Molecular Mechanisms for the Vicious Cycle between Insulin Resistance and the Inflammatory Response in Obesity

Abstract

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

The Potential Effects of Dietary Antioxidants in Obesity: A Comprehensive Review of the Literature

“…ROS can directly impair insulin signalling by modifying insulin receptor substrates and downstream signalling molecules, hindering glucose uptake and utilisation. This disruption in insulin signalling promotes hyperglycaemia and compensatory hyperinsulinemia, ultimately contributing to the development of insulin resistance [42,43]. Moreover, the development of insulin resistance is influenced by the metabolism of lipids and the storage of excess fat calories in the adipose tissue, which promote increased free fatty acids in circulation.…”

“…Importantly, antioxidants have the potential to improve insulin sensitivity, a crucial factor in obesity-related insulin resistance. By reducing oxidative stress, antioxidants can help to restore normal insulin signalling pathways [42,43]. Notably, antioxidants such as alpha-lipoic acid and resveratrol have been demonstrated to enhance insulin sensitivity by activating the signalling pathways involved in glucose uptake and utilisation in skeletal muscle and adipose tissue [59,60].…”

Nutrition support, carbohydrate feeding and insulin sensitivity in the critically ill patient: a complex relationship

“…Strict blood glucose arms in the Leuven studies [10,14] received far more insulin than their respective comparator arms. Insulin has been shown to downregulate inflammatory processes, specifically circulating cytokines, which are responsible for reduced insulin sensitivity [16–19]. Subsequently, one would expect that patients in the arm receiving increased insulin would benefit from this, especially in the instance of an ongoing intravenous infusion of carbohydrate, which tends to mitigate the risk of an increase in hypoglycaemic episodes as seen in other studies [12].…”

White blood cells and type 2 diabetes: A Mendelian randomization study

“…Low-grade chronic inflammation is a process of the activation of immune system and the increased circulating cytokines and chemokines, wherein the adipose tissue appears to be a major source of pro-inflammatory factors [2]. Chronic inflammation might promote the occurrence of T2D by increasing insulin resistance, affecting insulin signaling, and promoting beta-cell dysfunction [3][4][5].…”