Jimenez-Chillaron Josep C, Hernandez-Valencia Marcelino, Reamer Carolyn, Fisher Simon, Joszi Allison, Hirshman Michael, Oge Aysin, Walrond Shana, Przybyla Roberta, Boozer Carol, Goodyear Laurie J, Patti Mary-Elizabeth
Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
Diabetes. 2005 Mar;54(3):702-11. doi: 10.2337/diabetes.54.3.702.
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 beta-cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5-fold 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.
低出生体重（LBW）是2型糖尿病的一个重要风险因素。我们已经建立了一种因孕期营养不良导致低出生体重的小鼠模型。在孕期第12.5天至18.5天限制母体食物摄入量，可使出生体重降低23%（P < 0.001），出生后体重恢复正常。然而，营养不良孕期的后代在6个月时会逐渐出现严重的葡萄糖不耐受。为了确定导致这种表型的早期缺陷，我们在葡萄糖不耐受出现之前，对2个月大的营养不良孕期小鼠进行了分析。营养不良孕期小鼠的空腹胰岛素水平比对照组高1.7倍（P = 0.01）。然而，营养不良孕期小鼠的胰岛素敏感性正常，胰岛素耐受性、胰岛素刺激的葡萄糖处置以及分离的肌肉和脂肪葡萄糖摄取均正常。尽管营养不良孕期小鼠的胰岛素清除略有受损，但营养不良孕期幼鼠的主要代谢表型是胰岛素分泌失调。尽管β细胞质量正常，但来自血糖正常的营养不良孕期小鼠的胰岛显示基础胰岛素分泌过多、对葡萄糖完全无反应以及己糖激酶活性增加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低出生体重相关的2型糖尿病发病机制中起重要作用。
