title: GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats.
abstract: The role of islet GPR40 protein in the pathogenesis of diabetes is unclear. We explored the influence of GPR40 protein levels on hormone secretion in islets from two rat models of spontaneous type 2 diabetes displaying either hyperlipidaemia or hyperglycaemia. GPR40 expression was analysed by confocal microscopy, Western blot and qPCR in islets from preobese Zucker (fa/fa) rats, diabetic Goto-Kakizaki (GK) rats, and controls. Confocal microscopy of control islets showed expression of GPR40 protein in insulin, glucagon and somatostatin cells. GPR40 expression was strongly increased in islets of hyperlipidaemic fa/fa rats and coincided with a concentration-related increase in palmitate-induced release of insulin and glucagon and its inhibition of somatostatin release. Conversely, hyperglycaemic GK islets displayed an extremely faint expression of GPR40 as did high-glucose-cultured control islets. This was reflected in abolished palmitate-induced hormone response in GK islets and high-glucose-cultured control islets. The palmitate antagonist rosiglitazone promoted reappearance of GPR40 in high-glucose-cultured islets and served as partial agonist in glucose-stimulated insulin release. GPR40 protein is abundantly expressed in pancreatic islets and modulates stimulated hormone secretion. Mild hyperlipidaemia in obesity-prone diabetes creates increased GPR40 expression and increased risk for an exaggerated palmitate-induced insulin response and lipotoxicity, a metabolic situation suitable for GPR40 antagonist treatment. Chronic hyperglycaemia creates abrogated GPR40 expression and downregulated insulin release, a metabolic situation suitable for GPR40 agonist treatment to avoid glucotoxicity. GPR40 protein is interactively modulated by both free fatty acids and glucose and is a promising target for pharmacotherapy in different variants of type 2 diabetes.
authors.affiliation: Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Sweden; Department of Stem Cell Biology, State Research Institute Centre of Innovative Vilnius, Lithuania.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meidute Abaraviciene
authors.forename: Sarheed J
authors.initials: SJ
authors.lastname: Muhammed
authors.forename: Stefan
authors.initials: S
authors.lastname: Amisten
authors.forename: Ingmar
authors.initials: I
authors.lastname: Lundquist
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010169:Palmitic Acids / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: D001786:Blood Glucose; C473035:G-protein-coupled receptor 40, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D010169:Palmitic Acids; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005947:Glucose
keywords: Free fatty acid; G-protein coupled receptor 40; Hormone secretion; Obesity; Receptor