Abstract
BackgroundGPR40 is a G-protein coupled receptor regulating free fatty acid induced and also glucose induced insulin secretion. We generated neonatally-streptozotocin-treated female rats (n-STZ) and treated them with CNX-011-67, a GPR40 agonist to examine the role of GPR40 in modulation of glucose metabolism, insulin secretion and content.MethodsFemale n-STZ animals were orally administered with CNX-011-67 (15 mg/kg body weight, twice daily) or with vehicle for 8 weeks (n = 8 per group). Glucose tolerance in treated animals and insulin secretion, islet insulin content and gene expression in isolated islets were determined. Islets from type 2 diabetic mellitus (T2DM) patients were treated with different concentrations of glucose in presence or absence of CNX-011-67 and insulin secretion was measured.ResultsTreatment of n-STZ rats with GPR40 agonist CNX-011-67 enhanced insulin secretion in response to oral glucose load on day 0 and this response persisted during the treatment period. The treatment also produced a ‘memory effect’ during which insulin secretion in response to oral glucose load remained enhanced, for a week, even in absence of the agonist. Activation of GPR40 enhanced responsiveness of islets to glucose and increased glucose induced insulin secretion and islet insulin content. An increase in islet mRNA expression of GCK, PDX1, insulin and PC was also observed. Acute treatment of islets from n-STZ rats with GPR40 agonist enhanced cellular ATP content. Activation of GPR40 enhanced mitochondrial calcium level in NIT-1 insulinoma cells. CNX-011-67 increased insulin secretion in islets from T2DM patients which were non-responsive to increased glucose concentrationConclusionsOur data provide evidence that activation of GPR40 with CNX-011-67 stimulates glucose metabolism, enhances glucose responsiveness, increases insulin secretion and content and that pharmacological activation of GPR40 will prove beneficial for treatment of T2DM.
Highlights
G protein coupled receptor 40 (GPR40) is a G-protein coupled receptor regulating free fatty acid induced and glucose induced insulin secretion
CNX-011-67 increased glucose stimulated insulin secretion in human islets from Type 2 Diabetes Mellitus (T2DM) patient. These results suggest that activation of GPR40 by CNX-011-67 will provide a novel therapeutic approach to improve long-term glycemic control in T2DM patients by regulating β-cell biology
There was no significant difference in body weight and fasting glucose between the sham control and neonatally-streptozotocin-treated female rats (n-STZ) groups but the n-STZ animals displayed decreased insulin area under curve (AUC) and severe glucose intolerance during ‘Oral Glucose Tolerance Test’ (OGTT)
Summary
GPR40 is a G-protein coupled receptor regulating free fatty acid induced and glucose induced insulin secretion. Different GPR40 agonists such as GW9508, TAK-875, AS2575959, AMG837 and phenyl propanoic acid derivatives have shown increased insulin secretion in both insulinoma cells and/or in animal models [16,17,18,19,20] Among these agonists, TAK-875 has been shown to prevent β-cells dysfunction [21] in animal model of diabetes and improves glycemic control in T2DM patients [22,23]. TAK-875 has been shown to prevent β-cells dysfunction [21] in animal model of diabetes and improves glycemic control in T2DM patients [22,23] None of these abovementioned molecules have been reported to increase insulin secretion in n-STZ model which has high β-cell stress
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