title: Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice.
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-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.
authors: Departments of Medicine, and Molecular and Cellular Pharmacology, University of California, San Francisco, California 94107-2140, USA.
authors: Li-Jun
authors: LJ
authors: Yao
authors: James A
authors: JA
authors: McCormick
authors: Jian
authors: J
authors: Wang
authors: Katherine Y
authors: KY
authors: Yang
authors: Atif
authors: A
authors: Kidwai
authors: Gian Luca
authors: GL
authors: Colussi
authors: Krishna M
authors: KM
authors: Boini
authors: Morris J
authors: MJ
authors: Birnbaum
authors: Florian
authors: F
authors: Lang
authors: Michael S
authors: MS
authors: German
authors: David
authors: D
authors: Pearce
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D049109:Cell Proliferation; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010179:Pancreas / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D001786:Blood Glucose; D005947:Glucose; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C494922:Akt2 protein, mouse; C523602:Sgk3 protein, mouse; D000099184:Serum-Glucocorticoid Regulated Kinases