Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes

被引:74
作者
Petersen, Kitt Falk [1 ]
Dufour, Sylvie [1 ,4 ]
Morino, Katsutaro [1 ,4 ]
Yoo, Peter S. [2 ]
Cline, Gary W. [1 ]
Shulman, Gerald I. [1 ,3 ,4 ]
机构
[1] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06536 USA
[2] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06536 USA
[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06536 USA
[4] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06536 USA
关键词
adipocytokines; insulin sensitivity index; mitochondria; diacylglycerols; visceral fat; FATTY LIVER-DISEASE; PROTEIN-KINASE-C; GLUCOSE-TRANSPORT; MITOCHONDRIAL DYSFUNCTION; GLYCOGEN-SYNTHESIS; HEPATIC STEATOSIS; ACID OXIDATION; PIMA-INDIANS; INFLAMMATION; HUMANS;
D O I
10.1073/pnas.1205675109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
To examine the role of intramyocellular lipid (IMCL) accumulation as well as circulating cytokines, branched-chain amino acids and acylcarnitines in the pathogenesis of muscle insulin resistance in healthy, young, lean insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured these factors in plasma and used H-1 magnetic resonance spectroscopy to assess IMCL content and hyperinsulinemic-euglycemic clamps using [6,6-H-2(2)] glucose to assess rates of insulin-stimulated peripheral glucose metabolism before and after weight reduction. Seven lean (body mass index < 25 kg/m(2)), young, sedentary IR offspring were studied before and after weight stabilization following a hypocaloric (1,200 Kcal) diet for similar to 9 wks. This diet resulted in an average weight loss of 4.1 +/- 0.6 kg (P < 0.0005), which was associated with an similar to 30% reduction of IMCL from 1.1 +/- 0.2% to 0.8 +/- 0.1% (P = 0.045) and an similar to 30% improvement in insulin-stimulated muscle glucose uptake [3.7 +/- 0.3 vs. 4.8 +/- 0.1 mg/(kg-min), P = 0.01]. This marked improvement in insulin-stimulated peripheral insulin responsiveness occurred independently of changes in plasma concentrations of TNF-alpha, IL-6, total adiponectin, C-reactive protein, acylcarnitines, and branched-chain amino acids. In conclusion, these data support the hypothesis that IMCL accumulation plays an important role in causing muscle insulin resistance in young, lean IR offspring, and that both are reversible with modest weight loss.
引用
收藏
页码:8236 / 8240
页数:5
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