Obesity is associated with metabolic alterations related to glucose homeostasis and cardiovascular risk factors. These metabolic alterations are associated with low-grade inflammation that contributes to the onset of these diseases. We and others have provided evidence that gut microbiota participates in whole-body metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders. Recently, we defined gut microbiota-derived lipopolysaccharide (LPS) (and metabolic endotoxemia) as a factor involved in the onset and progression of inflammation and metabolic diseases. In this review, we discuss mechanisms involved in the development of metabolic endotoxemia such as the gut permeability. We also discuss our latest discoveries demonstrating a link between the gut microbiota, endocannabinoid system tone, leptin resistance, gut peptides (glucagon-like peptide-1 and -2), and metabolic features. Finally, we will introduce the role of the gut microbiota in specific dietary treatments (prebiotics and probiotics) and surgical interventions (gastric bypass).

Aims/hypothesis In vitro studies point to a toxic effect of high glucose and non-esterified fatty acids on beta cells. Whether elevated levels of glucose and lipids induce beta cell loss in vivo is less clear. The domestic cat has recently been proposed as a valuable animal model for human type 2 diabetes because feline diabetes shows several similarities with diabetes in humans, including obesity-induced insulin resistance, impaired beta cell function, decreased number of beta cells and pancreatic amyloid deposition. Methods We infused healthy cats with glucose or lipids for 10 days to clamp their blood concentrations at the approximate level found in untreated feline diabetes (glucose: 25-30 mmol/l; triacylglycerols: 3-7 mmol/l).Results Glucose and lipid levels were adequately targeted. Plasma non-esterified fatty acids were increased by lipid infusion 1.7-fold. A dramatic and progressive decline of plasma insulin levels was observed in glucose-infused cats beginning after 2 days of hyperglycaemic clamp. In contrast, plasma insulin concentration and glucose tolerance test were not affected by hyperlipidaemia. Compared with controls, glucose-infused cats had a 50% decrease in beta cells per pancreatic area. Apoptotic islet cells and cleaved caspase-3-positive beta cells were observed in glucose-infused cats only. Conclusions/interpretation Sustained hyperglycaemia but not hyperlipidaemia induces early and severe beta cell dysfunction in cats, and excess glucose causes beta cell loss via Diabetologia (2009)

Background: The Guardian REAL-Time is a continuous glucose-monitoring system (CGMS) recently developed to provide instantaneous interstitial glucose concentrations; the system does not require a monitor being fixed to the animal.Hypothesis: The CGMS provides accurate and reproducible real-time readings of glucose concentration in cats. Animals: Thirty-two diabetic cats, 2 cats with suspected insulinoma, and 5 healthy cats. Methods: Prospective, observational study. CGMS accuracy was compared with a reference glucose meter at normal, high, and low blood glucose concentrations using error grid analysis. Reading variability of 2 simultaneously used CGMS was determined in diabetic cats by calculating correlation and percentage of concordance of paired data at different glycemic ranges. The time interval between increasing glycemia and a rise in interstitial fluid glucose measured by the CGMS was assessed in healthy cats receiving glucose IV; the time point of maximal increase in interstitial glucose concentrations was calculated.Results: The CGMS was 100, 96.1, and 91.0% accurate at normal, high, and low blood glucose concentrations. Measurements deviated from reference by À12.7 AE 70.5 mg/dL at normal, À12.1 AE 141.5 mg/dL at high, and À1.9 AE 40.9 mg/dL at low glucose concentrations. Overall, paired CGMS readings correlated significantly (r 5 0.95, P o .0001) and concordance was 95.7%. The median delay after IV administration of glucose to an increase in interstitial glucose was 11.4 minutes (range: 8.8-19.7 minutes).Conclusions and Clinical Importance: Although some readings substantially deviated from reference values, the CGMS yields reproducible results, is clinically accurate in cats with hyperglycemia and euglycemia, and is slightly less accurate if blood glucose concentrations are low. Rapidly increasing interstitial glucose after a glycemic rise suggests that the CGMS is suitable for real-time measurement under clinical conditions.

Background: Clinical remission is frequent in cats with well-controlled diabetes mellitus, but few studies explored predictors of this phenomenon.Hypothesis: Data retrieved from medical records at admission might be valuable to identify likelihood of remission and its duration in diabetic cats.Animals: Ninety cats with newly diagnosed diabetes, followed-up until death or remission. Methods: Retrospective cohort study. Data were collected from records at admission, including history, signalment, physical examination, haematology, and biochemical profile, and the occurrence and duration of remission, defined as normoglycemia without insulin for !4 weeks. Predictors of remission were studied with univariate and multivariate logistic regression. Factors associated with remission duration were analyzed with Kaplan-Meier and Cox proportional hazard models.Results: Forty-five (50%) cats achieved remission, after a median time of 48 days (range: 8-216). By study end, median remission duration was 114 days (range: 30-3,370) in cats that died and 151 days (range: 28-1,180) in alive cats. Remission was more likely with higher age (OR: 1.23, 95% CI: 1.04-1.46; P 5 .01) and less likely with increased serum cholesterol (OR: 0.36, 95% CI: 0.11-0.87; P 5 .04). Remission was longer with higher body weight (HR: 0.65, 95% CI: 0.42-0.99; P 5 .04) and shorter with higher blood glucose (HR: 1.01, 95% CI: 1.00-1.02; P 5 .02).Conclusions and Clinical Importance: Age, body weight, cholesterol, and glucose levels are suggested for prediction of remission or its duration in diabetic cats. Older cats developing diabetes may have a better outcome, possibly suggesting a slower disease progression.

BackgroundAccording to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR−/−) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity.Methodology/Principal FindingsIn order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance.Conclusions/SignificanceThis study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans.