IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome.

Individuals born small for gestational age (SGA) are at a higher risk of developing the metabolic syndrome later in life. IGF-1 resistance has been reported in placentae from SGA births and mutations in the Igf1 receptor gene have been reported in several cohorts of SGA subjects. We have used the Igf1r heterozygous (Igf1r) male mouse as a model to investigate the mechanisms by which Igf1r haploinsufficiency leads to insulin resistance.

Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats.

Aims: To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats.

Materials And Methods: For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v.

A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle.

Aims/hypothesis: Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.

Effect of lipopolysaccharide on inflammation and insulin action in human muscle.

Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance.

Effect of exercise on the skeletal muscle proteome in patients with type 2 diabetes.

Purpose: Exercise training alters protein abundance in the muscle of healthy individuals, but the effect of exercise on these proteins in patients with type 2 diabetes (T2D) is unknown. The aim of this study was to determine how exercise training alters the skeletal muscle proteome in patients with T2D.

Methods: Biopsies of the vastus lateralis were obtained before and after 4 wk of exercise training in six patients with T2D (54 ± 4 yr; body mass index (BMI), 29 ± 2) and six age- and BMI-matched control subjects (48 ± 2; BMI, 28 ± 3) studied at the baseline.

TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4.