363-OR: Weight Loss, Lifestyle Intervention, and Metformin Effects on the Longitudinal Relationship between Insulin Secretion and Sensitivity in the Diabetes Prevention Program (DPP)

Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies in either or both leading to diabetes. Using data from 2931 participants in the DPP repository, we investigate the effects of lifestyle and metformin interventions and of weight loss on the relationship between insulin secretion and sensitivity. Insulin secretion and sensitivity were estimated from insulin concentrations in fasting and 30-minute post-load serum samples at baseline and at 1, 2, and 3 years after randomization during the active intervention phase of the DPP. The relationship of secretion and sensitivity was evaluated by standardized major axis regression and was found to change over time for participants in the lifestyle and metformin interventions. Distances along and away from the regression line were taken to characterize insulin secretory demand and insulin secretion in compensation to the demand, respectively. Both the metformin and lifestyle interventions decreased secretory demand while increasing compensatory insulin secretion, with greater effects of the lifestyle intervention. Improvements were directly related to the amount of weight loss; decreases in weight significantly reduced secretory demand [b=-0.088 SD (-0.102, -0.074) /5 kg loss] and increased compensatory insulin secretion [b=0.169 SD (0.149, 0.189) /5 kg loss]. In time-dependent hazard models, increasing secretory demand associated with increased diabetes risk [hazard ratio (HR) =1.189 per baseline SD (1.004, 1.413) ] while increasing compensatory insulin secretion associated with lower risk [HR=0.1 (0.080, 0.145) ]. These results are consistent with earlier observations in the DPP that diabetes risk reduction was directly related to the amount of weight loss and suggest that this effect is mediated by lowered insulin secretory demand coupled with improved compensatory insulin secretion.