A concerted decline in insulin secretion and action occurs across the spectrum of fasting and postchallenge glucose concentrations

Abstract

Aims/hypothesis: Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the prediabetic range of fasting glucose.

Methods: We studied a cohort of 173 individuals with a fasting glucose concentration <7·0 mM after an overnight fast using a 75-g oral glucose tolerance test (OGTT). Insulin action (S(i)) was estimated using the oral glucose minimal model, and β-cell responsivity indices (φ) were estimated using the oral C-peptide minimal model. The disposition index (DI) for each individual was calculated. The relationship of DI, φ and S(i) with fasting and postchallenge glucose, as well as other covariates, was explored using a generalized linear regression model.

Results: In this cross-sectional study, S(i) and DI were inversely related to fasting glucose concentrations. On the other hand, φ was unrelated to fasting glucose concentrations. S(i), φ and DI were all inversely related to area above basal glucose concentrations after glucose challenge. Multiple parameters including body composition and gender contributed to the variability of S(i) and DI at a given fasting or postchallenge glucose concentration.

Conclusions/interpretation: Defects in insulin secretion and action interact with body composition and gender to influence postchallenge glucose concentrations. There is considerable heterogeneity of insulin secretion and action for a given fasting glucose likely because of patient subsets with isolated IFG and normal glucose tolerance.

Figure 1

Insulin action (top panel), insulin secretion (middle panel) and disposition index (lower panel) across groups classified by fasting glucose and glucose tolerance status. NFG = Normal Fasting Glucose i.e. < 5.56 mmol/l, IFG = Impaired Fasting Glucose i.e. > 5.56 and < 7.0 mmol/l. NGT = Normal Glucose Tolerance i.e. 2-hour post OGTT glucose < 7.78 mmol/l, IGT = Impaired Glucose Tolerance > 7.78 and < 11.1 mmol/l, DM = Diabetes Mellitus > 11.1 mmol/l.

Figure 2

Relationship of Insulin action (top panel), insulin secretion (middle panel) and disposition index (lower panel) with fasting glucose concentrations - Glucose₀ = Plasma glucose at 0 minutes (left) and area-above-basal after oral glucose challenge - Glucose_AAB (right). The inset panels represent the rank transformed values of S_i, ϕ and DI plotted against fasting and area above basal glucose values.

Figure 3

Relationship of measured S_i with % Body Fat in males (●) and females (○).The regression line for males (dashed) and females (solid) are included.

Figure 4

Relationship of Disposition index, adjusted for gender, %body fat and Glucose_AAB, with fasting glucose concentrations (top panel), and relationship of Disposition index, adjusted for gender, %body fat and Glucose₀, and area-above-basal after oral glucose challenge (bottom panel).

Figure 5

Relationship of Hepatic Extraction of secreted insulin (HE) with Disposition Index.