Abstract P069: Longitudinal Associations Between Metabolic Status, Insulin Clearance, and Insulin Sensitivity: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort

Abstract

Metabolically healthy obese individuals (MHO) are those with obesity but normal metabolic profiles. The relationship of MHO to type 2 diabetes mellitus (T2DM) risk is unclear. Limited data are available on metabolic status and declining insulin clearance (IC) and insulin sensitivity (IS), which are well-documented features in the pathogenesis of T2DM. Objective: To assess longitudinal changes in IC and IS among metabolically healthy and unhealthy obese and non-obese participants. Hypothesis: Longitudinal declines in IC and IS will be greater among participants classified as metabolically unhealthy and/or obese compared to metabolically healthy non-obese (MHN). Methods: Adults ≥30 years old at-risk for T2DM in PROMISE had three assessments over 6 years (n=558). Obesity was classified as BMI ≥30 kg/m 2 . Baseline metabolic parameters, including blood pressure, TAG, HDL, fasting glucose, waist circumference, and medication use, were used to determine metabolic status. Metabolically healthy status was defined as the presence of <3 metabolic abnormalities. Values from oral glucose tolerance tests at each visit were used to calculate Matsuda insulin sensitivity index (ISI), and the ratios of fasting C-peptide-to-insulin (IC FASTING ) and areas-under-the-curve of C-peptide-to-insulin (IC AUC ). Generalized estimating equations (GEE) evaluated the association of baseline metabolic status with longitudinal changes in IC and IS, adjusting for covariates. Results: The multivariate GEE model showed that MHO and MUO had greater declines in IC and IS over time compared to MHN ( Figure , both p<0.01). Metabolically unhealthy non-obese (MUN) had a longitudinal decline in IC FASTING but not IC AUC compared to MHN, and a more modest relative decline in IS. Conclusions: Compared to MHN, presence of a metabolically unhealthy and/or obese phenotype negatively impacted IC and IS over time. The more pronounced declines in IC in MUO and MHO may reflect a compensatory response to the poorer IS in these groups.