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 Steinberg, David E. Kelley

Research output: Contribution to journalArticle

3 Citations (Scopus)

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/m2/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.

Original languageEnglish (US)
Pages (from-to)83-89
Number of pages7
JournalCurrent Therapeutic Research - Clinical and Experimental
Volume77
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

pioglitazone
Insulin
Population
Insulin Resistance
Placebos
Hyperinsulinism
Therapeutics
Glucose
Glucose Clamp Technique
Adiponectin
Nonesterified Fatty Acids
Type 2 Diabetes Mellitus
Cardiovascular Diseases

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population. / Shankar, Sudha S.; Shankar, R. Ravi; Railkar, Radha A.; Beals, Chan R.; Steinberg, Helmut; Kelley, David E.

In: Current Therapeutic Research - Clinical and Experimental, Vol. 77, 01.12.2015, p. 83-89.

Research output: Contribution to journalArticle

Shankar, Sudha S. ; Shankar, R. Ravi ; Railkar, Radha A. ; Beals, Chan R. ; Steinberg, Helmut ; Kelley, David E. / Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population. In: Current Therapeutic Research - Clinical and Experimental. 2015 ; Vol. 77. pp. 83-89.
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