Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance
نویسندگان
چکیده
Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. Despite treatment with agents that enhance b-cell function and insulin action, reduction in b-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-3b (Gsk-3b). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3b to regulation of b-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir þ/À) exhibit insulin resistance and a doubling of b-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3b (Gsk-3b þ/À) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced b-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2 À/À), like the Ir þ/À mice, are insulin resistant, but develop profound b-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3b activity associated with a marked reduction of b-cell proliferation and increased apoptosis. Irs2 À/À mice crossed with Gsk-3b þ/À mice preserved b-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2 À/À mice had increased cyclin-dependent kinase inhibitor p27 kip1 that was limiting for b-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of b-cell mass in Gsk-3b þ/À Irs2 À/À mice was accompanied by suppressed p27 kip1 levels and increased Pdx1 levels. To separate peripheral versus b-cell–specific effects of reduction of Gsk3b activity on preservation of b-cell mass, mice homozygous for a floxed Gsk-3b allele (Gsk-3
منابع مشابه
Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance
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 gl...
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