Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

Abstract

ContextObesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity.ObjectivesWe compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development.Methods30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression.ResultsSystemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR.ConclusionOur results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.

Acute effects of physical exercise on the serum insulin-like growth factor system in women with fibromyalgia

“…Furthermore, BMI was associated with CRP in FM. This implies a peripheral low-grade inflammation and could potentially contribute to reduced muscular IGF-1 response in overweight women with FM [35–37]. However, in the present study, BMI did not correlate with the acute IGF-1 response.…”

Expression of macrophage genes within skeletal muscle correlates inversely with adiposity and insulin resistance in humans

“…A muscle defect in the activation of the insulin meta bolic pathway (Akt phosphorylation) was identified as an early mechanism of insulin resistance development in these populations (Amouzou et al 2016). Along with the study by Amouzou et al, recent animal data has also suggested the existence of alternative mechanisms, independent of previously proposed skeletal muscle inflammation, to generate insulin resistance (Evers-van Gogh et al 2016; Rivas et al 2016).…”

“…However, studies on humans are limited and reports are inconsistent. While some authors report an association between obesity and increased infiltration of skeletal muscle macrophages (Torres et al 2004; Varma et al 2009), others report little evidence of macrophage accumulation in skeletal muscle in obesity with or without type 2 diabetes (Xu et al 2003; Tam et al 2012; Amouzou et al 2016). Consequently, we conducted the present study in obese and lean humans with the goal of further clarifying if obese skeletal muscle becomes infiltrated with macrophages as it happens with obese adipose tissue.…”

Obesity and the dysregulation of fatty acid metabolism: implications for healthy aging

“…Amouzou et al (2016) report leptin increased from 14.7 ng/ml in nonobese controls to 44.6 and 44.7 ng/ml, respectively, in insulinsensitive and insulin-resistant obese postmenopausal women, 370 aged between 50 and 64-years old [97]. Interestingly, males appear to be more sensitive to the effects of leptin, and therefore exhibit lower concentrations compared with females; with leptin concentration and leptin receptor inversely correlated with serum testosterone [98].…”

“…Adiponectin promotes glucose utilization and fatty acid oxidation, and reduction of this adipocytokine is associated with insulin resistance [101]. For example, Amouzou et al (2016) 385 reported a decrease in adiponectin from 17.4 ng/ml in nonobese controls to 12.1 and 9.3 ng/ml in insulin-sensitive and insulin-resistant obese postmenopausal women, respectively [97]. Kim et al (2015) suggest the inhibition of adiponectin amongst the obese may be due to, obesity-induced 390 proinflammatory cytokines inducing the hypermethylation of compact chromatin structures in the adiponectin gene promoter by the methyl transfer enzyme DNA methyltransferase 1 (DNMT1), impeding the expression of adiponectin [102].…”