Elahi D, McAloon-Dyke M, Fukagawa N K, Meneilly G S, Sclater A L, Minaker K L, Habener J F, Andersen D K
Division on Aging, Harvard Medical School, Boston, MA 02215.
Regul Pept. 1994 Apr 14;51(1):63-74. doi: 10.1016/0167-0115(94)90136-8.
Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.
尽管血糖水平相似，但口服葡萄糖后胰岛素水平高于静脉注射。这种差异归因于肠促胰岛素效应，据信是由肠道释放的激素刺激β细胞介导的。主要的肠道激素候选物是葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽（GLP-1）。为了确定这些肽的相对促胰岛素活性，我们将GLP-1(7-37)和GIP注入正常受试者和非胰岛素依赖型糖尿病（NIDDM）患者体内。在正常受试者血糖正常期间，GLP-1(7-37)刺激胰岛素释放，而GIP则无此作用。我们使用安德烈斯钳夹技术建立了2小时的稳定高血糖状态（比基础水平高5.4 mmol/l）。在第二个小时期间，向正常健康志愿者和NIDDM患者体内注入GIP、GLP-1(7-37)或两者。在正常受试者中，血糖水平为10.4 mmol/l时，90 - 120分钟的胰岛素反应为279 pmol/l。剂量为1、2或4 pmol/kg/min的GIP使90 - 120分钟的胰岛素反应分别增加69、841和920 pmol/l，而剂量为1.5 pmol/kg/min的GLP-1(7-37)使胰岛素反应增加2106 pmol/l。当两种激素同时给药时，增加量是相加的——2813 pmol/l。在糖尿病受试者中，GIP无作用，而GLP-1(7-37)使胰岛素反应增加929 pmol/l。我们得出结论，在正常健康受试者中，在同等血糖条件下，按摩尔计算，GLP-1(7-37)的效力比GIP强几倍。相加的促胰岛素效应表明，与静脉途径相比，口服葡萄糖后观察到的更高胰岛素水平可能由多种肠促胰岛素负责。在NIDDM中，GIP无促胰岛素作用，而GLP-1(7-37)有显著作用。这表明GLP-1(7-37)作为NIDDM患者的降糖药物可能具有治疗潜力。
