Genetic deficiency of glycogen synthase kinase-3β corrects diabetes in mouse models of insulin resistance

Katsuya Tanabe, Zhonghao Liu, Satish Patel, Bradley W. Doble, Lin Li, Corentin Cras-Méneur, Sara C. Martinez, Cris M. Welling, Morris F. White, Ernesto Bernal-Mizrachi, James R. Woodgett, M. Alan Permutt

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81 Scopus citations

Abstract

Despite treatment with agents that enhance β-cell function and insulin action, reduction in β-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-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-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 β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β +/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-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 β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2 -/- mice crossed with Gsk-3β+/- mice preserved β-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 p27kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β+/-Irs2-/- mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell-specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell-specific knockout of Gsk-3β (βGsk-3β-/-). Like Gsk-3β+/- mice, βGsk-3β-/- 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 β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset.

Original languageEnglish (US)
Pages (from-to)307-318
Number of pages12
JournalPLoS biology
Volume6
Issue number2
DOIs
StatePublished - Feb 2008

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Tanabe, K., Liu, Z., Patel, S., Doble, B. W., Li, L., Cras-Méneur, C., Martinez, S. C., Welling, C. M., White, M. F., Bernal-Mizrachi, E., Woodgett, J. R., & Permutt, M. A. (2008). Genetic deficiency of glycogen synthase kinase-3β corrects diabetes in mouse models of insulin resistance. PLoS biology, 6(2), 307-318. https://doi.org/10.1371/journal.pbio.0060037