# Differential association of hyperglucagonemia with C-peptide levels in diabetic ketosis/ketoacidosis and hyperosmolar hyperglycemic state

## TL;DR

This study found that high glucagon levels are linked to different factors in diabetic ketoacidosis and hyperosmolar hyperglycemic state.

## Contribution

The study identifies distinct mechanisms behind hyperglucagonemia in DK/DKA and HHS using pancreas-specific glucagon measurements.

## Key findings

- Hyperglucagonemia is present in both DK/DKA and HHS, but with different contributing factors.
- Plasma glucagon levels correlate with ketone bodies in DK/DKA but not in HHS.
- Glucagon levels decrease after treatment in both DK/DKA and HHS.

## Abstract

Glucagon plays a pivotal role in the development of hyperglycemia in diabetes mellitus. The purpose of this study was to investigate the hypothesis that hyperglucagonemia based on measurements of pancreas-specific glucagon is present in diabetic ketosis/ketoacidosis (DK/DKA) and hyperosmolar hyperglycemic state (HHS), and if so, to explore factors contributing to that hyperglucagonemia.

A total of 109 patients (92 with DK/DKA, and 17 with HHS) were investigated. Pancreas-specific glucagon levels were measured with a sandwich enzyme-linked immunosorbent assay at treatment initiation. The relationships of plasma glucagon levels, serum ketone bodies levels, and endogenous insulin secretion were assessed. The change in plasma glucagon levels after treatment was also assessed.

The median plasma glucagon level was significantly higher in the HHS group (142.9 pg/mL) than in the DK/DKA group (63.6 pg/mL). In the DK/DKA group, the plasma glucagon level was positively correlated with the serum ketone bodies level (ρ = 0.55, P < 0.0001), but there was no correlation in the HHS group. In the DK/DKA group, a negative correlation was seen between the plasma glucagon level and the serum C-peptide immunoreactivity (CPR)/plasma glucose ratio in type 1 diabetes patients (n = 26) (ρ = − 0.67, P = 0.0002). In the HHS group, a positive correlation was seen between the plasma glucagon level and the serum CPR/plasma glucose ratio (ρ = 0.71, P = 0.0013). The plasma glucagon level was significantly lower after treatment in both the DK/DKA and HHS groups.

Hyperglucagonemia was found in DK/DKA and HHS with pancreas-specific glucagon measurements. The results suggest that the causes of hyperglucagonemia differ in DK/DKA due to type 1 diabetes mellitus and HHS.

The online version contains supplementary material available at 10.1007/s13340-025-00852-8.