Glucosamine links hyperglycemia to mTORC1 activation and glucose toxicity in diabetes.

Abstract

Hyperglycemia is a principal driver of β cell failure and multiple-organ complications in diabetes. Chronic exposure to hyperglycemia overstimulates mTORC1, disrupting glucose metabolism and promoting ER stress, oxidative stress, and inflammation; however, the upstream metabolic signal(s) linking glucose to mTORC1 activation remains unclear. Here, we identified glucosamine as a key metabolite connecting elevated glucose to mTORC1 signaling in pancreatic islets and kidney, both major targets of hyperglycemic damage. Using 13C6-glucose metabolic labeling in diabetic rodents treated with or without the SGLT2 inhibitor dapagliflozin or insulin, combined with targeted metabolomics and metabolic flux analysis, we found that tissue glucose concentrations strongly correlated with glucosamine. A similar correlation with plasma glucose was conserved in humans with or without type 2 diabetes, and inversely associated with β cell function. In vitro, low-dose glucosamine stimulated mTORC1 in islets and kidney proximal tubule cells in an O-GlcNAcylation-dependent manner. Broad phosphoproteomics and transcriptomics analyses in β cells showed that glucosamine activated mTORC1-regulating pathways, induced oxidative stress, ER stress, and dedifferentiation. Genetic inhibition of β cell mTORC1 via heterozygous Raptor knockout, as well as pharmacologic inhibition of the glucosamine/mTORC1 axis through SGLT2 inhibition, alleviated β cell stress, improved glycemic control, and restored β cell function. These findings identified the glucosamine/mTORC1 pathway as an important mediator of β cell and kidney dysfunction in diabetes.