Activation of the Parasympathetic Nervous System Is Necessary for Normal Meal-Induced Insulin Secretion in Rhesus Macaques1

Abstract

Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.

Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome

“…7i–n), replicating prior studies demonstrating atropine’s ability to suppress basal and glucose-stimulated insulin secretion indirectly in vitro and in vivo . 19,21–23 In order to further evaluate whether the effect of parasympathetic stimulation of GSIS is centrally mediated, we administered acetate intracerebroventricularly (ICV) at a dose chosen to increase cerebrospinal fluid acetate concentrations by 200 μM, mimicking the increases in plasma acetate concentrations measured with a 20 μmol/(kg-min) intra-arterial acetate infusion. ICV acetate tripled GSIS during a hyperglycemic clamp without any difference in systemic acetate concentrations; however, this effect was blocked by treatment with atropine, and was independent of changes in plasma glucagon concentrations (Fig.…”

An alternative pathway for sweet sensation: possible mechanisms and physiological relevance

“…GLP-1 exerts its action through its cognate receptor GLP-1-R. It is debated, whether this occurs in an endocrine [122] or paracrine manner [55,257]. Both, the facts that GLP-1 is rapidly (2 min) degraded by dipeptidyl peptidase-IV [63,116,192], and released also by pancreatic α cells [40], support the existence of a compartmented paracrine signaling in the pancreas.…”

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

“…The activity of SNS or PNS fibres influences secretion of both insulin and glucagon in ways that can potently impact blood glucose levels. Whereas nutrient-mediated secretion of insulin during a meal is augmented by an associated increase of PNS outflow to the pancreas [1], the hypoglycaemiainduced increase in SNS outflow to the islet [30] stimulates glucagon secretion and potently inhibits GSIS [31]. Sympathetic fibres supplying the liver are also activated as part of the CRR and, together with increased plasma adrenaline (arising from activation of the adrenal medulla) and glucagon, these responses drive increased hepatic glucose production in an effort to restore normoglycaemia [32].…”

“…While cephalic insulin release has become the defining feature of neural regulation of insulin secretion, neural factors also contribute to the postprandial insulin response. Meal consumption triggers parasympathetic outflow to the islet, and pharmacological blockade of these signals reduces prandial insulin in humans and animal models [1]. How CNS signals interact with endocrine control of the pancreas during meal absorption is incompletely understood but a component of brain regulation of prandial islet function seems likely.…”

“…As ingested nutrients are absorbed into the circulation following a meal, increased insulin secretion promotes glucose disposal into muscle and fat and inhibits endogenous glucose production by the liver, thereby minimising changes in blood glucose levels. The brain helps to coordinate not only the magnitude and timing of the insulin response [1] but also insulin-independent mechanisms that reduce glucose production while enhancing disposal [2]. Here, we review interactions between brain and pancreas that establish the defended blood glucose level and present evidence from humans and animals that both organs must sense the circulating glucose level for this process to function normally.…”