Search

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Diabetes mellitus is a common endocrinopathy in cats that is associated with pancreatic islets lesions. Research on isolated islets contributed to the understanding of the pathophysiology of human diabetes. Therefore, by improving the existing methods of isolation in cats, we aimed at increasing islet yield, purity and viability of feline isolated islets. Islet isolation was accomplished by pancreas perfusion with 80ml of Collagenase type IV through the pancreatic duct at the site of the major papilla. The enzymatic digestion was combined with mechanical disruption and controlled by dithizone staining. Purification was performed by filtration and handpicking. Purified islets were plated on extracellular matrix pre-coated plates and cultured for 48h. Feline islets with a high degree of viability and purity were isolated and cultured for the first time. Although the percentage of islet free from the acinar tissue relative to the total number of isolated islets was low compared to other species, the suggested protocol represents a promising progress in the procedure of islet isolation in cats.

Roux-en-Y gastric bypass (RYGB) surgery might modify the gut microbiota composition differently in the three distinct anatomical sections of the small intestine compared to sham surgery. We showed that RYGB induced changes in the microbiota of the alimentary limb and the common channel resembling those seen after prebiotic treatment or weight loss by dieting. These changes may be associated with altered production of intestinal hormones known to control energy balance. Postsurgical modulation of gut microbiota may significantly contribute to the beneficial metabolic effects of RYGB surgery. © 2013 Elsevier Inc.

Diabetes mellitus is a common endocrinopathy in humans and in cats. The general prevalence of diabetes mellitus, and in particular of type 2 diabetes, has risen dramatically in recent years. This increase has often been linked to the rise in the obesity pandemic because obesity and the ensuing metabolic consequences constitute major risk factors for human type 2 and for feline diabetes. Feline diabetes shares many features of human type 2 diabetes in respect to its pathophysiology, underlying risk factors and treatment strategies. This review will briefly summarize major characteristics in the human and the feline disease and where available, point out the current knowledge on similarities and differences.

Roux-en-Y gastric bypass (RYGB) surgery might modify the gut microbiota composition differently in the three distinct anatomical sections of the small intestine compared to sham surgery. We showed that RYGB induced changes in the microbiota of the alimentary limb and the common channel resembling those seen after prebiotic treatment or weight loss by dieting. These changes may be associated with altered production of intestinal hormones known to control energy balance. Postsurgical modulation of gut microbiota may significantly contribute to the beneficial metabolic effects of RYGB surgery.

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 apoptosis in vivo. Hyperglycaemic clamps in cats may provide a good model to study the pathogenesis of glucose toxicity in beta cells.

Isolation of pancreatic islets is necessary to study the molecular mechanisms underlying beta-cell demise in diabetic cats. Six collagenase-based methods of isolation were compared in 10 cat pancreata, including single and double course of collagenase, followed or not by Ficoll centrifugation or accutase, and collagenase plus accutase. Morphometric analysis was performed to measure the relative area of islet and exocrine tissue. Islet specific mRNA transcripts were quantified in isolates by real-time PCR. The single and double course of collagenase digestion was successful in each cat and provided similar islet-to-exocrine tissue ratio. Quantities of insulin mRNA did not differ between the two methods. However, on histological examination either method yielded only approximately 2% of pure islets. The other methods provided disrupted islets or insufficient samples in 1-7 cats. Although pancreas digestion with single and double course of collagenase was superior, further studies are needed to improve islet isolation in cats.

BACKGROUND: According 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 FINDINGS: In 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/SIGNIFICANCE: This 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.