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.