Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion.

Type 2 diabetes is characterised by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycaemia may differ due to heterogeneity of the disease. Under most circumstances, insulin resistance is the earliest detectable defect in pre-diabetic individuals but it is not known whether this is the primary defect or secondary to other abnormalities such as abdominal obesity with excessive free fatty acid turnover and increased lipid deposits in muscle. Initially, enhanced insulin secretion can compensate for the insulin resistance but early phase insulin secretion is impaired. In the transition from normal to impaired and diabetic glucose tolerance, insulin sensitivity deteriorates about 40% whereas insulin secretion deteriorates 3-4 fold. In addition to insulin resistance, the metabolic syndrome includes hypertension, dyslipidaemia, obesity and microalbuminuria. In patients with manifest diabetes, chronic hyperglycaemia can result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity). Abdominal obesity and insulin resistance are strongly correlated and studies have aimed at understanding the genetic basis. Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. Therefore, type 2 diabetes is multigenic and appears to represent a collision between thrifty genes and an affluent society. Successful management will require treatments targeted at defects of both insulin secretion and insulin resistance.