Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes

Julia Tonelli, Weijie Li, Preeti Kishore, Utpal B. Pajvani, Elize Kwon, Charles Weaver, Philipp E. Scherer, Meredith A. Hawkins

Research output: Contribution to journalArticle

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Abstract

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA1c, 10.9 ± 0.6%; BMI, 31.9 ± 1.5 kg/m2). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3- 3H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 ± 0.1 vs. P- = 1.7 ± 0.3 mg · kg-1 · min-1; P < 0.05) at physiologic hyperinsulinemia (∼50 μU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r2 = 0.90). Maximal insulin stimulation (∼400 μU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 ± 0.9 vs. P- = 8.9 ± 0.8 mg · kg-1 · min-1; P < 0.05), which did not correlate with HMW of total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

Original languageEnglish (US)
Pages (from-to)1621-1629
Number of pages9
JournalDiabetes
Volume53
Issue number6
DOIs
StatePublished - Jun 2004

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pioglitazone
Thiazolidinediones
Adiponectin
Type 2 Diabetes Mellitus
Insulin
Glucose
Molecular Weight
Adipokines
Hyperinsulinism
Somatostatin
Glucagon
Nonesterified Fatty Acids
Growth Hormone
Adipose Tissue
Placebos
Gene Expression
Liver
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. / Tonelli, Julia; Li, Weijie; Kishore, Preeti; Pajvani, Utpal B.; Kwon, Elize; Weaver, Charles; Scherer, Philipp E.; Hawkins, Meredith A.

In: Diabetes, Vol. 53, No. 6, 06.2004, p. 1621-1629.

Research output: Contribution to journalArticle

Tonelli, J, Li, W, Kishore, P, Pajvani, UB, Kwon, E, Weaver, C, Scherer, PE & Hawkins, MA 2004, 'Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes', Diabetes, vol. 53, no. 6, pp. 1621-1629. https://doi.org/10.2337/diabetes.53.6.1621
Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C et al. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes. 2004 Jun;53(6):1621-1629. https://doi.org/10.2337/diabetes.53.6.1621
Tonelli, Julia ; Li, Weijie ; Kishore, Preeti ; Pajvani, Utpal B. ; Kwon, Elize ; Weaver, Charles ; Scherer, Philipp E. ; Hawkins, Meredith A. / Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. In: Diabetes. 2004 ; Vol. 53, No. 6. pp. 1621-1629.
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