Reduced Skeletal Muscle Inhibitor of κBβ Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes: Reversal by Exercise Training

  title={Reduced Skeletal Muscle Inhibitor of $\kappa$B$\beta$ Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes: Reversal by Exercise Training},
  author={Apiradee Sriwijitkamol and Christine Y. Christ-Roberts and Rachele Berria and Phyllis A. Eagan and Thongchai Pratipanawatr and Ralph A. DeFronzo and Lawrence J. Mandarino and Nicolas Musi},
Skeletal muscle insulin resistance plays a key role in the pathogenesis of type 2 diabetes. It recently has been hypothesized that excessive activity of the inhibitor of κB (IκB)/nuclear factor κB (NFκB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IκB/NFκB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IκB/NFκB signaling in vastus lateralis muscle from six subjects with type 2 diabetes and… 

Figures and Tables from this paper

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions.

It is concluded that insulin-resistant subjects have increased basal NF-κB activity in muscle from nondiabetic subjects, and exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-kkB activity, suggesting that other factors promote gene expression of these cytokines during exercise.

Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.

c-Jun NH2-Terminal Kinase Activity in Subcutaneous Adipose Tissue but Not Nuclear Factor-κB Activity in Peripheral Blood Mononuclear Cells Is an Independent Determinant of Insulin Resistance in Healthy Individuals

JNK1/2 activity in adipose tissue but not NF-κB activity in PBMCs is an independent determinant of insulin resistance in healthy individuals.

Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight.

The data altogether do not support the notion that bed rest-induced insulin resistance is caused by increased muscle inflammation, and LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest.

Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB

The current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension.

Type 2 Diabetes Is Associated with Altered NF-κB DNA Binding Activity, JNK Phosphorylation, and AMPK Phosphorylation in Skeletal Muscle after LPS

It is indicated that pathways regulating glucose uptake in skeletal muscle may be involved in the development of inflammation-associated hyperglycemia and patients with type 2 diabetes exhibit changes in these pathways, which may ultimately render such patients more prone to develop dysregulated glucose disposal in the context of systemic inflammation.

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

IKKβ silencing prevents TNF-α–induced impairments in insulin action on Akt phosphorylation and glucose uptake and metabolism in human skeletal muscle.

Nitrosative stress and pathogenesis of insulin resistance.

Protein S-nitrosylation, a covalent attachment of NO moiety to thiol sulfhydryls, has emerged as a major mediator of a broad array of NO actions and has recently been proposed to play an important role in the pathogenesis of insulin resistance.

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy

Exercise-mediated SCFAs-upregulation may ameliorate insulin resistance (IR) through increasing autophagy of skeletal muscle cells by binding to GPR43.

Dissociation between skeletal muscle inhibitor-kappaB kinase/nuclear factor-kappaB pathway activity and insulin sensitivity in nondiabetic twins.

It is suggested that IKK/NF-kappaB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK /NF/p65 pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.



Diet-induced obesity and acute hyperlipidemia reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type dependent manner.

It is concluded that diet-induced obesity and acute HL reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type-dependent manner and cannot be explained by differential accumulation of triglyceride in Sol and Vas.

Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance.

  • S. ShoelsonJ. LeeM. Yuan
  • Medicine, Biology
    International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity
  • 2003
The findings showed that signaling pathways leading to I kappa B kinase beta (IKK beta) and NF-kappa B are activated in insulin-responsive tissues of obese and high-fat-fed animals, and high doses of salicylates improved insulin sensitivity in patients with type II diabetes.

Fatty Acid-induced Insulin Resistance in L6 Myotubes Is Prevented by Inhibition of Activation and Nuclear Localization of Nuclear Factor κB*

It is concluded that FAs induce insulin resistance and activates NFκB in L6 cells and inhibition ofNFκB activation, indirectly by preventing IKK activation or directly by inhibiting NFκBs nuclear translocation, prevents the detrimental effects of palmitate on the metabolic actions of insulin in L 6 myotubes.

Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.

Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS- 1 upon insulin stimulation, which defines a key step in insulin resistance.

Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle.

Increased expression of the PI 3-kinase adaptor subunits p85/55/50, as well as increased activity of the proinflammatory kinases JNK-1, PKC-theta, and, to a lesser extent, inhibitor of kappaB kinase-beta, may follow a common pathway to attenuate in vivo insulin sensitivity in insulin-resistant subjects.

Tumor Necrosis Factor α Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor κB Kinase in a p38 MAPK-dependent Manner*

It is demonstrated that pretreatment with PD169316 or SB203580, inhibitors of p38 MAPK, restored insulin signaling and normalized insulin-induced glucose uptake in the presence of TNF-α, which caused insulin resistance on glucose uptake and GLUT4 translocation.

Prevention of fat-induced insulin resistance by salicylate.

High-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blockingfat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.

Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α

The results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-betaII and -delta and a decrease in IkappaB-alpha.

Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.

The hypothesis that IKKbeta represents a new target for treating type 2 diabetes mellitus is supported.