Insulin Resistance: An Update on Biochemical and Pathophysiological Mechanisms and Impact on Various Diseases

ABSTRACT Insulin resistance is the biological phenomenon in which the human body's normal response to the metabolic hormone insulin is compromised. Insulin is a regulator of most of the essential metabolic steps in the body that control energy homoeostasis, so dysregulation leads to multiple diverse human diseases including, most prominently, Type 2 diabetes mellitus. Insulin resistance also leads to the development of a metabolic profile that is strongly atherogenic, thus accelerating the initiation and development of atherosclerosis and its cardiovascular disease consequences, namely heart attacks, strokes and limb amputations. More recently, insulin resistance has been recognised as a contributing factor and therapeutic target for an increasing number of diverse diseases. Insulin acts in the established ligand‐receptor manner of activating a tyrosine kinase receptor, which mediates multiple forms of well‐characterised downstream signalling, ultimately leading to a serine/threonine kinase cascade, resulting in the phosphorylation of transcription factors and the regulation of gene expression in normal physiology. Although it was originally suspected that insulin resistance was a result of aberrant insulin signalling, resulting from the action of an unspecified lipophilic metabolite, no such factor has been identified in the last several decades. However, modern research has identified a range of traditional and novel factors which modulate insulin resistance and hence pathophysiology. In this review, it is speculated that there may be multiple forms of insulin resistance, each susceptible to an individual therapeutic approach, and also potentially idiosyncratic insulin resistance requiring empirical therapies. Further research is required to develop therapies for the factors so far discovered and to continue to search for other factors that are also potentially vulnerable to therapeutic targeting. Insulin resistance remains a prominent factor compromising human health, and ongoing research is required to understand the aetiology and lessen the impact of this condition.