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Published on: May 10, 2018
Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population
Sudha S Shankar1, R Ravi Shankar1, Radha A Railkar1
1Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ.
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.
Insights
Pioglitazone rapidly improves insulin sensitivity in obese, non-diabetic individuals within two weeks. This insulin sensitizer enhances glucose disposal rates and adiponectin levels, offering early metabolic benefits.
Area of Science:
- Metabolic Medicine
- Pharmacology
- Endocrinology
Background:
- Insulin resistance is a key risk factor for type 2 diabetes and cardiovascular disease.
- Thiazolidinediones are insulin sensitizers that improve insulin action but their early onset of effects is not well-documented.
- Understanding early metabolic effects is crucial for managing insulin resistance.
Purpose of the Study:
- To evaluate the early metabolic effects of the thiazolidinedione pioglitazone.
- To determine if pioglitazone shows prominent early metabolic effects in obese, non-diabetic, insulin-resistant individuals.
- To assess these effects independent of glucotoxicity reversal.
Main Methods:
- A randomized, double-blind, placebo-controlled trial was conducted in men with non-diabetic insulin resistance.
- The hyperinsulinemic euglycemic clamp technique was used to measure insulin sensitivity.
- Pioglitazone (30 mg daily) or placebo was administered for 28 days, with clamps at baseline, 2 weeks, and 4 weeks.
Main Results:
- Pioglitazone significantly increased glucose disposal rates (GDR) by 39% at 2 weeks under high-dose insulin, an effect sustained at 4 weeks.
- Significant increases in GDR were also observed at 4 weeks under low-dose insulin.
- Treatment led to suppressed free fatty acids and increased total adiponectin levels at 2 and 4 weeks.
Conclusions:
- Pioglitazone demonstrates significant early improvements in insulin action across multiple tissues within two weeks.
- These findings highlight the rapid onset of insulin-sensitizing therapy in obese patients with non-diabetic insulin resistance.
- The study provides evidence for early therapeutic benefits of pioglitazone in metabolic health.
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