Peripheral neuropathy and hypoglycaemia unawareness are associated with cognitive impairment in type 1 diabetes
Aims: This cross-sectional study investigated clinical and metabolic determinants of cognitive impairment (CI) in adults with long-standing type 1 diabetes (T1D), focusing specifically on the independent and combined contribution of diabetic peripheral neuropathy (DPN), insulin treatment and impaired awareness of hypoglycaemia (IAH).
Methods: 252 adults with T1D of at least 10 years of disease duration underwent a single assessment including cognitive testing (MoCA), standardised neuropathy evaluation (monofilament, tuning fork, vibration perception threshold via neurothesiometer, Tip-Therm, ankle reflexes), IAH screening (Gold score, Clarke questionnaire, HypoA-Q), skin autofluorescence, and metabolic/biochemical profiling. Univariable and multivariable linear regression models were used, and an interaction model tested effect modification between IAH and DPN.
Results: Nearly half of participants (48%) showed CI (MoCA <26). DPN was present in 34% and IAH in 39%. Both conditions were associated with lower MoCA scores. Participants with DPN showed particular deficits in attention/working memory and orientation, while IAH was linked to a broader impairment pattern including memory, executive function, language and orientation. In multivariable analysis, IAH, male sex, higher HbA1c, and higher vibration perception threshold (a DPN marker) were independent predictors of reduced MoCA, while higher insulin dose was associated with better performance. In the interaction model, IAH and DPN each independently predicted a 1.2–1.5-point MoCA reduction, with no significant synergistic effect—suggesting additive, not multiplicative, contributions to cognitive dysfunction.
Conclusions: In long-standing subjects with T1D, DPN, IAH, history of severe hypoglycaemia, poorer glycaemic control, older age and male sex are associated with CI.
Comments: This well-designed Hypoglycaemia Awareness Study in Diabetes Type 1 (HAD‐1), conducted in Poland, offers valuable insights: the simultaneous evaluation of DPN and IAH as independent contributors to cognitive dysfunction in T1D. The novelty lies in the interaction analysis demonstrating additive—rather than synergistic—effects, supporting the hypothesis that neuropathy-related microvascular/neurodegenerative pathways and hypoglycaemia-related neuroglycopenic injury represent distinct, complementary pathways to cognitive decline. The use of quantitative sensory testing (VPT) alongside standard clinical neuropathy criteria strengthens the findings of DPN-cognition associations, and the multi-domain MoCA sub-analysis usefully highlights attention/working memory and orientation as particularly vulnerable domains in DPN.
Limitations include the cross-sectional design, precluding causal inference, absence of a non-diabetic control group, and reliance on a single cognitive screening instrument, which may not capture psychomotor speed deficits previously linked to DPN. The relatively young cohort (median age 41) also raises the question, acknowledged by the authors, of whether MoCA cut-offs validated in older populations are appropriate here.
Nonetheless, this study reinforces neuropathy as a clinically relevant, independent marker warranting cognitive screening in subjects with T1D, and calls for longitudinal research to clarify the temporal and mechanistic relationships between DPN, IAH and cognitive trajectories.
Luca D'Onofrio
Reference. Michalak M, Zozulińska-Ziółkiewicz D, Michalak M, Flotyńska J, Cieluch A, Michalski M, Araszkiewicz A. Clinical and Metabolic Predictors of Cognitive Impairment in Type 1 Diabetes: The Role of Peripheral Neuropathy and Hypoglycaemia Unawareness. Findings From a HAD-1 Study. Diabetes Metab Res Rev. 2026 May;42(4):e70180. doi: 10.1002/dmrr.70180. PMID: 42142068; PMCID: PMC13179733.
