Behme Margaret T, Dupré John, McDonald Thomas J
Department of Medicine, University of Western Ontario and London Health Sciences Centre, London, Ontario, N6A 5A5, Canada.
BMC Endocr Disord. 2003 Apr 10;3(1):3. doi: 10.1186/1472-6823-3-3.
Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 9.6 pmol/l, p <.05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 PlusMinus; 2.5 vs 3.1 PlusMinus; 1.9 ng/l, p <.04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 PlusMinus; 0.33 vs 0.34 PlusMinus; 0.26 mmol/l, p <.05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.
胰高血糖素样肽-1（GLP-1）及其激动剂因其抗糖尿病作用正在接受2型糖尿病治疗的评估，其作用包括刺激胰岛素分泌、抑制胰高血糖素释放以及延缓胃排空。我们研究了GLP-1在无内源性胰岛素分泌的1型糖尿病中改善血糖控制的潜力。
进行剂量探索研究以确定通过餐后胰多肽反应延迟来指示胃排空延迟的中等剂量。在医院进行的8小时研究中，在早餐和午餐前给予选定剂量0.63微克/千克的GLP-1，以确定GLP-1的疗效和安全性。在院外研究中，5名男性和3名女性C肽阴性且血糖控制良好的1型糖尿病患者连续5天在饭前双盲自行注射GLP-1或赋形剂，并同时注射常规胰岛素。患者自行监测饭前、早餐和晚餐后30分钟及60分钟以及就寝时的毛细血管血糖值。在5天研究的前一天和后一天进行GLP-1早餐试验。采用配对t检验和方差分析进行统计分析。
在8小时研究中，与赋形剂相比，GLP-1使8小时血浆葡萄糖的时间平均增量曲线下面积（AUC）降低（3.2±0.9，均值±标准误，对比5.4±0.8毫摩尔/升，p<0.05），对于作为胃排空指标的胰多肽，餐后30分钟的时间平均增量曲线下面积也降低（4.0±3.1对比37±9.6皮摩尔/升，p<0.05），且无不良反应。与赋形剂相比，GLP-1使餐后60分钟的胰高血糖素增量水平降低（-3.7±2.5对比3.1±1.9纳克/升，p<0.04）。在5天研究中，GLP-1组的毛细血管血糖水平AUC低于赋形剂组（-0.64±0.33对比0.34±0.26毫摩尔/升，p<0.05）。未发生低血糖辅助事件或胰岛素剂量变化。5天试验前后立即进行的早餐试验显示GLP-1的效果无变化。
我们已经证明，在既定的强化胰岛素治疗方案中，皮下注射GLP-1与常规胰岛素一起在饭前自行给药时，可改善1型糖尿病患者的血糖控制且无不良反应。
