Liver and Plasma metaboites for 13C-glucose load in wild type, LIRKO GTT 1 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mouse Mus Musculus
TISSUE(S): Liver
SUBMITTER: 
Maureen Kachman
PROVIDER: ST000215 | MetabolomicsWorkbench | Fri Jun 12 00:00:00 BST 2015
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| mwtab | Other |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description:Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes (T2D). In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have similar body weight as controls, but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1 and Akt in muscle and improved glucose tolerance compared to controls. When challenged with high fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating post-receptor insulin resistance. RNA sequencing reveals downregulation of several post-receptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the insulin receptor protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to post-receptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.
2020-09-01 | GSE149662 | GEO
Project description:Momordica charantia (MC) is a common vegetable in tropical areas and has been used for a long time as an alternative therapy for diabetes. Although several constituents of MC have displayed the hypoglycemic effects, the hypoglycemic targets of these constituents remain to be clarified. In this study, we analyzed and elucidated the therapeutic targets contributing to the hypoglycemic effect of aqueous extract of MC seeds (MCSE) by transcriptomic analysis. The protein ingredients aimed at the hypoglycemic target were further identified by proteomic, docking, and receptor-binding assays. Our data showed that MCSE, which was rich in small-molecular weight proteins, displayed hypoglycemic effects in normal and diabetic mice by glucose tolerance assay. MCSE significantly and primarily regulated the insulin signaling pathway in muscles and adipose tissues, suggesting that MCSE might target to insulin receptor (IR), stimulate the IR-downstream pathway, and subsequently display the hypoglycemic activity. We further identified that inhibitor against trypsin (TI) of MC directly docked into IR and activated the kinase activity of IR. In conclusion, our findings suggested that MCSE regulated glucose metabolism mainly via insulin signaling pathway. Moreover, we newly identified that TI was a novel IR-binding protein of MC that triggers the insulin signaling pathway via binding to IR. Mice were fasted for 4 h and MCSE or PBS was then orally given 15 min before intraperitoneal administration of glucose solution (1 g/kg body weight). Blood samples were collected from tails at 15 min before and at 15, 30, 60, 90, 120, 150, 180, and 240 min after glucose challenge. Blood glucose was measured by glucose oxidase method using a glucometer (ACCU-CHEK Advantage, Roche Diagnostics, Basel, Switzerland). Mice were sacrificed 4 h after glucose challenge. Muscles, adipose tissues, and livers were collected for microarray analysis.
2015-07-01 | E-GEOD-39689 | biostudies-arrayexpress
Project description:Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (MIRKO) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (QKO). Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in MIGIRKO muscle, and these were reversed with FoxO knockout. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.
2021-07-21 | GSE178356 | GEO
Project description:FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. 13C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted.
Research is published:
http://www.nature.com/ncomms/2015/150512/ncomms8079/full/ncomms8079.html
2015-06-10 | ST000198 | MetabolomicsWorkbench
Project description:Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist-2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of exogenous under-carboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion to control glucose homeostasis. We used microarrays to detail the global gene expression changes in response to insulin acting through insulin receptor in osteoblasts and identified distinct genes specifically involved in bone remodeling process. 4 groups and 3 time points (0h as a control, 6h, 12h, and 24h)
2010-05-27 | E-GEOD-21710 | biostudies-arrayexpress
Project description:Insulin resistance increases patient’s risk of developing type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and germline Grb14-knockout (KO) mice have improved insulin signaling in liver and muscle tissues. Here, we show that Grb14 knockdown in the liver and the heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and decreased systolic function, effects that could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in hemodynamic function as measured by echocardiography in DIO Grb14 and DIO sham mice for a period of four months. While additional studies are needed to further establish efficacy and to de-risk potential negative cardiac effects in pre-clinical heart failure models, our data support inhibiting Grb14 to treat diabetes and related conditions.
2020-04-14 | GSE143319 | GEO
Project description:Momordica charantia (MC) is a common vegetable in tropical areas and has been used for a long time as an alternative therapy for diabetes. Although several constituents of MC have displayed the hypoglycemic effects, the hypoglycemic targets of these constituents remain to be clarified. In this study, we analyzed and elucidated the therapeutic targets contributing to the hypoglycemic effect of aqueous extract of MC seeds (MCSE) by transcriptomic analysis. The protein ingredients aimed at the hypoglycemic target were further identified by proteomic, docking, and receptor-binding assays. Our data showed that MCSE, which was rich in small-molecular weight proteins, displayed hypoglycemic effects in normal and diabetic mice by glucose tolerance assay. MCSE significantly and primarily regulated the insulin signaling pathway in muscles and adipose tissues, suggesting that MCSE might target to insulin receptor (IR), stimulate the IR-downstream pathway, and subsequently display the hypoglycemic activity. We further identified that inhibitor against trypsin (TI) of MC directly docked into IR and activated the kinase activity of IR. In conclusion, our findings suggested that MCSE regulated glucose metabolism mainly via insulin signaling pathway. Moreover, we newly identified that TI was a novel IR-binding protein of MC that triggers the insulin signaling pathway via binding to IR.
2015-07-01 | GSE39689 | GEO
Project description:Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist-2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of exogenous under-carboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion to control glucose homeostasis. We used microarrays to detail the global gene expression changes in response to insulin acting through insulin receptor in osteoblasts and identified distinct genes specifically involved in bone remodeling process.
2010-05-07 | GSE21710 | GEO
Project description:Insulin and IGF-1 receptors (IR/IGF1R) are highly homologous and share similar signaling systems, but each has a unique physiological role, with IR primarily regulating metabolic homeostasis and IGF1R regulating mitogenic control and growth. Here, we show that replacement of a single amino acid at position 973, just distal to the NPEY motif in the intracellular juxtamembrane region, from leucine, which is highly-conserved in IRs, to phenylalanine, the highly-conserved homologous residue in IGF1Rs, results in decreased IRS-1-PI3K-Akt-mTORC1 signaling and increased of Shc-Gab1-MAPK-cell cycle signaling. As a result, cells expressing L973F-IR exhibit decreased insulin-induced glucose uptake, increased cell growth and impaired receptor internalization. Mice with knockin of the L973F-IR show similar alterations in signaling in vivo, and this leads to decreased insulin sensitivity, a modest increase in growth and decreased weight gain when challenged with high-fat diet. Thus, leucine973 in the juxtamembrane region of the IR acts is a crucial residue differentiating IR signaling from IGF1R signaling.
2022-12-21 | PXD038649 | Pride
Project description:The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic beta cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3-/-) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3-/- islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a Gαi/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3-/- and WT islets observed multiple genes with well known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through Gαi/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches. Analysis of total RNA from 3 biological replicates of pancreatic islets isolated from free fatty acid receptor 3 knockout (Ffar3 KO) and wildtype (Ffar3 WT) male mice
2016-07-03 | E-GEOD-67991 | biostudies-arrayexpress