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Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion

Author:
Wang, Fei, Kohan, Alison B., Kindel, Tammy L., Corbin, Kathryn L., Nunemaker, Craig S., Obici, Silvana, Woods, Stephen C., Davidson, W. Sean, Tso, Patrick
Source:
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.24 pp. 9641-9646
ISSN:
0027-8424
Subject:
absorption, animal disease models, blood glucose, calcium, cyclic AMP, diabetes mellitus, fasting, glucose, glucose tolerance, high fat diet, homeostasis, hyperglycemia, insulin, insulin secretion, islets of Langerhans, lipids, mice, small intestine
Abstract:
Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine in response to fat absorption. Here we demonstrate a potential role for apoA-IV in regulating glucose homeostasis. ApoA-IV–treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involves cAMP at a level distal to Ca ²⁺ influx into the β cells. Knockout of apoA-IV results in compromised insulin secretion and impaired glucose tolerance compared with WT mice. Challenging apoA-IV ⁻/⁻ mice with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in WT mice. Administration of exogenous apoA-IV to apoA-IV ⁻/⁻ mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet. Finally, we demonstrate that exogenous apoA-IV injection decreases blood glucose levels and stimulates a transient increase in insulin secretion in KKAy diabetic mice. These results suggest that apoA-IV may provide a therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes.
Agid:
1721172