Mechanisms of exercise-induced improvements in whole-body glycemia in RabGAP-deficient mice

• Applicant: Dr. Alexandra Chadt
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397423660

The two Rab-GTPase-activating proteins (RabGAPs) TBC1D1 and its close homologue TBC1D4 (AS160) are important regulators of insulin- and contraction-mediated glucose uptake and lipid metabolism in skeletal muscle. Mutations in the genes for TBC1D1 and TBC1D4 have been associated with obesity, insulin resistance and type 2 diabetes in both humans and mice. Despite marked postprandial glucose intolerance, whole-body glycaemia is only mildly affected upon depletion of either RabGAP, presumably due to compensatory mechanisms involving the homologous family member. However, double-deficient Tbc1d1/Tbc1d4 (D1/4KO) mice show substantially impaired glucose, insulin and AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide, stimulator of AMPK activity) tolerance as well as reduced exercise performance and running endurance. Consistently, intact isolated skeletal muscle from D1/4KO mice displayed strongly reduced insulin-, AICAR- and contraction-stimulated glucose uptake due to impaired regulation of GLUT4 glucose transporters. Unexpectedly, chronic interval training of D1/4KO mice on treadmills rescues the impairment in glucose tolerance, exercise performance and endurance, strongly indicating the presence of exercise-induced alternative pathways for skeletal muscle glucose metabolism and glycemic control. The present proposal aims at (i) investigating the molecular mechanism underlying the observed TBC1D1/TBC1D4-independent metabolic effects of chronic exercise on whole-body glycemia and skeletal muscle energy metabolism, and (ii) performing an in-depth analysis of individual RabGAP function in exercise-induced improvements of insulin sensitivity using novel tissue-specific knockout models for the Tbc1d1 and Tbc1d4.

• DFG Programme: Research Grants