Insulin resistance: the fundamental trigger of type 2 diabetes

Type 2 diabetes is a heterogeneous condition that is not attributable to a single pathophysiological mechanism. In general, both insulin resistance an d impaired insulin secretion are required for the disease to become manifes t. Thus, as long as the pancreatic beta cells can compensate for the degree of insulin resistance, glucose tolerance remains normal. Clustering of typ e 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. However, environmental factors such as obesity and a sedentary lifestyle are usually required to unmask the genes. Impaired insulin-stimulated glucose metabolism (particularly nonoxidative) in skeletal muscle represents a key feature of type 2 diabetes and is obser ved early in the pre-diabetic state. It is not clear, though, whether this represents an inherited defect in muscle or whether it develops secondarily , for example, to abdominal obesity. In favour of the latter hypothesis are findings that abdominal obesity and a low metabolic rate seem to precede t he development of insulin resistance in offspring of type 2 diabetic patien ts. According to the thrifty gene hypothesis, individuals living in an environm ent with an unstable food supply could increase their probability of surviv al if they could maximize storage of surplus energy, for instance, as abdom inal fat. Exposing this energy-storing genotype to the abundance of food ty pical of westernized societies is detrimental, causing insulin resistance a nd, subsequently, type 2 diabetes. There are a number of potential thrifty genes, including those that regulate lipolysis or code for the beta(3)-adre nergic receptor, the hormone-sensitive lipase, and lipoprotein lipase. Type 2 diabetes develops as a consequence of a collision between thrifty ge nes and a hostile affluent environment. Insulin resistance is a key trigger for the disease, and optimal management of type 2 diabetes should therefor e aim to ameliorate insulin resistance early.