TY - JOUR
T1 - Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice
AU - Yao, Li Jun
AU - McCormick, James A.
AU - Wang, Jian
AU - Yang, Katherine Y.
AU - Kidwai, Atif
AU - Colussi, Gian Luca
AU - Boini, Krishna M.
AU - Birnbaum, Morris J.
AU - Lang, Florian
AU - German, Michael S.
AU - Pearce, David
PY - 2011/12
Y1 - 2011/12
N2 - 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-kinasedependent 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 -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 -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 -cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of β-catenin.
AB - 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-kinasedependent 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 -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 -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 -cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of β-catenin.
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U2 - 10.1210/me.2010-0329
DO - 10.1210/me.2010-0329
M3 - Article
C2 - 21980074
AN - SCOPUS:82055191869
SN - 0888-8809
VL - 25
SP - 2106
EP - 2118
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 12
ER -