Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats

Abstract

Mitrani P, Srinivasan M, Dodds C, Patel MS. Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats. Am J Physiol Endocrinol Metab 292: E1069 -E1078, 2007. First published December 12, 2006 doi:10.1152/ajpendo.00477.2006.-An early dietary intervention in the form of a high-carbohydrate (HC) milk formula in neonatal rat pups results in immediate onset of hyperinsulinemia. While increased insulin secretion in HC rats has been shown to be related to hypersensitivity to glucose, the immediate onset of hyperinsulinemia and its persistence throughout the suckling period suggest involvement of multiple systems that enhance insulin secretion in response to increased demand. Evidence presented here in 12-day-old HC rats indicates that altered activity of the autonomic nervous system contributes to enhanced insulin secretory responses to glucose stimulation through increased parasympathetic and decreased sympathetic signaling. 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 ␣ 2a-adrenergic receptor (␣2aAR) agonist, was reduced. In addition, HC rats showed increased sensitivity to blockade of cholinergicinduced insulin secretion by the muscarinic type 3 receptor (M3R) antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide, as well as increased potentiation of glucose-stimulated insulin secretion by treatment with yohimbine. Increases in islets levels of M3R, phospholipase C-␤1, and protein kinase C␣ mRNAs, as well as decreased ␣ 2aAR mRNA, in 12-day-old HC rats provide a mechanistic connection to the changes in insulin secretion seen in HC rats. In conclusion, altered autonomic regulation of insulin secretion, due to the HC nutritional intervention, contributes to the development of hyperinsulinemia in 12-day-old HC rats.high-carbohydrate milk formula; parasympathetic nervous system; sympathetic nervous system RECENT EVIDENCE SUGGESTS that changes in the quality of nutrition during critical periods of early development (fetal and neonatal) may play a decisive role in the metabolic programming of early adaptive responses into adulthood which result in metabolic disease (6). Metabolic programming is the phenomenon in which a stimulus or insult that occurs during a critical period of organogenesis in early life results in permanent alterations in the structure and function of affected organs and increased susceptibility to adult onset of diseases (6). The late fetal and early postnatal periods of rat development constitute a period during which the ontogeny of the endocrine pancreas is vulnerable to nutritional perturbations that result in permanent structural and functional adaptations (9).Studies from our laboratory found that an early high-carbohydrate (HC) dietary intervention during the immediate postnatal period (days 4-24) in rats r...

Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction

“…The metabolic phenotype (body weight, serum hormone levels, insulin secretory capacity of islets, and hypothalamic characteristics) of the HF rats during both the preweaning and postweaning periods was similar to that of the MF rats, which suggests that the development of the HC phenotype was not influenced by the artificial rearing technique employed in our studies (11,16,18,19,30,33,34). Because of the similarity in the phenotype of MF and HF rats, we used only MF rats as control in the present study.…”

“…Although insulin secretion is regulated primarily by circulating glucose concentrations (15), the ANS also controls insulin secretion by islets (2,32). HC islets demonstrated aberrations at both of these levels of regulation of insulin secretion: 1) a leftward shift in the response to glucose (1,29) and 2) an increased PNS activity (increased response to ACh stimulation) and a compromised SNS activity (diminished inhibition by OM) (18,19). Our results indicate that although serum insulin levels were normalized in the adult HC/PF rats, the in vitro insulin secretory capacity of HC/PF islets did not differ from that observed for HC islets.…”

“…The stimulatory effect of the PNS is exerted via acetylcholine (ACh), whereas the inhibitory effect of the SNS is exerted via norepinephrine (2,32). In vivo and in vitro studies on the insulin secretory capacity of islets from HC rats indicated an augmented response to cholinergic stimulation and a reduced sensitivity to adrenergic inhibition, suggesting that an altered ANS regulation contributes to the hypersecretory capacity of the HC islet ␤-cells (19).…”

Metabolic programming: Role of nutrition in the immediate postnatal life

“…In addition to an altered sensitivity to glucose, the immediate onset of hyperinsulinaemia and its persistence throughout the period of the HC dietary modification was supported by an increase in the parasympathetic input and decrease in the sympathetic input (Mitrani et al 2007a). In normal rats, islet b-cell glucose-induced insulin secretion is stimulated by acetylcholine binding to muscarinic type 3 receptors, and inhibited by a 2 -adrenergic receptor catecholamine binding.…”

Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

“…Previous in vitro studies of insulin secretion have found that islets isolated from 12-day-old HC rats treated with ACh and GLP-1 resulted in greater increases in GSIS compared with MF islets, suggesting increased ␤-cell responsiveness to cholinergic and incretin stimulation during the neonatal period in HC rats (46,47). Furthermore, evidence in 12-day-old HC rats showed that altered autonomic activity is involved in the immediate onset of hyperinsulinemia in response to the HC dietary intervention (31).…”