Prevention of Diabetes With Pioglitazone in ACT NOW

Physiologic Correlates

Ralph A. DeFronzo; Devjit Tripathy; Dawn C. Schwenke; MaryAnn Banerji; George A. Bray; Thomas A. Buchanan; Stephen C. Clement; Amalia Gastaldelli; Robert R. Henry; Abbas E. Kitabchi; Sunder Mudaliar; Robert E. Ratner; Frankie B. Stentz; Nicolas Musi; Peter D. Reaven

Disclosures

Diabetes. 2013;62(11):3920-3926. 

In This Article

Results

Study Cohort

The study population (n = 441; 57% female) had a mean age of 53.2 ± 0.6 years and a mean BMI of 33.9 ± 0.3 kg/m2. Three hundred and four subjects had IGT/IFG, and 137 subjects had isolated IGT. Baseline HbA1c, FPG, and 2-h PG levels were 5.53 ± 0.03% (37 ± 0.08 mmol/mol), 105 ± 0.5 mg/dL, and 169 ± 1 mg/dL, respectively. There were no significant differences in any clinical, anthropometric, or laboratory parameters between the placebo and PGZ groups (Supplementary Table 2). The 441 subjects who underwent OGTTs at baseline and at study end/time of conversion to diabetes had (P > 0.40) clinical, anthropometric, and laboratory values similar to those of the entire cohort (Supplementary Table 1).

Follow-up Results

Diabetes developed in 45 of 228 individuals (19.7%) in the placebo group and 15 of 213 individuals (7.0%) in the PGZ group during a median follow-up period of 2.4 years. The annual diabetes incidence rates, adjusting for age, sex, and center and calculated using person-years, were 8.2 and 3.1%, respectively (P < 0.001). These conversion rates for the 441 subjects in the current analysis were similar to those for the entire cohort of 602 subjects.

Values at baseline and time of diabetes development or study end are shown in

Effect of PGZ on HbA1c, PG, Insulin, Lipids, and BMI

HbA1c levels differed between groups (P < 0.003) throughout the study, increasing by 0.28% (1.9 mmol/mol) in the placebo group and 0.07% (0.5 mmol/mol) in the PGZ group (P < 0.0001). At study end, decrements in FPG (−10.7 ± 0.9 vs. −4.0 ± 0.09 mg/dL) and 2-h PG (−28.7 ± 2.6 vs. −5.9 ± 2.6 mg/dL) levels were greater in the PGZ group versus placebo group (P < 0.0001). Fasting plasma insulin decreased by −3.3 ± 0.6 μU/mL in PGZ (P < 0.0001 vs. baseline) and did not change in placebo (Δ = 0.5 ± 0.5) (P < 0.0001, PGZ vs. placebo). Fasting plasma FFA levels did not change in the PGZ group and increased in the placebo group (P = 0.007). The adipocyte IR index decreased in the PGZ group (Δ = −1.8 ± 0.4 mmol/L × mU/L, P < 0.0001 vs. baseline) and increased in the placebo group (Δ = 0.7 ± 0.3, P = 0.03 vs. baseline, and P < 0.0001 vs. PGZ).

BMI increased in the placebo group (0.5 ± 0.2 kg/m2, P < 0.006) and PGZ group (1.6 ± 0.2 kg/m2, P < 0.0001), but the increment was greater with PGZ treatment (P < 0.0001). Compared with the placebo group, HDL cholesterol levels increased more (7.2 ± 0.8 vs. 4.3 ± 0.7 mmol/L, P < 0.007), whereas plasma triglyceride levels decreased more (−14.1 ± 3.9 vs. −1.7 ± 4.1 mmol/L, P < 0.01) in the PGZ group.

Effect of PGZ on Insulin Sensitivity, IS, and β-cell Function

The MI of insulin sensitivity increased by 92% in the PGZ group (3.9 ± 0.2 to 7.5 ± 0.3, P < 0.0001), but only by 17% in the placebo group (4.0 ± 0.2 to 4.7 ± 0.3, P = 0.002) (P < 0.0001, PGZ vs. placebo). The fasting ISR (from plasma C-peptide deconvolution) increased in the placebo group (420 ± 14 to 558 ± 21 pmol/min, P < 0.0001 vs. baseline) and did not change in the PGZ group (411 ± 14 to 446 ± 19) (P < 0.0001, PGZ vs. placebo). The total insulin secreted during the OGTT (0–120 min) increased in both groups (PGZ, 165 ± 3 to 189 ± 5 nmol; placebo, 167 ± 3 to 202 ± 6) (P < 0.0001 vs. baseline in both groups; P = NS, PGZ vs. placebo). The IS/IR (disposition) index (ΔI0–120/ΔG0–120 × MI) increased by 65% with PGZ treatment (3.2 ± 0.1 to 5.3 ± 0.3, P < 0.0001) and did not change significantly with placebo treatment (3.2 ± 0.1 to 3.7 ± 0.2, P = 0.13) (P < 0.0001, PGZ vs. placebo). When the IS/IR index was calculated as ΔISR0–120/ΔG0–120 × MI, the increase in β-cell function with PGZ (64 ± 3 to 198 ± 17, P < 0.0001) also was significantly greater than with placebo (66 ± 4 to 107 ± 8, P < 0.0001) (P < 0.0001, PGZ vs. placebo).

Relationship Between Final Glucose Tolerance Status and Measures of Insulin Sensitivity and IS

In PGZ-treated IGT subjects, the change in MI of insulin sensitivity was strongly related to final glucose tolerance status (Fig. 1). Subjects who reverted to NGT had the largest improvement in MI (4.6 ± 0.4, P < 0.0001), whereas subjects who converted to T2DM had no significant improvement in MI. The adipocyte IR index improved in IGT subjects who reverted to NGT and deteriorated in IGT subjects who progressed to T2DM (Fig. 1). Plasma insulin response to hyperglycemia (ΔI0–120/ΔG0–120) remained constant in subjects who reverted to NGT; consequently, the IS/IR index increased markedly (Fig. 1). In contrast, the plasma insulin response to hyperglycemia (ΔI0–120/ΔG0–120) declined significantly in IGT subjects who converted to T2DM, resulting in a modest but significant decrease in IS/IR index.

Figure 1.

Change from baseline to study end in MI (top left), IS (ΔI0-120/ΔG0-120 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.

In placebo-treated IGT subjects, relationships between the change in MI of insulin sensitivity and the change in IS/IR index versus final glucose tolerance status were analogous to PGZ-treated subjects, although with different distributions of subjects in each final glucose tolerance category (Fig. 2). In IGT subjects who reverted to NGT and had received placebo, insulin sensitivity (MI) and IS/IR index improved, while the opposite was observed in subjects who progressed to T2DM.

Figure 2.

Change in MI (top left), IS (ΔI0-120/ΔG0-120) (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.

Relationship Between IS/IR Index and Diabetes Risk

The risk of developing diabetes was strongly related to the ln of the IS/IR index. When all subjects (PGZ and placebo) were divided into eight equal groups (octiles), a strong curvilinear relationship between ln change in IS/IR index and diabetes incidence (r = 0.990, P < 0.0001) was observed (Fig. 3). In the placebo group, the relationship was shifted to the right (data not shown). IGT subjects with ≥80% improvement in IS/IR index had an ~2% incidence of diabetes compared with a 14% incidence in subjects in whom the IS/IR index declined by 60–80%.

Figure 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.

When IGT subjects treated with PGZ (r = 0.988, P < 0.0001) or placebo (r = 0.987, P < 0.001) were analyzed separately, the change in ln IS/IR index also was strongly related to the diabetes incidence.

Relationship Between Plasma Insulin Response to Hyperglycemia and Insulin Sensitivity

At baseline, the plot of insulin sensitivity (MI) versus plasma insulin response to hyperglycemia (ΔI0–120/ΔG0–120) during OGTT was curvilinear in all subjects, with little separation between the PGZ and placebo groups (data for separate groups not shown) (Fig. 4A). At study end or the time of diabetes diagnosis, the curve was shifted leftward in IGT subjects who converted to diabetes, was unchanged in subjects who remained with IGT, and was shifted rightward in subjects who reverted to NGT (Fig. 4B). For any level of IR, the plasma insulin response in T2DM subjects was less than that in subjects who remained with IGT, which, in turn, was less than in subjects who reverted to NGT. However, PGZ-treated IGT subjects who reverted to NGT still fell below the "control NGT" group, i.e., their plasma insulin response was not completely normalized (Fig. 4B).

Figure 4.

Relationship between IS (ΔI0-120/ΔG0-120) 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.

When the ln of ΔI0–120/ΔG0–120 was plotted against the ln of the MI in subjects who reverted to NGT, a strong linear relationship with a similar slope was observed in control NGT subjects, placebo-treated IGT subjects, and PGZ-treated IGT subjects at study end (Supplementary Fig. 1).

Relationship Between Glucose Tolerance Status Versus Plasma Insulin Response and Insulin Secretory Response in PGZ-treated Subjects

In PGZ-treated subjects who reverted to NGT, there was significant increase (P < 0.0001) in ISR (plasma C-peptide deconvolution) (Fig. 5). Nonetheless, plasma insulin response decreased markedly. Although not directly measured, this novel finding most likely is explained by a pronounced increase in the metabolic clearance rate (MCR) of insulin in response to PGZ. The change in insulin MCR cannot be explained by the change in glucose tolerance status, because PGZ-treated subjects who remained with IGT also manifested a significant increase in ISR, while the plasma insulin response still declined. These results clearly demonstrate that PGZ exerts independent effects on IS and insulin MCR, and that the balance between these two effects determines plasma insulin response.

Figure 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.

In subjects who converted to T2DM, PGZ had no effect on IS and the plasma insulin response to hyperglycemia did not change (declined slightly) significantly (Fig. 5).

Factors Associated With Improved β-cell Function After PGZ Treatment

The IS/IR index (ΔISR0–120/ΔG0–120 × MI) is determined by the following: 1) plasma insulin response (ΔISR0–120), 2) increment in PG (ΔG0–120) (i.e., the stimulus for IS), and 3) IR (1/MI). In PGZ-treated subjects who reverted to NGT or remained with IGT, the ISR increased by ~21% and the ISR related to increment in PG rose by 70%, whereas the MI of insulin sensitivity improved by 109% (IGT → NGT group) and 73% (IGT → IGT group), respectively. Thus, all three factors contributed to the improvement in β-cell function ([ΔISR0–120/ΔG0–120] × [MI]) (Fig. 5, bottom panels).

The plasma insulin concentration is the result of a balance between ISR and insulin MCR. In PGZ-treated subjects who reverted to NGT or remained with IGT, plasma insulin response declined (Fig. 5, middle panels), yet the ISR increased. This implies that the insulin MCR must have increased markedly. This is consistent with previous observations that IR is associated with a reduced insulin MCR,[26] whereas improved insulin sensitivity is associated with an increased insulin MCR.[27]

Chronic hyperglycemia, i.e., glucotoxicity, has been shown to impair β-cell function and cause IR in muscle and liver.[8] Consistent with this, the reductions in FPG (r = −0.39, P < 0.0001; r = −0.45, P < 0.0001) and glucose AUC during OGTT (r = −0.63, P < 0.0001; r = −0.49, P < 0.0001) correlated with improvements in ΔI0–120/ΔG0–120 × MI and MI.

Metabolic and Clinical Parameters Associated With Final Glucose Tolerance Status

Using the entire cohort of 441 IGT subjects, we performed multivariate logistic regression analysis to examine which factors were associated with end-of-study glucose tolerance status (NGT/IGT vs. T2DM). In the first analysis (after accounting for age, sex, clinical center, and BMI), PGZ treatment was associated with an OR of 0.28 (95% CI 0.15–0.49, P < 0.0001) of developing T2DM. After accounting for the previous variables, including PGZ/placebo, we found that a reduction in plasma insulin response (ΔI0–120/G0–120) (OR 0.44 [95% CI 0.40–0.80]), improvement in the MI of insulin sensitivity (0.83 [0.75–0.93]), and increases in ln IS/IR (0.10 [0.05–0.20]) and ln ISR/IR (0.08 [0.03–0.19]) were protective against the development of T2DM (all P < 0.001).

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