Etiology of insulin resistance
Etiology of insulin resistance
复制标题
DOI：
10.1016/j.amjmed.2006.01.009
复制
发表时间：
2006-05-01
影响因子：
5.9
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Petersen, KF;Shulman, GI
2型糖尿病是世界范围内发病率和死亡率的主要原因，并且在未来几十年中患病率将急剧增加。因此，了解导致2型糖尿病的代谢途径是一个重要的医疗目标。基于磁共振波谱（MRS）的新研究技术可以实时了解2型糖尿病患者的分子缺陷，揭示胰岛素抵抗是胰岛素刺激的骨骼肌糖原合成减少的产物，这主要归因于胰岛素刺激的葡萄糖转运（Glut 4）活性降低。这种缺陷似乎是细胞内脂质诱导的胰岛素刺激的胰岛素受体底物（IRS）-1酪氨酸磷酸化抑制的结果，导致IRS 1相关的磷脂酰肌醇3激酶活性降低。胰岛素抵抗是细胞内脂质代谢产物（如脂质代谢产物）积累的结果。例如，在一个实施例中，脂肪代谢障碍的患者和小鼠模型中的观察结果支持了骨骼肌和肝细胞中的脂肪酰辅酶A（脂肪酰辅酶A，二酰基甘油）。此外，在2型糖尿病患者体重减轻后观察到的肝脏胰岛素敏感性增加也伴随着肝内脂肪的显著减少，而循环脂肪细胞因子（白细胞介素-6，IFN，瘦素）没有任何变化。最后，最近的MRS研究在健康，瘦，老年受试者和瘦胰岛素抵抗的后代的父母与2型糖尿病已经证明，线粒体活性降低也可能导致增加肌内脂质含量和胰岛素抵抗的骨骼肌在这些人。总之，在体内MRS已被证明是一个重要的工具，阐明因果链的事件，导致胰岛素抵抗。了解胰岛素抵抗的细胞机制反过来又为治疗和预防2型糖尿病提供了更好的靶向和更有效的治疗干预的前景。(C)2006年爱思唯尔公司All rights reserved.
Type 2 diabetes mellitus is a major cause of morbidity and mortality worldwide, and the prevalence is set to increase dramatically over the coming decades. Understanding the metabolic pathways that lead to type 2 diabetes is therefore an important healthcare objective. Novel investigational techniques based on magnetic resonance spectroscopy (MRS) have allowed real-time insight into the molecular defects in patients with type 2 diabetes, revealing that insulin resistance is a product of decreased insulin-stimulated skeletal muscle glycogen synthesis, which can mostly be attributed to decreased insulin-stimulated glucose transport ( Glut 4) activity. This defect appears to be a result of intracellular lipid-induced inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation resulting in reduced IRS1 - associated phosphatidyl inositol 3 kinase activity. The hypothesis that insulin resistance is a result of accumulation of intracellular lipid metabolites ( e. g., fatty acyl CoAs, diacylglycerol) in skeletal muscle and hepatocytes is supported by observations in patients and mouse models of lipodystrophy. Furthermore, the increase in hepatic insulin sensitivity observed in patients with type 2 diabetes following weight loss is also accompanied by a significant reduction in intrahepatic fat without any changes in circulating adipocytokines (interleukin-6, resistin, leptin). Finally, recent MRS studies in healthy, lean, elderly subjects and lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial activity may also lead to increased intramyocellular lipid content and insulin resistance in skeletal muscle in these individuals. In summary, in vivo MRS has proved to be an important tool for elucidating the causal chain of events that causes insulin resistance. Understanding the cellular mechanism(s) of insulin resistance in turn offers the prospect of better targeted and more effective therapeutic interventions for treatment and prevention of type 2 diabetes. (C) 2006 Elsevier Inc. All rights reserved.