Salk Institute

Technologies Available for Licensing

Modulating Gluconeogenesis: Indirect Phosphorylation of TORC2 from Insulin.

Inventors: Marc R. Montminy
Potential Uses: Drug Discovery and Development, Type II Diabetes
Assays to identify compounds that modulate the role of TORCs

Figure 1. Insulin inhibits TORC2 activity during re-feeding. Live imaging of hepatic CRE-luciferase (Ad-CRE-Luc) activity in fasted or re-fed mice.

Glucose levels are maintained within a narrow range in humans through counter-regulatory effects of pancreatic hormones on hepatic gluconeogenesis, including insulin. During feeding, increases in circulating pancreatic insulin are known to inhibit hepatic glucose output. Our research has identified a modulator of gluconeogenesis, the gene TORC2 (also known as CRTC2).

We found that insulin suppresses hepatic glucose production during re-feeding by triggering the SIK2-mediated phosphorylation and COP1-dependent degradation of TORC2. The inhibition of TORC2 in the re-fed state protects against further increases in blood glucose due to inappropriate induction of the gluconeogenic program. By reducing the cellular pool of TORC2, COP1 also determines the timing and amplitude of the gluconeogenic response with subsequent fasting. This regulation was demonstrated in vivo in a murine model using in vivo imaging with a cAMP-responsive adenovirus—containing cAMP responsive elements (Figure 1).

Regulating TORC2 and SIK2 points to their potential as drug targets for regulating the level of fasting blood sugar. Since a majority of individuals with Type II diabetes exhibit fasting hyperglycemia due to elevated hepatic gluconeogenesis, compounds that enhance TORC2 phosphorylation will find use as therapeutic agents.

 

Salk No: S04005
Patent Status: U.S. Patent No. 7,485,434 issued February 3, 2009
Publications: Nature 449(20): 366 - 370 (September 2007)
License Terms: Exclusive, Partially Exclusive, Nonexclusive license negotiable
Contact: Rachel M. Mullen, MBS, 858.453.4100 x1275, rmullen@salk.edu

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