Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers
Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers
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DOI：
10.1210/jc.87.3.1239
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发表时间：
2002-03-01
影响因子：
5.8
通讯作者：
Schmiegel, WH
中科院分区：
文献类型：
--
作者：
Nauck, MA;Heimesaat, MM;Schmiegel, WH
胰高血糖素样肽1（GLP-1）及其类似物作为治疗2型糖尿病的新的治疗原则正在被评估。GLP-1抑制胰高血糖素分泌，这可能导致低血糖反调节紊乱。9名口服葡萄糖耐量正常的健康志愿者在空腹状态下接受了两次超过360分钟的常规胰岛素输注（1mU.kg（-1）.min（-1））。毛细血管葡萄糖浓度分别在4.3、3.7、3.0和2.3 mmol/L的平台下钳夹90 min（逐步低血糖钳夹）;一次静脉注射GLP-1（1.2 pmol.kg（-1）.min（-1））（稳态浓度，类似于125 pmol/L）;另一次给予NaCl作为安慰剂。测定胰高血糖素、皮质醇、GH（免疫测定）和儿茶酚胺（放射酶测定），评估自主和神经性葡萄糖减少症状，并在每个平台测试认知功能。通过去卷积（C肽动力学的二室模型）估计胰岛素分泌速率。在约45 mU/L的胰岛素浓度下，有和没有GLP-1的葡萄糖输注速率相似（P = 0.26）。仅在血糖正常平台期（4.3 mmol/L），GLP-1抑制胰高血糖素浓度（4.1 +/- 0.4 vs. 6.5 +/- 0.7 pmol/L; P = 0.012）;在所有低血糖平台期，胰高血糖素与GLP-1或安慰剂相似地增加，最大值大于20 pmol/L（P = 0.97）。其他反调节激素和自主或神经性葡萄糖减少症状评分增加，认知功能下降，随着葡萄糖浓度的降低，但有没有显着差异与GLP-1或安慰剂相比，除了显着减少GH反应在低血糖与GLP-1（P = 0.04）。GLP-1仅在血糖浓度至少为4.3 mmol/L时刺激胰岛素分泌。总之，GLP-1抑制胰高血糖素在正常血糖时发生，但在低血糖血糖浓度（小于或等于8.7 mmol/L）时不发生。GLP-1不损害总体低血糖反调节，但GH反应减少除外，这与证明GLP-1的垂体作用的其他结果一致。低于4.3 mmol/L的血浆葡萄糖浓度时，GLP-1的促胰岛素作用可忽略不计。
Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested.Nine healthy volunteers with normal oral glucose tolerance received infusions of regular insulin (1 mU.kg(-1).min(-1)) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one occasion, GLP-1 (1.2 pmol.kg(-1).min(-1)) was administered iv (steady-state concentration, similar to125 pmol/liter); on the other occasion, NaCl was administered as placebo. Glucagon, cortisol, GH (immunoassays), and catecholamines (radioenzymatic assay) were determined, autonomous and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics).At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P = 0.26). Only during the euglycemic plateau (4.3 mmol/liter), GLP-1 suppressed glucagon concentrations (4.1 +/- 0.4 vs. 6.5 +/- 0.7 pmol/liter; P = 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P = 0.97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses during hypoglycemia with GLP-1 (P = 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter.In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (less than or equal to8.7 mmol/liter). GLP-1 does not impair overall hypoglycemia counterregulation except for a reduction in GH responses, which is in line with other findings demonstrating pituitary actions of GLP-1. Below plasma glucose concentrations of 4.3 mmol/liter, the insulinotropic action of GLP-1 is negligible.