Disruption of G protein-coupled receptor 39 impairs insulin secretion in vivo.
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.
Tremblay
Frédéric
F
Department of Metabolic Diseases,Wyeth Research, Cambridge, Massachusetts 02140, USA.
Richard
Ann-Marie T
AM
Will
Sarah
S
Syed
Jameel
J
Stedman
Nancy
N
Perreault
Mylène
M
Gimeno
Ruth E
RE
D000375:Aging / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D020868:Gene Silencing / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D004041:Dietary Fats; C512928:GPR39 protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose