Lipid phosphatases as drug discovery targets for type 2 diabetes

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Abstract
The incidence of type 2 diabetes in the United States and worldwide has reached epidemic proportions and continues to rise at an alarming rate. It is clear that more effective pharmaceutical options for the treatment of this devastating and costly disease are urgently needed. Recent advances in our understanding of the molecular events by which insulin provokes its many biological responses should lead to new drug discovery opportunities. Insulin stimulation of phosphatidylinositol 3-kinase (PI3K) activity is essential for most of the hormone's metabolic responses and is reduced in insulin-resistant, diabetic individuals. The identification of compounds which potentiate insulin-stimulated PI3K signaling might prove useful in the treatment of type 2 diabetics. One possible mechanism to achieve this goal is through the inhibition of lipid phosphatases that antagonize insulin-dependent PI3K signaling. Phosphatase and tensin homologue on chromosome 10 (PTEN) is a lipid 3′-phosphatase which degrades PtdIns(3,4,5)P3, the important second messenger produced by PI3K activity, and antagonizes insulin signaling. While tissue-specific PTEN knockout studies in muscle and fat reveal 'therapeutic' potential, the positive metabolic impact of reduced PTEN expression in the liver is offset by the presence of hepatomegaly, liver steatosis and hepatic tumors. Sequence homology 2 (SH2)-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid 5′-phosphatase that also degrades PtdIns(3,4,5)P3 and attenuates insulin signaling. Genetic deletion of SHIP2 expression in mice appears to enhance insulin signaling and confer resistance to the detrimental effects of a high-fat diet, including providing dramatic protection from the development of obesity. The role of human PTEN as a tumor suppressor in numerous tissues argues against the development of small molecule PTEN inhibitors for the treatment of diabetes. The apparent absence of tumor formation in SHIP2 knockout mice combined with a lack of any compelling evidence for human SHIP2 acting as a tumor suppressor is more encouraging for the potential utility of a SHIP2 inhibitor. The absence of significant pharmaceutical experience in the identification and development of small-molecule inhibitors against lipid phosphatases, together with particular aspects of SHIP2 biology, present challenges to any drug discovery effort against this novel target. It is possible that recent technical advances combined with an enhanced understanding of SHIP2 biology might provide the solution required.

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