Central Role of mTORC1 in Mediating the Hyperglucagonemia of Diabetes

Introduction:
Hyperglucagonemia plays an important role in diabetes pathophysiology, however the mechanisms involved are poorly understood.

Aim:
Investigate the role of the nutrient sensor mTORC1 in alpha-cell dysfunction.

Methods:
Alpha-cell mTORC1 activity was assessed in models of T1D (Akita mice and diphtheria-toxin-induced beta-cell ablation; DT-diabetes) and T2D (db/db mice) by immunostaining pancreatic sections and FACS-sorted alpha-cells for glucagon and pS6, an mTORC1 downstream target. We generated conditional KO of Raptor, regulator of mTORC1, in adult Akita alpha-cells and tested effects on glucose tolerance by IPGTT and glucagon secretion by ELISA.

Results:
Plasma glucagon and pancreatic glucagon content were 2-3-fold higher in Akita mice than controls. mTORC1 activity was increased in alpha-cells of Akita, DT-diabetes and db/db mice. Treatment of Akita mice with insulin or SGLT2 inhibitor dapagliflozin prevented the stimulation of mTORC1. Surprisingly, ex-vivo incubation of WT islets at high glucose decreased alpha-cell mTORC1 activity. Metabolomic profiling of plasma of Akita mice showed that fructose, fructose 1-phosphate and sorbitol were increased. One-week feeding WT mice with 30% fructose in drinking water increased plasma glucagon and alpha-cell mTORC1 activity. Similarly, ex-vivo incubation of islets with high fructose increased glucagon secretion and alpha-cell mTORC1 activity. Finally, plasma glucagon of alpha-cell-Raptor KO Akita mice was decreased and glucose tolerance improved.

Conclusion:
In diabetes, plasma fructose is increased even without excess fructose intake, leading to activation of mTORC1 in alpha-cells, thereby increasing glucagon secretion. Inhibiting alpha-cell mTORC1 prevents hyperglucagonemia and ameliorates diabetes; this may provide a novel therapeutic strategy for diabetes.