body weight, increasing insulin resistance. Thus the prevalence of type 2 diabetes is much higher in older age groups.

Why is type 2 diabetes important?

People with type 2 diabetes are at risk of serious long-term complications.  The complications of type 2 diabetes may be divided into 'microvascular' and 'macrovascular' complications.  Microvascular complications are those that damage organs through their effects on small blood vessels.  The most common microvascular complications are:

  • Retinopathy: damage to the retina of the eye. Type 2 diabetes is the industrialised world's leading cause of blindness.
  • Nephropathy: kidney damage, which may result in the need for dialysis or kidney transplant.
  • Neuropathy: damage to nerves, which can ultimately lead to ulceration and amputation of the feet and lower leg.

Macrovascular complications are those that affect large blood vessels and result in cardiovascular diseases (CVD) i.e. coronary heart disease and stroke, and/or peripheral vascular disease.  Type 2 diabetes is a major risk factor for CVD.  About 80% of people with type 2 diabetes will die from CVD.  On average, people with type 2 diabetes will die 5-10 years before people without diabetes and most of this excess mortality is due to CVD.5

Research has shown that the complications associated with type 2 diabetes often begin to develop well before type 2 diabetes is diagnosed. Fifty per cent of people who are diagnosed with type 2 diabetes already have complications by the time they are diagnosed.

The treatment of cardiovascular diseases accounts for a large part of the huge healthcare costs attributable to type 2 diabetes. Thus from an economic perspective, prevention of CVD is key.

Type 2 diabetes is often associated with a syndrome known as the Metabolic Syndrome, Insulin Resistance Syndrome or Syndrome X. This syndrome is a cluster of inter-related cardiovascular risk factors, including hypertension, high LDL-cholesterol, and low HDL-cholesterol, which greatly increases cardiovascular risk.6

Impaired Glucose Tolerance

What is Impaired Glucose Tolerance (IGT)?

IGT is an intermediate state between normal blood glucose control and type 2 diabetes. In people with IGT, the rise in blood glucose that occurs after consuming 75g glucose is greater than normal (although not as great as in people with type 2 diabetes).  Fasting blood glucose levels are below the diabetic range.

IGT is an early sign that a person's carbohydrate metabolism is impaired.  It carries a high risk of progressing to type 2 diabetes.   
 
How is IGT diagnosed?

IGT is diagnosed if:

  • Plasma glucose two hours after consuming 75g glucose is at least 7.8mmol/l but below 11.1mmol/l i.e. between 'normal' and 'diabetic' levels.  This test is known as an oral glucose tolerance test (OGTT); and
  • Fasting plasma glucose is less than 7.0mmol/l i.e. it may be moderately raised, but it is below the threshold for diagnosis of diabetes.1

What causes IGT?

IGT (and type 2 diabetes) result from a combination of impaired secretion of insulin (the main hormone regulating blood glucose) and reduced sensitivity of the body's cells to insulin (insulin resistance). 

Individuals with IGT show a reduction in early insulin secretion i.e. the phase of insulin secretion that occurs prior to and immediately after eating.2 This, compounded by the fact that insulin resistance increases the need for insulin, means that blood glucose levels rise excessively after glucose is consumed.

The loss of early insulin secretion in IGT and type 2 diabetes is the result of malfunctioning of pancreatic ß-cells.  In the long-term, high blood glucose levels are toxic to ß-cells3 leading to further deterioration in ß-cell function and worsening blood glucose control.

As people age, ß-cell function declines. There also tends to be a decrease in physical activity and an increase in body weight, increasing insulin resistance. Thus the prevalence of IGT (and type 2 diabetes) is much higher in older age groups.

How common is IGT?

The most recent estimate for the prevalence of IGT in the USA comes from the third National Health and Nutrition Examination Survey (NHANES) carried out in 1988-1994.4  A sub-sample of the survey's participants, i.e. 2,844 adults with no history of diabetes, were tested for IGT.

Using WHO diagnostic criteria1, 15.6% of the survey's participants were found to have IGT. The prevalence of IGT increased with age. There was no significant difference in prevalence between men and women, but IGT was more common in Mexican-Americans (20.2%) than in blacks (14.0%) or whites (15.3%).

Why is IGT important?

IGT is a significant risk factor not only for diabetes, but also for cardiovascular morbidity and mortality. Research has shown that cardiovascular complications associated with type 2 diabetes (e.g. increased atherosclerosis) begin to develop well before type 2 diabetes is diagnosed.  By the time type 2 diabetes is diagnosed, macrovascular damage may already be well advanced.4 

Some large-scale studies indicate that blood glucose level two hours after consuming 75g glucose is a better predictor of mortality risk than fasting blood glucose. The DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) study, in which data were analysed from 13 prospective studies involving 25,000 participants, showed that raised blood glucose two hours after consuming 75g glucose is an independent risk factor for premature death.6

The DECODE study6 showed that people with type 2 diabetes were more than twice as likely to die during the follow-up period than people with normal blood glucose control.  People with IGT were over 50% more likely to die during follow-up than people with normal blood glucose control.  However, as there were four times as many people with IGT as with diabetes, there were more premature deaths attributable to IGT than to diabetes.

IGT is often associated with a syndrome known as the Metabolic Syndrome, Insulin Resistance Syndrome or Syndrome X. This syndrome is a cluster of inter-related cardiovascular risk factors, including hypertension, high LDL-cholesterol, and low HDL-cholesterol, which greatly increases cardiovascular risk.7

Does IGT always lead to diabetes?

Some people who develop IGT will revert to normal glucose tolerance. Others will remain in a state of IGT.  About 40-50% of people with IGT will develop type 2 diabetes within ten years.  This deterioration is accompanied by increased risk of cardiovascular disease and, once diabetes has developed, microvascular complications.

Can IGT be treated?

People who have IGT are rarely treated because the condition is rarely diagnosed.  However, people with IGT are the ideal population to target in programmes aiming to prevent type 2 diabetes and its associated risks.

People with IGT should be encouraged to increase their physical activity level, aim for a healthy weight, and follow a healthy, balanced diet.  Weight loss and increased physical activity can reduce insulin resistance and therefore make the insulin produced by ß-cells more effective at controlling blood glucose. 

Recently, large-scale clinical trials such as the Diabetes Prevention Program in the USA8 and the Diabetes Prevention Study in Finland9 have shown that people with IGT who receive regular lifestyle advice are much less likely to develop type 2 diabetes.   Further clinical trials are currently underway to investigate whether drugs that improve insulin secretion and insulin sensitivity can also reduce the risk of diabetes and cardiovascular diseases in people with IGT.

In August 2001, the International Diabetes Federation held a consensus meeting on IGT and impaired fasting glucose (IFG, another pre-diabetic condition). The expert panel agreed that IGT and IFG are significant risk factors for type 2 diabetes and CVD, and called for people with these conditions to be given intensive lifestyle advice followed by drug therapy if lifestyle advice is not effective. Unless action is taken to prevent people at high risk from developing type 2 diabetes, the global pandemic of diabetes will continue to escalate, with devastating effects on health services across the world.

Given the high risk of type 2 diabetes associated with IGT, people with IGT should be screened for diabetes at regular intervals.  Early treatment of diabetes is key to preventing complications.

Diabetes Prevention

The massive rise in type 2 diabetes in recent years, the serious health risks and healthcare costs associated with the condition, and the fact that several risk factors for the disease are modifiable, have created great interest in whether diabetes can be prevented. The importance of diabetes prevention cannot be underestimated.  Unless significant efforts are made to stem the rise in diabetes, healthcare services across the world will soon be crippled by the costs of treating the diseases and its complications.

Most programmes aiming to prevent diabetes have focused on high-risk groups, particularly people whose blood glucose is already moderately raised. Recent studies have shown that lifestyle advice can be extremely effective at reducing diabetes risk in these groups.

The Diabetes Prevention Study conducted in Finland1 involved 522 middle-aged, overweight people with impaired glucose tolerance (IGT). The study subjects were divided into two groups:

  • an intervention group who received individual counseling aiming to help them lose weight, reduce fat intake, and increase physical activity, at seven sessions in the first year and then every three months
  • a control group who received general diet and exercise advice once a year. After the subjects had been followed up for an average of 3.2 years, the incidence of diabetes was 58% lower in the intervention group than in the control group.

The Diabetes Prevention Program2 carried out in the USA had similar findings. This study involved 3,234 overweight people with IGT, 45% of whom were from an ethnic minority group at increased risk of diabetes.  The study subjects were divided into three groups, who received:

  • general lifestyle advice once a year, plus metformin (daily)
  • general lifestyle advice once a year, plus placebo (daily)
  • intensive lifestyle advice (16 sessions over 24 weeks) aiming to achieve weight loss and increased physical activity

The subjects were followed up for an average of 2.8 years.  Compared to the placebo group, the incidence of diabetes was 58% lower in the group that had received intensive lifestyle advice, and 31% lower in the group who had received metformin.

These studies, and earlier studies such as the Da Qing study in China, show that frequent lifestyle advice, given by a trained health professional, is effective at reducing the development of diabetes in people at high risk.   What remains a subject of debate is how applicable these findings are to the population at large, who are not as motivated to make lifestyle changes as people who choose to join clinical trials.  Debate also surrounds how feasible it would be to offer time-intensive and expensive lifestyle intervention programmes to all those at high risk of diabetes, or even to whole populations.

Even the most effective lifestyle advice will not work for everyone.  As diabetes carries such serious health risks, there is a growing feeling that people who are at high risk of developing diabetes and its complications (particularly cardiovascular disease), and who have not responded to lifestyle advice, should be given drugs to reduce their risk.  Studies have already shown that metformin and acarbose may be of use in some individuals. 

A number of large clinical trials are in progress to investigate whether drugs that improve insulin secretion or insulin sensitivity reduce risk of diabetes and cardiovascular disease in people at high risk.  The largest of these trials is the NAVIGATOR trial launched in November 2001, which will involve 7,500 people with IGT and at least one other cardiovascular risk factor (e.g. hypertension, raised cholesterol) or disease (e.g angina, previous heart attack).3

References

  1. World Health Organisation (1999). Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus.
  2. Byrne MM, Sturis J, Sobel RJ, Polonsky KS. Elevated plasma glucose 2-h postchallenge predicts defects in ß-cell function. American Journal of Physiology 1996; 270: E572-9.
  3. Alberti KGMM. The clinical implications of impaired glucose tolerance. Diabetic Medicine 1996; 13: 927-37.
  4. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer H-M, Byrd-Holt DD. Prevalence of diabetes, impaired fasting glucose and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care 1999; 21: 518-528.
  5. Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. Vascular complications of diabetes. British Medical Journal 2000; 320: 1062-6.
  6. The DECODE study group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetic Association diagnostic criteria. Lancet 1999; 354: 617-62.
  7. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607.
  8. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002; 346: 393-403.
  9. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine 2001; 344: 1343-50.
  10. Diabetes Prevention Program Research Group.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  The New England Journal of Medicine 2002; 346: 393-403.
  11. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine 2001; 344: 1343-50.
  12. For more information on the NAVIGATOR trial, please contact farrah.meherali@uk.ogilvypr.com

International Diabetes Federation (Federation Internationale du Diabete)
1  Rue Defacqz, B-1000 Brussels, Belgium
Tel : +322 / 538 5511 - Fax : +322 538 5114
Internet : www.idf.org  e-mail : info@idf.org

Posted: May 2002


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