Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L
Department of Medicine, Albert Einstein College of Medicine, New York 10461, USA.
J Clin Invest. 1998 Apr 1;101(7):1353-61. doi: 10.1172/JCI485.
Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, peripheral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old male Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or moderately calorie restricted (18 CR) up to 18 mo of age. Total fat mass (FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged. Most important, 18 CR had more FM (65+/-6 vs. 45+/-6 g) but less VF (7.8+/-0.6 vs. 12.3+/-3.3 g) compared with 4 AL (P < 0.01 for both). Thus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of young rats, while peripheral insulin sensitivity remained unchanged (by insulin clamp of 18 mU/kg/min). In fact, the rates of insulin infusion required to maintain basal hepatic glucose production in the presence of pancreatic clamp were 0.75+/-0.10, 1.41+/-0.13, and 0.51+/-0.12 mU/kg . min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreased by 32% (P < 0. 005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin resistance was induced. We propose that in this animal model the age-associated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin resistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate metabolism in aging.
高胰岛素血症和内脏/腹部脂肪（VF）增加是人类衰老的常见特征。为了研究VF、外周和肝脏胰岛素敏感性之间的关系，我们对4个月和18个月大的雄性Sprague-Dawley大鼠（n = 42）进行了研究，这些大鼠自由进食（4个月自由进食组和18个月自由进食组）或适度限制热量摄入（18个月热量限制组）直至18个月龄。18个月热量限制组的总脂肪量（FM）和VF降至18个月自由进食组的约三分之一（P < 0.001），而瘦体重（LBM）不变。最重要的是，与4个月自由进食组相比，18个月热量限制组的FM更多（65±6 vs. 45±6 g）但VF更少（7.8±0.6 vs. 12.3±3.3 g）（两者P < 0.01）。因此，可以独立于FM和年龄评估可变VF对高胰岛素血症的影响。随着衰老（18个月自由进食组）出现明显的肝脏胰岛素抵抗，热量限制将肝脏胰岛素敏感性恢复到年轻大鼠的水平，而外周胰岛素敏感性保持不变（通过18 mU/kg/min的胰岛素钳夹）。事实上，在胰腺钳夹存在的情况下维持基础肝脏葡萄糖生成所需的胰岛素输注速率在4个月自由进食组、18个月自由进食组和18个月热量限制组分别为0.75±0.10、1.41±0.13和0.51±0.12 mU/kg·min（所有组之间P < 0.01），并且在以与18个月自由进食组相似的速率（1.4 mU/kg/min）输注胰岛素的18个月热量限制组大鼠中，肝脏葡萄糖生成降低了32%（P < 0.005）。此外，当18个月热量限制组大鼠自由进食14天时，VF迅速且选择性增加，并诱导了严重的肝脏胰岛素抵抗。我们提出，在这个动物模型中，与年龄相关的肝脏（而非外周）胰岛素作用降低是空腹高胰岛素血症的主要决定因素，并且内脏脂肪增多在诱导肝脏胰岛素抵抗中起主要作用。因此，旨在防止VF积累的干预措施可能是改善衰老过程中碳水化合物代谢的有效手段。
