Abstract:
:Elevation of glucagon levels and increase in α-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and α-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size, and mass expansion. Hyperglucagonemia in αTSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), PEPCK, and genes involved in amino acid metabolism and urea production. Glucagon resistance in αTSC2KO mice was associated with improved glucose levels in streptozotocin-induced β-cell destruction and high-fat diet-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.
journal_name
Diabetesjournal_title
Diabetesauthors
Bozadjieva Kramer N,Lubaczeuski C,Blandino-Rosano M,Barker G,Gittes GK,Caicedo A,Bernal-Mizrachi Edoi
10.2337/db20-0440subject
Has Abstractpub_date
2021-02-01 00:00:00pages
477-491issue
2eissn
0012-1797issn
1939-327Xpii
db20-0440journal_volume
70pub_type
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