Insulin-like growth factor I (rhIGF-I) as a therapeutic agent for hyperinsulinemic insulin-resistant diabetes mellitus.
Insulin-like growth factor I (rhIGF-I) as a therapeutic agent for hyperinsulinemic insulin-resistant diabetes mellitus.
复制标题
胰岛素样生长因子 I (rhIGF-I) 作为高胰岛素血症胰岛素抵抗糖尿病的治疗剂。
DOI：
10.1016/0168-8227(95)01084-q
复制
发表时间：
1995
影响因子：
5.1
通讯作者：
Flier,JS
中科院分区：
文献类型：
--
作者：
Moses,AC;Morrow,LA;O'Brien,M;Moller,DE;Flier,JS
胰岛素抵抗是非胰岛素依赖型糖尿病（NIDDM）的主要基础异常之一，但其病理生理机制尚不清楚。许多关于胰岛素作用机制的线索来自于最严重的胰岛素抵抗患者，包括那些胰岛素信号转导级联遗传异常的患者。我们用rhIGF-I作为探针来区分胰岛素和IGF-I的作用，并研究IGF在胰岛素抵抗状态下的治疗潜力。到目前为止，我们已经研究了六个不同的严重胰岛素抵抗表型，但没有突变的胰岛素受体本身的主题。所有受试者在接受100 μg/kg体重的rhIGF-I s.c.之前进行基线生理监测，以定量碳水化合物耐受性、胰岛素分泌和胰岛素作用。每日两次，持续1个月，并定期检测血糖控制和胰岛素敏感性。6名受试者均未观察到rhIGF-I的显著副作用。在对照试验期间，6名受试者中有4名患有明显的糖尿病;其中3名受试者在rhIGF-I给药期间未接受其他治疗，空腹和餐后血糖浓度正常化。在第4例患者中，胰岛素需求和空腹高血糖降低，血糖控制没有改善。两名葡萄糖耐量正常的受试者（两名患有先天性脂肪营养不良的姐妹篇）在显著较低的胰岛素水平下维持正常的葡萄糖耐量，甘油三酯水平显著降低。IGF-I的疗效在研究期间持续增加。5/6例受试者的稳态血糖从对照期的280 ± 68降至rhIGF治疗期间的207 ± 43（rhIGF-I末次给药后14 h）。稳态血浆胰岛素从对照期的127 ± 120降至rhIGF-I期间的59 ± 55。因此，在较低的环境胰岛素浓度下血糖降低，表明胰岛素敏感性改善。这些数据表明，rhIGF-I可以有效地治疗一些严重的胰岛素抵抗患者，并建议rhIGF-I在II型糖尿病的潜在效用。
Insulin resistance is one of the major underlying abnormalities in NIDDM, however, its pathophysiologic mechanisms are not well understood. Many clues about the mechanisms of insulin action have come from patients with the most severe forms of insulin resistance, including those with genetic abnormalities in the insulin signal transduction cascade. We used rhIGF-I as a probe to differentiate insulin and IGF-I action and to study the therapeutic potential of IGF in states of insulin resistance. To date, we have studied six subjects with varying phenotypes of severe insulin resistance but without mutations in the insulin receptor itself. All subjects underwent baseline physiologic monitoring to quantitate carbohydrate tolerance, insulin secretion, and insulin action prior to receiving rhIGF-I at 100 μg/kg body wt s.c. bid for 1 month with interval testing of glycemic control and insulin sensitivity. None of the six subjects noted significant side effects from the rhIGF-I. Four of the six subjects had overt diabetes during control testing; three of these subjects demonstrated normalization of fasting and postprandial blood glucose concentrations during rhIGF-I administration on no other therapy. In the fourth patient, insulin requirements and fasting hypertriglyceridemia decreased without improvement in glycemic control. The two subjects with normal glucose tolerance (two sisters with congenital lipodystrophy) maintained normal glucose tolerance at dramatically lower insulin levels and had a dramatic reduction in triglyceride levels. The efficacy of IGF-I continued to increase over the duration of the study. Steady state plasma glucose decreased in five/six subjects from 280 ± 68 in the control period to 207 ± 43 during rhIGF treatment (14 h after last dose of rhIGF-I). Steady-state plasma insulin decreased from 127 ± 120 in the control period to 59 ± 55 during rhIGF-I. Thus, blood glucose was reduced at lower ambient insulin concentrations, demonstrating improved insulin sensitivity. These data demonstrate that rhIGF-I effectively can treat some patients with severe insulin resistance and suggest the potential utility of rhIGF-I in Type II diabetes mellitus.