Elevation of glucagon levels and increase in α cell proliferation is associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications for understanding abnormal responses to hypoglycemia in patients with diabetes and provide novel avenues for diabetes management. Using mice with inducible induction of Rheb1 in α cells (αRhebTg mice), we showed that short-term activation of mTORC1 signaling is sufficient to induce hyperglucagonemia through increased glucagon secretion. Hyperglucagonemia in αRhebTg mice was also associated with an increase in α cell size and mass expansion. This model allowed us to identify the effects of chronic and short-term hyperglucagonemia on glucose homeostasis by regulating glucagon signaling in the liver. Short-term hyperglucagonemia impaired glucose tolerance, which was reversible over time. Liver glucagon resistance in αRhebTg mice was associated with reduced expression of the glucagon receptor and genes involved in gluconeogenesis, amino acid metabolism, and urea production. However, only genes regulating gluconeogenesis returned to baseline upon improvement of glycemia. Overall, these studies demonstrate that hyperglucagonemia exerts a biphasic response on glucose metabolism: Short-term hyperglucagonemia lead to glucose intolerance, whereas chronic exposure to glucagon reduced hepatic glucagon action and improved glucose tolerance.
Bibliographical noteFunding Information:
The authors wish to acknowledge funding resources for this essential contribution to this work. EBM is mainly supported by a Merit Review Award IBX002728A from the Veterans Administration. Additional funding includes NIH grant R01-DK073716 and DK084236. NBK was supported by Department of Veterans Affairs IK2BX005715 and NIH 5T32DK108740, 5P30DK034933, and UL1TR002240. CL was supported by a Merit Review Award IBX002728A from the Veterans Administration and Diabetes Research Connection. We would like to acknowledge Oliver Umland at the Flow Cytometry Core Facility (Diabetes Research Institute; University of Miami). The figures were created with BioRender.com.
Copyright: © 2023, Lubaczeuski et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.