Diabetes susceptibility genes, part 1: The search for genes 21/4/05. Fernando Gibson and Philippe Froguel A five-part, in-depth series exploring how researchers are tracking down genes that increase our risk of developing diabetes. In part 1, Fernando Gibson and Philippe Froguel discuss the complexity of diabetes.

Diabetes mellitus is characterised by high sugar levels in the blood, caused by a deficiency of the hormone insulin or by resistance to the action of insulin. It is one of the most common chronic diseases in both developed and developing countries, affecting up to 8 per cent of the population in many parts of Europe and the USA. The worldwide incidence of diabetes continues to rise: current forecasts indicate that the world's diabetic population will double from 150 million in 2000 to 300 million by 2025.

Background: Introduction to diabetes

There are two major clinical categories of diabetes. Type 1 diabetes is an autoimmune disease in which T lymphocytes infiltrate the islets of the pancreas and orchestrate the destruction of the beta cells, which produce insulin. It accounts for 5 to10 per cent of cases, and has an earlier age of onset than is typically seen for type 2 diabetes.

Type 2 diabetes is closely associated with obesity, which leads to the body's tissues becoming resistant to the insulin-stimulated glucose uptake. It is by far the most common form of diabetes, accounting for approximately 90 per cent of all cases. Obesity is increasingly recognised as one of the major public health problems of our time and central obesity, in particular, is the foremost risk factor in determining the recent global explosion of type 2 diabetes. (As its name suggests, central obesity is obesity around the central trunk region: a waist-hip ratio of 0.95 and over in men and 0.85 and over in women.)

Diabetes is a complex disease

Like many of the common chronic human diseases – such as asthma, high blood pressure, psychoses and certain cancers – diabetes tends to run in families. Unlike simple Mendelian diseases such as cystic fibrosis, however, diabetes is not caused by a mutation in a single gene. Instead, diabetes is a 'complex' disease that arises as predisposing environmental factors interact with many genetic variants ('susceptibility' alleles) interspersed through the genome. Each susceptibility allele, considered in isolation, confers only a very small increased risk of disease (typically in the 1-1.5 fold range).

The lifetime risk of type 2 diabetes for a first-degree relative of a person with the disease is 3.5-fold that of someone in the general population. For type 1 diabetes, the increased risk for first-degree relatives is even higher – 15-fold – indicating that predisposing environmental factors are likely to play a stronger role in the development of type 2 diabetes than is the case for type 1.

These environmental and genetic factors influence a number of traits relevant to diabetes, including:

• mass of the pancreatic beta cells that produce insulin
• secretion of insulin from the beta cells
• production of antibodies directed against the islets of Langerhans in the pancreas (such antibodies against our own cells are termed autoantibodies)
• insulin-signalling pathways that regulate the uptake of glucose by the body's tissues
• control of fat metabolism and storage in the body.

By identifying the predisposing genes, we can advance our understanding of the pathways that maintain normal levels of glucose in the body and whose dysfunction leads to diabetes.

A greater understanding of these pathways will help the design of more effective antidiabetes drugs that specifically target dysfunctional pathways. At present, even with intensive therapy, treatments are unable to restore normal glucose control in diabetic patients. In the vast majority of cases of type 2 diabetes, the control of blood sugar shows an inexorable decline over time, leading to complications such as blindness, nerve and kidney disease, and cardiovascular disease.

A better understanding of the genetic basis of diabetes will also help to identify individuals most at risk, who may benefit from medical treatments and/or lifestyle changes before the disease develops. However, the sheer complexity of diabetes has made the task of identifying susceptibility genes a tough nut to crack.

So far, three general approaches have been adopted in the search for genes underlying complex traits such as diabetes:

• analysis of functional 'candidate' genes, which are thought to have a functional role in normal physiology and in the disease
• genome-wide searches for susceptibility genes
• analysis of animal models of disease.

All three approaches have brought new insights into diabetes, as we explore in the later articles in this series.

Part 2 of the five-part series examines diabetes candidate genes.

Related links

Diabetes susceptibility genes, part 3: Genome-wide searches for type 1 genes

Diabetes susceptibility genes, part 4: Genome-wide searches for type 2 genes

Diabetes susceptibility genes, part 5: Animal models of diabetes