Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study

Aims/hypothesis: The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study. Methods: In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (S_I) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants. Results: At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA_1c were 5.8 ± 0.02 mmol/l, 10.5 ± 0.05 mmol/l and 5.5 ± 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (ΔI _0-30/ΔG _0-30 × Matsuda index, where ΔI is change in insulin in the first 30 min and ΔG is change in glucose in the first 30 min) and total (ΔI_0-120/ΔG_0-120 × Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and S_I). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance. Conclusion: Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT.