胰淀素类似物普兰林肽对1型糖尿病患者肝脏胰高血糖素反应及中间代谢的影响。

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.

作者信息

Orskov L, Nyholm B, Yde Hove K, Gravholt C H, Møller N, Schmitz O

机构信息

Department of Medicine C, University Hospital of Arhus, Denmark.

出版信息

Diabet Med. 1999 Oct;16(10):867-74. doi: 10.1046/j.1464-5491.1999.00162.x.

DOI:10.1046/j.1464-5491.1999.00162.x

PMID:10547215

Abstract

AIMS

Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans.

METHODS

Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2).

RESULTS

Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2).

CONCLUSIONS

Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.

摘要

目的

在1型糖尿病患者中，肝脏糖原储备已被证明会耗尽，并且胰高血糖素刺激的肝脏葡萄糖生成会减少。在糖尿病动物模型中，共施用胰淀素和胰岛素已被证明可补充肝脏糖原储备。本研究的目的是调查胰淀素替代对人体肝脏胰高血糖素反应性的影响。

方法

13名1型糖尿病男性在皮下注射普兰林肽（30微克，每日4次）或安慰剂4周后，进行了一项双盲、安慰剂对照、交叉研究。经过一夜禁食后，通过以0.25 mU×kg⁻¹×min⁻¹的胰岛素输注速率使血浆葡萄糖保持在5 mmol/l以上（基线210 - 240分钟）。为了控制门静脉胰高血糖素水平，以200微克/小时的速率输注生长抑素。补充基础生长激素（2 ng×kg⁻¹×min⁻¹）和胰高血糖素（0.7 ng×kg⁻¹×min⁻¹）。在240 - 360分钟时将胰高血糖素输注增加到至2.1 ng×kg⁻¹×min⁻¹（步骤1），在360 - 420分钟时增加到4.2 ng×kg⁻¹×min⁻¹（步骤2）。

结果

基线血浆葡萄糖（5.59±0.16对5.67±0.25 mmol/l）和内源性葡萄糖生成（EGP）（1.32±0.22对1.20±0.13 mg×kg⁻¹·min⁻¹）相似，并且普兰林肽对胰高血糖素的反应没有影响（葡萄糖：步骤1；6.01±0.31对5.94±0.38 mmol/l，步骤2；6.00±0.37对5.96±0.50 mmol/l，EGP：步骤1；1.91±0.18对1.83±0.15 mg×kg⁻¹×min⁻¹，步骤2；2.08±0.17对1.96±0.16 ng×kg⁻¹×min⁻¹，普兰林肽对安慰剂）。基线时以及胰高血糖素激发期间的葡萄糖处置率相似（普兰林肽对安慰剂，2.44±0.13对2.28±0.09 mg×kg⁻¹×min⁻¹）（所有P值均>0.2）。