Aims/hypothesis Zinc is highly concentrated in pancreatic beta cells, is critical for normal insulin storage, and may regulate glucagon secretion from alpha cells. ZnT8 is a zinc efflux transporter highly expressed in beta cells and polymorphisms in the ZnT8 (slc30a8) gene in man are associated with increased risk of type 2 diabetes. Whilst global ZnT8 knockout (ZnT8KO) mice have been characterized, ZnT8 is also expressed in other islet cell types and extra-pancreatic tissues. Therefore, it is important to devise strategies to understand the role of ZnT8 in beta and alpha cells without the confounding effects of ZnT8 in these other tissues. Methods We have generated beta and alpha cell specific ZnT8 knockout (ZnT8BKO and ZnT8AKO) mice and performed in vivo and in vitro characterization of the phenotypes to determine the functional and anatomical impact of ZnT8 in these cells. Thus we assessed zinc accumulation, insulin granule morphology, insulin biosynthesis and secretion, and glucose homeostasis. Results ZnT8BKO mice are glucose intolerant, have reduced beta cell zinc accumulation and atypical insulin granules. They also display reduced first phase glucose-stimulated insulin secretion, reduced insulin processing enzyme transcripts and increased proinsulin levels. In contrast, ZnT8AKO mice show no evident abnormalities in plasma glucagon and glucose homeostasis. Conclusion/interpretation We provide the first report of specific beta and alpha cell deletion of ZnT8. Our data indicate that while ZnT8 is absolutely required for proper beta cell function, under the conditions studied, it is largely dispensable for alpha cell function.

Gestational diabetes (GDM) results from failure of the β cells to adapt to increased metabolic demands; however, the cause of GDM and the extremely high rate of progression to type 2 diabetes (T2D) remains unknown. Using metabolomics, we show that the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is elevated in the plasma of humans with GDM, as well as impaired glucose-tolerant and T2D patients. In mice, diabetic levels of plasma CMPF induced glucose intolerance, impaired glucose-stimulated insulin secretion, and decreased glucose utilization. Mechanistically, we show that CMPF acts directly on the β cell, causing impaired mitochondrial function, decreasing glucose-induced ATP accumulation, and inducing oxidative stress, resulting in dysregulation of key transcription factors and ultimately reduced insulin biosynthesis. Importantly, specifically blocking its transport through OAT3 or antioxidant treatment could prevent CMPF-induced β cell dysfunction. Thus, CMPF provides a link between β cell dysfunction and GDM/T2D that could be targeted therapeutically.

INS:GFP(+) cells can be purified from differentiated hESCs, providing a superior source of insulin-producing cells. Genomic analyses revealed that INS:GFP(+) cells collectively resemble immature endocrine cells. However, insulin(+) cells were heterogeneous, a fact that translated into important functional differences within this population. The information gained from this study may now be used to generate new iterations of functioning beta cells that can be purified for transplant.

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Taken together, these findings indicate that in beta cells the deacetylase SIRT1 regulates the expression of specific mitochondria-related genes that control metabolic coupling, and that a decrease in beta cell Sirt1 expression impairs glucose sensing and insulin secretion.