Lipid phosphatases as drug discovery targets for type 2 diabetes.
The soaring incidence of type 2 diabetes has created pressure for new pharmaceutical strategies to treat this devastating disease. With much of the focus on overcoming insulin resistance, investigation has focused on finding ways to restore activation of the phosphatidylinositol 3'-kinase pathway, which is diminished in many patients with type 2 diabetes. Here we review the evidence that lipid phosphatases, specifically PTEN and SHIP2, attenuate this important insulin signalling pathway. Both in vivo and in vitro studies indicate their role in regulating whole-body energy metabolism, and possibly weight gain as well. The promise and challenges presented by this new class of drug discovery targets will also be discussed.
Eli Lilly and Co., Endocrine Division, Lilly Research Laboratories, Indianapolis, Indianapolis 46285, USA. lazar_dan_f@lilly.com
Dan F
DF
Lazar
Alan R
AR
Saltiel
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases