Rat Model Of Insulin Resistance Research Articles

Anti‐hyperlipidemic actions of synthetic nordihydroguaiaretic acid analogs (767.1)

Previous studies have shown that creosote bush‐derived NDGA exerts beneficial actions on the key components of the Metabolic Syndrome including dyslipidemia, and insulin resistance (IR) in several relevant rodent models. Here we screened several synthetic analogs of NDGA with selective modification of the aromatic groups of NDGA and tested their efficacy against hepatic lipid metabolism in a high‐fructose fed (HFrD) Sprague‐Dawley (SD) rat model of insulin resistance, dyslipidemia and hypertension. Oral gavaging of HFrD‐fed SD rats for 4 days with NDGA analogs 1 and 2 (100 mg/kg, q.d.) suppressed the hepatic TG content, whereas treatment of rats with NDGA analogs 2, 3 and 4, like NDGA, decreased the plasma TG levels by 70‐75%. QRT‐PCR measurements demonstrated that among the NDGA analogs 1, 2 and 4, analog 4 was most effective in inhibiting the mRNA levels of genes and transcription factors involved in lipogenesis, while all three analogs almost equally inhibited the genes involved in TG synthesis. Unlike NDGA, none of these three NDGA analogs affected the genes of hepatic fatty acid oxidation or transport. Our data suggest that these NDGA analogs possess more potent anti‐hyperlipidemic properties than NDGA and have therapeutic potential to ameliorate dyslipidemia and associated IR.Grant Funding Source: Supported by Office of Research and Development, Medical Service, Dpt. of Veterans Affairs

Nitric oxide synthase inhibition exacerbates liver injury in an obese rat model of NAFLD (1115.3)

We tested the hypothesis that chronic disruption of constitutive nitric oxide (NO) production via the non‐selective NO synthase (NOS) inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). Obese Otsuka Long‐Evans Tokushima Fatty (OLETF) and lean Long‐Evans Tokushima Otsuka (LETO) rats (16‐wks) received either control or L‐NAME (65‐70 mg/kg/d) containing drinking water (n=10/group) for 4‐wks. L‐NAME treated OLETF and LETO rats had significantly (p < 0.05) reduced serum NO metabolites (NOX) and food intake. Despite reducing % body fat (‐2.5%; p < 0.05) in OLETF rats, L‐NAME treatment increased hepatic triacylglycerol (TAG) content (+40%; p < 0.05) compared to control OLETF rats. In addition, L‐NAME treatment caused a shift toward M1 macrophage polarity as indicated by elevated CD11c (p<0.05) and IL‐1β (p=0.07) mRNA in the OLETF rats. Markers of total and resident macrophages (CD68 and CD163 mRNA, respectively), fibrosis (TGFβ mRNA), and cell adhesion (MCP‐1 and ICAM mRNA) were unaffected by L‐NAME treatment in both groups. In conclusion, chronic NOS inhibition appears to aggravate liver injury by increasing expression of macrophage activation‐related genes associated with insulin resistance and by accelerating hepatic TAG accumulation in obese, insulin resistant rats.Grant Funding Source: Supported by a Life Sciences Fellowship (RDS), NIH HL‐36088 (MHL), and VHA‐CDA2 BX001299‐02 (RSR)

Effects of whey protein and leucine supplementation on insulin resistance in non-obese insulin-resistant model rats

ObjectiveWhey protein (WP) has been reported to reduce body weight gain and improve glucose metabolism in obese individuals. This study aims to assess and compare the effects of WP and its hydrolysate-leucine (Leu) supplementation in non-obese, insulin-resistant (IR) rat models, particularly the effects on insulin sensitivity, lipid profile, and antioxidant activity. MethodsWistar rats were fed a diet consisting of 38.5% fat for 12 wk and 51.3% fat for an additional 4 wk to establish non-obese IR rats. The IR rats were then switched to regular AIN-93 diet containing 0% WP, 5% WP, 15% WP or 1.6% Leu for 8 wk. The Leu content was the same in the 15% WP and 1.6% Leu groups based on high-performance liquid chromatography. The IR rats' body weight, fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance were measured before and after supplementation. An oral glucose tolerance test was performed after supplementation. Body composition, plasma concentrations of the lipids profile, and antioxidant index also were analyzed. ResultsNo significant difference was observed in body weight, energy intake, and fasting blood glucose in the non-obese IR rats at the end of the experiment. Compared with the 0% WP group, the fasting insulin and homeostasis model assessment-insulin resistance significantly decreased in the 15% WP and 1.6% Leu groups. Furthermore, the blood glucose area under the curve of the oral glucose tolerance test was significantly less in the 15% WP and 1.6% Leu groups. There were no differences in the lipids profile, except for the increase in the high-density lipoprotein cholesterol in the 15% WP and 1.6% Leu groups. For the antioxidant index, the 15% WP group had significantly increased plasma levels for total antioxidation capacity, superoxide dismutase, and glutathione, and a decreased malondialdehyde concentration. The 1.6% Leu group was shown to have the same effect as the 15% WP group, except for the glutathione. ConclusionOur findings demonstrate that the supplementation of WP and Leu may improve IR and antioxidant stress without resulting in changes in body weight and energy intake in non-obese IR rats.

Protective Effect of L-carnitine on Metabolic Disorders, Oxidative Stress, Antioxidant Status and Inflammation in a Rat Model of Insulin Resistance

The high-fructose diet induces insulin resistance, hyperinsulinaemia, hyperglycemia, alterations in lipid metabolism, and oxidative stress in rat tissues which Oxidative stress plays a vital role in pathology associated with insulin resistance. The present study was aimed to explore the effect of L-carnitine (CAR) on insulin resistance, inflammation, oxidative stress, antioxidant status, and lipid metabolism in male rats fed with high fructose diet. Insulin resistance was induced by feeding high fructose diet (60 g/100 g). sixty male albino rats were divided into four groups containing 15 rats each. Group Ι:( Control group ) rats received the control diets. Group II (fructose-fed group) rats received fructoseenriched diet (60 g /100g). Group III: (fructose + CAR group) animals received high fructose diet and were administered CAR (300 mg/Kg body weight /day,orally). Group IV: (control +CAR group) rats received the control diet and were administered CAR. After 45 and 60 days of treatment blood samples and liver tissue were collected for determination of serum glucose, insulin, insulin resistance, pyruvate, lactate, leptin, total cholesterol, triacylglycerols, phospholipids, free fatty acids, sialic acid, tumor necrosis factorα (TNFα), interleukin-6 (IL-6) and nitric oxide in addition to Lmalondialdehyde (L-MDA). Moreover, antioxidant enzymes (SOD,CAT and GPx) in liver tissues were also determined. The obtained results revealed that, high fructose diet induce a significant increased in serum glucose, insulin, insulin resistance, lipid profiles, pyruvate, lactate, lipten, TNF-α, IL-6, sialic acid, MDA and nitric oxide concentrations and decrease serum phospholipids with marked reduction in CAT, SOD and GpX concentrations in liver tissues compared to rats fed normal diet. L-carnitine treatment to high fructose fed rats reduced the effects of fructose and associated with significant normalization of all serum parameters level and was able to improve dyslipidemia, inflammation and insulin resistance, attenuated the increased MDA and enhanced antioxidant status in liver tissues. These results suggest that, Lcarnitine is effective in improving the high fructose induced oxidative stress, inflammation and insulin resistance in male rats. Also, the administration of of L-carnitine to rats fed a high fructose diet prevents the development of oxidative stress and its associated complications include hyperglycemia , hyperinsulinemia and dyslipidemia.

Assessment of Pharmacokinetic Interaction of Spirulina with Glitazone in a Type 2 Diabetes Rat Model

The objective of the current study was to assess the possible pharmacokinetic interactions of spirulina with glitazones in an insulin resistance rat model. Wistar male albino rats were equally divided into five groups: insulin resistant rats+spirulina (500 mg/kg)+pioglitazone (10 mg/kg), insulin resistant rats+pioglitazone (10 mg/kg), insulin resistant rats+spirulina (500 mg/kg)+rosiglitazone (10 mg/kg), insulin resistant rats+rosiglitazone (10 mg/kg), and insulin resistant rats+spirulina (500 mg/kg). Described doses of pioglitazone, rosiglitazone, or spirulina were per orally administered and the plasma drug concentrations were determined. The pharmacokinetic parameters such as Tmax, Cmax, AUC(0-α), t1/2, and Kel were determined by plotting the drug concentration as a function of time. The data observed in this acute study indicated that there was no statistically significant difference in any of the pharmacokinetic parameters (Tmax, Cmax, AUC(0-α), t1/2, and Kel) of glitazones (pioglitazone, rosiglitazone) or spirulina, when they were coadministered. Given the promising results, this study concludes that the coadministration of spirulina does not influence the pharmacokinetics of glitazones in a type 2 diabetes rat model. Further chronic in vivo studies are recommended to assess the real time effect.

Treating fatty liver and insulin resistance

Treating fatty liver and insulin resistance

Periodontitis as a Novel Contributor of Adipose Tissue Inflammation Promotes Insulin Resistance in a Rat Model

Recent studies have indicated that the chronic low-grade inflammation induced by periodontitis is related to obesity and type 2 diabetes mellitus. The purpose of this study is to investigate the effects of periodontitis on obesity-related adipose tissue inflammation and subsequent systemic insulin resistance in a rat model. Thirty-two rats were divided into four groups of eight: 1) obese rats with periodontitis (combination group); 2) obese rats without periodontitis (obesity group); 3) normal rats with periodontitis (periodontitis group); and 4) normal rats without periodontitis (control group). Monosodium glutamate was used to induce obesity during the early postnatal period. Periodontitis was induced by ligatures for 8 weeks. Morphologic features of white adipose tissue (WAT) and islets were observed, and fasting plasma glucose and insulin concentrations and homeostasis model assessment for insulin (HOMA-IR) were measured at 5 months. Differences among groups were compared with the Fisher post hoc least significant difference test. A slight increase of stromal vascular fractions (SVFs) and macrophage infiltration in the WAT of the periodontitis group was observed. Significant proliferation of SVFs and macrophage infiltration were induced in the combination group. HOMA-IR scores in the combination and periodontitis groups were higher than in the obesity and control groups, respectively. The disturbance of islet architecture was consistent with a high HOMA-IR score in the combination group. Periodontitis induced initial stages of WAT inflammation and acted as a contributing factor to exacerbate proinflammatory phenotype of WAT and promote the development of insulin resistance in the obese rat model.

Oral administration of angiotensin-(1–7) ameliorates type 2 diabetes in rats

Diabetes mellitus type 2 (DM2) is a disease with increasing importance in modern societies and insufficient treatment options. Pharmacological stimulation of insulin signaling, which is blunted in DM2, is a promising approach to treat this disease. It has been shown that activation of the angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system leads to an improved glucose uptake. In this study, we intended to evaluate, whether this effect could be exploited therapeutically. We first confirmed that Ang-(1-7) improves insulin signaling and glucose uptake in vitro in cultured cardiomyocytes. We then evaluated the therapeutic effect of a newly developed hydro-xypropyl-β-cyclodextrin-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation in blood glucose levels in these rats at a dose of 30 μg/kg, reversed the established hyperglycemic state at a dose of 100 μg/kg, and resulted in improved insulin sensitivity, reduced plasma insulin and decreased diabetic nephropathy. In conclusion, an oral Ang-(1-7) formulation reverses hyperglycemia and its consequences in an animal model of DM2 and represents a novel therapeutic option for the treatment of DM2 and other cardio-metabolic diseases. A novel rat model with inducible diabetes can be used to evaluate new therapies. Angiotensin-(1-7) is effective in an oral formulation packaged in cyclodextrine. Angiotensin-(1-7) is a promising antidiabetic drug.

Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi

Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3mg/kg, twice with an interval of 48h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8weeks (30mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.

Fatty Liver Is Associated with Transcriptional Downregulation of Stearoyl-CoA Desaturase and Impaired Protein Dimerization

Aims and MethodsWe evaluated the modulation of liver stearoyl-CoA desaturase-1 (Scd1) by dietary factors and insulin resistance (IR) in two experimental models of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). The first model included Sprague Dawley (SD) rats that developed NAFLD without IR, and the second one included a rat model of genetic IR and cardiovascular disease, the spontaneously hypertensive rats (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY). The adult rats were given standard chow diet (CD) or HFD for 10 weeks. In all the animals, we explored the hepatic Scd1 transcriptional activity and protein levels.ResultsHFD-fed rats of both strains developed severe NAFLD. Liver abundance of Scd1 mRNA was significantly decreased in HFD-fed rats regardless of the strain; SD-CD: 235±195 vs. SD-HFD 4.5±2.9, p<0.0004, and SHR-CD: 75.6±10.8 vs. SHR-HFD: 4.48±17.4, and WKY-CD: 168.7±17.4 vs. WKY-HFD: 12.9±17.4, p<0.000001 (mean±SE, ANCOVA adjusted by HOMA). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of high levels of a monomeric protein band (32.2–36.6 Kda, p<0.003) and decreased levels of a dimeric protein band (61.9–66.1 Kda, p<0.02) regardless of the rat strain. Pharmacologic intervention with the peroxisome proliferator-activated receptor α agonist clofibrate reverted the liver phenotype and significantly modified the hepatic Scd1 transcriptional activity and protein expression.ConclusionDiet-induced fatty liver is associated with the downregulation of hepatic Scd1 transcript and de-dimerization of the protein, and these changes were not much affected by the status of peripheral IR.

Codonopsis javanica root extracts attenuate hyperinsulinemia and lipid peroxidation in fructose-fed insulin resistant rats

From ancient times, Dǎngshēn (Codonopsis javanica) has been used in Chinese traditional medicine. In this study we investigated the anti-hyperinsulinemia and antioxidant properties of C. javanica root extracts in a rat model of insulin resistance (IR), induced by chronic fructose feeding. Twenty-four Sprague–Dawley rats were randomized into control, fructose-treated (10%, w/v), and fructose then C. javanica (Fru + Cod)-treated groups. After 8 weeks fructose feeding, increased fasting serum insulin levels (2.6 ± 0.45 μg/L) and insulin area under the curve confirmed the IR (p < 0.001). However, C. javanica treatment to fructose-fed rats significantly attenuated the hyperinsulinemia with correspondingly improved glucose tolerance. Weight gain in Fru + Cod group was comparably (p < 0.01) lower than in the fructose-fed group. Furthermore, IR-induced increased hepatic lipid peroxidation, as demonstrated by elevated malondialdehyde levels, were significantly (p < 0.001) alleviated by C. javanica treatment. These findings reveal that chronic fructose intake may facilitate IR and oxidative damage, which could be eradicated by improved antioxidant status. Accordingly, we found that C. javanica treatment significantly improved the antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase and glutathione reductase in the liver. These findings that fructose-induced hyperinsulinemia and associated oxidative stress could be attenuated by C. javanica root extracts.

Z‐2‐(β‐d‐glucopyranosyloxy)‐3‐phenylpropenoic acid, an α‐hydroxy acid from rooibos (Aspalathus linearis) with hypoglycemic activity

The rare enolic phenylpyruvic acid-2-O-glucoside, (PPAG:Z-2-(β-D-glucopyranosyloxy)-3-phenylpropenoic acid), is one of the major constituents of fermented rooibos infusions. 3-Phenylpyruvic acid (2-oxo-3-phenylpropanoic acid), without the sugar moiety and with a keto form instead of an enolic arrangement, has been shown to enhance insulin release and glucose uptake in muscle cells. The purpose of this study was to assess if PPAG has similar activity on glucose metabolism. Preliminary in vitro studies confirmed that PPAG, isolated from rooibos, enhanced glucose uptake. A dose-response study in Chang cells showed that PPAG enhanced glucose uptake in the concentration range 1.0-31.6 μM (EC50 = 3.6 μM). In obese insulin-resistant rats, oral administration of PPAG lowered fasting glucose concentrations and improved oral glucose tolerance values; messenger RNA expression of glucokinase, glucose transporter 1 and 2, insulin receptor, peroxisome proliferator-activated receptor alpha, and suppressor of cytokine signaling 3, were increased in the liver. This suggests that the liver is mainly responsible for PPAG bioactivity. This study describes for the first time that PPAG increases in vitro glucose uptake and improves glucose tolerance in an obese insulin-resistant rat model, suggesting that it has potential as a new class of antidiabetic therapeutics that would contribute to the antidiabetic effect of rooibos.

Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

Abstract Emerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

Effects of Sodium Butyrate and Its Synthetic Amide Derivative on Liver Inflammation and Glucose Tolerance in an Animal Model of Steatosis Induced by High Fat Diet

Background & AimsNonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD).MethodsAfter weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined.ResultsEvaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation.ConclusionsOur results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance.

Quercetin Protects against Diabetes-Induced Exaggerated Vasoconstriction in Rats: Effect on Low Grade Inflammation

Vascular complications are the leading cause of morbidity and mortality in patients with diabetes. Quercetin is an important flavonoid with antioxidant and anti-inflammatory activity. Here, the effect of quercetin on diabetes-induced exaggerated vasoconstriction in insulin deficient and insulin resistant rat models was investigated. Insulin deficiency was induced by streptozotocin while, insulin resistance by fructose. Rats were left 8 weeks or 12 weeks after STZ or fructose administration respectively. Quercetin was daily administered in the last 6 weeks. Then, tail blood pressure (BP) was recorded in conscious animals; concentration-response curves for phenylephrine (PE) and KCl were studied in thoracic aorta rings. Non-fasting blood glucose level, serum insulin level, insulin resistance index, serum tumour necrosis factor-α (TNF-α) and serum C-reactive protein (CRP) were determined. Nuclear transcription factor-κB (NF-κB) was assessed by immunofluorescence technique. Histopathological examination was also performed. The results showed that quercetin protected against diabetes-induced exaggerated vasoconstriction and reduced the elevated blood pressure. In addition, quercetin inhibited diabetes associated adventitial leukocyte infiltration, endothelial pyknosis and increased collagen deposition. These effects were accompanied with reduction in serum level of both TNF-α and CRP and inhibition of aortic NF-κB by quercetin in both models of diabetes. On the other hand, quercetin did not affect glucose level in any of the used diabetic models. This suggests that the protective effect of quercetin is mediated by its anti-inflammatory effect rather than its metabolic effects. In summary, quercetin is potential candidate to prevent diabetic vascular complications in both insulin deficiency and resistance via its inhibitory effect on inflammatory pathways especially NF-κB signaling.

Abstract 445: Niacin Beneficially Alters the Secretion of Intestinal-derived TRL and HDL in a Rat Model of Insulin Resistance

Introduction The intestine secretes discrete fractions of triglyceride (TG) rich apoB-chylomicrons (CM) and HDL particles into mesenteric lymph. Insulin resistance (IR) is associated with overproduction of intestinal CM however, the effect of IR on intestinal HDL secretion remains unknown. Niacin has been shown to reduce plasma TG while increasing HDL-C, however it is unknown if niacin modulates intestinal lymphatic CM and HDL secretion. Objective To determine the effect of niacin on the secretion and composition of intestinal lymphatic CM and HDL in a model of IR (JCR:LA- cp rat). Methods IR rats were fed control chow or chow supplemented with niacin (0.5% or 1% w/w) for 6 weeks. The mesenteric lymph duct was cannulated and lymph sampled following an intra-gastric intralipid ( fed ) infusion for 6hrs. The lymphatic CM (&lt;1.006g/ml) and HDL (1.063-1.21g/ml) fractions were separated by density ultracentrifugation. Results IR rats over-secreted (2-fold) lymph apoB-CMs, while simultaneously reducing lymphatic apoA1-HDL (-47%) secretion compared to non-IR rats. In addition, CM and HDL particles from IR rats were found to be enriched in TG (64 and 86% respectively). Interestingly, niacin stimulated the secretion of lymph HDL (&gt;60%), as well as attenuated lymph CM (-53%) secretion compared to control. Niacin treatment was also found to normalize the TG content of both lymph-CM and lymph-HDL particles. Conclusion IR appears to stimulate the intestine to over-secrete apoB-CM as well as reduce apoAI-HDL secretion into lymph, potentially contributing to particle dysfunction. Niacin may contribute to improving CVD risk by reducing the over-secretion of intestinal pro-atherogenic apoB-particles, whilst restoring the number and TG enrichment of intestinal anti-atherogenic apoAI-particles.

Nitric oxide mediates the insulin sensitizing effects of β-sitosterol in high fat diet-fed rats

β-Sitosterol has been shown to have antidiabetic and antioxidant effects in animal models. The objective of the study is to investigate the effects of β-sitosterol on insulin sensitivity, oxidative and nitrosative stress and lipid abnormalities in liver of high fat-fed rat model of insulin resistance (IR) and to assess whether nitric oxide (NO) is involved in its action. Adult male albino Wistar rats of body weight 150–180g were fed either control diet (CON) or high fat diet (HFD). Each dietary group was divided into two and treated or untreated with β-sitosterol (10mg/kgb.w.−1day−1) for 4weeks. Inhibition of total nitric oxide synthase (NOS) by administration of nitro-l-arginine methyl ester (L-NAME) and inducible NOS (iNOS) by aminoguanidine (AG) in HFD and HFD+ β-sitosterol groups were accomplished to identify the role of NO. After 28days, assays were performed in plasma and liver. HFD-fed rats showed hyperglycemia, hyperinsulinemia, IR, oxidative damage, nitrosative stress, lipid accumulation and elevated serum aminotransferases. Increased expression of iNOS and decreased expression of endothelial NOS (eNOS) were observed in them. Hepatic fat accumulation was further confirmed by histology. The biochemical and histological abnormalities associated with HFD feeding were significantly reduced by β-sitosterol administration. Administration of L-NAME to HFD-fed rats caused decrease in insulin sensitivity and increase in oxidative stress. Co-administration of L-NAME for the last seven days to β-sitosterol-treated HFD rats abolished the glucose lowering effect of β-sitosterol, but the ability to decrease oxidative stress remained unaltered. On the other hand, administration of AG resulted in improved glucose homeostasis and antioxidant levels but decreased oxidative stress and enhanced antioxidant potential in both HFD and HFD+ β-sitosterol treated groups. Thus, β-sitosterol promotes insulin sensitivity in rats fed HFD possibly by improving NO levels. With additional studies, β-sitosterol might be used as a functional drug or as an adjuvant in the management of IR and associated fatty liver disease.

Erratum

Acta PhysiologicaVolume 208, Issue 1 p. 136-136 ErratumFree Access Erratum This article corrects the following: The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance U. Rajamani, D. Joseph, S. Roux, M. F. Essop, Volume 202Issue 2Acta Physiologica pages: 151-157 First Published online: April 19, 2011 First published: 12 April 2013 https://doi.org/10.1111/apha.12069AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance. Rajamani U, Joseph D, Roux S, Essop MF For the above article, some of the values in Table 1 were incorrectly published. Here is the correct Table and associated text. Table 1. Values are expressed as mean ± SEM (n = 6 rats per experimental group) Control Insulin resistance Number of rats 6 6 Gender Male Male Body weight (g) 505.00 ± 13.27 557.17 ± 8.48aa P < 0.05. Glucose (mmol per L) 6.03 ± 0.20 8.22 ± 0.65aa P < 0.05. Insulin (μU) 32.62 ± 5.15 57.88 ± 9.96aa P < 0.05. HOMA–IR 8.80 ± 1.45 22.04 ± 5.64aa P < 0.05. a P < 0.05. First paragraph of results section Rats consuming the high-fat diet displayed a moderate increase in body weight (9.36%, P < 0.05 vs. controls) (Table 1). Fasting insulin and glucose plasma levels were significantly increased in response to the high-fat feeding regimen vs. matched controls, that is, 57.88 vs. 32.62 μU and 8.22 vs. 6.03 mmol/L respectively. High-fat feeding markedly increased the HOMA–IR (P < 0.05 vs. control) demonstrating insulin resistance (Table 1). Reference Rajamani, U., Joseph, D., Roux, S. & Essop, M.F. 2011. The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance. Acta Physiol (Oxf) 202, 151– 157. doi: 10.1111/j.1748-1716.2011.02275.x. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume208, Issue1May 2013Pages 136-136 ReferencesRelatedInformation

FXR Agonist INT-747 Upregulates DDAH Expression and Enhances Insulin Sensitivity in High-Salt Fed Dahl Rats

AimsGenetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity.Methods and ResultsIn this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls.ConclusionOur study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

Modulation of Skeletal Muscle Performance and Sarco-and Endoplasmic Reticulum Ca2+ ATPase by Exercise and Adiponectin Gene Therapy in Insulin Resistant Diabetic Rat Model

Modulation of Skeletal Muscle Performance and Sarco-and Endoplasmic Reticulum Ca2+ ATPase by Exercise and Adiponectin Gene Therapy in Insulin Resistant Diabetic Rat Model