title: Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance.
abstract: Despite treatment with agents that enhance beta-cell function and insulin action, reduction in beta-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3beta (Gsk-3beta). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3beta to regulation of beta-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/-) exhibit insulin resistance and a doubling of beta-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3beta (Gsk-3beta+/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced beta-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2-/-), like the Ir+/- mice, are insulin resistant, but develop profound beta-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3beta activity associated with a marked reduction of beta-cell proliferation and increased apoptosis. Irs2-/- mice crossed with Gsk-3beta+/- mice preserved beta-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2-/- mice had increased cyclin-dependent kinase inhibitor p27(kip1) that was limiting for beta-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of beta-cell mass in Gsk-3beta+/- Irs2-/- mice was accompanied by suppressed p27(kip1) levels and increased Pdx1 levels. To separate peripheral versus beta-cell-specific effects of reduction of Gsk3beta activity on preservation of beta-cell mass, mice homozygous for a floxed Gsk-3beta allele (Gsk-3(F/F)) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce beta-cell-specific knockout of Gsk-3beta (betaGsk-3beta-/-). Like Gsk-3beta+/- mice, betaGsk-3beta-/- mice also prevented the diabetes of the Irs2-/- mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within beta-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of beta-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve beta-cells and prevent diabetes onset.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanabe
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Liu
authors.forename: Satish
authors.initials: S
authors.lastname: Patel
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Corentin
authors.initials: C
authors.lastname: Cras-Méneur
authors.forename: Sara C
authors.initials: SC
authors.lastname: Martinez
authors.forename: Cris M
authors.initials: CM
authors.lastname: Welling
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D011972:Receptor, Insulin / Q000235:genetics
chemical_list: D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3