内分泌学
内科学
胰岛素
胰岛素受体
胰岛素抵抗
蛋白激酶B
PI3K/AKT/mTOR通路
骨骼肌
生物
葡萄糖摄取
人口
磷酸肌醇3激酶
AKT2型
医学
磷酸化
信号转导
AKT1型
细胞生物学
环境卫生
作者
Martin Friedrichsen,Pernille Poulsen,Erik A. Richter,Bo F. Hansen,Jesper B. Birk,Rasmus Ribel‐Madsen,Kirstine L. Stender-Petersen,Elisabet M. Nilsson,Henning Beck‐Nielsen,Allan Vaag,Jørgen F.P. Wojtaszewski
出处
期刊:Diabetologia
[Springer Nature]
日期:2010-05-29
卷期号:53 (9): 1998-2007
被引量:15
标识
DOI:10.1007/s00125-010-1795-8
摘要
Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population.We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic-hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase assays and phospho-specific western blotting.Proximal insulin signalling was not associated with obesity, age or sex. However, birthweight was positively associated with IRS-1-associated phosphoinositide 3-kinase (PI3K; IRS-1-PI3K) activity (p = 0.04); maximal aerobic capacity (VO2(max)), paradoxically, was negatively associated with IRS-1-PI3K (p = 0.02) and Akt2 activity (p = 0.01). Additionally, we found low heritability estimates for most measures of insulin signalling activity. Glucose disposal was positively associated with Akt-308 phosphorylation (p < 0.001) and Akt2 activity (p = 0.05), but not with insulin receptor tyrosine kinase or IRS-1-PI3K activity.With the exception of birthweight, 'classical' modifiers of insulin action, including genetics, age, sex, obesity and VO2(max) do not seem to mediate their most central effects on whole-body insulin sensitivity through modulation of proximal insulin signalling in skeletal muscle. We also demonstrated an association between Akt activity and in vivo insulin sensitivity, suggesting a role of Akt in control of in vivo insulin resistance and potentially in type 2 diabetes.
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