1330-P: Longitudinal Multiyear Prospective Study in 87 Diabetic Primates: Lack of Support for a Mechanistic Basis for the Disposition Index

Abstract

Cross-sectional studies of individuals before, during, and after the development of overt type 2 diabetes (ADA definition) , as well as those in which 3 to 5 subgroups have been analyzed, typically have applied DM progression analyses using the parameters of the Disposition Index (DI) . In such correlation-based analyses, the inferences drawn do not reflect the relationships we and others have drawn from longitudinal analyses of the same data obtained within-subject across time during the development of diabetes. The problems with the DI and its interpretation have been a subject of concern for many years, but, nevertheless, its assumptions and interpretations have dominated the diabetes scientific literature. As recently noted by Arreola, et al 2022, the form of the relationship between two measures, insulin sensitivity as measured by the “gold standard” euglycemic hyperinsulinemic clamp and beta-cell responsiveness based on the intravenous glucose tolerance test induced Acute Insulin Response (AIR, 0 to min) is clearly nonlinear, and likely is not hyperbolic. In our longitudinal laboratory study of adult nonhuman primates, 87 developed overt type 2 diabetes[LS1] while under study. The laboratory provided standard monkey chow ad libitum to all individually caged Macaca mulatta rhesus monkeys throughout the study. We found that ß cell function was not a result of or associated with a decline in insulin sensitivity as measured by a euglycemic hyperinsulinemic clamp. Furthermore, hyperglycemia is clearly not the stimulus for nor cause of hypersecretion of insulin, the latter significantly preceding the development of impaired glucose tolerance followed by progression to overt DM. We conclude that the disposition index failed to predict the natural progression from normal to overt type 2 diabetes mellitus in this longitudinal data analysis, and its value is best considered only in the context of an epidemiological study using cross-sectional data. Disclosure L.Shiver: None. C.Bellido: None. A.Rosado: None. B.C.Hansen: None. Funding National Institutes of Health (NO1 AG3 1012)