Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Muscle
DISEASE(S): Diabetes
PROVIDER: ST000115 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:The goal of this study was to analyse the effect of a 12 weeks treatment with rosiglitazone on insulin sensitivity in the muscle of type 2 diabetic patients. Ten diabetic patients were submitted to a 3 hours euglycemic-hyperinsulinemic clamp. Skeletal muscle biopsies were taken before and after the clamp. Samples from the same patients (obtained before and after the clamp) were hybridized on the same microarray. Biopsie taken before the clamp was considered as the control. Then, the patients were treated with rosiglitazone, agonist of PPAR gamma, during 12 weeks. After the treatment, all the patients were submitted to a second 3 hours euglycemic-hyperinsulinemic clamp. Skeletal muscle biopsies for 7 patients were taken before and after the clamp. Samples from the same patients (obtained before and after the clamp) were hybridized on the same microarray. Biopsie taken before the clamp was considered as the control. Set of arrays that are part of repeated experiments Compound Based Treatment: patient biopsies taken before (no) and after (yes) rosiglitazone (TZD) treatment`
2018-04-20 | GSE12844 | GEO
Project description:Ceramides contribute to obesity-linked insulin resistance and inflammation in vivo, but whether this is a cell-autonomous phenomenon is debated, particularly in muscle, which dictates whole-body glucose uptake. We comprehensively analyzed lipid species produced in response to fatty acids and examined the consequence to insulin resistance and pro-inflammatory pathways. L6 myotubes were incubated with BSA-adsorbed palmitate or palmitoleate in the presence of myriocin, fenretinide, or fumonisin B1. Lipid species were determined by lipidomic analysis. Insulin sensitivity was scored by Akt phosphorylation and glucose transporter 4 (GLUT4) translocation, while pro-inflammatory indices were estimated by IκBα degradation and cytokine expression. Palmitate, but not palmitoleate, had mild effects on Akt phosphorylation but significantly inhibited insulin-stimulated GLUT4 translocation and increased expression of pro-inflammatory cytokines Il6 and Ccl2 Ceramides, hexosylceramides, and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro-inflammatory indices. Inhibition of sphingolipid pathways led to marked changes in cellular lipids, but did not prevent palmitate-induced impairment of insulin-stimulated GLUT4 translocation, suggesting that palmitate-induced accumulation of deleterious lipids and insulin resistance are correlated but independent events in myotubes. We propose that muscle cell-endogenous ceramide production does not evoke insulin resistance and that deleterious effects of ceramides in vivo may arise through ancillary cell communication.
| S-EPMC6027910 | biostudies-literature
Project description:BackgroundC-peptide therapy exerts several positive actions on nerves, vasculature, smooth muscle relaxation, kidney function and bone. To date, the role of C-peptide in preventing type 1 diabetes-related muscle atrophy has not been investigated. Our aim was to evaluate if C-peptide infusion prevents muscle wasting in diabetic rats.MethodsTwenty-three male Wistar rats were randomly divided into three groups: normal control group, diabetic group and diabetic group plus C-peptide. Diabetes was induced by streptozotocin injection, and C-peptide was administered subcutaneously for 6 weeks. The blood samples were obtained at baseline, before streptozotocin injection and at the end of the study to assess C-peptide, ubiquitin and other laboratory parameters. We also tested the ability of C-peptide to regulate the skeletal muscle mass, the ubiquitin-proteasome system, the autophagy pathway as well as to improve muscle quality.ResultsC-peptide administration reversed hyperglycaemia (P = 0.02) and hypertriglyceridaemia (P = 0.01) in diabetic plus C-peptide rats compared with diabetic control rats. The diabetic-control animals displayed a lower weight of the muscles in the lower limb considered individually than the control rats and the diabetic plus C-peptide rats (P = 0.03; P = 0.03; P = 0.04; P = 0.004, respectively). The diabetic-control rats presented a significantly higher serum concentration of ubiquitin compared with the diabetic plus C-peptide and the control animals (P = 0.02 and P = 0.01). In muscles of the lower limb, the pAmpk expression was higher in the diabetic plus C-peptide than the diabetic-control rats (in the gastrocnemius, P = 0.002; in the tibialis anterior P = 0.005). The protein expression of Atrogin-1 in gastrocnemius and tibialis was lower in the diabetic plus C-peptide than in diabetic-control rats (P = 0.02, P = 0.03). After 42 days, the cross-sectional area in the gastrocnemius of the diabetic plus C-peptide group had been reduced by 6.6% while the diabetic-control rats had a 39.5% reduction compared with the control animals (P = 0.02). The cross-sectional area of the tibialis and the extensor digitorum longus muscles was reduced, in the diabetic plus C-peptide rats, by 10% and 11%, respectively, while the diabetic-control group had a reduction of 65% and 45% compared with the control animals (both P < 0.0001). Similar results were obtained for the minimum Feret's diameter and perimeter.ConclusionsC-peptide administration in rats could protect skeletal muscle mass from atrophy induced by type 1 diabetes mellitus. Our findings could suggest that targeting the ubiquitin-proteasome system, Ampk and muscle-specific E3 ubiquitin ligases such as Atrogin-1 and Traf6 may be an effective strategy for molecular and clinical intervention in the muscle wasting pathological process in T1DM.
| S-EPMC10067479 | biostudies-literature
Project description:DNA demethylation occurs in multiple cellular processes but its regulation is poorly understood. Here we report that a vital nutrient factor ascorbic acid (AA), or vitamin C (Vc), induces DNA demethylation in mammalian cells. The levels of active 5mC oxidation products, 5-formylcytosine and 5-carboxylcytosine, increase by more than one magnitude of order in mouse ES cells when cultured in the presence of AA. In cells deleted of Tet1 and Tet2 dioxygenase genes, AA does not facilitate 5mC oxidation. The AA effect is however restored when Tet2 was re-expressed in the mutant cells. The enhancing effect of AA on 5mC oxidation and DNA demethylation was also observed in a mouse model deficient in AA synthesis. Our results thus reveal a role of AA in the regulation of DNA modification, which might mediate a plethora of functions of AA. Examination of 5hmC levels with or without AA in mouse ES cells
2015-01-01 | E-GEOD-43262 | biostudies-arrayexpress
Project description:The effect of corticosterone on protein turnover in skeletal muscle was investigated in growing rats. Protein synthesis was measured in vivo by the constant infusion of [(14)C]tyrosine. The extent to which any effect of corticosterone is modulated by the hyperinsulinaemia induced by steroid treatment was examined by giving the hormone not only to adrenalectomized rats but also to streptozotocin-induced diabetic rats maintained throughout the treatment period on two dosages of insulin by an implanted osmotic minipump. Approximate rates of protein degradation were also estimated in some cases as the difference between synthesis and net change in muscle protein mass. Measurements were also made of free 3-methylhistidine concentration in muscle and plasma. At 10mg of corticosterone/100g body wt. per day, growth stopped and muscle wasting occurred, whereas at 5 mg of corticosterone/100g body wt. per day no net loss of protein occurred. However, this low dose did induce muscle wasting when insulin concentration was regulated by a dose of 1.2 units/day. Protein synthesis was markedly depressed in all treated groups, the depression in the insulin-maintained rats being marginally more than in the hyperinsulinaemic adrenalectomized rats. The oxidative soleus muscle appeared to be less susceptible to the effect of the corticosterone than was the more glycolytic plantaris or gastrocnemius muscle. Any effect of the corticosterone on protein degradation was much less than its effects on protein synthesis. Where increases in the degradation rates appeared to occur in the rats treated with 10mg of corticosterone/100g body wt. per day, the increases were less than 20%. The free intracellular 3-methylhistidine concentrations were doubled in all groups treated with 5 mg of corticosterone/100g body wt. per day and increased 5-fold in the adrenalectomized rats treated with 10mg of corticosterone/100g body wt. per day, with no change in plasma concentration in any of the groups. It is therefore concluded that: (a) the suppression of protein synthesis is the main effect of glucocorticoids in muscle; (b) marked increases in insulin afford only minor protection against this effect; (c) stimulation of protein degradation may occur, but to a much lesser extent.
| S-EPMC1158405 | biostudies-other
Project description:The aim of this study was to identify alterations associated with diabetes-induced functional dysregulation of the retina and the effects of chronic insulin therapy. Transcriptional profiling through microarray analysis was analyzed to find mRNA targets of interest in diabetic samples, as well as in the insulin treated group. Verification of targets shown to be unrecovered in the insulin group was validated. Diabetes was induced in Sprague-Dawley male rats (Charles River Laboratories, Wilmington, MA) by intraperitoneal injection of 65 mg/kg streptozotocin (STZ)(Sigma-Aldrich, St. Louis, MO) in 10mM sodium citrate pH 4.5 vehicle. Control rats were injected with an equal dose of vehicle only. Rats had free access to food and water, and were maintained on a 12 hour light/dark cycle. Blood glucose level and body weight were measured 6 days post-STZ or vehicle injection, and biweekly throughout the experiment. Only rats with blood glucose levels >250 mg/dL at the time of the original test and throughout the experiment were included in the diabetic groups. The insulin treatment group received one 26mg subcutaneous pellet (LinShin Canada, Scarborough, Canada) delivered via trocar 6 weeks post-STZ injection. An additional 26 mg implant was introduced when body weight exceeded 300 g or when midday non-fasting blood glucose exceeded 250 mg/dL. At the time of retina harvest, rats were given a lethal dose of pentobarbital, 100 mg/kg, (Ovation Pharmaceuticals Inc., Deerfield, IL) by intraperitoneal injection and sacrificed by decapitation. Retinas were rapidly excised snap- frozen in liquid nitrogen for subsequent experimentation.
2011-05-23 | E-GEOD-24423 | biostudies-arrayexpress
Project description:The aim of this study was to identify alterations associated with diabetes-induced functional dysregulation of the retina and the effects of chronic insulin therapy. Transcriptional profiling through microarray analysis was analyzed to find mRNA targets of interest in diabetic samples, as well as in the insulin treated group. Verification of targets shown to be unrecovered in the insulin group was validated.
2011-05-23 | GSE24423 | GEO
Project description:AimsStreptozotocin (STZ) is widely used to study diabetic complications. Owing to the nonspecific cytotoxicity of high-dose STZ, alternative models using moderate-dose or a combination of low-dose STZ and a high-fat diet have been established. This study aimed to investigate the effects of these models on muscle function.MethodsThe muscle function of two STZ models using moderate-dose STZ (100 mg/kg, twice) and a combination of low-dose STZ and high-fat diet (50 mg/kg for 5 consecutive days + 45% high-fat diet) were examined using in vivo electrical stimulation. Biochemical and gene expression analysis were conducted on the skeletal muscles of the models immediately after the stimulation.ResultsThe contractile force did not differ significantly between the models compared to respective controls. However, the moderate-dose STZ model showed more severe fatigue and blunted exercise-induced glycogen degradation possibly thorough a downregulation of oxidative phosphorylation- and vasculature development-related genes expression.ConclusionsModerate-dose STZ model is suitable for fatigability assessment in diabetes and careful understanding on the molecular signatures of each model is necessary to guide the selection of suitable models to study diabetic myopathy.
| S-EPMC11531449 | biostudies-literature
Project description:Purpose Although it has been well-acknowledged that insulin resistance (IR) plays a critical role in the development of hyperuricemia (HU), specific relationship between IR and HU in non-diabetic patients remains rarely studied, and there is still no large-scale research regarding this issue. This study aims to explore the association between triglyceride glucose (TyG), TyG with body mass index (TyG-BMI), the ratio of triglycerides divided by high-density lipoprotein cholesterol (TG/HDL-C), metabolic score for insulin resistance (METS-IR), and the risk of HU in non-diabetic patients in The United States of America. Patients and methods Data from the National Health and Nutrition Examination Survey (NHANES) enrolling a representative population aged ≥18-year-old were included to calculate these four indexes. Logistic regression analysis was applied to describe their associations and calculate odds ratios (OR) while the Receiver Operating Characteristic curve was utilized to assess the prediction ability of these four indexes. Results A total of 7,743 people (3,806 males and 3,937 females, mean age: 45.17 ± 17.10 years old) were included in this study, among whom 32.18% suffered from HU. After adjustment for sex, age, ethnicity, education background, smoking status, drinking status, systolic blood pressure (SBP), diastolic blood pressure (DBP), metabolic equivalent values (METs), total cholesterol, low-density lipoprotein cholesterol, and estimated glomerular filtration rate, it showed that all four indexes were closely related to HU. Compared with the lowest quartile, OR of the highest quartile of these four indicators for HU were as following respectively: TyG: 5.61 (95% CI: 4.29–7.32); TyG-BMI: 7.15 (95% CI: 5.56–9.20); TG/HDL-C: 4.42 (95% CI: 3.49–5.60); METS-IR: 7.84 (95% CI: 6.07–10.13). TyG, TyG-BMI, TG/HDL-C and METS-IR had moderate discrimination ability for HU, with an AUC value of 0.66 (95% CI: 0.65–0.68), 0.67 (95% CI: 0.65-0.68), 0.68 (95% CI: 0.67-0.69) and 0.68 (95% CI: 0.66–0.69) respectively. Each index showed better prediction ability for HU risk in females than in males. Conclusion It was found that the risk of HU was positively associated with the elevation of TyG, TyG-BMI, TG/HDL-C and METS-IR in a large-scale population of U.S., and TyG-BMI and METS-IR have a better ability to identify HU in both genders.
| S-EPMC9797589 | biostudies-literature
Project description:ObjectiveTo compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA).Research design and methodsIn a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34).ResultsThere were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose <70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03).ConclusionsRegular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.
| S-EPMC2699711 | biostudies-literature