title: Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling.
abstract: The adipocyte hormone leptin acts centrally and peripherally to regulate body weight and glucose homeostasis. The pancreatic beta-cell has been shown to be a key peripheral target of leptin, with leptin suppressing insulin synthesis and secretion from beta-cells both in vitro and in vivo. Mice with disrupted leptin signaling in beta-cells (lepr(flox/flox) RIPcre tg+ mice) display hyperinsulinemia, insulin resistance, glucose intolerance, obesity, and reduced fasting blood glucose. We hypothesized that hyperinsulinemia precedes the development of insulin resistance and increased adiposity in these mice with a defective adipoinsular axis. To determine the primary defect after impaired beta-cell leptin signaling, we treated lepr(flox/flox) RIPcre tg+ mice with the insulin sensitizer metformin or the insulin-lowering agent diazoxide with the rationale that pharmacological improvement of the primary defect would alleviate the secondary symptoms. We show that improving insulin sensitivity with metformin does not normalize hyperinsulinemia, whereas lowering insulin levels with diazoxide improves insulin sensitivity. Taken together, these results suggest that hyperinsulinemia precedes insulin resistance in beta-cell leptin receptor-deficient mice, with insulin resistance developing as a secondary consequence of excessive insulin secretion. Therefore, pancreatic beta-cell leptin receptor-deficient mice may represent a model of obesity-associated insulin resistance that is initiated by hyperinsulinemia.
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Christine
authors.initials: C
authors.lastname: Donald
authors.forename: Arif
authors.initials: A
authors.lastname: Jetha
authors.forename: Scott D
authors.initials: SD
authors.lastname: Covey
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005260:Female; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D008687:Metformin; D003981:Diazoxide