Effects of Pioglitazone on Intramyocellular Fat Metabolism in Patients with Type 2 Diabetes Mellitus

被引:64
作者
Bajaj, Mandeep [1 ]
Baig, Rais [1 ]
Suraamornkul, Swangjit [1 ]
Hardies, Lou Jean [1 ]
Coletta, Dawn K. [1 ]
Cline, Gary W. [2 ]
Monroy, Adriana [1 ]
Koul, Shailja [1 ]
Sriwijitkamol, Apiradee [1 ]
Musi, Nicolas [1 ]
Shulman, Gerald I. [2 ]
DeFronzo, Ralph A. [1 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Diabet Div, San Antonio, TX 77030 USA
[2] Yale Univ, Dept Med, Sch Med, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
HEPATIC INSULIN-RESISTANCE; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; GENE-EXPRESSION; SUSTAINED REDUCTION; ACID CONCENTRATION; ADIPOSE-TISSUE; PROTEIN-KINASE; KNOCKOUT MICE; GLUCOSE; MUSCLE;
D O I
10.1210/jc.2009-0911
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM). Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism. Research Design: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 +/- 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m(2).min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LC-FACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp. Results: In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Delta = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 mu mol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content. Conclusions: Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle. (J Clin Endocrinol Metab 95: 1916-1923, 2010)
引用
收藏
页码:1916 / 1923
页数:8
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