P38 MAPK activation upregulates pro-inflammatory pathways in skeletal muscle cells from insulin resistant type 2 diabetic patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55650 | GEO | 2014/12/02
SECONDARY ACCESSION(S): PRJNA240306
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC4281683 | biostudies-literature
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: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:Brännmark2013 - Insulin signalling in human adipocytes (diabetic condition)
The paper describes insulin signalling in human adipocytes under normal and diabetic states using mathematical models based on experimental data. This model corresponds to insulin signalling under diabetic condtion
This model is described in the article:
Insulin Signaling in Type 2 Diabetes: EXPERIMENTAL AND MODELING ANALYSES REVEAL MECHANISMS OF INSULIN RESISTANCE IN HUMAN ADIPOCYTES.
Brännmark C, Nyman E, Fagerholm S, Bergenholm L, Ekstrand EM, Cedersund G, Strålfors P.
J Biol Chem. 2013 Apr 5;288(14):9867-80.
Abstract:
Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multilevel model, at the whole body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.
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2013-04-19 | BIOMD0000000449 | BioModels
Project description:Diabetic nephropathy is a major cause of end-stage renal disease. Kidney podocytes play a central role in the pathogenesis of diabetic nephropathy. With their intercellular contacts they assemble part of the kidney filter. Many molecular mechanisms of the pathogenesis of diabetic nephropathy are not elucidated and targeted therapies are lacking. Nephron-specific TrkCknockout (TrkC-KO) and TrkC overexpressing mice exhibit features of diabetic nephropathy such as enlarged glomeruli with mesangial proliferation, basement membrane thickening, albuminuria and podocyte loss when aging. Insulin-like growth factor 1 receptor (Igf1R)- associated gene expression was regulated in TrkC-KO mice glomeruli by qPCR. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb) and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3(Nt-3) in a mass spectrometry analysis. Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Our results identify TrkC to be a potentially targetable mediator of diabetic nephropathy.
2021-09-10 | PXD017960 | Pride
Project description:Objective: To study if diabetic and insulin-resistant states lead to mitochondrial dysfunction in the liver, or alternatively, if there is adaption of mitochondrial function to these states in the long-term range. Results: High-fat diet (HFD) caused insulin resistance and severe hepatic lipid accumulation, but respiratory chain parameters were unchanged. Livers from insulin-resistant IR/IRS-1+/- mice had normal lipid contents and normal respiratory chain parameters, however showed mitochondrial uncoupling. Livers from severely hyperglycemic and hypoinsulimic, streptozotocin (STZ)-treated mice had massively depleted lipid levels, but respiratory chain abundance was unchanged. However, their mitochondria showed increased abundance and activity of the respiratory chain, which was better coupled compared to controls. Conclusions: Insulin resistance, either induced by obesity or by genetic manipulation, does not cause mitochondrial dysfunction in the liver of mice. However, severe insulin deficiency and high blood glucose levels in mice cause an enhanced performance of the respiratory chain, probably in order to maintain the high energy requirement of the unsuppressed gluconeogenesis. We performed gene expression microarray analysis on liver tissue derived from mice treated with STZ or standard diet (control).
2013-12-10 | E-GEOD-39752 | biostudies-arrayexpress
Project description: Not available
| S-EPMC3534568 | biostudies-literature
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53754 | GEO
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53753 | GEO
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy. 28 BKS.Cg-Dock7m +/+ Leprdb/J (000642) mice (12 week old ) were divided to 4 forms of treatment (n=7 per treatment group) consisting of 4 different shRNA adenoviruses (reference sample: control shRNA), LCN13 (LCN13 shRNA), TSC22D4 (TSC22D4 shRNA), TSC22D4 plus LCN13 (TSC22D4+LCN13 shRNA). 1 week after shRNA injection animals were sacrificed, liver, abdominal fat tissue, gastrocnemius tissue was immediately snap frozen. 3 representative animals of each treatment group were selected for microarray analysis (abdominal fat tissue).
2014-10-15 | E-GEOD-53753 | biostudies-arrayexpress