Insulin Resistance

Insulin resistance is typically considered a decrease in sensitivity or responsiveness to the metabolic actions of insulin, including insulin-mediated glucose disposal in insulin-sensitive tissues. ^[1] Type 2 diabetes is caused by a combination of defective insulin secretion by pancreatic beta-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. ^[2] Under physiological conditions insulin regulates glucose homeostasis by enhancing glucose disposal in insulin-sensitive tissues while also regulating nutrient delivery through its vasodilatory actions on small feed arteries. ^[1]

Increased circulating lipids and altered fatty-acid utilization, termed lipotoxicity, contribute to insulin resistance in muscle and liver through pathways such as novel protein kinase C and JNK-1 signalling. ^[3] Mitochondrial dysfunction and endoplasmic reticulum stress, mainly via increased oxidative stress, play important roles in the pathogenesis of insulin resistance, especially in non-alcoholic fatty liver disease. ^[3] Central accumulation of body fat and adipose tissue dysfunction drive insulin resistance, whereas peripheral fat distribution is metabolically less important. ^{[4] [5]} Excess visceral fat secretes adipokines and inflammatory cytokines that induce insulin resistance and hyperglycemia ^[6]

As global and US rates of obesity increase, there is an acceleration of the incidence and prevalence of insulin resistance along with associated cardiovascular disease. ^[1] Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of individuals with polycystic ovary syndrome, a condition affecting 5-20% of women of reproductive age. ^[7] The average prevalence of the metabolic syndrome, of which insulin resistance is a central feature, is around 31%, and it is associated with a roughly two-fold increase in the risk of coronary heart disease and cerebrovascular disease. ^[4] Insulin resistance is commonly quantified from fasting insulin, which together with fasting glucose forms the homeostatic model assessment (HOMA-IR

Insulin resistance and attendant hyperinsulinaemia promote cardiovascular disease in part by increasing vascular stiffness and reducing the bioavailability of nitric oxide in the vasculature. ^[1] Insulin resistance and chronic inflammation are key pathways in the pathogenesis linking type 2 diabetes and non-alcoholic fatty liver disease, whose combination increases morbidity and mortality risks. ^[9] The menopausal transition is associated with an increase in fat mass, insulin resistance, dyslipidaemia, and endothelial dysfunction, superimposing added cardiovascular risk onto that of ageing. ^[10]