Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. Mol Endocrinol

Departments of Medicine, and Molecular and Cellular Pharmacology, University of California, San Francisco, California 94107-2140, USA.
Molecular Endocrinology (Impact Factor: 4.02). 12/2011; 25(12):2106-18. DOI: 10.1210/me.2010-0329
Source: PubMed


The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet β-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired β-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower β-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that β-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within β-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of β-catenin.

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    • "However, it is possible that the phenotype of the sgk1−/−/sgk3−/− mouse is not more severe as SGK2 may be able to compensate and maintain some level of homeostasis, despite no detectable increase of SGK2 transcript levels in these mice.113 Characterization of an akt2−/−/sgk3−/− mouse found that the defect in hair growth is markedly worse in the double knockout mice than in sgk3−/− mice only114 and that they have a markedly greater impairment of glucose homeostasis than Akt2−/− mice.115 Akt2−/− mice also displayed insulin resistance, hyperinsulinemia and increased β-cell proliferation and mass.116 "
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    • "When AKT2 knockout mice were mated with mice deficient in serum- and glucocorticoid-regulated kinase 3 (SGK3) gene, an unexpected role was observed for SGK3 in islet β-cell function [62]. Double-knockout mice had worse glucose homeostasis than AKT2 null mice, including higher baseline glucose and increased blood glucose after glucose challenge. "
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