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Doctoral thesis
English

Dual role for glucagon-producing α-cells in diabetes: contribution to disease progression and to restoration of insulin production

ContributorsDamond, Nicolas
Defense date2015-09-08
Abstract

In type 1 diabetes massive loss of insulin-producing β-cells results in a severely impaired glycemic control. Here, we study glucagon-producing α-cells, which present a double interest in this context. First, glucagon secretion is exacerbated in diabetes, which worsens hyperglycemia. Second, a fraction of α-cells reprogram toward insulin production after massive β-cell loss, thus contributing to β-cell regeneration. Recent studies suggest that mice do not develop diabetes after β-cell loss if glucagon signaling is interrupted. On the contrary, we show that when β-cell loss is near complete, glucagon signaling blockade does not prevent diabetes. Maintenance of normoglycemia in previous models depends on the action of insulin secreted by residual β-cells escaping ablation. We also investigate the role of the chromatin-modifying enzymes DNMT1 and Ezh2 in α-to-β-cell conversion. Finally, we implement methods to study human islet cell plasticity, which we use to show that human α-cells can become insulin producers. Altogether, these results offer new insights into the role of α-cells and glucagon in diabetes.

eng
Keywords
  • Insulin
  • Glucagon
  • Beta-Cell
  • Alpha-Cell
  • Transgenic Mouse Models
  • Glucagon Receptor
  • Diabetes
  • Type 1 Diabetes
  • Cell Type Conversion
  • Cell Plasticity
  • Regeneration
  • DNMT1
  • Ezh2
  • Pdx1
Citation (ISO format)
DAMOND, Nicolas. Dual role for glucagon-producing α-cells in diabetes: contribution to disease progression and to restoration of insulin production. 2015. doi: 10.13097/archive-ouverte/unige:79448
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