内皮β1整合素是微血管功能和葡萄糖摄取的必要条件

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Nathan C Winn, Deborah A Roby, Penn Mason McClatchey, Ian M Williams, Deanna P Bracy, Michelle N Bedenbaugh, Louise Lantier, Erin Plosa, Ambra Pozzi, Roy Zent, David H Wasserman
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引用次数: 0

摘要

微血管向肌细胞输送胰岛素是胰岛素刺激肌肉摄取葡萄糖开始的速率限制。微血管毛细血管的结构完整性部分受称为整合素的跨膜粘附受体家族调节,整合素由 α 和 β 亚基组成。整合素 β1(itgb1)亚基在内皮细胞(EC)中高度表达。在胚胎发育过程中,血管内皮细胞 itgb1 是形成毛细血管网所必需的,敲除它可减弱缺血再灌注时表现出的反应性充血。我们以骨骼肌为重点,研究了EC itgb1对微循环功能和葡萄糖摄取的贡献。我们假设,在胰岛素刺激过程中,大血管内皮细胞 itgb1 的缺失会损害微血管血流动力学和葡萄糖摄取,从而产生 "传递 "介导的胰岛素抵抗。为了避免胚胎基因敲除的致死性和出生后早期诱导性基因缺失导致的健康恶化,我们开发了一种 itgβ1 基因敲除小鼠模型。在cre诱导后10天,表达(itgb1fl/flSCLcre)和不表达(itgb1fl/fl)他莫昔芬诱导的干细胞白血病cre重组酶(SLCcre)的小鼠具有相似的运动耐受性、肺功能和心脏功能。利用强大的体内实验平台(即显微镜观察和高胰岛素血糖钳夹),我们发现 itgb1fl/flSCLcre 小鼠与 itgb1fl/fl 小鼠相比,i)毛细血管流速、血流异质性和毛细血管密度存在缺陷;ii)尽管有足够的跨毛细血管胰岛素外流,但胰岛素刺激的葡萄糖摄取受损;iii)由于葡萄糖灌注受限,胰岛素刺激的葡萄糖摄取减少。因此,欧共体 itgb1 是微循环功能和应对胰岛素刺激代谢挑战所必需的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.

Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1fl/flSCLcre) and without (itgb1fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1fl/flSCLcre mice compared to itgb1fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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