Morrow L A, O'Brien M B, Moller D E, Flier J S, Moses A C
Harvard Thorndike Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215.
J Clin Endocrinol Metab. 1994 Jul;79(1):205-10. doi: 10.1210/jcem.79.1.8027228.
Recombinant human (rh) insulin-like growth factor-I (IGF-I) is a potential therapy for individuals with severe insulin resistance, but its efficacy, mechanism of action, or duration of effect for these patients have not been explored fully. Two subjects with the type A phenotype of severe insulin resistance without insulin receptor mutations were investigated to assess insulin secretion, insulin action, and carbohydrate tolerance before and after 3-4 weeks of rhIGF-I treatment (100 micrograms/kg, sc, twice daily). Tests included 24-h glucose and insulin profile (modal day), standardized liquid meal with Sustacal, insulin tolerance test, insulin suppression test, and iv glucose tolerance test. In subject 1, the 24-h mean blood glucose level was 8.1 +/- 2.7 mmol/L before rhIGF-I treatment and fell to 4.2 +/- 0.9 mmol/L during rhIGF-I treatment. The pretreatment 24-h mean serum insulin level was 10,251 +/- 8,849 pmol/L and fell to 1533 +/- 1198 pmol/L. Fasting blood glucose fell from 4.4 to 3.4 mmol/L, and 2-h blood glucose after Sustacal administration fell from 10.3 to 5.3 mmol/L. Fasting serum insulin declined from 808 to 246 pmol/L, and the 2-h serum insulin level fell from 5,491 to 3,443 pmol/L. After bolus iv insulin injection (0.15 U/kg), glucose fell by 20% before rhIGF-I treatment and by 67% during rhIGF-I treatment. The steady state plasma glucose level was 18.2 +/- 0.7 before rhIGF-I and 10.8 +/- 0.1 mmol/L during rhIGF-I. In subject 2, fasting blood glucose fell from 12.0 to 7.4 mmol/L and 24-h mean blood glucose fell from 12.7 +/- 1.9 to 6.6 +/- 1.3 mmol/L. Twenty-four-hour mean serum insulin fell from 892 +/- 635 to 521 +/- 293 pmol/L, and first phase insulin secretion was restored during the iv glucose tolerance test. We conclude that sc rhIGF-I can reduce blood glucose effectively in selected patients with the type A phenotype of severe insulin resistance who have diabetes mellitus. rhIGF-I also can enhance insulin sensitivity, as assessed by a decrease in endogenous insulin levels, normalization of response to iv insulin, and a reduced steady state plasma glucose. The cellular mechanisms for these effects remain undefined.
重组人（rh）胰岛素样生长因子-I（IGF-I）是治疗严重胰岛素抵抗个体的一种潜在疗法，但尚未充分探究其对这些患者的疗效、作用机制或作用持续时间。对两名具有严重胰岛素抵抗A型表型且无胰岛素受体突变的受试者进行了研究，以评估在rhIGF-I治疗（100微克/千克，皮下注射，每日两次）3 - 4周前后的胰岛素分泌、胰岛素作用和碳水化合物耐量。测试包括24小时血糖和胰岛素谱（典型日）、含苏达卡尔的标准化流食餐、胰岛素耐量试验、胰岛素抑制试验和静脉葡萄糖耐量试验。在受试者1中，rhIGF-I治疗前24小时平均血糖水平为8.1±2.7毫摩尔/升，治疗期间降至4.2±0.9毫摩尔/升。治疗前24小时平均血清胰岛素水平为10251±8849皮摩尔/升，降至1533±1198皮摩尔/升。空腹血糖从4.4降至3.4毫摩尔/升，给予苏达卡尔后2小时血糖从10.3降至5.3毫摩尔/升。空腹血清胰岛素从808降至246皮摩尔/升，2小时血清胰岛素水平从5491降至3443皮摩尔/升。静脉注射胰岛素推注（0.15单位/千克）后，rhIGF-I治疗前血糖下降了20%，治疗期间下降了67%。rhIGF-I治疗前稳态血浆葡萄糖水平为18.2±0.7，治疗期间为10.8±0.1毫摩尔/升。在受试者2中，空腹血糖从12.0降至7.4毫摩尔/升，24小时平均血糖从12.7±1.9降至6.6±1.3毫摩尔/升。24小时平均血清胰岛素从892±635降至521±293皮摩尔/升，静脉葡萄糖耐量试验期间恢复了第一相胰岛素分泌。我们得出结论，皮下注射rhIGF-I可有效降低患有糖尿病的严重胰岛素抵抗A型表型的特定患者的血糖。rhIGF-I还可增强胰岛素敏感性，这通过内源性胰岛素水平降低以及对静脉注射胰岛素反应的正常化和稳态血浆葡萄糖降低来评估。这些效应的细胞机制仍不明确。
