Impaired insulin secretion (beta-cell), increased hepatic
glucose production (liver), and decreased peripheral (muscle)
glucose utilization constitute the traditional primary defects responsible for the development and progression of
type 2 diabetes mellitus. beta-Cell failure, ultimately leading to decreased insulin secretion, is now known to occur much earlier in the natural history of
type 2 diabetes than originally believed. Additionally, a better understanding of the pathophysiology of
type 2 diabetes reveals other etiologic mechanisms beyond the classic triad, now referred to as the ominous octet. In addition to the beta-cell, liver, and muscle, other pathogenic mechanisms include adipocyte
insulin resistance (increased lipolysis), reduced
incretin secretion/sensitivity (gastrointestinal), increased
glucagon secretion (alpha-cell), enhanced
glucose reabsorption (kidney), and central nervous system
insulin resistance resulting from
neurotransmitter dysfunction (brain). Currently, the management of
type 2 diabetes focuses on
glucose control via lowering of
blood glucose (fasting and postprandial) and
hemoglobin A(1c). However, the goal of
therapy should be to delay
disease progression and eventual treatment failure. Treatment should target the known pathogenic disturbances of the disease (i.e., reducing the deterioration of beta-cell function and improving
insulin sensitivity). In recent years, treatment strategies have focused on the development of novel therapeutic options that affect many of the defects contributing to
type 2 diabetes and that provide durable
glucose control through a blunting of
disease progression. Optimal management of
type 2 diabetes should include early initiation of
therapy using multiple drugs, with different mechanisms of action, in combination.