Disruption of G Protein-Coupled Receptor 39 Impairs Insulin Secretion in Vivo
| Autor: | Ann-Marie T. Richard, Sarah Will, Frédéric Tremblay, Nancy Stedman, Mylene Perreault, Jameel Syed, Ruth E. Gimeno |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Aging medicine.medical_specialty G protein medicine.medical_treatment Blood sugar Adipose tissue Biology Receptors G-Protein-Coupled Islets of Langerhans Mice Endocrinology Internal medicine Insulin Secretion medicine Animals Insulin Gene Silencing Obesity Receptor Cells Cultured Pancreatic hormone Homeodomain Proteins Mice Knockout Gastrointestinal tract Dietary Fats Mice Inbred C57BL Disease Models Animal Glucose medicine.anatomical_structure Insulin Receptor Substrate Proteins Trans-Activators RNA Interference Insulin Resistance Pancreas |
| Zdroj: | Endocrinology. 150:2586-2595 |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes. |
| Databáze: | OpenAIRE |
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