Recent research has focused on identifying key agonists and

Recent research has focused on identifying key agonists and receptors mediating nutrient-induced GLP-1 and insulin secretion. The long-chain fatty 6-O-α-Maltosyl-β-cyclodextrin receptor GPR40 is the most abundant GPCR expressed in islet β cells and is also expressed on intestinal L-cells, where it contributes to GLP-1 release along with GPR120 (Itoh et al., 2003, Edfalk et al., 2008). GPR40 activation augments GSIS and improves glycemia in rodent T2D models (Itoh et al., 2003, Steneberg et al., 2005), and the GPR40 agonist TAK-875 lowers fasting and postprandial blood glucose and HbA1c levels in humans (Leifke et al., 2012, Burant et al., 2012). Because PAHSAs acutely augment GSIS directly from human islets (Yore et al., 2014), the third aim of this study was to determine whether PAHSAs activate GPR40 and whether this contributes to their beneficial effects in vivo. Here we show that PAHSAs directly activate GPR40, which is important for PAHSA effects on glucose homeostasis in both chow and HFD mice. Since PAHSAs augment GLP-1 secretion in insulin-resistant mice (Yore et al., 2014), we also investigated the role of the GLP-1 receptor (GLP-1R) in mediating PAHSA effects on glucose metabolism. GLP-1 potentiates insulin secretion and suppresses glucagon release (Holst, 2007), but its beneficial actions are not limited to the endocrine pancreas (Ayala et al., 2009, Christensen et al., 2015, Villanueva-Peñacarrillo et al., 2011). Here we show that the GLP-1R contributes to the beneficial PAHSA effects on insulin secretion and glucose tolerance, but not on insulin sensitivity, in chow mice. In addition, PAHSA-stimulated augmentation of GSIS in chow mice is directly mediated by GPR40, but their effects on GLP-1 secretion do not involve GPR40. Thus, PAHSAs improve glucose tolerance and insulin sensitivity in chow mice and these effects are sustained for 5 months. In HFD mice, glucose tolerance and insulin sensitivity are also improved by PAHSA treatment, but the effects are more modest. Furthermore, this study shows that PAHSAs directly activate GPR40, which contributes to their beneficial metabolic effects in mice on both chow and HFD.
Results and Discussion
STAR★Methods
Acknowledgments We thank Dr. Ji Lei, the director of BADERC Pancreatic Islet Core (NIH P30 DK57521), for providing human islets, and Dr. Douglas Hanahan for the STC-1 cells. We thank Dr. Susan Bonner-Weir, Director of the Joslin DRC Advanced Microscopy Core (NIH P30 DK036836), from the Joslin Diabetes Center for her expertise and conversations related to islet biology analyses. The Harvard Digestive Disease Center Core B (NIH P30DK034854) processed and immunostained samples. Imaging was performed at the Neuro Imaging Facility (NINDS P30 Core Center) for islet mass quantification. Supported by NIH grants R01 DK43051, P30 DK57521 (B.B.K.), and R01 DK106210 (B.B.K. and A. Saghatelian); a grant from the JPB Foundation (B.B.K.); and T32DK07516 (B.B.K. and J.L.).
Introduction Free fatty acids (FFAs) are an essential energy source, especially during starvation, exercise, and pregnancy, and they are also important modulators of various physiological responses. For pancreatic β-cells, FFAs are required for both basal and glucose-stimulated insulin secretion (GSIS).2, 3, 4 The insulinotropic effect of FFAs depends on the chain length and the degree of saturation; the less saturated long-chain FFAs have a greater effect. However, chronically elevated plasma FFA concentrations, which are closely associated with obesity and type 2 diabetes mellitus (T2DM), may lead to insulin resistance in the skeletal muscle and liver and pancreatic β-cell dysfunction and apoptosis.1, 6, 7 The effects of FFAs on insulin secretion are traditionally believed to be related to the malonyl-CoA/long-chain acyl-CoA signaling network and glucose-responsive triglyceride/FFA cycling. However, the deorphanization of G protein-coupled receptor 40 (GPR40) suggests the existence of a different mechanism. Activation of GPR40 in the presence of glucose increases cytosolic Ca concentrations mainly through Gq/11–phospholipase C (PLC) pathway and eventually amplifies GSIS. Therefore, GPR40 has become an attractive therapeutic target for T2DM, and numerous ligands of GPR40 have been developed.