Petrides A S, Stanley T, Matthews D E, Vogt C, Bush A J, Lambeth H
Department of Medicine and Gastroenterology, Academic Hospital of the Ruhr University, Bochum, Germany.
Hepatology. 1998 Jul;28(1):141-9. doi: 10.1002/hep.510280119.
Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-2H2-glucose isotope dilution), glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 microg/24 h) designed to continuously reduce plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8). During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P < .03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P < .04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximately 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; 3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant vs. control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase in muscle compared with pre-octreotide results (increment above baseline pre: 0.035 +/- 0.010 vs. post: 0.060 +/- 0.023 nmol/min/mg protein; P < .04). Fractional glycogen activity significantly correlated with non-oxidative glucose disposal during insulin infusion (r = .69; P < .03). Prolonged reduction of hyperinsulinemia for 96 hours in cirrhotic patients normalizes insulin-mediated glucose uptake and glycogen synthesis in muscle. We conclude that chronic hyperinsulinemia causes insulin resistance in cirrhosis.
几乎所有肝硬化患者都存在胰岛素抵抗，但其病因尚不清楚。慢性高胰岛素血症一直被怀疑是一个潜在因素，因此我们检验了这样一个假设：在肝硬化患者中，长期降低高胰岛素血症可恢复胰岛素敏感性。我们对8例临床稳定的肝硬化患者在连续皮下输注生长抑素类似物奥曲肽（200微克/24小时）4天之前及结束时，测量了全身胰岛素敏感性（正常血糖胰岛素钳夹技术）、葡萄糖周转率（6,6 - 2H2 -葡萄糖同位素稀释法）、葡萄糖氧化（间接测热法）、非氧化葡萄糖处置以及肌肉中的糖原合酶活性分数（活检），该输注旨在持续降低血浆胰岛素水平。将基线数据与在性别、年龄和体重匹配的健康个体（n = 8）中获得的结果进行比较。在基线（奥曲肽治疗前）研究期间，与对照组相比，患者胰岛素介导的葡萄糖摄取显著降低（5.75±0.21对7.98±0.84毫克/千克/分钟；P <.03），这完全是由非氧化葡萄糖处置受损所致（P <.04）。对肝硬化患者进行4天的奥曲肽输注：1）使空腹和餐后刺激后的血浆胰岛素水平降低约35%至45%，而不显著影响葡萄糖耐量；2）在空腹状态和进餐试验期间，未显著改变血浆游离脂肪酸（FFA）、生长激素和胰高血糖素水平；3）使胰岛素介导的全身葡萄糖处置恢复正常（奥曲肽治疗后为7.63±0.72毫克/千克/分钟；与对照组相比P无显著差异）。胰岛素介导的葡萄糖利用恢复完全是由非氧化葡萄糖处置恢复正常所致；4）与奥曲肽治疗前的结果相比，胰岛素对肌肉中糖原合酶活性分数的刺激作用明显更显著（基线前增加值：0.035±0.010对治疗后：0.060±0.023纳摩尔/分钟/毫克蛋白；P <.04）。在胰岛素输注期间，糖原活性分数与非氧化葡萄糖处置显著相关（r =.69；P <.03）。在肝硬化患者中，将高胰岛素血症持续降低96小时可使胰岛素介导的葡萄糖摄取和肌肉中的糖原合成恢复正常。我们得出结论，慢性高胰岛素血症导致肝硬化患者出现胰岛素抵抗。
