The Natural History of Insulin Sensitivity and Insulin Secretion in the Progression from Normal Glucose Tolerance to Impaired Fasting Glycemia and Impaired Glucose Tolerance – The Inter99 study

Abstract

Objective: The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined IFG/IGT.

Research design and methods: Baseline and five-year follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT or NGT at the five-year follow-up were examined with an OGTT (n=3,145). Insulin sensitivity index (ISI), homeostasis model assessment of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index, DI) were estimated.

Results: Five years prior to the pre-diabetic diagnoses (i-IFG, i-IGT and IFG/IGT), ISI, HOMA-IS, EPIR, and DI were lower than in individuals who remained NGT. During the five-year follow-up, individuals developing i-IFG only experienced a significant decline in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and DI. IFG/IGT individuals exhibited pronounced defects in ISI, HOMA-IS, EPIR, and DI during the five-year follow-up.

Conclusions: A stationary reduced insulin secretion followed by a decline in hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack of beta cell compensation is associated with the development of i-IGT. Thereby, i-IFG and i-IGT appear to result from different underlying mechanisms, which may have implications for the prevention and treatment of the diabetes that succeeds them.