β-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes -: A murine model
β-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes -: A murine model
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DOI：
10.2337/diabetes.54.3.702
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发表时间：
2005-03-01
期刊：
影响因子：
7.7
通讯作者：
Patti, ME
中科院分区：
文献类型：
--
作者：
Jimenez-Chillaron, JC;Hernandez-Valencia, M;Patti, ME
低出生体重（LBW）是2型糖尿病的重要危险因素。我们建立了一种由妊娠期营养不良引起的LBW小鼠模型。从怀孕第12.5天到18.5天限制母亲的食物摄入导致出生体重下降23% (P < 0.001)，出生后恢复正常。然而，营养不良妊娠的后代在6个月时出现进行性严重的葡萄糖耐受不良。为了确定导致这种表型的早期缺陷，我们分析了2个月时营养不良的怀孕小鼠，在葡萄糖耐受不良发作之前。营养不良妊娠小鼠的胰岛素水平是对照组的1.7倍（P = 0.01）。然而，在营养不良的妊娠小鼠中，胰岛素敏感性正常，胰岛素耐量正常，胰岛素刺激的葡萄糖处理正常，孤立的肌肉和脂肪葡萄糖摄取正常。尽管营养不良妊娠小鼠的胰岛素清除率轻度受损，但营养不良妊娠幼鼠的主要代谢表型是胰岛素分泌失调。尽管p细胞质量正常，但营养不良妊娠的血糖正常小鼠的胰岛显示胰岛素的基础高分泌，对葡萄糖完全缺乏反应，己糖激酶活性增加2.5倍。综上所述，这些数据表明，至少在小鼠中，原发性β细胞功能障碍可能在lbw相关的2型糖尿病发病机制中发挥重要作用。
Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight (P < 0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies (P = 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal P-cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary beta-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes.