Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation, which drives glucagon production – published online 22/07/2023

Yael Riahi, Aviram Kogot‑Levin, Liat Kadosh, Bella Agranovich, Assaf Malka, Michael Assa, Ron Piran, Dana Avrahami, Benjamin Glaser, Eyal Gottlieb, Fields Jackson III, Erol Cerasi, Ernesto Bernal‑Mizrachi, Aharon Helman, Gil Leibowitz

Diabetes is characterised by hyperglucagonemia as well as insulin deficiency, making it a dual hormone disease; however, the mechanisms involved in alpha cell dysfunction are unclear. In this issue, Riahi et al (https://doi.org/10.1007/s00125-023-05967-8) highlight the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) as a key player in diabetes-related hyperglucagonemia. They show that mTORC1 activity was increased in alpha cells from type 1 and type 2 diabetes models, and its inhibition by inducible Rptor knockout in alpha cells from a type 1 diabetes model dampened glucagon secretion and ameliorated diabetes. Metabolomics, metabolic flux and gene expression studies revealed that alpha cell exposure to hyperglycaemia enhanced glucose-derived amino acid synthesis and transport, culminating in increased glutamate, branched-chain amino acid and methionine cycle activity, all contributing to stimulation of mTORC1 activation. The authors highlight that prolonged high glucose exposure therefore alters amino acid metabolism, which may drive persistent mTORC1 activation and subsequent excessive glucagon secretion. They conclude that early normalisation of blood glucose levels is crucial to prevent alpha cell dysfunction in diabetes and suggest targeting nutrient(s) metabolism and mTORC1 signalling in alpha cells as an appealing avenue for diabetes treatment.

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