Vaag A, Jensen C Bjørn, Poulsen P, Brøns C, Pilgaard K, Grunnet L, Vielwerth S, Alibegovic A
Steno Diabetes Centre, Gentofte, Denmark.
Horm Res. 2006;65 Suppl 3:137-43. doi: 10.1159/000091519. Epub 2006 Apr 10.
Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19-23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-zeta, the two subunits of phosphoinositol 3-kinase (i.e., p85alpha and p110beta) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.
众多研究表明，一方面出生时体重低和小于胎龄儿（SGA）与另一方面发生胰岛素抵抗和2型糖尿病的风险之间存在关联。我们对双胞胎的研究表明，与小于胎龄出生相关的胰岛素抵抗和2型糖尿病具有非遗传的年龄依赖性起源。为了深入了解将小于胎龄儿与胰岛素抵抗和2型糖尿病联系起来的分子代谢缺陷及机制，我们在年轻和年长的双胞胎中进行了一系列实验，特别是在出生时体重处于足月最低第10百分位数且无糖尿病家族史的年轻男性（19 - 23岁）中进行。对照组包括足月出生体重处于正常上限范围且年龄匹配的男性。虽然小于胎龄出生的个体与对照组的体重指数和腰臀比相似，但双能X线吸收法研究表明，出生体重低的男性腹部肥胖程度更高。使用金标准的高胰岛素-正常血糖钳夹技术结合葡萄糖示踪剂以及前臂葡萄糖摄取研究，我们发现尽管全身葡萄糖摄取正常，但胰岛素刺激的糖酵解通量受损且前臂（肌肉）葡萄糖摄取减少。此外，在校正胰岛素作用（处置指数）后，我们发现口服葡萄糖摄入期间胰岛素分泌率显著降低，肝葡萄糖生成的胰岛素抑制出现反常增强且空腹血浆甘油水平降低，提示脂肪分解受损。最后，对骨骼肌活检组织的分析显示，出生体重低的个体中，参与胰岛素信号传导和葡萄糖转运的几种关键蛋白的肌肉表达减少，包括蛋白激酶C-ζ、磷脂酰肌醇3-激酶的两个亚基（即p85α和p110β）以及胰岛素敏感的葡萄糖转运蛋白Glut-4。总之，小于胎龄出生且出生体重低以非遗传方式与2型糖尿病相关，肌肉胰岛素作用和信号传导的程序化是造成这种关联的早期机制。
