Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non-glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by b-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucosestimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak-mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid-stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.
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Acknowledgments. The authors thank Drs. Paolo Bernardi (University of Padova, Padova, Italy), Jude Deeney and Barbara Corkey (Boston University), Marc Prentki (Montreal Diabetes Research Center, Centre de Recherche du CHUM, Montreal, Quebec, Canada), Lisa Norquay (Janssen Pharmaceuticals, Spring House, PA), and Daniel Dagan (Technion Israel Institute of Technology, Haifa, Israel) for valuable feedback and discussion during the preparation of the manuscript. The authors also thank Dr. Kyle Hoehn (University of Virginia, Charlottesville, VA, and University of New South Wales, Sydney, New South Wales, Australia) for generously supplying BAM15 and Janssen Pharmaceuticals (Horsham, PA) for supplying NIM811. Finally, the authors are grateful to Dr. Yijun Chen (UCLA) for helping to coordinate and design the Western diet obesity mouse model. Funding. N.A. was funded by a fellowship from Kuwait University. This project was supported by a grant from the Kuwait Foundation for the Advancement of Sciences under project code CB17-63 MM-01 awarded to N.A.; National Institutes of Health (NIH), National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK), funding mechanism R01-DK-110181 awarded to R.G.K.; UCLA Department of Medicine Chair commitment and University of California, San Diego/UCLA Diabetes Research Center grant NIH P30-DK063491 awarded to M.L.; and NIH NIDDK funding mechanisms 5R01-DK-074778-10 and R01-DK-099618 and American Diabetes Association funding mechanism 1-19-IBS-049 awarded to O.S.S. Duality of Interest. This project was supported by a Sponsored Research Agreement from Janssen Research and Development (UCLA code #2016-1342). E.P.T., M.L., and O.S.S. are cofounders of Enspire Bio, Inc., a drug discovery company currently developing inhibitors of proton leak–mediated insulin secretion for treatment of obesity and prediabetes. No other potential conflicts of interest relevant to this article were reported. Author Contributions. E.P.T. and N.A. wrote the manuscript. E.P.T., N.A., S.B., J.D.W., E.R., S.S., K.E., J.L., and L.S. performed experiments and analyzed data. E.P.T., N.A., M.L., and O.S.S. edited the manuscript and revised the manuscript for resubmission. E.P.T. and S.B. performed experiments during the revision process. S.S., J.J.W., M.L., and O.S.S. contributed to the project conception. M.A., Z.S., and J.J.W. isolated and shipped islets from human patients with pancreatitis undergoing total pancreatectomy with islet autotransplantation at the University of Minnesota. M.D.B. obtained patient consent for human islet studies and evaluated patients before and after pancreas removal and islet transplantation. R.G.K. aided in experimental planning. M.L. and O.S.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in poster form at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22–26 June 2018.
© 2019 by the American Diabetes Association.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't