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

## TL;DR

This study tested if blocking glucagon receptors affects metabolism in people without a pancreas, finding no significant changes in glucose, lipid, or amino acid levels.

## Contribution

The study provides empirical evidence that extrapancreatic glucagon does not significantly influence metabolism in totally pancreatectomised individuals.

## Key findings

- Blocking glucagon receptors had no detectable effect on glucose, lipid, or amino acid metabolism in pancreatectomised individuals.
- In healthy controls, glucagon receptor antagonism lowered fasting glucose and increased amino acid levels.
- Extrapancreatic glucagon appears to have minimal physiological role in glucose regulation in pancreatectomised individuals.

## Abstract

Previous studies have indicated that 29-amino-acid glucagon (i.e. ‘pancreatic’ glucagon) circulates in totally pancreatectomised individuals and that a postprandial glucagon response can be detected. 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.

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. 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]). 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. Key inclusion criteria for the pancreatectomised individuals were age >18 years, haemoglobin in the normal range and informed consent. The primary endpoint was the difference in plasma glucose excursions between study days.

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. 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.

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.

ClinicalTrials.gov (NCT02944110).

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

The online version of this article (10.1007/s00125-025-06534-z) contains peer-reviewed but unedited supplementary material.