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

Kristine Faerch, Allan Vaag, Jens J Holst, Torben Hansen, Torben Jørgensen, Knut Borch-Johnsen, Kristine Faerch, Allan Vaag, Jens J Holst, Torben Hansen, Torben Jørgensen, Knut Borch-Johnsen

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 5-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 5-year follow-up were examined with an oral glucose tolerance test (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) were estimated.

Results: Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI, HOMA-IS, EPIR, and disposition index during the 5-year follow-up.

Conclusions: A stationary reduced insulin secretion followed by a decline in primarily 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.

Figures

Figure 1
Figure 1
Baseline and 5-year values of ISI (A), HOMA-IS (B), EPIR (C), and DI (D) in 3,145 individuals developing i-IFG (□), i-IGT (▵), or IFG/IGT (○) or maintaining NGT status (⋄). Data are presented as medians. P values for differences in changes (5-year minus baseline) between groups are adjusted for age, sex, family history of diabetes, and risk/intervention group as well as for changes in BMI, smoking, physical activity, and dietary quality during the 5 years of follow-up. Wald test from linear models (P < 0.05): a, i-IFG vs. NGT; b, i-IGT vs. NGT; c, IFG/IGT vs. NGT; d, i-IGT vs. i-IFG, e, IFG/IGT vs. i-IFG; f, IFG/IGT vs. i-IGT.

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