Research Day March 2019
Poster by Camila Lubaczeuski
Type 2 Diabetes (T2D) is characterized by defective adaptation of β-cells to insulin resistance. Most of the research effort has focused on elucidating the physiological, molecular, and genetic components that regulate β-cell mass and insulin secretion, presenting diabetes as a unihormonal disorder. Contrary to this current approach, clinical data and animal experiments have shown that increased glucagon secretion by α-cells play a role in the pathogenesis of hyperglycemia in diabetes.
The current data suggest that insulin receptor signaling in α-cells controls α-cell mass and glucagon secretion through IR/mTORC1 activation. In these studies, we tested the hypothesis that insulin induces α-cell mass expansion and regulates glucagon secretion mainly by inducing mTORC1 signaling. To test this hypothesis, we increased mTORC1 activity in α-cells by deletion of TSC2, a negative mTORC1 regulator, specifically in α-cells (αTSC2KO). αTSC2KOexhibited severe hyperglucagonemia as a result of increased α-cell mass (hyperplasia and hypertrophy). Despite hyperglucagonemia, these mice had normal fed blood glucose levels and reduced fasting blood glucose. αTSC2KO mice have improved glucose tolerance, which was attributed to improved insulin secretion and decreased glucagon sensibility and hepatic glucose production. β-cell destruction after Streptozotocin (STZ) treatment showed that these mice exhibited further increase in glucagon levels, but have decreased blood glucose compared to the hyperglycemic STZ-treated controls. These studies demonstrate that activation of mTORC1 signaling in a-cells is sufficient to induce a-cell mass expansion and hyperglucagonemia. However, chronic glucagon levels in αTSC2KO mice lead to glucagon resistance and not to the development of hyperglycemia.
Poster by Flavia Pecahna
This poster is focused in understanding the role of 4EBP2 in the pathogenesis and progression of type 1 diabetes.
