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Abstract

The present disclosure describes an unexpected and novel insight into hepatic insulin resistance through the description of the ability of VEGF inhibitors to revert hyperglycemia and hyperinsulimenia in murine Type 2 diabetes mellitus models through modulation of a HIF-2α-IRS-2 axis operative in hepatocytes. As such, the data of the present disclosure uncover a novel pathway regulating hepatic IRS-2 expression, and identify VEGF inhibitors as an FDA-approved class of therapeutics capable of increasing liver IRS levels and ameliorating Type 2 diabetes mellitus. Accordingly, this disclosure identifies stabilization of HIF-2α as a robust method for improving glucose metabolism. The disclosure provides embodiments of a method of modulating the level of glucose metabolism of a mammalian cell, comprising: contacting a mammalian cell with an effective amount of a composition, where the composition can modulate the levels of HIF-2α and IRS-2 activity in said cell, thereby modulating the level of glucose metabolism by said cell. The disclosure also provides embodiments of a pharmaceutical composition and methods for their use for the treatment of Type 2 diabetes in an animal or human subject, the method comprising administering to an animal or human subject a effective amount of a pharmaceutically acceptable composition, the composition, when administered to an animal or human subject, increasing the activity of HIF-2α and IRS-2 in the animal or human subject, thereby reducing the level of blood glucose in the animal or human subject.

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First Claim