Objective Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. Design VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5−/− (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. Results VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic infiammation and islet morphology after VSG were attenuated in Tgr5−/− relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5−/− relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. Conclusions These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.

(T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic ␤-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations Ͼ250 and Ͼ450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of ␤-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for ␤-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM. diabetic rodent model; hyperglycemia; insulin; ␤-cell TYPE 2 DIABETES MELLITUS (T2DM) is a devastating metabolic disease presently affecting at least 16 million people in the United States alone (33, 49). The prevalence of T2DM is also increasing in children and adolescents (42). With the increasing incidence of T2DM, the identification of preventative measures has become crucial, necessitating the development of effective preclinical models for studying approaches for both diabetes prevention and treatment.The most commonly used rodent models of T2DM include the Zucker diabetic fatty (ZDF) rat, the Otsuka Long Evans Tokushima fatty (OLETF) rat, and the db/db mouse, all of which exhibit obesity-associated insulin resistance and impaired ␤-cell function, resulting in diabetes (5, 25, 38). While these animal models have contributed substantially to understanding the pathophysiology and treatment of T2DM and its complications, the basic mechanisms underlying the pathogenesis of diabetes in these models do not correspond with what occurs in most human patients with T2DM. These differences in etiology are likely to hinder effective translational research.Obesity and insulin resistance in most animal models of T2DM result from monogenic mutations that are rare in human and animal populations and present multiple problems in terms of applying these models to clinical T2DM. For example, mutat...

In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

The incidence of insulin resistance has increased dramatically over the past several years, and we and others have proposed that this increase may at least in part be attributable to increased dietary fructose consumption. However, a major limitation to the study of diet-induced insulin resistance is the lack of relevant animal models. Numerous studies, mostly in rodents, have demonstrated that diets high in fructose induce insulin resistance; however, important metabolic differences exist between rodents and primates. Thus, the results of metabolic studies performed in primates are substantively more translatable to human physiology, underscoring the importance of establishing nonhuman primate models of common metabolic conditions. In this report, we demonstrate that a high-fructose diet in rhesus monkeys produces insulin resistance and many features of the metabolic syndrome, including central obesity, dyslipidemia, and inflammation within a short period of time; moreover, a subset of monkeys developed type 2 diabetes. Given the rapidity with which the metabolic changes occur, and the ability to control for many factors that cannot be controlled for in humans, fructose feeding in rhesus monkeys represents a practical and efficient model system in which to investigate the pathogenesis, prevention, and treatment of diet-induced insulin resistance and its related co-morbidities.