Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat
Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat
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DOI：
10.1172/jci485
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发表时间：
1998-04-01
影响因子：
15.9
通讯作者：
Rossetti, L
中科院分区：
文献类型：
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作者：
Barzilai, N;Banerjee, S;Rossetti, L
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，我们研究了4和18月龄雄性Sprague-Dawley大鼠（n = 42），（4 AL和18 AL）或中度热量限制（18 CR），直至18月龄，18例CR患者的总脂肪量（FM）和VF降低至18例AL患者的约三分之一（P < 0.001），而瘦体重（LBM）不变，最重要的是，与4例AL相比，18例CR的FM（65 +/- 6 vs 45 +/- 6 g）更多，但VF（7.8 +/- 0.6 vs 12.3 +/- 3.3 g）更少（两者均P < 0.01）。因此，可变VF对HIS的影响可以独立于FM和年龄进行评估。随着年龄的增加，肝脏胰岛素抵抗明显增加（18 AL），CR使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，在胰腺钳夹存在下维持基础肝葡萄糖产生所需的胰岛素输注速率为0.75 ± 0.10，1.41 ± 0.13，4AL、18 AL和18 CR大鼠分别为0.51 +/-0.12mU/kg·min和0.51 +/-0.12mU/kg·min（所有组间P < 0.01），18 CR大鼠以与18 AL相似的速率（1.4mU/kg/min）输注胰岛素，肝葡萄糖产生减少32%（P < 0.005）。此外，当18只CR大鼠喂AL 14天时，VF迅速和选择性地增加，并诱导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（而不是外周）胰岛素作用的减少是空腹高胰岛素血症的主要决定因素，内脏脂肪增加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中碳水化合物代谢的有效手段。
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.