Metabolic programming in the pathogenesis of insulin resistance
Metabolic programming in the pathogenesis of insulin resistance
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DOI：
10.1007/s11154-007-9050-4
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发表时间：
2007-06-01
影响因子：
8.2
通讯作者：
Thamotharan, Manikkavasagar
中科院分区：
文献类型：
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作者：
Devaskar, Sherin U.;Thamotharan, Manikkavasagar
这篇综述的重点是营养扰动的不同动物模型，包括限制性和过度的状态，模仿人类在怀孕和哺乳期间的情况，导致后代的畸变。这些异常包括在胰岛素产生缺陷的情况下胰岛素敏感性降低。这些表型变化是由于外周组织胰岛素受体后信号传导机制的改变和胰岛胰岛素合成和分泌缺陷。虽然这些变化在子宫或出生后的生活中作为克服不利条件的基本适应，但它们随后变得不适应，并为2型糖尿病奠定了基础。妊娠导致妊娠糖尿病与胰岛素抵抗表型的跨代传播。这是对母体在子宫环境中代谢异常的反应，以及组织特异性的表观遗传扰动，这些扰动永久地改变了传递给后代的关键基因的表达。这些遗传畸变包括DNA甲基化和组蛋白修饰改变染色质并影响关键基因的转录。随着子宫环境的改变，这些染色质修饰导致了2型糖尿病在世界范围内的流行，在发达国家主要是营养过剩，而在发展中国家主要是营养限制。
This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic beta-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries.