Pathogenesis of Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes is characterized by multiple pathophysiologic abnormalities which collectively have been referred to as the Ominous Octet: – Muscle insulin resistance → reduced glucose uptake – Hepatic insulin resistance → excessive glucose production – Adipocyte insulin resistance → accelerated lipolysis and elevated circulating levels of FFA and insulin-resistance provoking adipocytokines – Progressive β-cell failure and apoptosis – Increased alpha cell secretion of glucagon and increased hepatic sensitivity to glucagon – Reduced incretin effect due to beta cell resistance to GLP-1 and GIP – Increased renal glucose production – Elevated renal tubular glucose reabsorption – Brain insulin resistance and altered neurotransmitter dysfunction leading to impaired appetite suppression and weight gain. • Insulin resistance in muscle and liver are the earliest detectable abnormalities in the natural history of type 2 diabetes. • With time, progressive β-cell failure ensues and, in the presence of insulin resistance, individuals progress from normal glucose tolerance to impaired glucose tolerance to overt type 2 diabetes.