The exoWAT, endoWAT and ectoWAT Dictate Dysmetabolism, Dyslipidemia and Diabetes

Abstract

Background & Objective: Three-tier model depicting physiology of metabolism and a timeline of dyslipidemia and diabetes is proposed. Methods & Results: OGTT glucose profiles of 1456 individuals, aged 15 to 80 years, who were not previously diagnosed as having T2D are analysed. A clinical model is conceptualized to explain the integrated physiology of pancreatic islet, hypothalamus, gut and peripheral tissues regulating the carbohydrate, fat, protein and energy metabolism. The beta cells regulate anabolism via insulin, somatostatin (delta) and amylin (gamma). The ‘Delta-Gamma system’ controls catabolism via glucagon and pancreatic polypeptide. Leptin regulates satiety and lipogenesis while ghrelin and fibroblast growth factor-21 regulate hunger and lipolysis by modulating insulin secretion. Dietary fat is deposited in the white adipose tissue (WAT) as exoWAT. Leptin induces ‘selective insulin resistance’ by simultaneously stimulating beta cells and microsomal triglyceride transfer protein (MTTP). Leptin regulates de-novo lipogenesis, endogenous fat deposition as endoWAT and promotes dyslipidemia and euglycemic hyperinsulinemia. WAT storage capacity (cWAT) is genetically determined. When cWAT is exceeded, fat deposition occurs ectopically in non-adipose tissues as ectoWAT and stimulates growth hormone, ghrelin and hyperglycemia. EctoWAT suppresses insulin, stimulates glucagon and ghrelin, leading to lipolysis, hyperglycemia, beta cell suppression-cum-failure. Calorie surplus, superimposed on genetic insulin resistance drives the timeline of dysmetabolism, which marches from healthy (exoWAT) and unhealthy (endoWAT) WAT stage, hepatic followed by peripheral ectoWAT stage, and finally the lipolytic stage. Conclusions: This model can explain the pathogenesis of T2D, its phenotypes and complications, GDM, PCOS as well as the mechanism of action of most antidiabetic drugs.