DNA Methylation Profiling of Hepatic Insulin Response in Young and Aged Mice
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens Macaca mulatta Rattus
PROVIDER: GSE295416 | GEO | 2025/05/14
REPOSITORIES: GEO
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Project description:Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR? ligands. We transcriptionally profiled 364 biopsies gathered from 72 human subjects harvested before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Subjects range from insulin-sensitive to insulin-resistant. Insulin resistant subjects responded to TZD treatment with varied improvements in insulin sensitivity, thus they were ranked by their degree of TZD response to define responder and non-responder subgroups. Skeletal muscle biopsies were obtained from vastus lateralis before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Adipose tissue biopsies were obtained from abdominal subcutaneous before clamp, at baseline and after three-month TZD treatment. *** CEL files not provided for 40 Samples. ***
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Project description:Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ ligands. We transcriptionally profiled 364 biopsies gathered from 72 human subjects harvested before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Subjects range from insulin-sensitive to insulin-resistant. Insulin resistant subjects responded to TZD treatment with varied improvements in insulin sensitivity, thus they were ranked by their degree of TZD response to define responder and non-responder subgroups.
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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 adipose tissue of type 2 diabetic patients. Diabetic patients were submitted to a 3 hours hyperinsulinemic- euglycemic clamp. Adipose tissue biopsies were taken before and after the clamp, labelled A & B respectively. 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 hyperinsulinemic-euglycemic clamp. Adipose tissue biopsies were taken before and after the clamp, labelled C & D respectively.
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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:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Cotadutide or GCGR monoagonist treatment resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment.
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Project description:Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
2020-07-08 | GSE139015 | GEO
Project description:To identify insulin responsive genes in humans, in the first protocol, skeletal muscle biopsies from six non-diabetic subjects were obtained before and after a two-hour of hyperinsulinaemic (infusion rate 40 mU/m2/min) euglycemic clamp. A variable infusion of glucose (180 g/l) enriched with tritiated glucose (100 μCi/500 ml) maintained euglycemia during insulin infusion, with monitoring of plasma glucose concentration every 5 to 10 min during the basal and clamp periods using an automated glucose oxidation method (Glucose Analyzer 2, Beckman Instruments, Fullerton, CA). In the second protocol, skeletal muscle biopsies from six non-diabetic subjects were obtained before and after a 3-hour hyperinsulinemic (infusion rate 40 mU/m2/min) euglycemic clamp in order to increase the effects of insulin on gene expression. A variable infusion of glucose (180 g/l) was used to maintain euglycemia during insulin infusion with monitoring of plasma glucose concentration every 5 to 10 min using an automated glucose oxidation method (Glucose Analyzer 2, Beckman Instruments, Fullerton, CA). Keywords: dose response The muscle biopsies were obtained from the vastus lateralis muscle under local anesthesia before and after hyperinsulinaemic (infusion rate 40 mU/m2/min) euglycemic clamp
2007-03-01 | E-GEOD-7146 | biostudies-arrayexpress
Project description:BACKGROUND. Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice. METHODS. Fourteen lean, healthy individuals randomly received either palm oil (PO) or vehicle (VCL). Hepatic metabolism was analyzed using in vivo 13C/31P/1H and ex vivo 2H magnetic resonance spectroscopy before and during hyperinsulinemic-euglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses. RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION. Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.
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Project description:This study was undertaken to test the hypothesis that short term exposure (4 hours) to physiologic hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response, independently of glycemic status. We performed euglycemic hyperinsulinemic (80 mU/m2/min) clamps in 12 healthy, insulin sensitive subjects with no family history of diabetes followed by biopsies of the vastus lateralis muscle taken basally and after 30 and 240 minutes of insulin infusion. Gene expression profiles were generated using Affymetrix HG-U133A arrays. No probe sets had significantly altered expression at 30 minutes of the insulin clamp, but 121 probe sets (117 upregulated and 4 downregulated) were significantly altered after 240 minutes. Hyperinsulinemia in normal, healthy human subjects increased the mRNAs for a number of inflammatory genes and transcription factors. Microarray and quantitative RT-PCR revealed the upregulation of chemokine, cc motif, ligand 2 (CCL2), CCL8, thrombomodulin (THBD), ras-related associated with diabetes (RRAD), metallothionein (MT), and serum/glucocorticoid regulated kinase (SGK), and downregulation of CITED2 (a CREB-binding protein-interacting transactivator), a known coactivator of PPAR-alpha. Interestingly, SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to hyperinsulinemia. A control saline infusion performed on 3 normal, healthy subjects without a family history of diabetes demonstrated that the genes altered following the euglycemic-hyperinsulinemic clamp were due to insulin and independent of biopsy removal. This study demonstrates that insulin acutely regulates the expression of genes involved in inflammation and transcription, and identifies several candidate genes/pathways for further investigation. Experiment Overall Design: Twelve subjects received a vastus lateralis muscle biopsy followed by a 180-min euglycemic, hyperinsulinemic (80 mU/m2.min) clamp. Muscle biopsies from each subject were homogenized in RNAStat solution (Tel-Test Inc., Friendswood, TX), using a Polytron homogenizer (Brinkmann Instruments Westbury, NY). Total RNA was purified with RNeasy and DNase I treatment (Qiagen, Chatsworth, CA). RNA was prepared for hybridization to Affymetrix (Santa Clara, CA) HG-U133A arrays according to the manufacturerâs instructions.
2008-06-16 | E-GEOD-9105 | biostudies-arrayexpress