Rat Model Of Insulin Resistance Research Articles

Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats

In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro &invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance

BACKGROUND Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

Histological and immunohistochemical study of the neuroprotective potentials of trans-cinnamaldehyde in Wistar rat model of insulin resistance

Histological and immunohistochemical study of the neuroprotective potentials of trans-cinnamaldehyde in Wistar rat model of insulin resistance

Mechanisms Leading to Increased Insulin-Stimulated Cerebral Glucose Uptake in Obesity and Insulin Resistance: A High-Fat Diet and Exercise Training Intervention PET Study with Rats (CROSRAT).

Recent studies have shown that obesity and insulin resistance are associated with increased insulin-stimulated glucose uptake (GU) in the brain. Thus, insulin sensitivity seems to work differently in the brain compared to the peripheral tissues like skeletal muscles, but the underlying mechanisms remain unknown. Regular exercise training improves skeletal muscle and whole-body insulin sensitivity. However, the effect of exercise on glucose metabolism in the brain and internal organs is less well understood. The CROSRAT study aims to investigate the effects of exercise training on brain glucose metabolism and inflammation in a high-fat diet-induced rat model of obesity and insulin resistance. Male Sprague Dawley rats (n = 144) are divided into nine study groups that undergo different dietary and/or exercise training interventions lasting 12 to 24 weeks. Insulin-stimulated GU from various tissues and brain inflammation are investigated using [18F]FDG-PET/CT and [11C]PK11195-PET/CT, respectively. In addition, peripheral tissue, brain, and fecal samples are collected to study the underlying mechanisms. The strength of this study design is that it allows examining the effects of both diet and exercise training on obesity-induced insulin resistance and inflammation. As the pathophysiological changes are studied simultaneously in many tissues and organs at several time points, the study provides insight into when and where these pathophysiological changes occur.

Glucocorticoid excess and insulin resistance in rat models of vascular contributions to cognitive impairment and dementia

AbstractBackgroundHypertension and insulin resistance are major risk factors for the development of dementia. While insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that vascular disease could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We previously showed that bilateral carotid artery stenosis results in HPA‐axis dysfunction and insulin resistance (Lansdell et al., 2022). We hypothesized that hypertension would also cause glucocorticoid excess and insulin resistance.MethodTo test this hypothesis, we measured fecal corticosterone and the expression of steroid biosynthetic genes in the adrenal glands of six‐month‐old spontaneously hypertensive rat/stroke‐prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To assess glycemic control, rats were subjected to glucose and insulin tolerance tests.ResultSHRSP were hypertensive and cognitively impaired. Corticosterone was elevated in hypertensive compared to normotensive rats (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P<0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P = 0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P = 0.0009; Females 710±59, P = 0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P = 0.0028). Female, but not male, hypertensive rats had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (female SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P = 0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P = 0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P = 0.0368). When fasting rats were challenged with insulin, both male and female hypertensive rats had decreased clearance of glucose compared to normotensive rats (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P< 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P = 0.0007).ConclusionThese results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female hypertensive rats developing hyperglycemia at an earlier age than males.

How Does CBG Administration Affect Sphingolipid Deposition in the Liver of Insulin-Resistant Rats?

Cannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance. In a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma. The results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations. The results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance.

Nano cerium oxide and cerium/zinc nanocomposites characterization and therapeutic role in combating obesity via controlling oxidative stress and insulin resistance in rat model

BackgroundCeO2NPs and ZnONPs can curb the increase of cholesterol and triglycerides observed in rats with non-alcoholic fatty liver disease. It was suggested that CeO2 NPs could potentially have an insulin-sensitizing effect, specifically on adipose tissue and skeletal muscle. It was reported that ZnONPs combat the increase of insulin resistance observed in obese rats and could be beneficial value in NAFLD. In our previous work, ZnO-NPs manifested valuable anti-obesity effects via lowering body weight gain, oxidative stress, BMI, lipids, and insulin resistance. MethodsIn the present study, cerium oxide nanoparticles (A-1) and cerium/zinc nanocomposites (A-2 and A-3) were synthesized by solgel to investigate their role on oxidative stress, adipocyte hormones, and insulin resistance in an obese rat model. X-ray diffraction, HRTEM, SEM, and XPS were carried out to confirm the crystal structure, the particle size, the morphology of the nanoparticles and the oxidation states. ResultsThe Rietveld refinement has also been executed on A-1 (chi2 = 1.00; average Bragg = 2.92%; R-factor = 2.45%) and on A-2 (Rw = 9.87%, Rex= 9.68%, χ2 = 1.04, GoF = 1.02). The XPS spectra indicated the presence of Ce in + 4 and + 3 oxidation states and Zn as ZnO and ZnO.OH. Cerium oxide and ZnO crystal sizes lie in the range 40.53–45.01 and 40.53–45.01 nm, respectively. The results indicated that treating obese rats with any of the tested nano compounds (5 mg or 10 mg/Kg) lowered plasma cholesterol, triglycerides, LDL, insulin resistance, glucose, and BMI significantly relative to obese group values. On the other hand, HDL increased significantly in obese rats after treatment with either A-2 or A-3 compared to obese rats. The current investigation showed antioxidant activities for A-1, A-2, and A3 as evidenced by the significant increase in GSH level and a significant decrease in MDA. ConclusionIt was found that A-1, A-2, and A-3 have an efficient therapeutic role in treating of obesity-related hyperlipidemia, oxidative stress and insulin resistance. The results of A-2 and A-3 were more pronounced than those of A-1. The use of Zn/Ce nanocomposite (that have positive characteristics) in combating obesity and its complications could be become a new trend in therapeutic application for a management of obesity.

Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513mg/kg, 3mg/kg, and 5mg/kg) and donepezil (5mg/kg) as a standard for 8weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aβ (1-42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Alpha-Mangosteen lessens high-fat/high-glucose diet and low-dose streptozotocin induced-hepatic manifestations in the insulin resistance rat model

Context α-Mangosteen (α-MG) attenuates insulin resistance (IR). However, it is still unknown whether α-MG could alleviate hepatic manifestations in IR rats. Objective To investigate the effect of α-MG on alleviating hepatic manifestations in IR rats through AMP-activated protein kinase (AMPK) and sterol-regulatory element-binding protein-1 (SREBP-1) pathway. Materials and methods IR was induced by exposing male Sprague-Dawley rats (180–200 g) to high-fat/high-glucose diet and low-dose injection of streptozotocin (HF/HG/STZ), then treated with α-MG at a dose of 100 or 200 mg/kg/day for 8 weeks. At the end of the study (11 weeks), serum and liver were harvested for biochemical analysis, and the activity of AMPK, SREBP-1c, acetyl-CoA carboxylase (ACC), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, insulin receptor substrate (IRS)-1, Bax and liver histopathology were analyzed. Results α-MG at both doses significantly lowered ALT, AST, triglyceride, and cholesterol total by 16.5, 15.7, 38, and 36%, respectively. These beneficial effects of α-MG are associated with the downregulation of the IR-induced inflammation in the liver. Furthermore, α-MG, at both doses, activated AMPK by 24–29 times and reduced SREBP-1c by 44–50% as well as ACC expression by 19–31% similar to metformin. All treatment groups showed liver histopathology improvement regarding fat deposition in the liver. Conclusions Based on the findings demonstrated, α-MG protected against HF/HG/STZ-induced hepatic manifestations of the IR rats, at least in part via the modulation of the AMPK/SREBP-1c/ACC pathway and it could be a potential drug candidate to prevent IR-induced hepatic manifestations.

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.

The synergistic ameliorative activity of peroxisome proliferator-activated receptor-alpha and gamma agonists, fenofibrate and pioglitazone, on hippocampal neurodegeneration in a rat model of insulin resistance.

Insulin resistance (IR) is a risk factor for metabolic disorders and neurodegeneration. Peroxisome proliferator-activated receptor (PPAR) agonists have been proven to mitigate the neuronal pathology associated with IR. However, the synergetic efficacy of these agonists is yet to be fully described. Hence, we aimed to investigate the efficacy of PPARα/γ agonists (fenofibrate and pioglitazone) on a high-fat diet (HFD) and streptozotocin (STZ)-induced hippocampal neurodegeneration.Male Wistar rats (200 ± 25 mg/body weight [BW]) were divided into five groups. The experimental groups were fed on an HFD for 12 weeks coupled with 5 days of an STZ injection (30 mg/kg/BW, i.p) to induce IR. Fenofibrate (FEN; 100 mg/kg/BW, orally), pioglitazone (PIO; 20 mg/kg/BW, orally), and their combination were administered for 2 weeks postinduction. Behavioral tests were conducted, and blood was collected to determine insulin sensitivity after treatment. Animals were killed for assessment of oxidative stress, cellular morphology characterization, and astrocytic evaluation.HFD/STZ-induced IR increased malondialdehyde (MDA) levels and decreased glutathione (GSH) levels. Evidence of cellular alterations and overexpression of astrocytic protein was observed in the hippocampus. By contrast, monotherapy of FEN and PIO increased the GSH level (p < 0.05), decreased the MDA level (p < 0.05), and improved cellular morphology and astrocytic expression. Furthermore, the combined treatment led to improved therapeutic activities compared to monotherapies. In conclusion, FEN and PIO exerted a therapeutic synergistic effect on HFD/STZ-induced IR in the hippocampus.

Portal Glucose Infusion, Afferent Nerve Fibers, and Glucose and Insulin Tolerance of Insulin-Resistant Rats

BackgroundThe role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance. ObjectivesWe assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal. MethodsMale Wistar rats, 8 weeks old, weighing 250–275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle. ResultsIn experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin. ConclusionsStimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.

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.

Combination Therapy with GABA and MgSO4 Improves Insulin Sensitivity in Type 2 Diabetic Rat.

Background Gamma-aminobutyric acid (GABA) and magnesium sulfate (MgSO4) play a crucial role in glycemic control. Therefore, we studied the effect of combination therapy with GABA and MgSO4 to improve insulin sensitivity in diabetes induced by streptozotocin as well as high-fat diet in a diabetic rat model. Design and Methods. Forty randomly selected rats were assigned to four groups: nondiabetic control group was fed the normal diet, insulin-resistant diabetic rat model was induced by streptozotocin and high-fat diet, GABA + MgSO4 group received GABA and MgSO4, and insulin group was treated with insulin. Body weight, abdominal fat, blood glucose, serum insulin, and glucagon concentration were measured. The glucose clamp technique, glucose tolerance test, and insulin tolerance test were performed to study insulin sensitivity. Also, the expressions of glucose 6 phosphatase, glucagon receptor, and phosphoenolpyruvate carboxykinase genes in liver were assessed for the gluconeogenesis pathway. Protein translocation and glucose transporter 4 (Glut4) genes expression in muscle were also assessed. Results Combination of GABA + MgSO4 or insulin therapy enhanced insulin level, glycemic control, glucose and insulin tolerance test, some enzymes expression in the gluconeogenesis pathway, body fat, body weight, and glucagon receptor in diabetic rats. Moreover, an increase was observed in protein and gene expression of Glut4. Insulin sensitivity in combination therapy was more than the insulin group. Conclusions GABA and MgSO4 enhanced insulin sensitivity via increasing Glut4 and reducing the gluconeogenesis enzyme and glucagon receptor gene expressions.

Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models.

Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

Exercise ameliorates insulin resistance and improves ASK1-mediated insulin signalling in obese rats.

Increasing evidence reveals that physical exercise is an efficient therapeutical approach in the treatment of insulin resistance (IR) and related metabolic diseases. However, the potential beneficial effects of exercise on insulin resistance and its underlying mechanisms remain unclear. Recent findings elucidated the negative role of ASK1 in repressing the glucose uptake through JNK1‐IRS1‐Akt signalling in liver. Thus, a detailed investigation of the effect of ASK1‐mediated insulin signalling on exercise‐mediated improvement of insulin sensitivity and its underlying mechanism was implemented in this study. Using a high‐fat diet‐induced IR rat model of chronic or acute swimming exercise training, we here showed that body weight and visceral fat mass were significantly reduced after chronic exercise. Moreover, chronic exercise reduced serum FFAs levels and hepatic triglyceride content. Both chronic and acute exercise promoted glucose tolerance and insulin sensitivity. Meanwhile, both chronic and acute exercise decreased ASK1 phosphorylation and improved JNK1‐IRS1‐Akt signalling. Furthermore, exercise training decreased CFLAR, CREG and TRAF1 protein levels in liver of obese rats, which are positive regulator of ASK1 activity. These results suggested that swimming exercise demonstrated to be an effective ameliorator of IR through the regulation of ASK1‐mediated insulin signalling and therefore, could present a prospective therapeutic mean towards the treatment of IR and several metabolic diseases based on IR, containing NAFLD and type Ⅱ diabetes.

Insight into Shenqi Jiangtang Granule on the improved insulin sensitivity by integrating in silico and in vivo approaches

Ethnopharmacological relevancePresently, insulin resistance has been a growing concern that urgently needs to be addressed, because it not only places patients at risk of developing type 2 diabetes mellitus but also results in metabolic syndrome and different aspects of cardiovascular diseases. Shenqi Jiangtang Granule (SJG) is a classic traditional Chinese medicine (TCM) prescription that is widely used to treat diabetes mellitus and its complications in clinical practice. While studies have revealed that SJG with multi-ingredients and multi-targets characteristics possesses potential anti-insulin resistance pharmacological properties, its mechanisms of action and molecular targets for the treatment of insulin resistance are still obscure, which prompt us to conduct an in-depth research. Aim of the studyThis study was purposed to uncover the pharmacological mechanism of SJG against insulin resistance through integrating network pharmacology and experimental validation. Materials and methodsThe putative ingredients of SJG and its related targets were discerned from the TCMSP database. Subsequently, insulin resistance-associated targets were retrieved from GeneCard, OMIM, and GEO database. Compound-target, protein-protein interaction (PPI), and compound-target-pathway networks were established using Cytoscape software. GO and KEGG pathway analyses were performed to identify possible enrichment of genes with specific biological themes. Molecular docking was used to verify the correlation between the main active ingredients and hub targets. Optimal docking conformation was further analyzed by molecular dynamics (MD) simulation. Finally, the potential molecular mechanisms of SJG acting on insulin resistance, as predicted by the network pharmacology analyses, were validated experimentally in insulin-resistant rat model. Results136 active compounds, 211 corresponding targets in addition to 1463 disease-related targets were collected, of which 94 intersection targets were obtained. 29 key targets including AKT1, VEGFA, IL-6, CASP3, and PTGS2 were identified through PPI network analysis. Hub module of PPI network was closely associated with inflammation. GO and KEGG analyses also revealed that inflammation-related pathways may be a central factor for SJG to modulate insulin resistance. Molecular docking test showed a good binding potency between primary active ingredients and core targets, and the binding mode of optimal docking conformation was stable in MD simulation. A rat model of insulin resistance was successfully induced by chronic high-fat diet (HFD) consumption. Through a series of in vivo studies, including HEC, ITT, and HOMA-IR measurement, it was revealed that SJG exhibited a beneficial effect on ameliorating insulin resistance, as demonstrated by a significant increase of GIR and a significant decrease of AUCITT and HOMA-IR index value. Further molecular biological analysis showed that SJG can decrease the mRNA expression level and serum concentration of inflammatory cytokines (TNF-α, IL-6, and IL-1β), along with suppressing the p-NFκB protein overexpression, indicating its anti-inflammatory activity. Also, it can contribute to the reversal of the impaired hepatic insulin signaling pathway, as evidenced by up-regulated protein expression of p-Akt and GLUT2. ConclusionsThrough in silico and in vivo approaches, the present study not only provides a unique insight into the possible mechanism of SJG in insulin resistance after successfully filtering out associated key target genes and signaling pathways, but also suggests a novel promising therapeutic strategy for curing insulin resistance.

The Effect of Strawberry Juice on Homa-IR Level in Rat Model of Type 2 Diabetes Mellitus

Background: Strawberries contain high level of antioxidants and polyphenols, especially anthocyanins as powerful antioxidants. These ingredients can recover insulin resistance, oxidative stress, and pancreatic beta-cell function, which can affect blood sugar levels. This study aimed to evaluate the effect of strawberry juice in recovering insulin resistance in rat model of type 2 diabetes mellitus (T2DM) by homeostatic model assessment of insulin resistance (HOMA-IR) indicators.Methods: In an experimental study, 21 male rats (Rattus norvegicus) of Wistar strain were enrolled and received streptozotocin and nicotinamide to induce DM. They were divided into groups of P1 as negative control group in absence of any treatment, P2 as positive control group that were given metformin HCl (0.9 mg/Kg BW/day), and P3 as intervention group receiving strawberry juice (3.6 mL/200 g BW/day) for 14 days. The HOMA-IR level was determined for all groups and compared.Results: HOMA-IR level in P1 was 8.32±0.26, in P2 was 4.89±0.29, and in P3 was 5.16±0.20. Among groups, prior to treatment, there were no signifcant differences (p =0.66). A signifcant decrease was noted in HOMA-IR in P2 group (-3.75±0.09; p <0.001) and P3 group (-3.26±0.12; p <0.001), while in P1 group was not signifcant (0.03±0.12; p =0.46).Conclusion: Strawberry fruit like metformin was effective in reducing HOMA-IR in rat model of T2DM, when administered alone.

Magnolia officinalis Ameliorates Dehydroepiandrosterone-Induced Polycystic Ovary Syndrome in Rats

Background: Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder. Insulin resistance (IR) is highly associated with PCOS and aggravates its symptoms. Thiazolidinediones (TZDs), as insulin sensitizing agents, are PPARγ agonists that improve many of the symptoms of PCOS. The Magnolia officinalis extract (MOE) is a natural peroxisome proliferator activated receptor gamma (PPARγ) agonist that improves insulin sensitivity in experimental models. Objectives: Using a dehydroepiandrosterone (DHEA)-induced rat model of PCOS and IR, this study aimed to explore both the potential beneficial effects and the molecular mechanisms of action of MOE. Methods: Post-pubertal female Sprague Dawley rats were subcutaneously injected daily with DHEA (6 mg/100 g body weight) dissolved in sesame oil for 28 days (n = 30). Age- and weight-matched control rats received only sesame oil (n = 12). Afterward, 16 of the DHEA-injected rats, along with five control rats, were sacrificed for blood and tissue collection. The 14 remaining DHEA-injected rats received either treatment of 30 days of oral MOE (500 mg/kg) dissolved in dimethyl sulfoxide (DMSO) (n = 7), or oral DMSO only (n = 7). Meanwhile, the remaining control rats (n = 7) continued to receive daily oral DMSO for 30 days. At the end of the treatments, the rats were sacrificed for blood and tissue collection. Results: After 28 days, the DHEA-treated rats exhibited an increase in body weight as compared to controls (P &lt; 0.05). DHEA injection induced a PCOS phenotype as evident by a statistically significant (P &lt; 0.05) elevated serum luteinizing hormone (LH), and an increased number of cystically dilated follicles with thicker granulosa compared to controls. PCOS rats showed a statistically significant rise in fasting insulin with an increased homeostatic model assessment index of insulin resistance (HOMA-IR) as compared to controls (P &lt; 0.05). Compared to the control group, PCOS rats had a statistically significant lower ovarian protein expression of PPARγ, insulin receptor substrate 1 (IRS1), and protein kinase B (Akt) by Western Blot (P &lt; 0.05). Conversely, the PCOS group showed an increased mammalian target of rapamycin (mTOR) pathway activity as evident by an increase in the fraction of phosphorylated mTOR to total mTOR compared to the control group (P &lt; 0.05). When treated for 30 days with oral MOE (500 mg/kg), the PCOS rats showed a statistically significant decrease in body weight and serum LH levels as compared to the non-treated PCOS rats (P &lt; 0.05). The number of cystically dilated follicles in the MOE-treated PCOS rats was significantly reduced compared to the non-treated PCOS rats. In the MOE-treated PCOS rats, the ovarian protein expression of PPARγ, IRS1, and Akt was significantly increased, while the p-mTOR/mTOR expression was decreased compared to the non-treated PCOS group (P &lt; 0.05). Conclusions: According to our results, the MOE ameliorated the DHEA-induced PCOS phenotype histologically, hormonally, and metabolically. Fundamentally, this explores the elusive pathophysiologic association between IR and PCOS by targeting pathways common to both disorders.

The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance.

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.