Serial visualization of Glucose-insulin metabolism in thin young Indians with prediabetes reveals early failure of beta cell secretion in relation to decreasing insulin sensitivity

Background & Objective Defective beta cell function in relation to impaired insulin sensitivity results in glucose intolerance. There are few studies documenting the lifecourse evolution of this relationship. The Pune Maternal Nutrition Study (PMNS) longitudinal birth cohort offered the opportunity to document these parameters from childhood in young, rural prediabetic participants and compare them to normal glucose tolerant (NGT). Methods PMNS subjects were classified as NGT or Glucose intolerant according to their OGTT results at 18 years of age. Insulin Sensitivity (HOMA-S) and β-cell function (HOMA-β) were estimated at 6,12 and 18 years. Their inter-relationship was estimated using HOMA-β as a nonlinear function of HOMA-S, separately for NGT and Glucose intolerant individuals at 6,12 and 18 years. Rates of change of HOMA-S and HOMA-β were estimated using a linear mixed effect model and visualized using LOESS plots. Result Of 619 participants, 177 had glucose intolerance at 18 years of age. A nonlinear hyperbolic relationship between HOMA-S and HOMA-B was observed at all time points. There was a progressive fall in HOMA-S and rise in HOMA-B with increasing age. Glucose intolerant participants had lower HOMA-B for all levels of HOMA-S as compared to NGT, manifesting as shift towards the origin in the hyperbolic curve. Conclusion We provide evidence for early life dysregulation in glucose insulin metabolism leading to pre-diabetes at 18 years of age. Prediabetic individuals started with lower beta cell function and lower insulin sensitivity from an early age. Diabetes prevention should start from early life.