New Clues Into Hypoglycemia Awareness: Protein Levels May Signal Brain Adaptations in Type 1 Diabetes

A recent proteomics study has identified a potential biomarker linked to impaired awareness of hypoglycemia (IAH), a dangerous complication of type 1 diabetes that leaves patients unable to sense when their blood glucose drops too low. Researchers found that levels of agouti-related protein (AGRP)—a key neuropeptide involved in energy regulation and glucose sensing—were significantly reduced in individuals with IAH compared to those who retain normal hypoglycemia awareness.

The study, part of the Dutch Type 1 Diabetes Biomarker initiative, analyzed blood samples from 162 adults with long-standing type 1 diabetes. Using targeted proteomics via the Olink Cardiovascular II panel, the research team compared protein profiles between 67 individuals with IAH and 95 with normal awareness (NAH). AGRP emerged as the top differentially expressed protein, with a notably lower median level in the IAH group.

AGRP is produced in the hypothalamus and is best known for stimulating appetite, but it also plays a crucial role in activating the hypothalamic-pituitary-adrenal (HPA) axis during metabolic stress. Its reduced presence in people with IAH may point to maladaptive changes in central glucose-sensing pathways that blunt physiological responses to falling blood sugar—a hallmark of this condition.

While the precise cause-and-effect relationship remains uncertain, the study suggests that recurrent hypoglycemia may alter AGRP signaling thresholds in the brain, leading to a weakened counter-regulatory response. Animal models have shown that such adaptations can occur in the arcuate nucleus of the hypothalamus, a region rich in AGRP neurons. These changes could explain why individuals with IAH often fail to mount the usual epinephrine and cortisol surges that help restore blood glucose levels.

Other proteins were also found to be differentially expressed in participants with IAH, including increased levels of dienoyl-CoA reductase (DECR1), which plays a role in fatty acid metabolism and may serve as an adaptive response to energy deficits. Conversely, levels of SERPINA12, a protein associated with insulin sensitivity, were lower in the IAH group—a finding that could reflect complex metabolic shifts or compensatory mechanisms.

Interestingly, while AGRP’s differential expression remained the strongest signal, it narrowly missed statistical significance after adjusting for sex and diabetes duration in multivariate analysis (FDR-adjusted p = 0.057). Nonetheless, the consistent trend across models, combined with prior evidence that plasma AGRP levels mirror those in the brain and can cross the blood-brain barrier, strengthens the biological plausibility of its role in IAH.

If validated, AGRP could serve as a biomarker to identify patients at higher risk and open the door to therapeutic strategies aimed at restoring central glucose sensing.