| Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling. | |
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MedLine Citation:
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PMID: 20631001 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarah L Gray; Christine Donald; Arif Jetha; Scott D Covey; Timothy J Kieffer |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-14 |
Journal Detail:
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Title: Endocrinology Volume: 151 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-25 Completed Date: 2010-10-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 4178-86 Citation Subset: AIM; IM |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adiposity
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drug effects Animals Blood Glucose / metabolism Body Weight / drug effects Diazoxide / pharmacology Eating / drug effects Female Hyperinsulinism / blood, genetics, physiopathology* Hypoglycemic Agents / pharmacology Insulin / blood Insulin Resistance / genetics, physiology* Insulin-Secreting Cells / metabolism* Male Metformin / pharmacology Mice Mice, Knockout Receptors, Leptin / deficiency, genetics, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 0/Hypoglycemic Agents; 0/Receptors, Leptin; 0/leptin receptor, mouse; 11061-68-0/Insulin; 364-98-7/Diazoxide; 657-24-9/Metformin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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