Our understanding about the pathways of insulin action downstream from the insulin receptor is rapidly expanding (see Figure 4). Every step of the insulin receptor pathway has the potential to serve as a target for pharmacological intervention in the treatment of T2DM and obesity. Two such examples are summarized here in GSK-3 and PTP1B.
Glycogen synthase kinase 3 (GSK-3) is a protein kinase the activity of which is inhibited by insulin.91 GSK-3 serves a regulatory function to phosphorylate glycogen synthase and thereby inactivate it. Insulin action stimulates the PI-3 kinase pathway, resulting in Akt activation, which phosphorylates and inactivates GSK-3. Elevated levels of GSK-3 have been observed in the skeletal muscle of individuals with T2DM. Thus, compounds that inhibit GSK-3 suggest that specific inhibitors of GSK-3 could mimic some of the actions of insulin and hold the potential as novel therapeutics for diabetes. The identification of a phosphorylation site unique to GSK-3 in the insulin-signaling pathway allows for the development of non-ATP competitive inhibitors that would selectively inhibit some functions of GSK-3 but not others, diminishing the possibility of unwanted side effects. These drugs are predicted to be of particular therapeutic relevance to the treatment of diabetes in the future.
Protein tyrosine phosphatase-1B (PTP1B) dephosphorylates the insulin receptor, thus blunting its ability to initiate the signal transduction cascade upon insulin binding.92 Genetically modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide inhibit PTP1B and thereby restore activity to the insulin receptor, resulting in increased insulin sensitivity, improved glycemic control, and resistance to diet-induced obesity. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of overnutrition, and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cell studies suggesting that PTP1B may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors, which may serve as a novel type of 'insulin sensitizer' in the management of T2DM and the metabolic syndrome.
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