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Summary: Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health. : Jesinkey et al. report that mitochondrial GTP (mtGTP) is an integrative nutrient sentinel regulating β cell function. Signaling from mtGTP raises calcium independent of oxidative phosphorylation to promote insulin secretion. Without overworking the β cell, mtGTP cycling potentiates insulin secretion, nutrient sensing, and mitochondrial expansion alongside promoting health and increasing insulin reserves. Keywords: mitochondrial GTP, PEPCK-M, insulin secretion, oxidative phosphorylation, phosphoenolpyruvate, anaplerosis, succinyl-CoA synthetase, stable isotope, metabolic flux, MIMOSA

Insulin receptor levels at the cell surface are reduced in insulin resistance, for reasons that are not fully understood. Here, the authors identify the E3 ubiquitin ligase MARCH1 as a direct regulator of basal insulin receptor surface levels and, therefore, insulin signalling.