International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 191 - MICE WITH HAPLOINSUFFICIENCY FOR THE LIPID PHOSPHATASE PTEN EXHIBIT INSULIN HYPERSENSITIVITY

Wong J T
University of British Columbia

Co-Authors: 2) Parsons R, 1) Verchere C B, 1) Ong C J
Institutions: 1) University of British Columbia, 2) Columbia University

Impairment of insulin production or function is implicated in the etiology of diabetes mellitus. Signalling through phosphatidylinositol 3-kinase (PI3K) is a key pathway whereby insulin regulates the uptake and storage of glucose. Pten, an inositol 3' phosphatase, negatively regulates the PI3K pathway by catalyzing the reverse enzymatic reaction of PI3K; however, its role in insulin sensitivity in vivo is unclear. Here we report that Pten heterozygous (Pten+/-) mice, which have decreased Pten protein levels and activity, exhibit insulin hypersensitivity and increased glucose tolerance. Following insulin challenge, Pten+/- mice displayed delayed recovery to euglycemia. In a glucose tolerance test, blood glucose in the Pten+/- mice returned to fasting levels in approximately half the time as wild type mice. Insulin production and pancreas histology were similar in both sets of mice. Uptake of [3H]2-deoxyglucose was monitored in primary myocytes cultured from Pten+/- and wild type mice. In the presence and absence of insulin, glucose uptake by Pten+/- myocytes was significantly enhanced over wild type cells. An early downstream effector of PI3K signalling is the serine/threonine kinase Akt, which is phosphorylated and activated in a PI3K-dependent manner. In the presence of insulin, Akt remained highly phosphorylated in Pten+/- myocytes for up to 4 h, whereas phosphorylation peaked and began to decrease after 2 h in wild type cells. Our results show that Pten is a negative regulator of insulin sensitivity in vivo and is a possible drug target for type 2 diabetes.


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