Insulin Resistance In Rats Research Articles

The prerequisites for the development of type 2 diabetes or prediabetes in rats fed a high-fat diet

It is known that the pathogenesis of type 2 diabetes in humans is based on two main factors – insulin resistance and inappropriate secretory activity of β-cells of the pancreas. In animals, the role of these mechanisms has not been clearly characterized, and the differences in the manifestations of experimental diabetes under the same conditions are not sufficiently substantiated. In order to study the prerequisites and mechanisms of the development of experimental type 2 diabetes or prediabetes under lipid overload, 6-month-old male Wistar rats were fed a high-fat diet for 4 weeks; after 2 weeks of the experiment, 20 or 25 mg/kg of streptozotocin was administrated. The development of insulin resistance was assessed using the insulin tolerance test. We evaluated the dynamics of glycemia in animals, subcellular signs of liver steatosis, and determined expression of the precursor and mature protein SREBP-1 by immunoblotting. It was found that in rats fed with a high-fat diet during the 2–4th weeks of the experiment, regardless of the administration of streptozotocin, stable insulin resistance and symptoms of prediabetes were detected. The severity of carbohydrate metabolism lesion, which appeared as type 2 diabetes or prediabetes after streptozotocin administration, depended on the level of hepatosteatosis due to high-fat diet, whereas the dose of streptozotocin influenced severity of type 2 diabetes. The use of a high-fat diet led to increased processing and activation of SREBP-1, which was clearly inhibited in type 2 diabetes. Therefore, the level of lipid infiltration of the liver and deregulation of the transcription factor SREBP-1 are risk factors defining development of type 2 diabetes or prediabetes in experimental rats with lipid overloading. Changes in the maturation of SREBP-1 with the use of a high-fat diet confirm that insulin resistance in rats revealed β-cell dysfunction, which closely approximates the mechanisms of experimental type 2 diabetes to main pathways in humans. At the same time, the predisposition to β-cell dysfunction can be a prerequisite that determines compensatory reserves for maintaining carbohydrate and lipid homeostasis under the influence of lipid load in both humans and laboratory animals.

Effect of Ficus lacor Buch. Ham. Fruit Extract on Dexamethasone Induced Insulin Resistant Rats

Fruits of plant Ficus lacor Buch. Ham. were evaluated for its antidiabetic efficacy in dexamethasone induced insulin resistant rats. Extraction of fruits was done by soxhlation method to get fruit extract. Acute toxicity study of fruit extract was performed as per OECD 425 guidelines using wistar rats. Rats weighing between 200 to 250 g were selected for experimental work and divided randomly in to five groups normal control, diabetic Control, standard control (metformin, 2mg/kg), fruit extract (200mg/kg), fruit extract (400mg/kg) with five animals in each group. Dexamethasone (10mg/kg s.c) was used to induce insulin resistance in wistar rats weighing between 200 to 250g for 11 days. Animals in treatment group were treated with metformin (40mg/kg), fruit extract (200 and 400mg/kg) for 11 days daily. At the end of 11 days study, different parameters like body weight, food intake, water intake, glucose, cholesterol, triglyceride, HDL, LDL, VLDL, urea, uric acid, creatinine, aspartate aminotransferase (AST) and alanine transaminase (ALT) were determined. Liver and muscle was isolated for estimation of glycogen level. The result indicates significant (P ˂ 0.05) improvement in different biochemical parameters when compared with diabetic control group. The liver glycogen level was increased significantly (P ˂ 0.001) when compared with diabetic control group. The antidiabetic effect of fruit extract of plant Ficus Lacor Buch. Ham. was found to be dose dependent.

Serum Phospholipids Are Potential Therapeutic Targets of Aqueous Extracts of Roselle (Hibiscus sabdariffa) against Obesity and Insulin Resistance

Roselle (Hibiscus sabdariffa) is rich in phenolic compounds with antiobesogenic and antidiabetic effects. In this study, the effects of aqueous extracts of two varieties of Hibiscus sabdariffa, Alma blanca (white-yellow color) and Cuarenteña (purple color), were evaluated for the prevention of obesity and insulin resistance in rats fed a high-fat and high-fructose diet (HFFD), identifying targeted molecules through global metabolomics. After sixteen weeks, both roselle aqueous extracts prevented body weight gain, and white roselle extract ameliorated insulin resistance and decreased serum free fatty acid levels. Moreover, white roselle extract decreased 18:0 and 20:4 lysophosphatidylethanolamines and purple roselle extract increased 16:0 and 20:4 lysophosphatidylinositol compared to HFFD-fed rats. These results demonstrate that roselle's beneficial health effects are variety-dependent. Interestingly, the white roselle extract showed a greater beneficial effect, probably due to its high contents of organic and phenolic acids, though its consumption is not as popular as that of the red/purple varieties.

Preoperative administration of branched-chain amino acids reduces postoperative insulin resistance in rats by reducing liver gluconeogenesis

BackgroundPostoperative insulin resistance (PIR) represents an important characteristic of metabolic response following surgical injury. Clinical outcomes are negatively correlated to postoperative insulin resistance and hyperglycemia, indicating a novel treatment for reducing postoperative insulin resistance is urgently needed. The current work aimed to assess the protective effects of branched-chain amino acids (BCAA) on glucose metabolism disorders induced surgically in a rat model, and to explore the underpinning mechanism.Methods and resultsRats were randomly assigned to 2 groups, including the control and BCAA groups. Rats were given a compulsory oral 3 mL load by gavage two hours before surgery. The results showed that BCAA remarkably reduced glycemia by suppressing liver gluconeogenesis via reduction of cAMP-response element-binding protein-regulated transcription coactivator 2 (CRTC2) and glucose-6-phosphatase (G6PC) gene and protein expression levels (all Ps < 0.05).ConclusionsThis study revealed that BCAA lower blood glucose levels by reducing liver gluconeogenesis without significant elevation of plasma insulin levels. We anticipate that preoperative BCAA supplementation may be a means for preventing postoperative insulin resistance.

Resistant starch from black rice, Oryza sativa L. var. ameliorates renal inflammation, fibrosis and injury in insulin resistant rats.

It has recently been reported that black rice (BR) extract has anti-obesity, anti-diabetic, and anti-osteoporosis effects. It has been shown to reduce obese-related kidney dysfunction in animal models. This study aimed to investigate the effect of resistant starch from BR (RS) on renal inflammation, oxidative stress, and apoptosis in obese insulin resistant rats. Male Wistar rats were divided into six groups: normal diet (ND), ND treated with 150 mg of RS (NDRS150), high-fat (HF) diet, HF treated with 100 and 150 mg of RS (HFRS100), (HFRS150), and HF treated with metformin as a positive control. Insulin resistance was shown in the HF rats by glucose intolerance, increased insulin, total area under the curve of glucose and homeostasis model assessment of insulin resistance and dyslipidemia. The resulting metabolic disturbance in the HF rats caused renal inflammation, fibrosis and apoptosis progressing to kidney injury and dysfunction. Prebiotic RS including anthocyanin from BR at doses of 100 and 150 mg ameliorated insulin resistance, dyslipidemia and liver injury. Treatment with RS reduced TGF-β fibrotic and apoptotic pathways by inhibition of NF-κB and inflammatory cytokines which potentially restore kidney damage and dysfunction. In conclusion, prebiotic RS from BR ameliorated obesity induced renal injury and dysfunction by attenuating inflammatory, fibrotic, and apoptotic pathways in insulin resistant rats induced by HF.

Abstract 11222: Differential Perivascular Adipose Response to Metabolic Challenge Leads to Sexually Dimorphic Cardiovascular Impairment in Early Prediabetes: Possible Role of Estrogen

Cardiovascular (CV) risk associated with metabolic dysfunction commences in early stages preceding the emergence of diagnostic markers. In this regard, a protective role of female sex hormones has been observed where males and postmenopausal females are at a higher risk of these complications. Our previous work on non-obese insulin resistant male rats revealed a crucial role for perivascular adipose tissue (PVAT) inflammation in developing CV dysfunction in early prediabetes. This resulted from PVAT hypoxia evoked by increased uncoupling protein 1 (UCP1) expression and adipocyte hypertrophy in response to a dietary metabolic challenge of mild hypercaloric (MHC) feeding . Here, we examined whether estrogen modulated MHC-induced PVAT dysfunction and its CV consequences. Male and female Sprague-Dawley rats (4-5weeks) were randomly allocated into 2 dietary groups: control or MHC diet for 24 weeks. To control for estrogen effect, bilateral ovariectomy was performed on female rat sub-groups after 12 weeks of feeding with or without daily treatment with an oral dose of 17 β -estradiol (E2) of 2.8 μg/ 100 gm of body weight for an additional 12 weeks. Daily food intake, body weight, body composition, blood glucose and insulin levels, echocardiographic parameters, and blood pressure were measured. At week 24; rats were catheterized for invasive hemodynamic examination. Cardiac autonomic neuropathy was assessed by measuring baroreceptor sensitivity using the vasoactive method. After sacrifice, aortic contractility and endothelial function were examined and molecular investigation were performed. Indeed, the absence of endogenous E2 seemed to precipitate an obese phenotype in MHC-fed female rats and instigate CV impairment together with hallmarks of early PVAT dysfunction reminiscent of those observed in male rats. Intriguingly, E2 replacement restored the protective phenotype observed in intact females. E2 treatment mitigated PVAT inflammation without affecting UCP1 expression levels possibly suggesting a direct anti-inflammatory role. Our results present a novel framework for the protective role of E2 interrupting the inflammatory machinery in PVAT, as well as the subsequent CV dysfunction in presence of a dietary metabolic challenge.

The involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in anti-inflammatory activity of N-stearoylethanolamine

BackgroundN-stearoylethanolamine (NSE) is a bioactive lipid amine with a wide range of biological activities. Anti-inflammatory properties of NSE were previously confirmed on multiple animal models. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, we examined the involvement of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the NF-kB –dependent pathway of anti-inflammatory action of NSE using different methodological approaches. MethodsMolecular modeling calculated the possibility of NSE binding PPAR. Ex vivo experiment, using selective agonist of PPARα/γ - LY-171883 and antagonist of PPARγ - GW9662, examined the role of PPARα/γ in the NSE’s effect on nuclear NF-kB translocation in LPS-activated rat peritoneal macrophages. Finally, the NSE’s action on mRNA level of PPARγ-dependent genes was studied in the liver of insulin-resistant rats. ResultsThe results of molecular docking showed that NSE could bind to PPARγ and compete for the binding site with antagonist GW9662 and agonist LY-171883. These data was supported by in vitro study where pre-treatment with NSE prevented further LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages. NSE treatment before GW9662 and LPS addition normalized the level of NF-kB translocation and IL-1β content. This finding confirmed a competitive binding of NSE with GW9662 for the ligand-binding domain of PPARγ. Additional in vivo study showed that NSE administration changed the mRNA expression of several PPARγ target genes, including SLC27A1 encoding fatty acid transport protein-1 and IL1RN - interleukin-1 receptor antagonist in insulin resistant rats. ConclusionNSE suppressed nuclear translocation of NF-κB in LPS-stimulated peritoneal macrophages via PPARγ and changed hepatic mRNA expression of PPARγ target genes (SLC27A1, IL1RN) in insulin resistant rats.

Effect of chronic administration of 17β-estradiol on the vasopressor responses induced by the sympathetic nervous system in insulin resistance rats

Several studies have demonstrated that the underlying mechanism of insulin resistance (IR) is linked with developing diseases like diabetes mellitus, hypertension, metabolic syndrome, and polycystic ovary syndrome. In turn, the dysfunction of female gonadal hormones (especially 17β-estradiol) may be related to the development of IR complications since different studies have shown that 17β-estradiol has a cardioprotector and vasorelaxant effect. This study aimed was to determine the effect of the 17β-estradiol administration in insulin-resistant rats and its effects on cardiovascular responses in pithed rats. Thus, the vasopressor responses are induced by sympathetic stimulation or i.v. bolus injections of noradrenaline (α1/2), methoxamine (α1), and UK 14,304 (α2) adrenergic agonist were determined in female pithed rats with fructose-induced insulin resistance or control rats treated with: 1) 17β-estradiol or 2) its vehicle (oil) for 5 weeks. Thus, 17β-estradiol decreased heart rate, prevented the increase of blood pressure induced by ovariectomy, but with the opposite effect on sham-operated rats; and decreased vasopressor responses induced by i.v. bolus injections of noradrenaline on sham-operated (control and fructose group) and ovariectomized (control) rats, and those induced by i.v. bolus injections of methoxamine (α1 adrenergic agonist). Overall, these results suggest 17β-estradiol has a cardioprotective effect, and its effect on vasopressor responses could be mediated mainly by the α1 adrenergic receptor. In contrast, IR with ovariectomy 17β-estradiol decreases or loses its cardioprotector effect, this could suggest a possible link between the adrenergic receptors and the insulin pathway.

Tert-butylhydroquinone abrogates fructose-induced insulin resistance in rats via mitigation of oxidant stress, NFkB-mediated inflammation in the liver but not the skeletal muscle of high fructose drinking rats.

The effect of 21% fructose drinking water (FDW) (w/v) on some parameters of metabolic syndrome, hepatic, and skeletal muscular histology of rats was studied using standard techniques. Twenty male albino rats were divided into four groups of 5 rats each in this in vivo study. Group I received distilled water, group 2 received FDW, group 3 received FDW and metformin (300 mg/kg body weight daily, orally), group 4 received FDW and 1% tert-butylhydroquinone feed. FDW changed the serum leptin, triacylglycerol, very low-density lipoprotein, and C-reactive protein levels of the rats, inducing hypertriglyceridemia, oxidative stress, and inflammation in their liver (but not the skeletal muscle) and insulin resistance which were modulated with metformin and tBHQ as corroborated by liver and muscle histology. The study reveals the potentials of metformin and tBHQ in mitigating hepatic and skeletal muscular morphological changes arising from exposure to high fructose drinks. PRACTICAL APPLICATIONS: There has been an increase in the global consumption of fructose (either as a sweetner in beverages or soft and carbonated drinks) in the last few decades and this has been positively correlated with the global increase in metabolic complications. Regular intake of fructose contributes to the pathogenesis of lipid disorders, oxidant stress, and chronic inflammation, which are linked with the metabolic syndrome components (MetS) (obesity, insulin resistance, and cardiovascular diseases) as well as increased morbidity and mortality. Given that the approaches that have been applied to treat the MetS have not been able to totally arrest it, currenty study which showed that tBHQ abrogated fructose-induced insulin resistance, dyslipidemia, hepatic, and skeletal muscular pathology in the rats places tBHQ in the spotlight as a nutraceutical that could be of relevance in mitigating high dietary fructose-induced hepatic and skeletal muscular pathology.

Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects

Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.

Effect of pioglitazone on oxidative stress of skeletal muscle in the insulin resistance rat model induced by high sucrose diet

Background: Metabolic syndrome is associated with some medical disorders such as central obesity, being overweight, insulin resistance and hypertension. This study was designed to determine the effect of pioglitazone on oxidative stress in the insulin resistance rat model.Methods: In this study, the model was induced by high sucrose (935 mm) diet for 20 weeks. Three groups were used in the experiment. Control group received standard laboratory diet and drinking water. Metabolic syndrome induced group received 32% sucrose containing drinking water for 20 weeks. Pioglitazone-treated metabolic syndrome group has received pioglitazone treatment (30 mg/kg/day, via oral gavage) for two weeks at the end of the 18th week of metabolic syndrome group. After experimental period, skeletal muscle tissues were homogenized to measure important enzymes such as aspartate aminotransferase, lactate dehydrogenase and as the marker of oxidative stress; total-antioxidant-status, total-oxidant-status and malondialdehyde. Western blot technique was used to determine protein level of thioredoxin1.Results: Aspartate aminotransferase and lactate dehydrogenase levels increased in metabolic syndrome group but pioglitazone treatment decreased these levels. In metabolic syndrome group the oxidative stress status increased but the treatment of pioglitazone decreased the level of oxidative stress in the skeletal muscle. In addition, thioredoxin1 decreased in metabolic syndrome group but administration of pioglitazone increased this level.Conclusions: There was an elevated effect of oxidative stress in high sucrose fed rats but the treatment of pioglitazone improved glucose tolerance and insulin sensitivity.

Metformin alleviates long-term high-fructose diet-induced skeletal muscle insulin resistance in rats by regulating purine nucleotide cycle

Nutrient excess caused by excessive fructose intake can lead to insulin resistance and dyslipidemia, which further causes the development of metabolic syndrome. Metformin is a well-known AMPK activator widely used for the treatment of metabolic syndrome, while the mechanism of AMPK activation remains unclear. The present study aimed to investigate the pharmacological effects of metformin on fructose-induced insulin resistance rat, and the potential mechanism underlying AMPK activation in skeletal muscle tissue. Results indicated that metformin significantly ameliorated features of insulin resistance, including body weight, Lee's index, hyperinsulinemia, dyslipidemia, insulin intolerance and pancreatic damage. Moreover, treatment with metformin attenuated the inflammatory response in serum and enhanced the antioxidant capacity in skeletal muscle tissue. The therapeutic effects of metformin on fructose-induced insulin resistance may be related to the activation of AMPK to regulate Nrf2 pathway and mitochondrial abnormality. Additionally, metformin suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and up-regulated the expression of adenylosuccinate synthetase (ADSS) in the purine nucleotide cycle (PNC), which facilitated the increase of AMP level and the ratio of AMP/ATP. Therefore, we proposed a novel mechanism that metformin activated AMPK via increasing AMP by regulating the expression of AMPD1 and ADSS in PNC pathway.

Alternative to Sugar, Honey Does Not Provoke Insulin Resistance in Rats Based on Lipid Profiles, Inflammation, and IRS/PI3K/AKT Signaling Pathways Modulation.

Insulin resistance (IR) is the central link to metabolic syndrome (MS), and IR prevention has become the key to overcoming this worldwide public health problem. A diet rich in simple sugars is an important pathogenic factor in IR development. To investigate the effect of honey on IR compared to the sugar-water diet, we analyzed phenolics and oligosaccharides in jujube honey and rape honey based on LC-MS and silane derivatization/GC-MS. The effects of different diets on glucose and lipid profile, histopathology and IR-related mechanism pathways were analyzed and compared by equal sugar levels intervention of fructose, fructose + glucose and two kinds of unifloral honey (high-/low-dose) in rats. The results suggested that sugar-equivalent honey, which differs from sugar solution, especially 17.1 g/kg BW jujube honey rich in phenolics (1.971 mg/100 g of isoquercitrin) and oligosaccharides (2.18 g/100 g of turanose), suppressed IR via maintaining glucose (OGTT and ITT) and lipid (TC, TG, LDL-C, HDL-C, and NEFA) homeostasis, improving histological structural abnormalities of the liver, adipose and skeletal muscle, reducing oxidative stress (GSH-Px and MDA) and inflammation (IL-6 and TNF-α), modulating the NF-κB (NF-κB gene expression was down-regulated to 0.94) and IRS/PI3K/AKT signaling pathways (e.g., AKT and GLUT2 expression in liver increased by 4.56 and 13.37 times, respectively) as well as reshaping the gut microbiota. These revealed a potential nutritional contribution of substituting honey for simple sugar in the diet, providing a theoretical basis for controlling IR development via dietary modification and supplementation.

N-Stearoylethanolamine Inhibits Integrin-Mediated Activation, Aggregation, and Adhesion of Human Platelets.

N-stearoylethanolamine (NSE), a lipid mediator that belongs to the N-acylethanolamine (NAE) family, has anti-inflammatory, antioxidant, and membranoprotective actions. In contrast to other NAEs, NSE does not interact with cannabinoid receptors. The exact mechanism of its action remains unclear. The aim of this study is to evaluate the action of NSE on activation, aggregation, and adhesion of platelets that were chosen as a model of cellular response. Aggregation of platelets was measured to analyze the action of NSE (10^-6-10^-10 M) on platelet reactivity. Changes in granularity and shape of resting platelets and platelets stimulated with ADP in the presence of NSE were monitored by flow cytometry, and platelet deganulation was monitored by spectrofluorimetry. In vivo studies were performed using obese insulin-resistant rats. Binding of fibrinogen to the GPIIb/IIIa receptor was estimated using indirect ELISA and a scanning electron microscopy (SEM). It was found that NSE inhibits the activation and aggregation of human platelets. Our results suggest that NSE may decrease the activation and subsequent aggregation of platelets induced by ristocetin, epinephrine, and low doses of ADP. NSE also reduced the binding of fibrinogen to GPIIb/IIIa on activated platelets. These effects could be explained by the inhibition of platelet activation mediated by integrin receptors: the GPIb-IX-V complex for ristocetin-induced activation and GPIIb/IIIa when epinephrine and low doses of ADP were applied. The anti-platelet effect of NSE complements its anti-inflammatory effect and allows us to prioritize studies of NSE as a potent anti-thrombotic agent. SIGNIFICANCE STATEMENT: N-stearoylethanolamine (NSE) was shown to possess inhibitory action on platelet activation, adhesion, and aggregation. The mechanism of inhibition possibly involves integrin receptors. This finding complements the known anti-inflammatory effects of NSE.

Preferential effect of Montelukast on Dapagliflozin: Modulation of IRS-1/AKT/GLUT4 and ER stress response elements improves insulin sensitivity in soleus muscle of a type-2 diabetic rat model

AimsMontelukast (MNK), a leukotriene receptor antagonist, has proven its antioxidant/anti-inflammatory capacity to guard against diabetes-induced complications and to enhance metformin antidiabetic effect. Nevertheless, here we evaluated the involvement of endoplasmic reticulum (ER) stress and insulin signaling cascade in the effect of MNK and/or dapagliflozin (DAPA) using the soleus muscle of type 2 diabetic (T2D)/insulin resistant (IR) rats. Main methodsTo induce T2D/IR, rats were fed a westernized diet (WD) for 8 weeks followed by a sub-diabetogenic dose of streptozotocin (STZ). Animals were divided into control (receiving normal diet; ND), diabetic untreated, and diabetic treated for 4 weeks with DAPA, MNK, or their combination (DAPA+MNK). Blood glucose and serum lipid profile were determined, and the soleus muscle was tested for ER stress-induced IR, besides histopathological examination. Key findingsTreatment with DAPA, MNK, and especially their combination decreased the fasting plasma levels of glucose and insulin while improving insulin sensitivity and lipid profile. This was achieved via the activation of insulin signaling IRS-1/AKT/GLUT4 pathway in the soleus muscle consequent to the deactivation of the ER stress response elements, namely IRE1α, ATF6, and PERK to suppress p-JNK and p-eIF2α. SignificanceImproved insulin signaling along with the deactivation of the ER stress response by MNK comparable to the DAPA are partly responsible for the enhanced soleus muscle insulin sensitivity, effects that nominate MNK as an add-on to DAPA to enhance its antidiabetic efficacy.

JNK affects on neutral lipids accumulation in the liver of different age insulin resistant rats

Background and Aims : JNK activation is one of the important stages in development of resistance to insulin and could be mediated by oxidative stress and neutral lipids accumulation, the processes which are associated with eldering. The purpose of the experiment was to compare the importance of liver JNK under IR development in young and old rats.

Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1–7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1–7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1–7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d × 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1–7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

Alpha-mangostin counteracts hyperuricemia and renal dysfunction by inhibiting URAT1 renal transporter in insulin resistance rat model

BackgroundAlpha-mangostin (AM) has been shown to have hypoglycemic activity. This study aimed to analyze the effects of AM at a dose of 100 mg/kg and 200 mg/kg to alleviate hyperuricemia and renal dysfunction on high-fat/high-glucose diet and low dose streptozotocin (HF/HG/STZ) injection-induced IR rat model. IR was induced in male Wistar rats by giving a HF/HG diet for 11 weeks and single injection of STZ (35 mg/kg, i.p.), then divided randomly into IR rats, IR rats treated with AM 100 and 200 mg/kgBW given by gavage for 8 weeks. At the end of the 11th week, all rats were killed, and the kidneys were taken to be analyzed for urate transporters 1 (URAT1) and glucose transporters 9 (GLUT9). We also assessed serum uric acid, proteinuria, BUN, creatinine clearance, HOMA-IR, and fasting blood glucose (FBG).ResultsWe have found the significant increase in HOMA-IR and FBG levels of the IR rats, in comparison with its control groups, which were decreased significantly after AM administration at both doses. URAT1 and GLUT9 mRNA and protein expressions in kidney in the IR + AM at both doses groups also decreased compared those in the IR without treatment group, though the decrease in GLUT9 did not appear to be statistically significant. Consequently, hyperuricemia and renal dysfunction were attenuated by AM treatment at both doses.ConclusionAfter considering all findings, AM might be a potential candidate to ameliorate IR-induced hyperuricemia and renal dysfunction at least in part by modulating the renal URAT1.

Ameliorating Inflammation in Insulin-resistant Rat Adipose Tissue with Abdominal Massage Regulates SIRT1/NF-κB Signaling

It was the aim of this study to determine whether abdominal massage reverses high-fat diet-induced insulin resistance compared with RSV treatment. A total of sixty male Sprague-Dawley rats were randomly placed in one of four groups:the non-fat diet (NFD), the high-fat diet (HFD), the HFD with abdominal massage (HFD+ AM), and the HFD plus resveratrol (HFD+ RSV). For eight weeks, rats were fed high-fat diets to create insulin resistance, followed by six weeks of either AM or RSV. Molecular mechanisms of adipogenesis and cytokine production in rats with high-fat diets were investigated. The model rat adipose tissue showed significant improvements in obesity, glucose intolerance, and the accumulation of lipid in the body [the total cholesterol level (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)], metabolic effects of glucose [The fasting blood glucose (FBG), Fasting insulin levels (FINS)], inflammatory status [interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α, C-reactive protein (CRP)], and macrophage polarization after AM or RSV treatment. Further, AM increased SIRT1/NF-κB signaling in rat adipose tissue. Accordingly, in rat adipose tissue, our results indicate that AM regulates the secretion of proinflammatory cytokines, blood sugar levels, and related signaling pathways, contributing to improvement of IR, which may serves as a new therapeutic approach for the treatment for IR.

Efficacy of Emilia coccinea aqueous extract on inhibition of α-amylase enzyme activity and insulin resistance in dexamethasone treated-rats

BackgroundDiabetes mellitus is one of the most common chronic metabolic diseases throughout the world, characterized by hyperglycemia and insulin resistance. The purpose of this study was to evaluate the effects of aqueous extract of Emilia coccinea (AEEC) leaves on dexamethasone-induced insulin resistance in rats and on in vitro α-amylase enzyme activity. MethodsInsulin resistance was induced by intraperitoneal injection of dexamethasone (1 mg/kg) for 8 days in rats. The animals were concomitant received extracts at doses of 107.5; 215; 430 mg/kg for this period. At the end of the treatment, blood glucose level, lipid profile, transaminases, triglyceride glucose (TyG) index, body mass and relative organ weight were evaluated. ResultsThe results showed that AEEC inhibits α-amylase enzyme with an IC50 of 34.10 μg/ml in vitro. AEEC significantly reduced blood glucose level, triglycerides, TyG index, total and LDL cholesterol, liver weight and increased HDL cholesterol. Moreover, it reduced ALAT and ASAT activity. These parameters were strongly modify by dexamethasone. ConclusionAEEC plays antidiabetic roles by ameliorating insulin resistance and reducing postprandial blood glucose level through α-amylase enzyme inhibition.