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

Li Jun Yao, James (Jim) McCormick, Jian Wang, Katherine Y. Yang, Atif Kidwai, Gian Luca Colussi, Krishna M. Boini, Morris J. Birnbaum, Florian Lang, Michael S. German, David Pearce

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2106-2118
Number of pages13
JournalMolecular Endocrinology
Volume25
Issue number12
DOIs
StatePublished - Dec 2011

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Homeostasis
Glucose
Knockout Mice
Insulin
Phosphatidylinositol 3-Kinase
Catenins
Islets of Langerhans
Insulin Resistance
Hair Follicle
serum-glucocorticoid regulated kinase
C-Peptide
Hyperinsulinism
Blood Glucose
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Yao, L. J., McCormick, J. J., Wang, J., Yang, K. Y., Kidwai, A., Colussi, G. L., ... Pearce, D. (2011). Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. Molecular Endocrinology, 25(12), 2106-2118. https://doi.org/10.1210/me.2010-0329

Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. / Yao, Li Jun; McCormick, James (Jim); Wang, Jian; Yang, Katherine Y.; Kidwai, Atif; Colussi, Gian Luca; Boini, Krishna M.; Birnbaum, Morris J.; Lang, Florian; German, Michael S.; Pearce, David.

In: Molecular Endocrinology, Vol. 25, No. 12, 12.2011, p. 2106-2118.

Research output: Contribution to journalArticle

Yao, LJ, McCormick, JJ, Wang, J, Yang, KY, Kidwai, A, Colussi, GL, Boini, KM, Birnbaum, MJ, Lang, F, German, MS & Pearce, D 2011, 'Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice', Molecular Endocrinology, vol. 25, no. 12, pp. 2106-2118. https://doi.org/10.1210/me.2010-0329
Yao, Li Jun ; McCormick, James (Jim) ; Wang, Jian ; Yang, Katherine Y. ; Kidwai, Atif ; Colussi, Gian Luca ; Boini, Krishna M. ; Birnbaum, Morris J. ; Lang, Florian ; German, Michael S. ; Pearce, David. / Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. In: Molecular Endocrinology. 2011 ; Vol. 25, No. 12. pp. 2106-2118.
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