Following autoimmune-mediated destruction of insulin secreting β-cells in type 1 diabetes (T1D), regenerative and repair pathways aim to restore β-cell mass and maintain euglycemia. However, these pathways are often unable to compensate for the loss of β-cell mass, resulting in insufficient insulin secretion and chronic hyperglycemia. Our lab previously demonstrated that this inability to compensate for the loss of β-cell mass may be at least in part due to mitogen inducible gene 6 (Mig6), an anti-proliferative negative feedback inhibitor of epithelial growth factor receptor signaling, which is induced by proinflammatory cytokines central to macrophage-mediated β-cell destruction in T1D. Both Mig6 haploinsufficient mice (Mig6+/-) and mice with pancreas-specific Mig6 knockout (PKO) have increased β-cell mass and improved glucose tolerance when compared to littermate controls in a β-cell ablation model. We sought to determine the extent to which β-cell specific loss of Mig6 confers resistance to depletion of β-cell mass by streptozotocin (STZ, 35 mg/kg). We hypothesized that mice with β-cell specific loss of Mig6 (βKO) would have increased β-cell mass and improved glucose tolerance following STZ treatment when compared to control mice. We treated βKO and littermate controls with multiple low doses of STZ and measured both glucose tolerance and β-cell mass for up to 20 days following STZ treatment. At baseline, Mig6 expression was reduced by 63 ± 3% in βKO mice, and βKO mice had normal glucose homeostasis, insulin sensitivity, and islet architecture compared to littermate control. Unlike Mig6+/- and PKO mice, βKO mice had no improvements in β-cell mass or glucose tolerance compared to STZ-treated control littermates. Therefore, whereas both Mig6+/- and Mig6 PKO mice are able to preserve or restore β-cells with STZ treatment, loss of Mig6 in β-cells alone does not confer the same level of protection, suggesting a potential role for Mig6 in beta β-cell transdifferentiation or neogenesis.


B.M. Bauer: None. K. El: None. P.T. Fueger: None.

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