van der Wal P S, Draeger K E, van Iperen A M, Martini C, Aarsen M, Heine R J
Free University Hospital Amsterdam, The Netherlands.
Diabet Med. 1997 Jul;14(7):556-63. doi: 10.1002/(SICI)1096-9136(199707)14:7<556::AID-DIA389>3.0.CO;2-6.
The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.
本研究旨在评估14例非胰岛素依赖型糖尿病（NIDDM）患者（7例男性）在高血糖钳夹期间及之后口服格列美脲后的β细胞反应。这些患者年龄为62.5（标准差7.7）岁，体重指数为27.3（2.8）kg/m²，基线糖化血红蛋白（HbA₁c）为7.0（0.7）%，该研究为安慰剂对照研究。所有患者在随机分组前至少8周一直使用第二代磺脲类药物进行稳定治疗，随机分组后接受安慰剂（P）或每日5mg格列美脲（G），共7天，在进行高血糖钳夹（血糖10.9mmol/L，持续60分钟，钳夹前静脉输注胰岛素以使空腹血糖水平稳定在4.0mmol/L）前给予10mg。5例受试者在钳夹后有2小时的观察期，另外9例受试者有3.5小时的观察期，在此期间定期测量血糖、血浆胰岛素、C肽和胰岛素原水平，以确定格列美脲对血糖变化与β细胞产物血浆水平之间相互作用的影响。格列美脲组和安慰剂组均未引发第一相胰岛素反应。在1小时高血糖钳夹期间，血浆胰岛素曲线下面积在格列美脲组和安慰剂组分别为94.2（39.5）与69.1（26.5）pmol·h/L（p = 0.002）。血浆胰岛素曲线下总面积在格列美脲组和安慰剂组分别为377（145）与271（113）pmol·h/L（<0.05）。C肽的总曲线下面积在格列美脲组和安慰剂组分别为309（96）和259（102）pmol·h/L，p = 0.01。胰岛素原的总曲线下面积在格列美脲组和安慰剂组分别为176（77）与119（56）pmol·h/L，p = 0.004。给予格列美脲和安慰剂5小时后，格列美脲组血糖水平为4.7（1.9）mmol/L，安慰剂组为6.2（1.9）mmol/L（p = 0.001）。在3.5小时观察期内，格列美脲组低血糖事件（血糖<3.0mmol/L）的发生次数为3次，安慰剂组为0次（p = 无显著差异）。总之，格列美脲刺激第二相胰岛素和胰岛素原分泌。血糖水平降低并未伴随胰岛素分泌的相应抑制。需要进一步研究将这种新药与目前可用的口服降糖药在血糖控制和低血糖风险方面进行比较。
