Precision Prediction & Precision Medicine


Rita Varkevisser, Alexander Cecil, Cornelia Prehn, Dick Mul, Henk-Jan Aanstoot, Andrew Paterson, Bruce Wolffenbuttel, Melanie van der Klauw

Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes. Sci Rep. 2024 Feb 23;14(1):4485.

Impaired awareness of hypoglycemia (IAH), the inability to detect the onset of hypoglycemia, is a serious consequence of long-duration diabetes mellitus. About 20% – 40% of people with type 1 diabetes (PWDs) develop IAH. With increasing age, symptom intensity decreases and IAH prevalence increases. It has already been shown that IAH is associated with higher risk of asymptomatic and severe hypoglycemia and a lower quality of life. Specific signaling and metabolic pathways involved in the counter-regulatory response to hypoglycaemia are especially affected in PWDs with IAH. These pathways are currently not well-understood, but are suggested to result in adaptive changes in the brain (e.g. increase in glucose transport, alternate fuel use), leading to IAH. In this publication, co-authored by Henk-Jan Aanstoot and Dick Mul of Diabeter, metabolomics and genome-wide association methodologies were combined to look for metabolites that are expressed differentially between PWDs with IAH and PWDs without IAH.


This was a nested case-control study including 171 (68 cases and 108 controls) PWDs from the Dutch type 1 diabetes Biomarker study (NCT04977635).

Key findings:

  • Compared with controls, PWDs with IAH:
    • were significantly older
    • had longer diabetes duration
    • had lower daily insulin dose
    • had higher antihypertensive medication and lipid lowering medication use
  • HbA1c was comparable between groups
  • After correction for multiple testing, no significant differences in expression of metabolites were observed
  • However, before multiple testing correction, 12 metabolites were identified that showed higher expression in PWDs with IAH
  • These were sphingomyelins and glycerophospholipids:
    • this suggests differences in nerve functioning
    • it has been previously shown that after hypoglycemia, increased conversion of sphingomyelin into ceramide and phosphorylcholine can be observed
  • A genome-wide significant SNP significantly associated with the levels of a number of metabolites, was found in a gene coding for guanylin, an activator of intestinal guanylate cyclase (important in electrolyte reabsorption and implied in intestinal injury and inflammation)


Concluding, the authors state

"In conclusion, glycerophospholipids and sphingomyelins appeared to be associated with IAH, ............... . Future studies in the relationship between ceramides, phosphatidylcholines, and sphingomyelins may be interesting to investigate in the context of IAH " -

Please click here for the PubMed link.

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