Gil Leibowitz - Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation which drives glucagon production
Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation which drives glucagon production
https://pubmed.ncbi.nlm.nih.gov/37480416/
Yael Riahi 1, Aviram Kogot-Levin 1, Liat Kadosh 1, Bella Agranovich 2, Assaf Malka 3, Michael Assa 3, Ron Piran 3, Dana Avrahami 1 4, Benjamin Glaser 1, Eyal Gottlieb 2 5, Fields Jackson 3rd 6, Erol Cerasi 1, Ernesto Bernal-Mizrachi 7, Aharon Helman 8, Gil Leibowitz 9
Affiliations Expand
- PMID: 37480416
Diabetologia 2023 (Editor's Pick)
Abstract
Aim/Hypothesis Hyperglycaemia is associated with alpha-cell dysfunction leading to dysregulated glucagon secretion in type 1 and type 2 diabetes, however the mechanisms involved are still elusive. The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) plays a major role in the maintenance of alpha-cell mass and function. We studied the regulation of the alpha-cell mTORC1 by nutrients and its role in the development of hyperglucagonaemia in diabetes.
Methods Alpha-cell-mTORC1 activity was assessed by immunostaining for the phosphorylation of its downstream target, the ribosomal protein S6 (pS6) and glucagon, followed by confocal microscopy on pancreatic sections and flow cytometry on dispersed human and mouse islets and the alpha-cell line, αTC1-6. Metabolomics and metabolic flux analysis was studied by 13C glucose labeling at 2.8 or 16.7 mmol/l followed by LC-MS analysis. To study the role of mTORC1 in mediating the hyperglucagonaemia of diabetes, we generated an inducible alpha-cell specific Raptor knockout in diabetic Akita mice and tested the effects on glucose tolerance by intra-peritoneal glucose tolerance test and glucagon secretion.
Results mTORC1 activity was increased in alpha-cells from diabetic Akita mice in parallel to the development of hyperglycaemia and hyperglucagonaemia (2-8-fold increase). Acute exposure of rodent and human islets to amino acids, stimulated (3.5 fold increase), whereas high glucose inhibited (1.4-fold decrease) the alpha-cell mTORC1. The mTORC1 response to glucose was abrogated in human and rodent diabetic alpha-cells following prolonged islet exposure to high glucose, resulting in sustained activation of mTORC1, along with increased glucagon secretion. Metabolomics and metabolic flux analysis showed that exposure to high glucose enhanced glycolysis, glucose oxidation, and the synthesis of glucose-derived amino acids. In addition, chronic exposure to high glucose increased the expression of the amino acid transporters Slc7a2 and Slc38a4, along with increased branched-chain amino acids and methionine cycle metabolites (~1.3-fold increase). Finally, conditional Raptor knockout in alpha-cells of adult diabetic animals inhibited mTORC1, thereby inhibiting glucagon secretion (~6-fold decrease) and improving diabetes, despite persistent insulin deficiency.
Conclusions/Interpretation Alpha-cell exposure to hyperglycaemia enhances amino acids synthesis and transport, resulting in sustained activation of mTORC1, thereby increasing glucagon secretion. mTORC1, therefore, plays a major role in mediating the alpha-cell dysfunction of diabetes.
Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation which drives glucagon production
Diabetes is characterized not only by insulin deficiency but also by hyperglucagonemia, hence its acceptance as a bihormonal disease. The mechanisms of diabetic alpha-cell dysfunction are poorly understood. We show here that the nutrient sensor mTORC1 plays a central role in mediating the hyperglucagonemia of diabetes. Alpha-cell mTORC1 activity was increased in models of T1D and T2D. Metabolomics, metabolic flux, and gene expression analyses showed that exposure to high glucose enhanced the synthesis of glucose-derived amino acids, as well as amino acid transport, leading to increased glutamate, branched-chain amino acids and methionine cycle metabolites. Conditional Raptor knockout in alpha-cells of diabetic animals inhibited mTORC1, thereby inhibiting glucagon secretion and improving diabetes. Our findings suggest that alpha-cell exposure to hyperglycaemia modulates amino acid metabolism, resulting in sustained activation of mTORC1, which in its turn increases glucagon secretion. Early normalization of glycaemia in diabetes is thus important to prevent alpha-cell dysfunction. Targeting nutrient(s) metabolism and mTORC1 signaling in alpha-cells can therefore become an attractive approach to treat diabetes.
What is already known about this subject?
· Normally, glucagon secretion is stimulated by amino acids and inhibited by acute exposure to glucose.
- Glucagon secretion is dysregulated in patients with type 1 and type 2 diabetes.
- The mammalian target of rapamycin (mTORC1) regulates alpha cell proliferation and mediates the development of hyperglucagonaemia in response to glucagon receptor antagonism.
What is the key question?
Does mTORC1 mediate the development of hyperglucagonaemia in diabetes?
What are the new findings?
· mTORC1 activity is increased in alpha-cells of diabetic animals in parallel to the development of hyperglycaemia and hyperglucagonaemia.
- Chronic hyperglycaemia augments amino acid transport and synthesis in alpha -cells, leading to accumulation of mTORC1-stimulating metabolites. mTORC1 inhibition in alpha-cells mitigates glucagon secretion and improves glucose tolerance in diabetes, despite persistent insulin deficiency.
How might this impact on clinical practice in the foreseeable future?
Our findings emphasize the importance of early normalization of glycaemia in diabetes to prevent alpha-cell dysfunction. Targeting nutrient(s) metabolism and mTORC1 signaling in alpha-cells can become an attractive approach to treat both type 1 diabetes and type 2 diabetes.