Abstract

Objective: Methods to assess β-cell function in clinical studies are limited. The aim of the current study was to compare a direct measure of insulin secretion with fasting surrogate markers in relation to glucose tolerance status.

Research Design and Methods: In n=1380 individuals from the IRAS (Insulin Resistance Atherosclerosis Study), β-cell function was assessed using a frequently sampled intravenous glucose tolerance test (first phase insulin secretion; AIR), homeostasis model assessment (HOMA-%B), proinsulin (PI) levels and the PI/insulin ratio. β-cell function was cross-sectionally analyzed by glucose tolerance categories [NGT: n=712; IGT: n=353; newly diagnosed diabetes by 2h glucose from an OGTT (DM2h): n=80; or by fasting glucose (DMf): n=135; or by fasting and 2h glucose and established diabetes on diet/exercise only (DM): n=100].

Results: In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly – inversely - related to AIR (r values from -0.02 to -0.27), and AIR was strongly related to HOMA-%B (r values 0.56 and 0.58). HOMA-%B markedly underestimated the magnitude of the β-cell defect across declining glucose tolerance, especially for IGT and new DM by OGTT compared AIR. Analyses adjusting for insulin sensitivity showed that β-cell function was compromised in IGT, DM2h, DMf, and DM, relative to NGT, by 13%, 12%, 59%, and 62% (HOMA-B), and as much as 40%, 60%, 80%, 75%, using AIR.

Conclusions: Subjects with IGT and early stage, asymptomatic type 2 diabetic patients have more pronounced β-cell defects than previously estimated from epidemiological studies using HOMA.