Gene Calorie Hypothesis—Proposed to Decode T2DM Pathogenesis

Insulin and glucose parabolas of OGTT were studied in 1030 subjects, not previously diagnosed as having T2DM. The parabola shape was mainly influenced by adiposity, peripheral Insulin resistance (PIR), beta cell(BC) mass and glucose dose. Fasting hyperinsulinemia(HI) was strongly related to body mass index(BMI). Continued calorie excess(CCE) and BMI along with increase in insulin area under curve, which suggested recruitment of new insulin receptors, acted as BC stressor leading to HI. Fasting HI appears to be a physiological response to incremental BMI, independent of PIR. The rate of rise of insulin (RIR) sustained an angle theta with baseline and both were related to BMI and PIR. The RIR was directly related to rising BMI, fasting insulin and glucose but was inversely related to PIR, 120 min insulin and glucose. CCE affected the Degree of HI whereas PIR affected the Duration of HI (Fig 1). From NoDM category as CCE begins, RIR and theta increase until PIR becomes unmasked. RIR, which is related to PIR, can not rise further. As CCE continues, at variable maximum level of insulin, the individual’s BC capacity, betamax, is reached. The RIR and theta start falling hereafter, until the final values for DM category. Gene-Calorie hypothesis proposes that PIR is an inherited predisposing factor where as CCE with adiposity is an acquired precipitating factor which together cause continuous BC stress and subsequent BC failure leading to T2DM. Disclosure S.N. Shinde: Advisory Panel; Self; USV Private Limited, Alkem Laboratories, Lupin Laboratories, Troikka Ltd, IPCA laboratories. R.S. Shinde: None.