Insulin resistance and hyperinsulinemia are considered as risk factors for coronary heart disease (reviewed in ref. 1). Growing evidence suggests that free fatty acids (FFA) play a key role in insulin action and insulin secretion and that they may be the common factor producing the alterations leading to peripheral insulin resistance and to β-cell dysfunction (reviewed in ref.2). However, the precise role of high lipid levels on insulin secretion is far from being elucidated and remains largely controversial.Based on in vitro studies, a long-term exposure (48 hours) to FFA results in a decreased insulin response to glucose in pancreatic β cells (3-5). In contrast, a chronic increase in FFA levels exerts insulinotropic effects when insulin secretion is studied in vivo (2, 6, 7).The discrepancy between in vivo and in vitro studies concerning the effect of a long-term increase in FFA concentrations on β-cell function suggests the involvement of extrapancreatic factors. Among these factors, those of neural origin may be crucial. On one hand, the neuronal inputs of the pancreas include the parasympathetic and sympathetic system, whose activation results in the stimulation or the inhibition of insulin secretion, respectively (8). On the other hand, several experiments clearly showed that lipids may alter autonomic nervous system (ANS) activity both in humans (9-11) and in rats (12, 13).To study the possible interplay between a chronic elevation of FFA levels, insulin secretion, and ANS activity, normal rats were infused with a triglyceride emulsion over 48 hours, with subsequent measurements of (a) the overall parasympathetic and sympathetic activities and (b) insulin secretion in response to glucose either in vitro (batch incubation islets) or in vivo after acute glucose loading. In addition, given that FFA increase the β-cell mass in vitro (14), the possible in vivo trophic effect of lipids on pancreatic islets was also investigated. MethodsAnimals. All rats were treated in accordance with the European Community guidelines, and the experimentation was approved by our local institution. Three-month-old female Wistar rats weighing 220-240 g were used. They were allowed free access to water and standard laboratory chow pellets (UAR 113; Usine d'Alimentation Rationnelle, Villemoisson sur Orge, France). A catheter was implanted under ketamine anesthesia (125 mg/kg, intraperitoneally; Imalgène, Mérieux, Lyon, France) in the right atrium via the jugular vein. A technique described previously (15, 16) for a 48-h infusion in unrestrained rats was used for triglyceride or saline infusion. The infusion period started on day 2 after surgery. Rats were randomly divided into two groups. In the first group, rats were infused with a mixture of a We investigated the possible involvement of the autonomic nervous system in the effect of a long-term elevation of plasma free fatty acid (FFA) concentration on glucose-induced insulin secretion (GIIS) in rats. Rats were infused with an emulsion of triglycerides (Intralipid) for 48 hours (I...
Aims/hypothesis Drug and surgical-based therapies in type 2 diabetes are associated with altered gut microbiota architecture. Here we investigated the role of the gut microbiome in improved glucose homeostasis following bariatric surgery. Methods We carried out gut microbiome analyses in gastrectomised (by vertical sleeve gastrectomy [VSG]) rats of the Goto-Kakizaki (GK) non-obese model of spontaneously occurring type 2 diabetes, followed by physiological studies in the GK rat. Results VSG in the GK rat led to permanent improvement of glucose tolerance associated with minor changes in the gut microbiome, mostly characterised by significant enrichment of caecal Prevotella copri. Gut microbiota enrichment with P. copri in GK rats through permissive antibiotic treatment, inoculation of gut microbiota isolated from gastrectomised GK rats, and direct inoculation of P. copri, resulted in significant improvement of glucose tolerance, independent of changes in body weight. Plasma bile acids were increased in GK rats following inoculation with P. copri and P. copri-enriched microbiota from VSG-treated rats; the inoculated GK rats then showed increased liver glycogen and upregulated expression of Fxr (also known as Nr1h4), Srebf1c, Chrebp (also known as Mlxipl) and Il10 and downregulated expression of Cyp7a1. Conclusions Our data underline the impact of intestinal P. copri on improved glucose homeostasis through enhanced bile acid metabolism and farnesoid X receptor (FXR) signalling, which may represent a promising opportunity for novel type 2 diabetes therapeutics.
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