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Am J Physiol Endocrinol Metab 292: E1364-E1377, 2007. First published January 16, 2007; doi:10.1152/ajpendo.00672.2006
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Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

Paul Mitrani, Malathi Srinivasan, Catherine Dodds, and Mulchand S. Patel

Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York

Submitted 18 December 2006 ; accepted in final form 11 January 2007

Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy-N-methylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase Cbeta1, and protein kinase C-{alpha} and decreased levels of {alpha}2a-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period.

high-carbohydrate milk formula; parasympathetic nervous system; and sympathetic nervous system



Address for reprint requests and other correspondence: M. S. Patel, Dept. of Biochemistry, School of Medicine and Biomedical Sciences, Univ. at Buffalo, State University of New York, 140 Farber Hall, 3435 Main St., Buffalo, NY 14214 (e-mail: mspatel{at}buffalo.edu)




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M. Srinivasan, P. Mitrani, G. Sadhanandan, C. Dodds, S. Shbeir-ElDika, S. Thamotharan, H. Ghanim, P. Dandona, S. U Devaskar, and M. S Patel
A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity
J. Endocrinol., June 1, 2008; 197(3): 565 - 574.
[Abstract] [Full Text] [PDF]




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