Targeted proteomics analysis in type 1 diabetes identifies lower agouti-related protein levels in individuals with impaired hypoglycaemia awareness

Impaired awareness of hypoglycaemia (IAH) is a complication of diabetes treatment, whereby individuals are no longer able to feel an oncoming hypoglycaemic event. IAH may be a result of central nervous system adaptation to low recurrent hypoglycaemias, however the precise pathways involved remain unknown. This study employed proteomics analysis to explore potential pathophysiological pathways in IAH, using a nested case-control design within the Dutch Type 1 Diabetes Biomarker study. The Olink<sup>®</sup> Cardiovascular II panel was used for targeted proteomics, comparing 67 individuals with IAH to 108 age- and sex-matched individuals with normal awareness of hypoglycaemia (NAH). Univariate analysis revealed that agouti-related protein (AGRP) levels were significantly lower in individuals with IAH compared to NAH (6.12 NPX vs. 6.44 NPX, FDR-adjusted P = 0.012). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (P < 0.001) but not after adjusting for false discovery rate (FDR) (P = 0.057). AGRP, known for its orexigenic effects and expression in the arcuate nucleus of the hypothalamus, is involved in glucose sensing and hypothalamic-pituitary-adrenal (HPA) axis stimulation, suggesting its potential role in the pathophysiology of IAH. This study highlights the need for further research to clarify AGRP's role and its possible implications for managing IAH in diabetes.

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Publication Details

Journal
Scientific Reports
Published
2025-10-17
DOI
https://doi.org/10.1038/s41598-025-20491-y
Primary Topic
Diabetes Management and Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Targeted proteomics analysis in type 1 diabetes identifies lower agouti-related protein levels in individuals with impaired hypoglycaemia awareness

Henk J. Veeze, Peter R. van Dijk, Theo Sas, Rita Delphine Maiko Varkevisser et al.
Scientific Reports
Diabetes Management and Research
article

Targeted proteomics analysis in type 1 diabetes identifies lower agouti-related protein levels in individuals with impaired hypoglycaemia awareness

Henk J. Veeze, Peter R. van Dijk, Theo Sas, Rita Delphine Maiko Varkevisser, Giesje Nefs, Martine de Vries, Dick Mul, Erwin Birnie, Agnese Petrera, Stefanie M. Hauck, Michael P. Brugts, Klaas Hoogenberg, Adriaan Kooy, Rob K. Gonera, Andrew D. Paterson, Sandra Loves, Bruce H. R. Wolffenbuttel, Pim Dekker, Henk‐Jan Aanstoot, Esther Latres, Lianne S.M. Boesten, Charlotte E. Vollenbrock, Melanie M. van der Klauw, Petronella Geelhoed-Duijvestijn, Christine Fransman, Marleen J. Vosjan-Noeverman, Sanjoy Dutta
article en

Abstract

Impaired awareness of hypoglycaemia (IAH) is a complication of diabetes treatment, whereby individuals are no longer able to feel an oncoming hypoglycaemic event. IAH may be a result of central nervous system adaptation to low recurrent hypoglycaemias, however the precise pathways involved remain unknown. This study employed proteomics analysis to explore potential pathophysiological pathways in IAH, using a nested case-control design within the Dutch Type 1 Diabetes Biomarker study. The Olink<sup>®</sup> Cardiovascular II panel was used for targeted proteomics, comparing 67 individuals with IAH to 108 age- and sex-matched individuals with normal awareness of hypoglycaemia (NAH). Univariate analysis revealed that agouti-related protein (AGRP) levels were significantly lower in individuals with IAH compared to NAH (6.12 NPX vs. 6.44 NPX, FDR-adjusted P = 0.012). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (P < 0.001) but not after adjusting for false discovery rate (FDR) (P = 0.057). AGRP, known for its orexigenic effects and expression in the arcuate nucleus of the hypothalamus, is involved in glucose sensing and hypothalamic-pituitary-adrenal (HPA) axis stimulation, suggesting its potential role in the pathophysiology of IAH. This study highlights the need for further research to clarify AGRP's role and its possible implications for managing IAH in diabetes.

Scientific ReportsVol. 15(1)
University Medical Center Groningen (NL), Radboud University Nijmegen (NL), University of Groningen (NL), University of Toronto (CA), Tilburg University (NL), Hospital for Sick Children (CA), Erasmus MC (NL), Radboud University Medical Center (NL), Helmholtz Zentrum München (DE), Breakthrough T1D (US), Medisch Centrum Haaglanden (NL), Ikazia Ziekenhuis (NL), Treant Zorggroep (NL), Martini Ziekenhuis (NL), Ziekenhuis Bethesda (NL), Public Health Ontario (CA), IJsselland Ziekenhuis (NL), Erasmus MC - Sophia Children’s Hospital (NL)
Haaglanden Medisch Centrum, Universitair Medisch Centrum Groningen
Openalex Percentile: Top 61%
Diabetes Management and Research
DOIOpen Access PDFOpenAlex
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