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^® 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.