Taurine Alters Respiratory Gas Exchange and Nutrient Metabolism in Type 2 Diabetic Rats

Objective: To assess the effect of taurine supplementation on respiratory gas exchange, which might reflect the improved metabolism of glucose and/or lipid in the type 2 diabetic Otsuka Long‐Evans Tokushima Fatty (OLETF) rats. Research Methods and Procedures: Male OLETF rats (16 weeks of age) were randomly divided into two groups: unsupplemented group and taurine‐supplemented (3% in drinking water) group. After 9 weeks of treatment, indirect calorimetry and insulin tolerance tests were conducted. The amounts of visceral fat pads, tissue glycogen, the blood concentrations of glucose, triacylglycerol, taurine, and electrolytes, and the level of hematocrit were compared between groups. A nondiabetic rat strain (Long‐Evans Tokushima Otsuka) was used as the age‐matched normal control. Results: The indirect calorimetry showed that the treatment of OLETF rats with taurine could reduce a part of postprandial glucose oxidation possibly responsible for the increase of triacylglycerol synthesis in the body. Taurine supplementation also improved hyperglycemia and insulin resistance and increased muscle glycogen content in the OLETF rats. Supplementation with taurine increased the blood concentration of taurine and electrolyte and fluid volume, all of which were considered to be related to the improvement of metabolic disturbance in OLETF rats. Discussion: Taurine supplementation may be an effective treatment for glucose intolerance and fat/lipid accumulation observed in type 2 diabetes associated with obesity. These metabolic changes might be ascribed, in part, to the alteration of circulating blood profiles, where the improved hyperglycemia and/or the blood accumulation of taurine itself would play roles.     

Rare sugar d-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats

A rare sugar, d-psicose has progressively been evaluated as a unique metabolic regulator of glucose and lipid metabolism, and thus represents a promising compound for the treatment of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine the underlying effector organs of d-psicose in lowering blood glucose and abdominal fat by exploiting a T2DM rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Rats were fed 5% d-psicose or 5% d-glucose supplemented in drinking water, and only water in the control for 13 weeks and the protective effects were compared. A non-diabetic Long-Evans Tokushima Otsuka (LETO), fed with water served as a counter control of OLETF. After 13 weeks feeding, d-psicose treatment significantly reduced the increase in body weight and abdominal fat mass. Oral glucose tolerance test (OGTT) showed the reduced blood glucose and insulin levels suggesting the improvement of insulin resistance in OLETF rats. Oil-red-O staining elucidated that d-psicose significantly reduced lipid accumulation in the liver. Immunohistochemical analysis showed d-psicose induced glucokinase translocation from nucleus to cytoplasm of the liver which enhances glucokinase activity and subsequent synthesis of glycogen in the liver. d-psicose also protected the pathological change of the β-cells of pancreatic islets. These data demonstrate that d-psicose controls blood glucose levels by reducing lipotoxicity in liver and by preserving pancreatic β-cell function.     

Combined effect of ACE inhibitor and exercise training on insulin resistance in type 2 diabetic rats

The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions.     

Effect of AOB, a fermented-grain food supplement, on oxidative stress in type 2 diabetic rats

Reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic complications. Antioxidant Biofactor (AOB) is a mixture of commercially available fermented grain foods and has strong antioxidant activity. This study investigated the effect of AOB supplementation of standard rat food on markers of oxidative stress and inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes. Blood glucose, hemoglobin A1c, plasma free fatty acid, triacylglycerol and plasminogen activator inhibitor-1 (PAI-1) were significantly higher in OLETF rats than in non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats at 29 weeks. AOB (6.5% of diet) was given to rats during 29-33 weeks of diabetic phase in OLETF rats. OLETF rats with AOB supplementation showed decreased blood glucose, hemoglobin A1c, triacyglycerol, low density lipoprotein, cholesterol and PAI-1. Mitochondrial ROS production was significantly increased in heart, aorta, liver and renal artery of OLETF rats. Uncoupling protein 2 (UCP2) is known to regulate ROS production. We found aortic UCP2 protein expression increased in OLETF rats, and AOB returned UCP2 expression to normal. Aortic endothelial NO synthase (eNOS) was also increased in OLETF rats more than in LETO rats at 33 weeks. In contrast, phosphorylated vasodilator-stimulated phosphoprotein, an index of the NO-cGMP pathway, was significantly diminished. AOB increased eNOS proteins in LETO and OLETF rats. In conclusion, AOB significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. The data suggest that dietary supplementation with AOB contributes to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.     

Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model

The maintenance of normal body weight either through dietary modification or being habitually more physically active is associated with reduced incidence of nonalcoholic fatty liver disease (NAFLD). However, the means by which weight gain is prevented and potential mechanisms activated remain largely unstudied. Here, we sought to determine the effects of obesity prevention by daily exercise vs. caloric restriction on NAFLD in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. At 4 wk of age, male OLETF rats (n = 7-8/group) were randomized to groups of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETF-EX), or caloric restriction (OLETF-CR; 70% of SED) until 40 wk of age. Nonhyperphagic, control strain Long-Evans Tokushima Otsuka (LETO) rats were kept in sedentary cage conditions for the duration of the study (LETO-SED). Both daily exercise and caloric restriction prevented obesity and the development of type 2 diabetes observed in the OLETF-SED rats, with glucose tolerance during a glucose tolerance test improved to a greater extent in the OLETF-EX animals (30-50% lower glucose and insulin areas under the curve, P < 0.05). Both daily exercise and caloric restriction also prevented excess hepatic triglyceride and diacylglycerol accumulation (P < 0.001), hepatocyte ballooning and nuclear displacement, and the increased perivenular fibrosis and collagen deposition that occurred in the obese OLETF-SED animals. However, despite similar hepatic phenotypes, OLETF-EX rats also exhibited increased hepatic mitochondrial fatty acid oxidation, enhanced oxidative enzyme function and protein content, and further suppression of hepatic de novo lipogenesis proteins compared with OLETF-CR. Prevention of obesity by either daily exercise or caloric restriction attenuates NAFLD development in OLETF rats. However, daily exercise may offer additional health benefits on glucose homeostasis and hepatic mitochondrial function compared with restricted diet alone.     

Effect of obesity and troglitazone on expression of two glutathione peroxidases: Cellular and extracellular types in serum,kidney and adipose tissue

To determine the effect of obesity on expression of cellular- (C-) and extracellular (EC-) glutathione peroxidase (GPX) in serum, kidney and adipose tissue, we measured GPX in serum, kidneys and adipose tissue of the obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat and its lean counterpart (LETO). We also investigated the effect of troglitazone. Five each of OLETF and LETO rats were fed diet with or without 0.2% troglitazone for 10 days. Final body weight, kidney weight, blood glucose and serum tumor necrosis factor-α (TNF-α) level were higher in OLETF rats than in LETO rats. Serum and kidney GPX activities were higher, but adipose tissue GPX activity was lower, in OLETF rats than in LETO rats. Troglitazone treatment decreased adipose tissue GPX activity and abolished overproduction of TNF-α in OLETF rats. Immunoblot analysis, for the first time, revealed that both obesity and troglitazone suppressed the protein signals for C-GPX and EC-GPX in adipose tissue. Serum protein carbonyl groups were increased in OLETF rats and troglitazone completely blocked this increase. Increased serum GPX activity in obese rat was due to the increased secretion of EC-GPX from the kidney. Troglitazone protected against the enhanced oxidative stress induced by obesity independently of the serum GPX concentration.     

Effect of obesity and troglitazone on expression of two glutathione peroxidases: cellular and extracellular types in serum, kidney and adipose tissue

To determine the effect of obesity on expression of cellular- (C-) and extracellular (EC-) glutathione peroxidase (GPX) in serum, kidney and adipose tissue, we measured GPX in serum, kidneys and adipose tissue of the obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat and its lean counterpart (LETO). We also investigated the effect of troglitazone. Five each of OLETF and LETO rats were fed diet with or without 0.2% troglitazone for 10 days. Final body weight, kidney weight, blood glucose and serum tumor necrosis factor-alpha (TNF-alpha) level were higher in OLETF rats than in LETO rats. Serum and kidney GPX activities were higher, but adipose tissue GPX activity was lower, in OLETF rats than in LETO rats. Troglitazone treatment decreased adipose tissue GPX activity and abolished overproduction of TNF-alpha in OLETF rats. Immunoblot analysis, for the first time, revealed that both obesity and troglitazone suppressed the protein signals for C-GPX and EC-GPX in adipose tissue. Serum protein carbonyl groups were increased in OLETF rats and troglitazone completely blocked this increase. Increased serum GPX activity in obese rat was due to the increased secretion of EC-GPX from the kidney. Troglitazone protected against the enhanced oxidative stress induced by obesity independently of the serum GPX concentration.     

Differential expression of lipoprotein lipase gene in tissues of the rat model with visceral obesity and postprandial hyperlipidemia

Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity.     

Identification of genes specifically expressed in the accumulated visceral adipose tissue of OLETF rats

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is an animal model of type 2 diabetes, characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. To elucidate the underlying molecular mechanism of obesity and its related complications, we used representational difference analysis and identified the genes more abundantly and specifically expressed in the visceral adipose tissue (VAT) of obese OLETF rats compared with the diabetes-resistant counterpart, that is, Long-Evans Tokushima Otsuka (LETO) rats. By Northern blot analysis, we confirmed the differential expression of 13 genes, including 3 novel genes. The upregulated expression of well-characterized lipid metabolic enzymes, such as lipoprotein lipase, phosphoenolpyruvate carboxykinase, and cholesterol esterase, were observed in VAT of OLETF rats. We demonstrated the differential expression of secreted proteins in VAT of OLETF rats, such as thrombospondin 1 and contrapsin-like protease inhibitor. In contrast to lipid enzymes, the secreted proteins revealed exclusive mRNA expression and they were not detected in VAT of LETO rats. Furthermore, the novel genes OL-16 and OL-64 were also expressed specifically in VAT of OLETF rats and were absent in that of LETO rats and other tissues, including subdermal and brown adipose tissues. The C-terminal partial amino acid sequence of OL-64 revealed that it showed approximately 40% homology with alpha(1)-antitrypsin and it seemed to be a new member of the serine proteinase inhibitor (SERPIN) gene family. VAT of OLEFT rats had a unique gene expression profile, and the accumulated VAT-specific known and novel secreted proteins may play a role(s) in the pathogenesis of obesity and its related complications.     

Reversal of elevated cardiac expression of TGFbeta1 and endothelin-1 in OLETF diabetic rats by long-acting calcium antagonist

The effects of calcium channel blockers (CCBs) on complications associated with diabetes mellitus (DM) have been well studied in clinical and basic science investigations. Cardiovascular complications are a common feature of type 2 DM, and insulin resistance is an early clinical manifestation of type 2 DM. CCBs are widely used to treat cardiovascular diseases in patients with DM. In this study, we used a spontaneous type 2 diabetic rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, at a highly insulin-resistant stage with modest hyperglycemia. We examined cardiac expression of transforming growth factor-beta(1) (TGFbeta(1)) and endothelin-1 (ET-1) in male OLETF rats. At 8 weeks of age, OLETF rats were treated for 12 weeks with the long-acting CCB benidipine (1 mg/kg/day or 3 mg/kg/day, po, n = 12), with hydralazine hydrochloride (3 mg/kg/day, po, n = 12), or with vehicle (OLETF, n = 12), and male age-matched genetic control Long-Evans Tokushima Otsuka (LETO, n = 12) rats were used. Blood pressure was significantly higher in OLETF rats than in LETO rats, and benidipine treatment at both dosages in OLETF rats for 12 weeks did not significantly reduce blood pressure, whereas hydralazine treatment significantly lowered blood pressure in OLETF rats. Hydralazine and both dosages of benidipine significantly reduced upregulated cardiac ET-1 levels in OLETF rats. Plasma and cardiac TGFbeta1 levels were remarkably higher in OLETF rats compared with LETO rats and were normalized by treatment with benidipine (3 mg/kg/day). Our results suggest that CCBs are effective in normalizing upregulated cardiac TGFbeta1 and ET-1 levels at the insulin-resistant stage in OLETF rats, which may improve cardiac morphology and function in this rat model without altering blood pressure and plasma glucose levels. In contrast, hydralazine treatment also normalizes cardiac ET-1 levels while significantly reducing blood pressure.     

Selenium Significantly Inhibits Adipocyte Hypertrophy and Abdominal Fat Accumulation in OLETF Rats via Induction of Fatty Acid β-Oxidation

A combination of selenium (Se) with other trace element is associated with partially modulate fatty acid distribution as well as reduction of the body weight and feed efficiency. To investigate whether or not Se treatment has an impact on lipid metabolism, we examined the levels of lipid metabolism-related factors, including abdominal fat, adiponectin, cholesterol, very long chain dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) in 20-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats following sodium selenite treatment for 2?weeks. Herein, we observed that (a) Se treatment induced insulin-like effects by lowering the serum glucose level in rats; (b) Se-treated rats showed significance values decreases in abdominal fat mass, adipocyte size, and adiponectin, which are associated with lipid metabolism; (c) Se treatment led to reduced levels of cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol; (d) fat tissue in Se-treated rats displayed significantly lower expression of adipocyte marker genes along with increased expression of VLCAD and MCAD; and (e) fatty liver formation and ??-oxidation gene expression were both significantly reduced in liver tissue of Se-treated rats. Therefore, our results suggest that Se may induce inhibition of adipocyte hypertrophy and abdominal fat accumulation along with suppression of fatty liver formation by the differential regulation of the gene expression for fatty acid ??-oxidation in the OLETF model.     

Genetic evidence for obesity loci involved in the regulation of body fat distribution in obese type 2 diabetes rat, OLETF

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese type 2 diabetes in human. Obesity is essential for the onset of type 2 diabetes in this rat. Our present investigation was designed to identify quantitative trait loci (QTLs) contributing to obesity by performing a whole-genome search using 214 F(2) intercross progeny between OLETF and F344 rats. We have identified six QTLs responsible for adiposity indices of fat pads on rat chromosomes 2 (Obs1 for mesenteric fat), 4 (Obs2 for retroperitoneal fat), 8 (Obs3 for mesenteric fat), 9 (Obs4 for retroperitoneal fat), and 14 (Obs5 and Obs6 for retroperitoneal fat), demonstrating that the adiposity indices of individual fat pads were under the control of different genes. As expected, the OLETF allele corresponds to increased adiposity indices for all QTLs, except for Obs3, in which the F344 allele leads to an increase in the index.     

Altered dipeptidyl peptidase-4 activity during the progression of hyperinsulinemic obesity and islet atrophy in spontaneously late-stage type 2 diabetic rats

Altered dipeptidyl peptidase-4 (DPP4) activity during the progression of late-stage type 2 diabetes was measured in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Compared with OLETF rats subjected to 30% food restriction, food-satiated OLETF rats exhibited spontaneous hyperphagic obesity, insulin resistance, hyperglycemia, hyperinsulinemia, and increased plasma DPP4 activity during the early phase of the experiment (up to ～30 wk). Subsequently, their plasma DPP4 activity as well as their body weight, body fat, and plasma insulin concentration declined to control levels during the late phase, resulting in excessive polyuria, proteinuria, dyslipidemia, pancreatic islet atrophy, hypoinsulinemia, and diabetes, which changed from insulin-resistant diabetes to hypoinsulinemic diabetes secondary to progressive islet insufficiency, and their fasting blood glucose level remained high. Since plasma DPP4 activity demonstrated significant positive correlations with body weight and the fasting plasma insulin level but not with the fasting blood glucose level during the late stage of diabetes, body fat and fasting plasma insulin levels may be useful factors for predicting the control of plasma DPP4 activity. In contrast, pancreatic DPP4 activity was significantly increased, and the expression of pancreatic insulin was significantly reduced in late-stage diabetic OLETF rats, suggesting that a relationship exists between the activation of pancreatic DPP4 and insulin depletion in pancreatic islet atrophy. In conclusion, it is suggested that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy. DPP4 activity may play an important role in insulin homeostasis.     

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.     

Calorie restriction improves whole-body glucose disposal and insulin resistance in association with the increased adipocyte-specific GLUT4 expression in Otsuka Long-Evans Tokushima fatty rats

Calorie restriction (CR) has been shown to improve peripheral insulin resistance and type 2 diabetes in animal models. However, the exact mechanism of CR on GLUT4 expression and translocation in insulin-sensitive tissues has not been well elucidated. In the present study, we examine the effect of CR on the expression of glucose transporter 4 (GLUT4), GLUT4 translocation, and glucose transport activity in adipose tissue from Otsuka Long-Evans Tokushima Fatty (OLETF) rat and control (LETO) rats. CR (70% of satiated group) ameliorated hyperglycemia and improved impaired glucose tolerance (IGT) in OLETF rats. In skeletal muscle, the expression levels of GLUT4 and GLUT1 were not significantly different between LETO and OLETF rats, and were not affected by CR. By contrast, the expression level of GLUT4 was markedly decreased in the adipose tissue of OLETF rats, but was dramatically increased by CR. The GLUT4 recruitment stimulated by insulin was also improved in OLETF rat adipocytes by CR. The insulin-stimulated 2-deoxyglucose (2DG) uptake was significantly increased in adipocytes from the CR OLETF rats, as compared with the satiated OLETF rats. Taken together, these results suggest that CR improves whole body glucose disposal and insulin resistance in OLETF rats, and that these effects may associate with the increased adipocyte-specific GLUT4 expression.     

Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors

Prior data demonstrated differential roles for cholecystokinin (CCK)1 receptors in maintaining energy balance in rats and mice. CCK1 receptor deficiency results in hyperphagia and obesity of Otsuka Long-Evans Tokushima Fatty (OLETF) rats but not in mice. To ascertain the role of CCK1 receptors in high-fat-diet (HFD)-induced obesity, we compared alterations in food intake, body weight, fat mass, plasma glucose, and leptin levels, and patterns of hypothalamic gene expression in OLETF rats and mice lacking CCK1 receptors in response to a 10-wk exposure to HFD. Compared with Long-Evans Tokushima Otsuka (LETO) control rats, OLETF rats on HFD had sustained overconsumption over the 10-wk period. High fat feeding resulted in greater increases in body weight and plasma leptin levels in OLETF than in LETO rats. In situ hybridization determinations revealed that, while HFD reduced neuropeptide Y (NPY) mRNA expression in both the arcuate nucleus (Arc) and the dorsomedial hypothalamus (DMH) of LETO rats, HFD resulted in decreased NPY expression in the Arc but not in the DMH of OLETF rats. In contrast to these results in OLETF rats, HFD increased food intake and induced obesity to an equal degree in both wild-type and CCK1 receptor(-/-) mice. NPY gene expression was decreased in the Arc in response to HFD, but was not detectable in the DMH in both wild-type and CCK1 receptor(-/-) mice. Together, these data provide further evidence for differential roles of CCK1 receptors in the controls of food intake and body weight in rats and mice.     

Chronic administration of ezetimibe increases active glucagon-like peptide-1 and improves glycemic control and pancreatic beta cell mass in a rat model of type 2 diabetes

Ezetimibe is a cholesterol-lowering agent targeting Niemann-Pick C1-like 1, an intestinal cholesterol transporter. Inhibition of intestinal cholesterol absorption with ezetimibe may ameliorate several metabolic disorders including hepatic steatosis and insulin resistance. In this study, we investigated whether chronic ezetimibe treatment improves glycemic control and pancreatic beta cell mass, and alters levels of glucagon-like peptide-1 (GLP-1), an incretin hormone involved in glucose homeostasis. Male LETO and OLETF rats were treated with vehicle or ezetimibe (10 mg kg⁻¹ day⁻¹) for 20 weeks via stomach gavage. OLETF rats were diabetic with hyperglycemia and significant decreases in pancreatic size and beta cell mass compared with LETO lean controls. Chronic treatment of OLETF rats with ezetimibe improved glycemic control during oral glucose tolerance test compared with OLETF controls. Moreover, ezetimibe treatment rescued the reduced pancreatic size and beta cell mass in OLETF rats. Interestingly, ezetimibe significantly decreased serum dipeptidyl peptidase-4 activity and increased serum active GLP-1 in OLETF rats without altering serum total GLP-1. These findings demonstrated that chronic administration of ezetimibe improves glycemic control and pancreatic beta cell mass, and increases serum active GLP-1 levels, suggesting possible involvement of GLP-1 in the ezetimibe-mediated beneficial effects on glycemic control.     

Genetic determinants of plasma triglyceride levels in (OLETF x BN) x OLETF backcross rats

Altered lipid metabolism is closely associated with diabetes in humans, although predisposing genetic factors that affect hyperlipidemia have not yet been clarified. Our previously established OLETF strain is an obese rat model of type II diabetes, exhibiting hypertriglycemia as well as hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. To identify genetic factors responsible for dyslipidemic phenotypes in OLETF rats, we performed a whole-genome scan using 293 male (OLETF x BN) x OLETF backcross rats. Our analysis identified two significant quantitative trait loci (QTLs), on rat chromosomes 1 and 8, that are related to fasting triglyceride levels. The chromosome 1 QTL colocalized with Dmo1 (diabetes mellitus, OLETF type 1), a locus previously shown to associate strongly with both fat levels and body weight. The other significant QTL localizes to the chromosome 8 marker D8Mit2, in a region where several apo-lipoprotein genes are clustered.