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.
The search for putative precursor cells within the pancreas has been the focus of extensive research. Previously, we identified rare pancreas-derived multipotent precursor (PMP) cells in the mouse with the intriguing capacity to generate progeny in the pancreatic and neural lineages. Here, we establish the embryonic pancreas as the developmental source of PMPs through lineage-labeling experiments. We also show that PMPs express insulin and can contribute to multiple pancreatic and neural cell types in vivo. In addition, we have isolated PMPs from adult human islet tissue that are also capable of extensive proliferation, self-renewal, and generation of multiple differentiated pancreatic and neural cell types. Finally, both mouse and human PMP-derived cells ameliorated diabetes in transplanted mice. These findings demonstrate that the adult mammalian pancreas contains a population of insulin(+) multipotent stem cells and suggest that these cells may provide a promising line of investigation toward potential therapeutic benefit.
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.
Gestational diabetes mellitus (GDM) affects 3–14% of pregnancies, with 20–50% of these women progressing to type 2 diabetes (T2D) within 5 years. This study sought to develop a metabolomics signature to predict the transition from GDM to T2D. A prospective cohort of 1,035 women with GDM pregnancy were enrolled at 6–9 weeks postpartum (baseline) and were screened for T2D annually for 2 years. Of 1,010 women without T2D at baseline, 113 progressed to T2D within 2 years. T2D developed in another 17 women between 2 and 4 years. A nested case-control design used 122 incident case patients matched to non–case patients by age, prepregnancy BMI, and race/ethnicity. We conducted metabolomics with baseline fasting plasma and identified 21 metabolites that significantly differed by incident T2D status. Machine learning optimization resulted in a decision tree modeling that predicted T2D incidence with a discriminative power of 83.0% in the training set and 76.9% in an independent testing set, which is far superior to measuring fasting plasma glucose levels alone. The American Diabetes Association recommends T2D screening in the early postpartum period via oral glucose tolerance testing after GDM, which is a time-consuming and inconvenient procedure. Our metabolomics signature predicted T2D incidence from a single fasting blood sample. This study represents the first metabolomics study of the transition from GDM to T2D validated in an independent testing set, facilitating early interventions.
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