Diabetes, a chronic metabolic disorder, affects about 5% of the population in the industrialized nations and accounts for over $200 billion in medical costs. In the year 2005, diabetes, directly and indirectly, accounted for about 3 million deaths worldwide. Type l diabetes often manifests in childhood and may result from autoimmune destruction of the b-cells. Type II diabetes, a more widespread metabolic disorder, generally manifests after the age of 40 and involves progressive development of insulin resistance leading to overt hyperglycemia.

Insulin is the major hormone that counters the concerted action of a number of hyperglycemia-generating hormones. It enhances glucose uptake in muscle and adipose tissue, and reduces gluconeogenesis and lipolysis. Insulin resistance, caused by obesity, can result in elevated fasting and postprandial glucose levels and predispose individuals to the risk of type II diabetes. Action of insulin on target cells is mediated via its interaction with insulin receptor (IR), a heterotetrameric glycoprotein consisting of two extracellular a-subunits (135 kDa) and two transmembrane b-subunits (95 kDa). IR functions as an allosteric enzyme in which the a-subunit inhibits the tyrosine kinase activity of the b-subunit. Insulin binding to the a-subunits results in the stimulation of the tyrosine kinase activity of the b-subunits.

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PI 3-K plays a critical role in the metabolic actions of insulin. Inhibitors of class 1a PI 3-K, such as LY 294002 block most metabolic actions of insulin, including stimulation of glucose transport, and glycogen and lipid synthesis. Activated PI 3-K phosphorylates PIP₂ to generate PIP₃, which then enlists PI 3-K-dependent kinase (PDK1) and Akt from the cytoplasm to the plasma membrane. This leads to conformational changes in Akt, allowing it to be phosphorylated on Thr³⁰⁸ and Ser⁴⁷³ (for Akt1) or Thr³⁰⁹ and Ser⁴⁷⁴ (for Akt2) by PDK1 and mTORC2, respectively to achieve full activation. Akt phosphorylates GSK-3 and inactivates it, which then allows the activation of glycogen synthase to proceed. GSK-3 has been implicated in the multi-factorial etiology of skeletal muscle insulin resistance in obese animal models and in obese type II diabetics. Overexpression and hyperactivity of GSK-3 in skeletal muscle of obese type 2 diabetics has been linked with an impaired ability of insulin to activate glucose disposal and glycogen synthase. Selective inhibition of GSK-3 in insulin-resistant skeletal muscle tissue is shown to improve insulin-stimulated glucose transport.