Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population

Sudha S Shankar, R Ravi Shankar, Radha A Railkar, Chan R Beals, Helmut O Steinberg, David E Kelley, Sudha S Shankar, R Ravi Shankar, Radha A Railkar, Chan R Beals, Helmut O Steinberg, David E Kelley

Abstract

Background: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity.

Objective: The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population.

Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m(2)/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment.

Results: Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43-2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17-0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment.

Conclusions: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

Keywords: free fatty acids; glucose clamp; insulin resistance; insulin sensitivity; nondiabetic; pioglitazone.

Figures

Figure 1
Figure 1
Means and SE for change (Δ) from baseline in glucose disposal rate per kilogram body weight (mg/kg/min) (M) across the entire duration of the clamp performed at Day 14 of treatment with 30 mg pioglitazone or placebo. Insulin was administered at a low dose (10 mU/m2/min) from 0 to 180 minutes, and at a high dose (40 mU/m2/min) from 180 to 360 minutes.
Figure 2
Figure 2
Means and SE for change (Δ) from baseline in glucose disposal rate per kg body weight (mg/kg/min) (M) across the entire duration of the clamp performed at Day 28 of treatment with 30 mg pioglitazone or placebo. Insulin was administered at a low dose (10 mU/m2/min) from 0 to 180 minutes, and at a high dose (40 mU/m2/min) from 180 to 360 minutes.
Figure 3
Figure 3
(A) Mean glucose disposal rate (GDR) (mg/kg/min) in the placebo group. (B) Mean insulin concentration (mcIU/mL) in the placebo group.

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