The pathophysiology of diabetes in aging

Glucose levels are tightly regulated by the combined function of the muscle to dispose of postprandial glucose, the liver to provide for fasting glucose production, and the β-cells of the pancreas to regulate both by secreting appropriate amounts of insulin. Aging is known to be an insulin resistant state because hyperinsulinemia is required to maintain fasting and postprandial glucose levels in the normal range. Insulin resistance is associated with increases in total and visceral fat mass which are typical of aging. Insulin resistance is also associated with risk factors for accelerated atherosclerosis and coronary artery disease, hypertension and hyperlipidemia. The liver maintains normal glucose levels postprandially and during fasting, but with aging more insulin is required to appropriately regulate hepatic glucose production and avoid hyperglycemia. While β-cell insulin secretion may compensate for the resistance to insulin action of the muscle and liver, elderly subjects with and without obesity may fail to respond by secreting adequate amounts of insulin, and will develop diabetes mellitus. The onset of frank diabetes mellitus is accompanied by further deterioration in muscle, liver, and β-cell function, a phenomenon referred to as 'glucose toxicity.' Understanding the multi-organ pathophysiology of diabetes in the elderly is clinically relevant, because present and future pharmacologic therapies aim to reverse specific organ defects, and often act synergistically to decrease hyperglycemia.