Pathogenesis of type 2 diabetes mellitus

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β cell (Triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the Omnious Octet and dictate that: (i) multiple drugs used in combination will be required to correct the multiple pathophysiologic defects, and (ii) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1c.