Role of the autonomic nervous system in the metabolic programming of hyperinsulinemia in the high-carbohydrate rat model
Mitrani, Paul Anthony
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Metabolic programming due to an early dietary intervention in the form of a highcarbohydrate (HC) milk formula results in the immediate onset of hyperinsulinemia and its persistence throughout life. While increased insulin secretion in HC rats has been shown to be related to hypersensitivity to glucose, present studies in 12- and 100-day-old HC rats indicates that altered activity of the autonomic nervous system contributes to enhanced ß-cell insulin secretory responses to glucose stimulation through increased parasympathetic and decreased sympathetic signaling. The autonomic nervous system is involved in regulation of insulin secretion through the parasympathetic nervous system, which stimulates insulin secretion, and the sympathetic nervous system, which inhibits insulin secretion. Both in vivo and in vitro studies have shown that HC rats secrete significantly higher levels of insulin in response to glucose in the presence of acetylcholine, a cholinergic agonist, while sensitivity to inhibition of insulin secretion by oxymetazoline, an α 2a -adrenergic receptor (α 2a AR) agonist, was reduced. In addition, HC rats showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor (M3R) antagonist 4-DAMP. Furthermore, vagotomized HC rats showed significantly greater reductions in plasma insulin levels compared to vagotomized MF rats, suggesting that insulin secretion in HC rats is more dependent on intact parasympathetic stimulation. Vagotomy studies also suggested that the maintenance of hyperinsulinemia in HC rats involves a complex system of communication between the parasympathetic and sympathetic nervous systems that favors enhanced insulin secretory responses in response to glucose. Increases in the levels of the parasympathetic signaling molecules M3R, phospholipase C-ß1 (PLCß1), and protein kinase Ca (PKCα) mRNA, as well as decreased levels of α 2a AR mRNA in HC rats provides a mechanistic connection to the changes in insulin secretion seen in HC rats. Protein analysis in 100-day-old HC rats confirmed increases in PLCß1 and PKCα, as well as decreases in α 2a AR. Studies of the effects of the HC dietary intervention on the regulation of energy homeostasis and autonomic activity showed that HC rats exhibit chronic hyperphagia, which contributes to hyperinsulinemia and the development of obesity. Interestingly, serum leptin levels in 12-day-old HC rats were significantly decreased, suggesting impaired development of the hypothalamus, which is involved in the regulation of energy homeostasis. Furthermore, adult HC rats showed significant increases in serum leptin levels, associated with obesity, suggesting a state of leptin resistance. Evaluation of mRNA levels of orexigenic and anorexigenic neuropeptides in the hypothalamus found increases in neuropeptide Y and agouti-related peptide and decreases in pro-opiomelanocortin, cocaine- and amphetamineregulated transcript, and corticotropin-releasing factor in HC rats, which are consistent with a state of hyperphagia, as well as increases in parasympathetic and decreases in sympathetic activities. In conclusion, an early nutritional intervention, in the form of a high-carbohydrate milk formula, results in significant changes in the regulation of insulin secretion both peripherally, at the level of pancreatic islets, and centrally, at the level of the hypothalamus and autonomic control centers. The fact that changes in autonomic activity are present during the suckling period and persist throughout adulthood suggests that the overlap of the HC dietary intervention with continued postnatal development of the nervous system results in permanent reprogramming of autonomic regulation of insulin secretion.