Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates

Abstract

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0-120/ΔG0-120, ΔIS rate [ISR]0-120/ΔG0-120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15-0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54-0.80]), IS (OR 0.61 [95% CI 0.50-0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19-0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.

FIG. 1.

Change from baseline to study end in MI (top left), IS (ΔI_0–120/ΔG_0–120 AUC) (bottom left), IS/IR index (bottom right), and adipose tissue IR index (top right) in PGZ-treated subjects. Data are given as means ± SE. Change represents the difference between the absolute value at the study end minus baseline value. *P < 0.05 for NGT vs. IGT or T2DM; #P < 0.05 for IGT vs. T2DM using nonparametric tests.

FIG. 2.

Change in MI (top left), IS (ΔI_0–120/ΔG_0–120) (bottom left), IS/IR index (bottom right), and adipose tissue IR index (top right) in placebo-treated subjects. Data are given as means ± SE. Change represents the difference between the absolute value at the study end minus baseline value. *P < 0.05 for NGT vs. IGT or T2DM; #P < 0.05 for IGT vs. T2DM using nonparametric tests.

FIG. 3.

Relationship between the annual diabetes incidence rate and change in the IS/IR index in the combined PGZ-treated and placebo-treated groups. Cohort members were ordered from smallest to largest change and then divided into octiles. Means ± SEM of each octile are represented by solid circles. SEM values for diabetes incidence are not shown if they fall within the height of the solid circle.

FIG. 4.

Relationship between IS (ΔI_0–120/ΔG_0–120) and MI at baseline (A) and at study end (B). NGT subjects, yellow circles; IGT subjects who converted to NGT, blue triangles; IGT subjects who remained with IGT, red squares; IGT subjects who converted to T2DM, green diamonds.

FIG. 5.

PG (top) and insulin (middle) concentrations and ISR (bottom) in PGZ-treated IGT subjects who reverted to NGT (left), remained with IGT (middle), or converted to T2DM (right). Data at baseline and at the end of PGZ treatment are shown. For comparison, data for control NGT individuals identified during the screening of participants for the ACT NOW Study are shown.