Pathogenesis of Type 2 Diabetes Mellitus

Excerpt

Numerous distinct pathophysiologic abnormalities have been associated with type 2 diabetes mellitus (T2DM). It is well established that decreased peripheral glucose uptake (mainly muscle) combined with augmented endogenous glucose production are characteristic features of insulin resistance. Increased lipolysis, elevated free fatty acid levels, along with accumulation of intermediary lipid metabolites contributes to further increase glucose output, reduce peripheral glucose utilization, and impair beta-cell function. Adipocyte insulin resistance and inflammation have been identified as important contributors to the development of T2DM. The presence of non-alcoholic fatty liver disease [NAFLD] is now considered an integral part of the insulin resistant state. The traditional concepts of “glucotoxicity” and lipotoxicity, which covers the process of beta cell deterioration in response to chronic elevations of glucose and lipids, has been expanded to encompass all nutrients [‘nutri-toxicity”]. The delayed transport of insulin across the microvascular system is also partially responsible for the development of tissue insulin resistance. Compensatory insulin secretion by the pancreatic beta cells may initially maintain normal plasma glucose levels, but beta cell function is already abnormal at this stage, and progressively worsens over time. Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post-prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in T2DM are secondary to an “incretin defect”, defined primarily as inadequate release or response to the gastrointestinal incretin hormones upon meal ingestion. To a certain extent, the gut microbiome appears to play a role in the hormonal and metabolic disturbances seen in T2DM. Moreover, hypothalamic insulin resistance (central nervous system) also impairs the ability of circulating insulin to suppress glucose production, and renal tubular glucose reabsorption capacity may be enhanced, despite hyperglycemia. These pathophysiologic abnormalities should be considered for the treatment of hyperglycemia in patients with T2DM. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.