TY - JOUR
T1 - Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes
AU - Tonelli, Julia
AU - Li, Weijie
AU - Kishore, Preeti
AU - Pajvani, Utpal B.
AU - Kwon, Elize
AU - Weaver, Charles
AU - Scherer, Philipp E.
AU - Hawkins, Meredith
PY - 2004/6
Y1 - 2004/6
N2 - 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.
AB - 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.
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U2 - 10.2337/diabetes.53.6.1621
DO - 10.2337/diabetes.53.6.1621
M3 - Article
C2 - 15161771
AN - SCOPUS:2542523201
SN - 0012-1797
VL - 53
SP - 1621
EP - 1629
JO - Diabetes
JF - Diabetes
IS - 6
ER -