OBJECTIVE—The G-protein–coupled receptor GPR40 is expressed in pancreatic β-cells and is activated by long-chain fatty acids. Gene deletion studies have shown that GPR40 mediates, at least in part, fatty acid–amplification of glucose-induced insulin secretion (GSIS) but is not implicated in GSIS itself. However, the role of GPR40 in the long-term effects of fatty acids on insulin secretion remains controversial. This study aimed to test the hypothesis that GPR40 plays a role in insulin secretion after high-fat feeding. RESEARCH DESIGN AND METHODS—GPR40 knockout (KO) mice on a C57BL/6 background and their wild-type (WT) littermates were fed a high-fat diet (HFD) for 11 weeks. Glucose tolerance, insulin tolerance, and insulin secretion in response to glucose and Intralipid were assessed during the course of the diet period. RESULTS—GPR40 KO mice had fasting hyperglycemia. They became as obese, glucose intolerant, and insulin resistant as their WT littermates given HFD and developed a similar degree of liver steatosis. Their fasting blood glucose levels increased earlier than those of control mice during the course of the HFD. The remarkable increase in insulin secretory responses to intravenous glucose and Intralipid seen in WT mice after HFD was of much lower magnitude in GPR40 KO mice. CONCLUSIONS—GPR40 plays a role not only in fatty acid modulation of insulin secretion, but also in GSIS after high-fat feeding. These observations raise doubts on the validity of a therapeutic approach based on GPR40 antagonism for the treatment of type 2 diabetes.

OBJECTIVE: The G-protein–coupled receptor GPR40 mediates fatty acid potentiation of glucose-stimulated insulin secretion, but its contribution to insulin secretion in vivo and mechanisms of action remain uncertain. This study was aimed to ascertain whether GPR40 controls insulin secretion in vivo and modulates intracellular fuel metabolism in islets. RESEARCH DESIGN AND METHODS: Insulin secretion and sensitivity were assessed in GPR40 knockout mice and their wild-type littermates by hyperglycemic clamps and hyperinsulinemic euglycemic clamps, respectively. Transcriptomic analysis, metabolic studies, and lipid profiling were used to ascertain whether GPR40 modulates intracellular fuel metabolism in islets. RESULTS: Both glucose- and arginine-stimulated insulin secretion in vivo were decreased by ∼60% in GPR40 knockout fasted and fed mice, without changes in insulin sensitivity. Neither gene expression profiles nor intracellular metabolism of glucose and palmitate in isolated islets were affected by GPR40 deletion. Lipid profiling of isolated islets revealed that the increase in triglyceride and decrease in lyso-phosphatidylethanolamine species in response to palmitate in vitro was similar in wild-type and knockout islets. In contrast, the increase in intracellular inositol phosphate levels observed in wild-type islets in response to fatty acids in vitro was absent in knockout islets. CONCLUSIONS: These results indicate that deletion of GPR40 impairs insulin secretion in vivo not only in response to fatty acids but also to glucose and arginine, without altering intracellular fuel metabolism in islets, via a mechanism that may involve the generation of inositol phosphates downstream of GPR40 activation.

G‐protein coupled receptors (GPCRs) are targets of approximately 30% of currently marketed drugs. Over the last few years, a number of GPCRs expressed in pancreatic β‐cells and activated by lipids have been discovered. GPR40 was shown to be activated by medium‐ to long‐chain fatty acids (FAs). It has since been shown that GPR40 contributes to FA amplification of glucose‐induced insulin secretion. Although some controversy still exists as to whether GPR40 agonists or antagonists should be designed as novel type 2 diabetes drugs, data obtained in our laboratory and others strongly suggest that GPR40 agonism might represent a valuable therapeutic approach. GPR119 is expressed in pancreatic β‐cells and enteroendocrine L‐cells, and augments circulating insulin levels both through its direct insulinotropic action on β‐cells and through FA stimulation of glucagon‐like peptide 1 (GLP‐1) secretion. GPR120 is expressed in L‐cells and was also shown to mediate FA‐stimulated GLP‐1 release. Finally, GPR41 and GPR43 are receptors for short‐chain FAs and may indirectly regulate β‐cell function via adipokine secretion. Although the discovery of these various lipid receptors opens new and exciting avenues of research for drug development, a number of questions regarding their mechanisms of action and physiological roles remain to be answered.

Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive β-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems.