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

ABSTRACT: 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.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.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.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.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.

SUBMITTER: Shankar SS

PROVIDER: S-EPMC4589823 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Shankar Sudha S SS Shankar R Ravi RR Railkar Radha A RA Beals Chan R CR Steinberg Helmut O HO Kelley David E DE

Current therapeutic research, clinical and experimental 20150814

<h4>Background</h4>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.<h4>Objective</h4>The goal of our study was to test whether the thiazo ...[more]

PMID: 26543510

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Project description:The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals.We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ? 2 arteries with ? 70% stenosis (or ? 50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (P(trend) = 0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07-1.60]) and quartile 4 (1.29 [1.03-1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein).We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome.

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

Publications

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

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