Catabolic and anabolic faces of insulin resistance and their disorders: a new insight into circadian control of metabolic disorders leading to diabetes

Abstract

Maintenance of glucose homeostasis during circadian behavioral cycles is critical. The processes controlling the switch between predominant lipolysis/fatty oxidation during fasting and predominant lipid storage/glucose oxidation following feeding are determined principally by insulin. Chronic elevated threshold of insulin resistance (IR) is a key pathological feature of obesity, Type 2 diabetes, sepsis and cancer cachexia; however, a temporal reduced threshold of IR is widely met in fasting/hibernation, pregnancy, antibacterial immunity, exercise and stress. Paradoxically, some of these cases are associated with catabolic metabolism, whereas others are related to anabolic pathways. This article considers the possible causes of circadian disorders in glucose and lipid metabolism that act as a driving force for obesity-promoted development of Type 2 diabetes. This is intended to provide improved insight into the pathogenesis of chronic circadian disorders that increase the risk of diabetes, and consider new targets for its metabolic and drug correction.

Lay abstract:

Insulin resistance (IR) is a common adaptive mechanism, acting under opposite anabolic and catabolic conditions. However, chronic IR is a key pathological feature of obesity, Type 2 diabetes and cancer cachexia, whereas a temporal IR is widely seen in fasting, pregnancy, exercise and stress. Therefore, it is important to understand when this transient IR-mechanism shifts to chronic IR-associated diseases. What factors result in the switch between the anabolic and catabolic conditions and what defect(s) in this switch is associated with chronic IR induction? The present opinion article aimed to address these questions to the metabolic changes typical for circadian regulation in lean, obese and diabetic patients.

Graphical abstract: Early circadian IR disorders caused by overweight and obesity are associated with increased risk for diabetes via formation of a vicious cycle between lipid anabolic and catabolic programs thus distorting insulin and lipid levels in day/night period.