Op028 the Impact of Insulin-Induced Oxidative Stress on Inflammation and Mitochondrial Oxidative Capacity Is Modulated by Free Fatty Acid Availability in Rat Skeletal Muscle in Vivo

Insulin resistance in obesity: an overview of fundamental alterations

“…These observations directly suggest that at least under the above acute experimental conditions, saturated fatty acids may not be solely responsible of fat-induced metabolic derangements in vivo [1]. Albeit less investigated, the involvement of glucose metabolism in inflammation and oxidative stress particularly at skeletal muscle level is supported by both clinical observations in patients with diabetes mellitus and by experimental models.…”

“…Recent evidence however also indicated that acute increments in saturated and monounsaturated circulating fatty acids through i.v. infusion in the presence of physiological hyperinsulinemia directly caused skeletal muscle and systemic insulin resistance through enhanced mitochondrial ROS production and IKB-NF-kB pathway activation in rodents [1].…”

“…Besides its pivotal role in the regulation of intermediate substrate metabolism, insulin also regulates a wide range of fundamental cell and organ functions that largely fall beyond the scope of this work [1][2][3]. The main physiological impact of insulin in the regulation of nutrient utilization and intermediate metabolism occurs in the post-prandial state, when variable rises in plasma glucose trigger insulin secretion [4,5].…”

“…Among possible causes of obesity-induced metabolic derangements, adipose organ dysfunction and altered adipose metabolic processes clearly play a fundamental role [15,16]. Oxidative stress resulting from imbalanced reactive oxygen species (ROS) generation and antioxidant defences as well as chronic inflammation in non-adipose tissues are also major regulators of insulin sensitivity [1,[17][18][19][20][21][22][23][24]; in particular, elevated proinflammatory stimuli may be enhanced by excess ROS and directly impair insulin signalling in insulin target tissues [1,17,18,[25][26][27]. Complex systemic networks including responses to nutrients and substrates, the gut and its microbiota are also key players acting by regulating substrate utilization and balance, thereby modulating oxidizing and inflammatory stimuli [28,29].…”

“…infusion leading to high circulating fatty acids comparable to those observed following a high-fat meal directly causes systemic insulin resistance in humans and experimental models [56][57][58][59][60], and elevated plasma free fatty acids are common in obese individuals (40,41) due to both potential elevated dietary intake and enhanced lipolysis from adipocytes. Fatty acids levels importantly cause inflammation and oxidative stress in vitro in muscle cell cultures [61][62][63]; inflammation and oxidative stress along with additional mechanisms including endoplasmic reticulum stress are accordingly among proposed pathogenetic derangements linking excess fatty acid availability with insulin resistance [1,57,58,61,60,64,65]. Under conditions of chronic excess fat availability with development of overweight or obesity, lipotoxicity and insulin resistance may chronically result through different mechanisms from lipid deposition in non-adipose insulin target tissues [59].…”