Defining the genetic contribution of type 2 diabetes mellitus.

Abstract

Type 2 diabetes mellitus is a common multifactorial genetic syndrome, which is determined by several different genes and environmental factors. It now affects 150 million people world wide but its incidence is increasing rapidly because of secondary factors, such as obesity, hypertension, and lack of physical activity. Many studies have been carried out to determine the genetic factors involved in type 2 diabetes mellitus. In this review we look at the different strategies used and discuss the genome wide scans performed so far in more detail. New technologies, such as microarrays, and the discovery of SNPs will lead to a greater understanding of the pathogenesis of type 2 diabetes mellitus and to better diagnostics, treatment, and eventually prevention. (J Med Genet 2001;38:569-578)

Keywords: diabetes mellitus type 2; genetic factors; genome screen; candidate gene

Diabetes mellitus (DM) affects over 150 million people world wide, with a prevalence that varies markedly from population to population. [1] Estimates predict that almost 300 million people will suffer from DM by 2025 (fig 1) with the vast majority being cases of diabetes mellitus type 2. Many risk factors have been identified which influence the prevalence (total number of cases as a percentage of the total population) or incidence (total number of new cases per year as a percentage of the total population). Factors of particular importance are a family history of diabetes mellitus, age, overweight, increased abdominal fat, hypertension, lack of physical exercise, and ethnic background. Several biochemical markers have also been identified as risk factors, including fasting hyperinsulinaemia, increased fasting proinsulin, and decreased HDL cholesterol. [2] Both diabetes mellitus types 1 and 2 show a familial predisposition, which is a strong indication for the involvement of genes in people's susceptibility to the disease. However, the aetiology underlying types 1 and 2 is different and different genes are likely to be involved in each type of diabetes mellitus. The following discussion focuses on a genetic dissection of type 2 diabetes mellitus.

The two most common forms of diabetes mellitus, type 1 and type 2, are both characterised by raised plasma glucose levels. Normal glucose homeostasis depends on the balance between glucose production by the liver and kidneys and glucose uptake by the brain, kidneys, muscles, and adipose tissue. Insulin, the predominant anabolic hormone involved, increases the uptake of glucose from the blood, enhances its conversion to glycogen and triglyceride, and also increases glucose oxidation. Plasma glucose levels are normally kept within a small range (4 to 6 mmol/l) by multiple mechanisms. After a meal, a small increase in plasma glucose will lead to an increased insulin secretion by the pancreatic [beta] cells (fig 2). This is associated with a decrease in glucose production by the liver and enhanced glucose uptake in muscle and adipose tissue. These actions result from a combination of short term rapid effects and longer term slow effects, which involve changes in gene transcription and in the rate of translation of enzymes involved in glycogen synthesis, the glycolytic pathway, and lipid metabolism. [3] The effect on gene expression can be either positive or negative, depending on the physiological role of the gene product.

There are a number of glucose counter-regulatory hormones, such as glucagon, cortisol, epinephrine, and norepinephrine, which raise plasma glucose levels and therefore counteract hypoglycaemia. The balance between the insulin action and the effects of the counter-regulatory hormones ensures normal glucose homeostasis. Criteria for diabetes have heavily relied on plasma glucose levels after an oral glucose load (usually 75 g glucose in water). Two hour values over 11.1 mmol/l (=200 mg/dl) are still used as diagnostic for diabetes. [4] This value was originally chosen when prospective studies indicated that subjects with a two hour post-glucose load plasma glucose level of [greater than]11.1 mmol/l were at significant risk of developing (diabetic) retinopathy.

The diagnostic criteria for diabetes have recently been modified: a fasting glucose level of 7.0 mmol/l and higher is now sufficient for the diagnosis, since this (fasting) level has been shown to be associated with the two hour post-glucose load plasma glucose levels of [greater than]11.1 mmol/l. [5] However, a random plasma glucose level of 11.1 mmol/l and higher is still diagnostic for diabetes mellitus.

Patients with type 1 diabetes mellitus require insulin therapy to prevent diabetic ketoacidosis. Since this form of the disease is usually established before the age of 20, it was formerly referred to as "juvenile onset type diabetes mellitus". The major cause of type 1 diabetes mellitus is the autoimmune destruction of the pancreatic [beta] cells. [6]

Type 2 diabetes mellitus accounts for around 90% of all cases of diabetes mellitus. Since type 2 diabetes mellitus usually develops after the age of 40, the disease was also called "adult onset type diabetes mellitus". Unlike type 1 diabetes mellitus, type 2 is not usually caused by autoimmune destruction of the pancreatic [beta] cells, but is characterised by multiple defects in both insulin action and insulin secretion. Both insulin's inhibitory effect on liver glucose production and its stimulatory effect on peripheral glucose uptake are diminished. Although many type 2 diabetes mellitus patients have a basal hyperinsulinaemia, rises in plasma glucose have a characteristically reduced stimulatory effect on insulin secretion. Type 2 diabetes mellitus patients are often treated by adapting their diet or with oral hypoglycaemic drugs, but many will eventually need exogenous insulin to overcome their hyperglycaemia.

Most patients with type 2 diabetes mellitus are obese, which led to the finding that obesity is associated with diminished insulin action both in the liver and in the periphery. The association between type 2 diabetes mellitus and obesity is probably the result of multiple mechanisms, including rises in plasma free fatty acids (FFA) and tumour necrosis factoralpha (TNF[alpha]) released from "full" adipocytes. [7 8] 8 Furthermore, lack of physical exercise is also associated with diabetes mellitus, which led to the finding that exercise enhances the action of insulin, presumably via upregulation of glucose transporters in muscle. [9]

Apart from the short term complications such as thirst, malaise, tiredness, and ketoacidosis, diabetes mellitus often leads to a number of long term complications, generally subdivided into micro- and macrovascular complications. It is these long term chronic complications that have the greatest impact on the health and quality of life of patients. The microvascular complications include retinopathy, neuropathy, and nephropathy, with type 2 diabetes mellitus being one of the main causes of blindness, lower limb amputations, and renal failure in adults. The macrovascular complications mean that type 2 diabetes mellitus is a major risk factor for cardiovascular disease and stroke. These chronic complications have a high socioeconomic cost and put a heavy burden on public health services. [10]

Genetics of type 2 diabetes mellitus

Unlike single gene disorders, where expression of the disease is influenced by a mutant allele at one gene locus, in common diseases like type 2 diabetes mellitus the disease expression depends on many gene loci which all have small to moderate effects. Type 2 diabetes mellitus is a so-called multifactorial disease in which the genes (loci) not only interact with each other but also with environmental factors. It is probable that both insulin activity and secretion are subject to genetic variance at several loci. According to this multifactorial model, predisposition to the disease could be determined by many different combinations of genetic variants (genotypes) and environmental factors; the genetically predisposed subjects [11] will not necessarily develop the overt syndrome unless they are also exposed to particular environmental factors. It is well known that exogenous factors such as age, physical activity, diet, and obesity, play a major role in the disease aetiology of type 2 diabetes mellitus. [12]

The following demographic observations have shown the effect of changes in environmental factors and the prevalence of type 2 diabetes mellitus has been estimated for various populations. The prevalence spectrum ranges from very low levels of about 1% in some populations, such as tribes of non-Austronesian ancestry in Papua New Guinea or in the Chinese population living in mainland China, to extremely high levels of 50% in Pima Indians (North America). The Pima Indians have changed from a traditional agricultural lifestyle to a sedentary one, with a diet similar to the general US population. However, the large variation in the prevalence of type 2 diabetes mellitus in different populations is probably a result of different environmental as well as genetic determinants. It is particularly interesting to see that the prevalence increases as ethnic groups migrate from lesser developed areas of the world to more urbanised or westernised regions. This is illustrated by the higher prevalence of type 2 diabetes mel litus seen among Japanese who …