Alteration of the lipid composition of rat testicular plasma membranes by dietary (n-3) fatty acids changes the responsiveness of Leydig cells and testosterone synthesis

Experiments were conducted to assess whether changing dietary fat composition altered phospholipid composition of rat testicular plasma membranes in a manner that altered receptor-mediated action of luteinizing hormone (LH)/human chorionic gonadotropin (hCG). Weanling rats were fed diets that provided high or low cholesterol intakes and that were enriched with linseed oil, fish oil or beef tallow for 4 wk. Feeding diets high in (n-3) fatty acids decreased plasma and testicular plasma membrane 20:4(n-6) content. A marked reduction of the 22:5(n-6) content and an increase in the 22:6(n-3) content of testicular plasma membrane was found only in animals fed fish oil. A decrease in binding capacity of the gonadotropin (LH/hCG) receptor in the plasma membrane, with no change in receptor affinity, was observed for animals fed either linseed oil or fish oil diets. Dietary treatments that raised plasma membrane cholesterol content and the cholesterol to phospholipid ratio in the membrane were associated with increased binding capacity of the gonadotropin receptor. Feeding diets high in 18:3(n-3) vs. those high in fish oil altered receptor-mediated adenylate cyclase activity in a manner that depended on the level of dietary cholesterol. Feeding diets high in cholesterol or fish oil increased basal and LH-stimulated testosterone synthesis relative to that in animals fed the low cholesterol diet containing linseed oil. It is concluded that changing the fat composition of the diet alters the phospholipid composition of rat testicular plasma membranes and that this change in composition influences membrane-mediated unmasking of gonadotropin receptor-mediated action in testicular tissue.     

Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes

Type 2 diabetes is a chronic metabolic disease characterized by the presence of both fasting and postprandial hyperglycemia which is a result of pancreas beta-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. More recently, the role of other glucoregulatory hormones, including glucagon, amylin, and the gut peptide glucagon-like peptide (GLP)-1, and an increase in the rate of postmeal carbohydrate absorption have also been included as important pathophysiologic defects. Existing anti-diabetes medications are often unefficient at achieving sustained glycemic control because they predominantly address only a single underlying defect. A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DPP-IV), the major enzyme responsible for degrading the incretins in vivo. DPP-IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 diabetic patients. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion, peripheral insulin sensitization and important effects on beta-cell differentiation and survival can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetic patients. The present article focuses on the preclinical and clinical data of DPP-IV inhibitors that make it unique therapeutic agents representing the next generation of antidiabetes drugs.     

Taspoglutide, a novel human once-weekly GLP-1 analogue, protects pancreatic β-cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo

Aim: Glucagon‐like peptide‐1 (GLP‐1) has protective effects on pancreatic β‐cells. We evaluated the effects of a novel, long‐acting human GLP‐1 analogue, taspoglutide, on β‐cells in vitro and in vivo. Methods: Proliferation of murine pancreatic β (MIN6B1) cells and rat islets in culture was assessed by imaging of 5‐ethynyl‐2′‐deoxyuridine‐positive cells after culture with taspoglutide. Apoptosis was evaluated with the transferase‐mediated 2′‐deoxyuridine 5′‐triphosphate nick‐end labelling assay in rat insulinoma (INS‐1E) cells and isolated human islets exposed to cytokines (recombinant interleukin‐1β, interferon‐γ, tumour necrosis factor‐α) or lipotoxicity (palmitate) in the presence or absence of taspoglutide. Islet morphology and survival and glucose‐stimulated insulin secretion in perfused pancreata were assessed 3–4 weeks after a single application of taspoglutide to prediabetic 6‐week‐old male Zucker diabetic fatty (ZDF) rats. Results: Proliferation was increased in a concentration‐dependent manner up to fourfold by taspoglutide in MIN6B1 cells and was significantly stimulated in isolated rat islets. Taspoglutide almost completely prevented cytokine‐ or lipotoxicity‐induced apoptosis in INS‐1E cells (control 0.5%, cytokines alone 2.2%, taspoglutide + cytokines 0.6%, p < 0.001; palmitate alone 8.1%, taspoglutide + palmitate 0.5%, p < 0.001) and reduced apoptosis in isolated human islets. Treatment of ZDF rats with taspoglutide significantly prevented β‐cell apoptosis and preserved healthy islet architecture and insulin staining intensity as shown in pancreatic islet cross sections. Basal and glucose‐stimulated insulin secretion of in situ perfused ZDF rat pancreata was normalized after taspoglutide treatment. Conclusions: Taspoglutide promoted β‐cell proliferation, prevented apoptosis in vitro and exerted multiple β‐cell protective effects on islet architecture and function in vivo in ZDF rats.     

Taspoglutide,a novel human once‐weekly analogue of glucagon‐like peptide‐1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat

Aim: Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are a novel class of pharmacotherapy for type 2 diabetes. We investigated the effects of a novel, long‐acting human GLP‐1 analogue, taspoglutide, in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. Methods: Blood glucose and plasma levels of insulin, peptide YY (PYY), glucose‐dependent insulinotropic polypeptide (GIP) and triglycerides were measured during oral glucose tolerance tests (oGTT) conducted in ZDF rats treated acutely or chronically with a single long‐acting dose of taspoglutide. Pioglitazone was used as a positive control in the chronic study. Postprandial glucose, body weight, glycaemic control and insulin sensitivity were assessed over 21 days in chronically treated animals. Results: Acute treatment with taspoglutide reduced glucose excursion and increased insulin response during oGTT. In chronically treated rats, glucose excursion and levels of GIP, PYY and triglycerides during oGTT on day 21 were significantly reduced. Postprandial glucose levels were significantly lower than vehicle controls by day 15. A significant reduction in body weight gain was noticed by day 8, and continued until the end of the study when body weight was approximately 7% lower in rats treated with taspoglutide compared to vehicle. Glycaemic control (increased levels of 1,5‐anhydroglucitol) and insulin sensitivity (Matsuda index) were improved by taspoglutide treatment. Conclusions: Taspoglutide showed typical effects of native GLP‐1, with improvement in glucose tolerance, postprandial glucose, body weight, glycaemic control and insulin sensitivity.     

Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome

AIMS/HYPOTHESIS: Hypertriglyceridaemia is an important risk factor for coronary heart disease, especially in the context of the insulin resistance syndrome where it often occurs with hypertension. The two phenotypes are also associated in the hereditary hypertriglyceridaemic (hHTg) rat. The aim of this study was to map quantitative trait loci that affect plasma triglyceride concentration in the hHTg rat and determine whether they co-localize with loci for blood pressure. METHODS: Second filial generation progeny (n=189) from a cross of the hHTg rat with the Brown Norway rat were phenotyped for fasting plasma triglyceride, glucose and insulin concentrations, and direct unrestrained resting blood pressure. A partial genome-scan was conducted using 153 microsatellite markers that were polymorphic between the two strains. RESULTS: A major locus (lod score 6.5) influencing plasma triglyceride concentration in a co-dominant fashion was mapped to chromosome 4 between D1Mit 5 and D1Mit17. Chromosome 8 contained multiple peaks with a lod score greater than 4.0 influencing triglyceride concentration. Importantly, none of the triglyceride loci had an effect on blood pressure. The triglyceride locus on chromosome 4 co-localized with a locus for fasting plasma insulin (lod score 4.1), although the effect on insulin concentration was in the opposite direction to that on triglyceride. CONCLUSION/INTERPRETATION: We have mapped the major loci that affect plasma triglyceride concentration in the hHTg rat. These loci do not influence blood pressure suggesting that these commonly associated phenotypes of the insulin resistance syndrome are not be due to pleiotropic effects of the same gene(s).     

Search for Extrapancreatic Effects of New Oral Hypoglycemic Agent A-4166: 1. Oral Glucose Tolerance Tests in Normal and Hereditary Insulin Resistant Rats

OBJECTIVE: To test the effect of new oral hypoglycemic compound A-4166 on insulin secretion during oral glucose challenge in normal and hereditary non-obese, hypertriglyceridemic, insulin resistant and hypertensive rats fed either a normal or high fat diet. METHODS: The rats used were 15 weeks old males of Wistar Charles River strain (controls) and Wistar-derived hereditary hypertriglyceridemic (hHTg) rats of our own colony. They were fed either basal (12 cal% of fat) or high fat diet (70 cal% fat). After 3 weeks of feeding the above diets, the oral glucose tolerance tests (2 g/kg) were carried out in unrestrained conscious rats kept in special metabolic cages after overnight fasting and ten minutes after the administration of A-4166 (100 mg/kg) or placebo by the stomach tube. Plasma glucose, triglycerides, free fatty acids and insulin levels were measured by routine analytical methods. RESULTS: High fat diet feeding resulted in an increase in fasting plasma insulin in both rat strains, while fasting plasma glucose in high fat diet fed animals remained unchanged as compared to those fed basal diet. No differences in the fasting FFA levels were found. The glucose area under curve (AUC) did not differ between the two strains used and high fat diet resulted in a higher glucose AUC in both strains. The administration of A-4166 improved the glucose tolerance in all animals, namely in those fed the basal diet. Insulin AUC showed very similar pattern in both rat strains proving the stimulatory effect of A-4166 on insulin secretion during an oral glucose challenge. High fat feeding resulted in an impairment of insulin action, but the administration of A-4166 restored the antilipolysis in both strains to the normal range. CONCLUSIONS: The previously reported hypoglycemic action of A-4166 resulting from the increased insulin secretion was confirmed. Moreover, some beneficial action of A-4166 on antilipolysis in vivo was demonstrated.