Differential signalling in Impaired Hypoglycemia Awareness
Rita D. M. Varkevisser, Agnese Petrera, Stefanie M. Hauck, Dick Mul, Henk-Jan Aanstoot, Andrew Paterson, Bruce H. R. Wolffenbuttel, Melanie M. van der Klauw & the Dutch Type 1 Diabetes Biomarker Group
Targeted proteomics analysis in type 1 diabetes identifies lower agouti-related protein levels in individuals with impaired hypoglycaemia awareness. Sci Rep. 2025 Oct 17;15(1):36448.
Impaired awareness of hypoglycaemia (IAH) is a major complication in type 1 diabetes, increasing the risk of severe hypoglycaemic events up to sixfold. The mechanisms underlying IAH are thought to involve central nervous system adaptations to recurrent hypoglycaemia, but the exact biological pathways remain unclear.
This nested case–control study used targeted plasma proteomics (Olink® Cardiovascular II panel) to explore proteins associated with IAH within the Dutch Type 1 Diabetes Biomarker cohort. A total of 162 individuals (67 with IAH, 97 with normal awareness) met quality control criteria for proteomic analysis.
Key findings:
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AGRP (Agouti-related protein) was significantly lower in individuals with IAH than in controls (6.12 vs. 6.44 NPX; FDR-adjusted P = 0.012).
After adjustment for sex and diabetes duration, AGRP remained nearly significant (FDR-adjusted P = 0.057).
AGRP is highly relevant biologically: it is expressed in the hypothalamus, crosses the blood–brain barrier, and plays a role in glucose sensing and counterregulatory responses.
Eight additional proteins showed differential expression before or after adjustment, including IL-4RA, PTX3, SERPINA12, NEMO, DECR1, IL1RL2, and IL16.
Receiver-operating characteristic analysis for AGRP yielded AUC = 0.66, indicating modest discriminatory value.
Findings were consistent in sensitivity analyses adjusting for HbA1c, C-peptide, fasting glucose, and medication use.
Concluding, the authors state
"In conclusion, we found significantly lower levels of AGRP in individuals with IAH. IL-4RA, NEMO, PTX3, SERPINA12, DECR1, IL1RL2, and IL16 were also differentially expressed between those with and without IAH. Findings in this study will need to be confirmed and validated in future studies but provides interesting new pathways to investigate in relation to IAH." -
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