Petersen K F, Jacob R, West A B, Sherwin R S, Shulman G I
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Am J Physiol. 1997 Dec;273(6):E1189-93. doi: 10.1152/ajpendo.1997.273.6.E1189.
To determine the effect of insulin-like growth factor I (IGF-I) on glucose metabolism in cirrhosis, a 2-h euglycemic clamp with IGF-I (0.65 nmol.kg-1.min-1) or insulin (12 pmol.kg-1.min-1) was performed in awake rats with carbon tetrachloride-induced liver cirrhosis. Rates of [3-3H]glucose-determined whole body glucose turnover were similar in the fasting state in cirrhotic and control rats (36.4 +/- 2.6 and 37.7 +/- 2.8 mumol.kg-1.min-1, respectively). In the control group, IGF-I and insulin had similar effects on turnover (81.6 +/- 27.0 and 76.1 +/- 9.9 mumol.kg-1.min-1), muscle glycogen synthesis (47.5 +/- 12.3 and 37.5 +/- 2.5 nmol.g muscle-1.min-1), and suppression of endogenous glucose production (EGP; -54 +/- 14 and -60 +/- 12%). Cirrhotic rats were markedly insulin resistant, reflected by a 43% reduction of turnover (43.8 +/- 9.4 mumol.g muscle-1.min-1; P = 0.03), a 73% reduction in muscle glycogen synthesis (10.2 +/- 3.4 nmol.g muscle-1.min-1; P < 0.0001), and a diminished suppression of EGP (-32 +/- 17% vs. control: -56 +/- 14%; P < 0.05). In contrast, during the IGF-I clamps, turnover increased threefold in the cirrhotic rats (P = 0.001), rates of muscle glycogen synthesis were 7.4 times higher than during the insulin stimulation (P < 0.0001), and EGP was suppressed by 80 +/- 12% (P < 0.05). In conclusion, insulin resistance in cirrhotic rats is mostly due to defects in insulin-stimulated muscle glycogen synthesis, and the ability of IGF-I to stimulate muscle glycogen synthesis as well as suppress EGP is maintained in cirrhotic rats. These findings suggest that alterations in both hepatic and peripheral glucose metabolism in patients with cirrhosis might be amenable to IGF-I therapy.
为了确定胰岛素样生长因子I（IGF-I）对肝硬化患者葡萄糖代谢的影响，对四氯化碳诱导的肝硬化清醒大鼠进行了2小时的正常血糖钳夹实验，分别给予IGF-I（0.65 nmol·kg-1·min-1）或胰岛素（12 pmol·kg-1·min-1）。肝硬化大鼠和对照大鼠在禁食状态下，[3-3H]葡萄糖测定的全身葡萄糖周转率相似（分别为36.4±2.6和37.7±2.8 μmol·kg-1·min-1）。在对照组中，IGF-I和胰岛素对周转率（81.6±27.0和76.1±9.9 μmol·kg-1·min-1）、肌肉糖原合成（47.5±12.3和37.5±2.5 nmol·g肌肉-1·min-1）以及内源性葡萄糖生成（EGP）的抑制作用（-54±14和-60±12%）相似。肝硬化大鼠存在明显的胰岛素抵抗，表现为周转率降低43%（43.8±9.4 μmol·g肌肉-1·min-1；P = 0.03）、肌肉糖原合成降低73%（10.2±3.4 nmol·g肌肉-1·min-1；P < 0.0001）以及EGP抑制减弱（-32±17%，对照组为-56±14%；P < 0.05）。相反，在IGF-I钳夹期间，肝硬化大鼠的周转率增加了三倍（P = 0.001），肌肉糖原合成速率比胰岛素刺激时高7.4倍（P < 0.0001），EGP被抑制了80±12%（P < 0.05）。总之，肝硬化大鼠的胰岛素抵抗主要是由于胰岛素刺激的肌肉糖原合成缺陷所致，而IGF-I刺激肌肉糖原合成以及抑制EGP的能力在肝硬化大鼠中得以保留。这些发现表明肝硬化患者肝脏和外周葡萄糖代谢的改变可能适合采用IGF-I治疗。
