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.

Dexamethasone has well-described effects to induce insulin resistance and increase insulin secretion. Herein, we examined potential contributors to the effect of dexamethasone to increase insulin secretion in rhesus macaques. Six male rhesus macaques received daily injections of either saline or dexamethasone (0.25 mg/kg i.m. for 7 days) in random order with 3 weeks between treatments. At the end of the treatment period, animals were fasted overnight and underwent a feeding study the next day, during which blood samples were taken before and for 60 min after a meal in order to assess islet hormone and incretin secretion. Dexamethasone induced marked increases in fasting plasma insulin, glucagon, leptin, and adiponectin concentrations (P<0.05). Surprisingly, the glycemic response after meal ingestion was decreased twofold during dexamethasone treatment (P<0.05). Dexamethasone-treated animals exhibited a significant increase in both insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion during the feeding study (P<0.05). However, glucagon-like peptide-1 secretion was significantly lower in dexamethasone-treated animals compared with controls (P<0.01). Fasting and meal-stimulated pancreatic polypeptide concentrations (an index of the parasympathetic input to the islet) did not differ between saline and dexamethasone treatments. However, the proinsulin:insulin ratio was decreased throughout the feeding study with dexamethasone treatment suggesting an improvement of β-cell function (P<0.05). In conclusion, the maintenance of euglycemia and reduction of postprandial glycemia with short-term dexamethasone treatment appears to be due to the marked elevations of fasting and meal-stimulated insulin secretion. Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion.

Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.

Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery; however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG-operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar postoperative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals. However, VSG improved glucose tolerance and markedly enhanced insulin secretion during oral nutrient and i.p. glucose challenges compared with controls. Islets from VSG mice displayed a unique transcriptional signature enriched for genes involved in Ca2+ signaling and insulin secretion pathways. This finding suggests that bariatric surgery leads to intrinsic changes within the islet that alter function. Indeed, islets isolated from VSG mice had increased glucose-stimulated insulin secretion and a left-shifted glucose sensitivity curve compared with islets from PF-Sham mice. Isolated islets from VSG animals showed corresponding increases in the pulse duration of glucose-stimulated Ca2+ oscillations. Together, these findings demonstrate a weight-independent improvement in glycemic control following VSG, which is, in part, driven by improved insulin secretion and associated with substantial changes in islet gene expression. These results support a model in which β cells play a key role in the adaptation to bariatric surgery and the improved glucose tolerance that is typical of these procedures.