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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.

In the version of this article originally published, the V.sub.PC and V.sub.CS flux data shown in Fig. 6e,f were inadvertently duplicated from Fig. 5j,k. The correct data are now shown in Fig. 6e,f. In these corrected data, V.sub.PC flux in response to chronic oral metformin treatment was still significantly decreased (Fig. 6e), and there was still no impact of metformin on V.sub.CS flux (Fig. 6f). Therefore, the text describing these data remains the same and this correction does not change the conclusion of this study., Author(s): Anila K. Madiraju [sup.1] [sup.2] [sup.3] , Yang Qiu [sup.1] [sup.4] , Rachel J. Perry [sup.1] , Yasmeen Rahimi [sup.1] , Xian-Man Zhang [sup.1] , Dongyan Zhang [sup.1] , [...]

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ζ (PKCζ) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCζinhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site [Thr.sup.1160] as a PKCζ substrate in the functionally critical INSR kinase activation loop. We hypothesized that [Thr.sup.1160] phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCζ in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue [Thr.sup.1150] ([Insr.sup.T1150A] mice) were protected from high fat diet-induced hepatic insulin resistance. InsrTm0A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR [Thr.sup.1160] phosphorylation and provide further mechanistic links between PKCζ and INSR in mediating NAFLD-induced hepatic insulin resistance., Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized nations (1). NAFLD is observed in nearly 100% of obese people with type 2 diabetes (T2D) [...]