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Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes

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Abstract

Type 2 diabetes is a major health problem worldwide, and one of its key features is the inability of elevated glucose to stimulate the release of sufficient amounts of insulin from pancreatic beta cells to maintain normal blood glucose levels1,2. New therapeutic strategies to improve beta cell function are therefore believed to be beneficial3,4. Here we demonstrate that the short-chain fatty acid receptors FFA2 (encoded by FFAR2) and FFA3 (encoded by FFAR3) are expressed in mouse and human pancreatic beta cells and mediate an inhibition of insulin secretion by coupling to Gi-type G proteins. We also provide evidence that mice with dietary-induced obesity and type 2 diabetes, as compared to non-obese control mice, have increased local formation by pancreatic islets of acetate, an endogenous agonist of FFA2 and FFA3, as well as increased systemic levels. This elevation may contribute to the insufficient capacity of beta cells to respond to hyperglycemia in obese states. Indeed, we found that genetic deletion of both receptors, either on the whole-body level or specifically in pancreatic beta cells, leads to greater insulin secretion and a profound improvement of glucose tolerance when mice are on a high-fat diet compared to controls. On the other hand, deletion of Ffar2 and Ffar3 in intestinal cells did not alter glucose tolerance in diabetic animals, suggesting these receptors act in a cell-autonomous manner in beta cells to regulate insulin secretion. In summary, under diabetic conditions elevated acetate acts on FFA2 and FFA3 to inhibit proper glucose-stimulated insulin secretion, and we expect antagonists of FFA2 and FFA3 to improve insulin secretion in type 2 diabetes.

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Figure 1: FFA2 and FFA3 expression in pancreatic islets and the effects of acetate on insulin secretion from beta cells in vitro.
Figure 2: Regulation of insulin secretion from pancreatic islets via FFA2 and FFA3 and release of acetate from islets.
Figure 3: Glucose tolerance, glucose-simulated insulin secretion, insulin tolerance test and hyperinsulinemic-euglycemic clamp experiments in HFD-fed Ffar2-, Ffar3- and double-knockout Ffar2−/−Ffar3−/− mice.
Figure 4: Loss of Ffa2 and Ffa3 in beta cells improves glucose tolerance and insulin secretion in vivo.

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Acknowledgements

The authors wish to thank S. Hümmer and S. Meaney-Gardian for secretarial help and K. Adolph and S. Kreutzer for technical support. H. Pijl (Leiden University Medical Centre) helped set up the hyperinsulinemic-euglycemic clamp, and P. Ravassard and R. Scharfmann (INSERM, Paris) provided EndoC-βH1 cells. This work was supported by funds through the Collaborative Research Center 1039 of the German Research Foundation and by the Max Planck Society.

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Contributions

C.T. performed most of the experiments and analyzed and interpreted data; K.A. generated mice lacking Ffar2 and Ffar3; A.G. generated Ffar2 and Ffar3 reporter mice; S.L. helped with some of the in vivo experiments and with the histology; H.-J.G. performed histological analysis; S.T. performed expression analysis; S.O. analyzed and interpreted data, supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Stefan Offermanns.

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The authors declare no competing financial interests.

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Tang, C., Ahmed, K., Gille, A. et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21, 173–177 (2015). https://doi.org/10.1038/nm.3779

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