Insulin resistance (IR) is the impairment in insulin action at target cells such as liver cells, adipocytes and muscle cells. In 1939, Harold Himsworth, while addressing the Royal College of Physicians in London, challenged the conventional wisdom of insulin deficiency as the cause of all diabetes and suggested that “a state of diabetes might result from inefficient action of insulin as well as from a lack of insulin”. In 1979, the classification of two types of diabetes as type 1 and type 2 diabetes, emphasized the central role of IR in development of type 2 diabetes (T2DM). Studies carried out in Pima Indians and children of parents who both had diabetes had shown IR as a strong predictor of future T2DM.

Most of the metabolic and anti-apoptotic effects of insulin are mediated by the signaling pathway involving the phosphorylation of the insulin receptor substrate (IRS) proteins and circulating free fatty acids (FFAs) and the adipokine tumor necrosis factor (TNF) may increase serine phosphorylation of IRS proteins, thereby causing impaired insulin signal transduction.

Studies by Prof Yajnik and his team suggested that Indian newborn babies are having more amount of adipose tissue (especially abdominal) relative to muscle mass and over-nutrition in early childhood and adolescence, together with physical inactivity, further exaggerate central adiposity which leads to the abnormal secretion of various pro-inflammatory mediators and adipokines which activate various inflammatory pathways impairing the phosphorylation of various insulin signaling pathways in adipocytes and/or peripheral tissues resulting in the development of IR. Oxidative stress and mitochondrial dysfunction also contribute to the development of IR in such conditions.

By achieving sustained weight loss through bariatric surgery or structured lifestyle intervention as well as by insulin sensitizing therapy with metformin, one can prevent diabetes in high risk individuals. Also, reversal or remission of diabetes can be achieved through sustained weight loss through bariatric surgery or low calorie diet-based structured weight loss program targeting IR, thereby suggesting that IR plays a pivotal role in development of T2DM.

Suggested Reading: 1Reaven G. Circulation. 2005;112:3030-2. 2Saini V. World J Diabetes. 2010;1(3):68-75. 3Carlsson MSL, et al. N Engl J Med. 2012;367:695-704. 4Diabetes Prevention Program Research Group, Knowler WC, et al. Lancet. 2009;374(9702):1677-86. 5Koliaki C, et al. BMC Endocr Disord. 2017;17:50. 6Lean ME, et al. Lancet. 2018;391:541-51.