Using glucagon receptor antagonism to evaluate the physiological effects of extrapancreatic glucagon in totally pancreatectomised individuals: a randomised controlled trial.

Using a glucagon receptor antagonist (GRA), we investigated the possible role of extrapancreatic glucagon on glucose, lipid and amino acid metabolism in totally pancreatectomised individuals.

我们使用胰高血糖素受体拮抗剂（GRA），研究了胰腺外胰高血糖素在完全切除胰腺的个体中对葡萄糖、脂质和氨基酸代谢的可能作用。

method

In a randomised, crossover study, nine totally pancreatectomised individuals and nine matched healthy control individuals were given, in randomised order (planned on the website www.random.org ), 300 mg GRA (LY2409021; Eli Lilly) or placebo 10 h before two 3 h OGTTs.

在一项随机交叉研究中，九名全胰切除患者和九名匹配的健康对照者被随机给予（计划在网站www.random.org上进行），在两次3小时口服葡萄糖耐量测试（OGTT）前10小时，300 mg的GRA（LY2409021；礼来公司）或安慰剂。

The experiment was double-masked (i.e. both participants and investigator were masked for the type of the experimental day [day A vs day B]).

该实验是双盲的（即参与者和研究人员都被蒙蔽了实验日的类型[天A与天B]）。

The key inclusion criteria for the healthy control participants were age >18 years, normal fasting plasma glucose and HbA1c 31-44 mmol/mol (5.0-6.2%), haemoglobin >7.0 mmol/l (men) / >6.5 mmol/l (women) and informed consent.

健康对照组的主要纳入标准是年龄>18岁，空腹血浆葡萄糖正常，HbA1c在31-44毫摩尔/摩尔（5.0-6.2%）之间，血红蛋白>7.0毫摩尔/升（男性）/ >6.5毫摩尔/升（女性），并已获得知情同意。

Key inclusion criteria for the pancreatectomised individuals were age >18 years, haemoglobin in the normal range and informed consent.

全胰切除个体的主要纳入标准是年龄>18岁，血红蛋白在正常范围内，并已获得知情同意。

The primary endpoint was the difference in plasma glucose excursions between study days.

主要终点是研究日之间血浆葡萄糖波动的差异。

Results

Glucagon concentrations remained unchanged from fasting concentrations during the OGTT in the totally pancreatectomised individuals on both study days and circulating glucose, lipids and amino acid levels were unaffected by treatment with LY2409021 compared with placebo.

在完全胰腺切除的个体中，无论是研究日，OGTT期间胰高血糖素浓度都保持与空腹浓度不变，且与安慰剂相比，LY2409021治疗对循环中的葡萄糖、脂质和氨基酸水平没有影响。

In the control group, LY2409021 resulted in relevant pharmacodynamic effects, including lower fasting plasma glucose (4.7 [0.1] vs 5.2 [0.1] mmol/l, p=0.001) and augmented concentrations of amino acids in plasma, compared with placebo.

在对照组中，LY2409021产生了相关的药理动力学效应，包括较低的空腹血浆葡萄糖（4.7 [0.1] vs 5.2 [0.1] mmol/l, p=0.001）和血浆中氨基酸浓度的增加，与安慰剂相比。

conclusions/interpretation

We conclude that inhibition of the glucagon receptor using LY2409021 during OGTT in totally pancreatectomised individuals does not produce detectable effects on glucose, lipid or amino acid metabolism, ruling out metabolic effects of extrapancreatic glucagon.

我们得出结论，在完全胰腺切除的个体中，使用LY2409021在口服葡萄糖耐量测试（OGTT）期间抑制胰高血糖素受体，并未产生对葡萄糖、脂质或氨基酸代谢的可检测效应，排除了胰腺外胰高血糖素的代谢效应。

trial_registration

ClinicalTrials.gov (NCT02944110).

临床试验注册（NCT02944110）。

funding

This study was supported by grants from the Aase and Ejnar Danielsen's Foundation and the Novo Nordisk Foundation.

本研究得到了Aase和Ejnar Danielsen基金会以及诺和诺德基金会的资助。