scholarly journals Immobilization rapidly induces thioredoxin-interacting protein gene expression together with insulin resistance in rat skeletal muscle

2018 ◽  
Vol 125 (2) ◽  
pp. 596-604 ◽  
Author(s):  
Emi Kawamoto ◽  
Keigo Tamakoshi ◽  
Song-Gyu Ra ◽  
Hiroyuki Masuda ◽  
Kentaro Kawanaka
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Expression ◽  
Glucose Uptake ◽  
Rapid Development ◽  
Plaster Cast ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Transcription Inhibitor ◽  
Male Wistar Rats

Acute short duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Because thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-h hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral nonimmobilized hindlimbs were excised and examined. The 6-h immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats euthanized 6 h after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMP-dependent protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide) also suppressed the increase in TXNIP protein expression in 6-h-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue. NEW & NOTEWORTHY The cellular mechanism by which disuse rapidly induces muscle insulin resistance for glucose uptake remains to be identified. Using a rat hindlimb immobilization model, our findings suggest the possibility that transcriptional upregulation of thioredoxin-interacting protein is associated with the immobilization-induced rapid development of insulin resistance in skeletal muscle.

Thioredoxin interacting protein mediates lipid-induced impairment of glucose uptake in skeletal muscle

2016 ◽  
Vol 479 (4) ◽  
pp. 933-939 ◽  
Author(s):  
Ashok Mandala ◽  
Nabanita Das ◽  
Sudarshan Bhattacharjee ◽  
Bidisha Mukherjee ◽  
Satinath Mukhopadhyay ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

Time course of insulin resistance associated with feeding dogs a high-fat diet

1997 ◽  
Vol 272 (1) ◽  
pp. E147-E154 ◽  
Author(s):  
A. P. Rocchini ◽  
P. Marker ◽  
T. Cervenka
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Glucose Uptake ◽  
Dose Response ◽  
High Fat Diet ◽  
Time Course ◽  
Rapid Development ◽  
Diet Group ◽  
Whole Body ◽  
High Fat

The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.

scholarly journals Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7228
Author(s):  
Ching-Chia Wang ◽  
Huang-Jen Chen ◽  
Ding-Cheng Chan ◽  
Chen-Yuan Chiu ◽  
Shing-Hwa Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

scholarly journals NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3622-3627 ◽  
Author(s):  
Sanjeev Choudhary ◽  
Sandeep Sinha ◽  
Yanhua Zhao ◽  
Srijita Banerjee ◽  
Padma Sathyanarayana ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Muscle Insulin Resistance ◽  
Akt Phosphorylation ◽  
Skeletal Muscle Insulin Resistance ◽  
Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPKα/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice

2021 ◽  
pp. 1-19
Author(s):  
Chih-Chieh Chen ◽  
Chong-Kuei Lii ◽  
Chia-Wen Lo ◽  
Yi-Hsueh Lin ◽  
Ya-Chen Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Time Dependent ◽  
Antidiabetic Activity ◽  
C2c12 Myotubes ◽  
Dependent Manner ◽  
Compound C

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

scholarly journals Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle

2018 ◽  
Vol 115 (3) ◽  
pp. 590-601 ◽  
Author(s):  
Dino Premilovac ◽  
Emily Attrill ◽  
Stephen Rattigan ◽  
Stephen M Richards ◽  
Jeonga Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Heart Rate ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Microvascular Blood Flow ◽  
Euglycaemic Clamp ◽  
Hyperinsulinaemic Euglycaemic Clamp ◽  
Skeletal Muscle Glucose Uptake

Abstract Aims Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin’s microvascular and metabolic actions in skeletal muscle. Methods and results Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals’ systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin’s effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Conclusions Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin’s microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

scholarly journals MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

2014 ◽  
Vol 35 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Mohan R. Kaadige ◽  
Jingye Yang ◽  
Blake R. Wilde ◽  
Donald E. Ayer
Keyword(s):  
Glucose Uptake ◽  
Leucine Zipper ◽  
Aerobic Glycolysis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Nutrient Status ◽  
Regulatory Relationship ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Helix Loop Helix

Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular and organismal growth. How mTOR regulates transcriptional programs in response to these diverse stimuli is poorly understood. MondoA and its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) transcription factors that sense and execute a glucose-responsive transcriptional program. MondoA-Mlx complexes activate expression of thioredoxin-interacting protein (TXNIP), which is a potent inhibitor of cellular glucose uptake and aerobic glycolysis. Both mTOR and MondoA are central regulators of glucose metabolism, yet whether they interact physically or functionally is unknown. We show that inhibition of mTOR induces MondoA-dependent expression of TXNIP, coinciding with reduced glucose uptake. Mechanistically, mTOR binds to MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Further, we show that mTOR inhibitors and reactive oxygen species (ROS) regulate interaction between MondoA and mTOR in an opposing manner. Like mTOR's suppression of the MondoA-TXNIP axis, MondoA can also suppress mTOR complex 1 (mTORC1) activity via its direct transcriptional regulation of TXNIP. Collectively, these studies reveal a regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis.

Hemodynamic actions of insulin

1994 ◽  
Vol 267 (2) ◽  
pp. E187-E202 ◽  
Author(s):  
A. D. Baron
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Pressor Response ◽  
Physiological Role ◽  
Oxide System ◽  
Maximal Response ◽  
Insulin Resistant ◽  
The Right

There is accumulating evidence that insulin has a physiological role to vasodilate skeletal muscle vasculature in humans. This effect occurs in a dose-dependent fashion within a half-maximal response of approximately 40 microU/ml. This vasodilating action is impaired in states of insulin resistance such as obesity, non-insulin-dependent diabetes, and elevated blood pressure. The precise physiological role of insulin-mediated vasodilation is not known. Data indicate that the degree of skeletal muscle perfusion can be an important determinant of insulin-mediated glucose uptake. Therefore, it is possible that insulin-mediated vasodilation is an integral aspect of insulin's overall action to stimulate glucose uptake; thus defective vasodilation could potentially contribute to insulin resistance. In addition, insulin-mediated vasodilation may play a role in the regulation of vascular tone. Data are provided to indicate that the pressor response to systemic norepinephrine infusions is increased in obese insulin-resistant subjects. Moreover, the normal effect of insulin to shift the norepinephrine pressor dose-response curve to the right is impaired in these patients. Therefore, impaired insulin-mediated vasodilation could further contribute to the increased prevalence of hypertension observed in states of insulin resistance. Finally, data are presented to indicate that, via a yet unknown interaction with the endothelium, insulin is able to increase nitric oxide synthesis and release and through this mechanism vasodilate. It is interesting to speculate that states of insulin resistance might also be associated with a defect in insulin's action to modulate the nitric oxide system.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 20140: Minibrain Relate Kinase / Dyrk1B Links Skeletal Muscle Glycolytic Metabolism with Insulin Resistance and Causes Metabolic Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mohsen Fathzadeh ◽  
Ali Reza Keramati ◽  
Gwang Go ◽  
Rajvir Singh ◽  
Kazem Sarajzadeh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Protein Expression ◽  
Ppar Gamma ◽  
Glycolytic Metabolism ◽  
Expression Levels ◽  
Fiber Composition ◽  
Mutation Carriers ◽  
Fast Twitch

We have identified a novel nonconservative mutation in Minibrain related serine/threonine kinase (Mirk/ Dyrk1B) in outlier kindreds with metabolic syndrome. The mutation substitutes cysteine for arginine (R102C) and segregates with most traits of metabolic syndrome, including central obesity, diabetes and hypertension. Oral glucose tolerance test (OGTT) in young nondiabetic mutation carriers revealed insulin resistance compared to noncarrier family members. Since skeletal muscle (SM) is the largest organ for glucose uptake and metabolism, we obtained Vastus Lateralis biopsies of mutation carriers and their unaffected relatives and examined them for gene/protein expression by deep RNA sequencing (RNA-Seq) and Western blot analysis and for fiber composition by immunostaining. The fiber composition data demonstrated fewer slow-twitch fibers (35% vs. 75%) and more fast -twitch fibers (65% vs. 25%) in SM of mutation carriers vs. controls. Interestingly, there were increased protein expression levels of fast-twitch fiber type proteins (MYH11, MYLPF), pyruvate dehydrogenase kinase, pyruvate kinase, and neuronal nitric oxide synthase in SM of mutation carriers vs. noncarriers. Consistent with these findings, the protein expression levels of the master regulator of cellular energy metabolism mitochondrial biogenesis, PPAR-gamma coactivator (PGC-1a), were reduced and the nuclear expression levels of FOXO1 and NFAT were increased. Similar findings were observed when wildtype and mutant (R102C) Dyrk1B were overexpressed in C2C12 cells. The overexpression of the kinase deficient Dyrk1B (Y271/273F) similarly resulted in reduced expression of PGC-1a and increased expression of nuclear FOXO1, suggesting kinase independent effects. Taken together, these findings suggest that enhanced kinase-independent activities of Dyrk1B, either through increased expression or by its gain of function mutation R102C induce insulin resistance by promoting glycolytic metabolism and reducing oxidative phosphorylation. In conclusion, Dyrk1B is a potential target for development of novel drugs that aim to enhance skeletal muscle insulin sensitivity.

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