, Volume 62, Issue 10, pp 1948–1958 | Cite as

Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial

  • Malin NilssonEmail author
  • Nicole Jensen
  • Michael Gejl
  • Marianne L. Bergmann
  • Heidi Storgaard
  • Mette Zander
  • Kamilla Miskowiak
  • Jørgen Rungby



Previous studies have demonstrated a relationship between cognitive impairment and hypoglycaemia (<3 mmol/l). This study hypothesised that non-severe insulin-induced hypoglycaemia reduces cognitive function in individuals with type 2 diabetes.


In this randomised crossover study, 25 participants with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping: one hypoglycaemic clamp (plasma glucose 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (plasma glucose 6.0 ± 0.2 mmol/l). Participants were eligible if their diabetes was treated with diet or glucose-lowering medications (except sulfonylureas or insulin), age was 35–70 years, BMI was 23–35 kg/m2 and HbA1c was below 75 mmol/mol (9%). Cognitive function was assessed with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed. From the examined cognitive domains, a global cognition score was constructed estimating global cognition. A measurement for psychomotor speed was selected as the primary outcome. Participants and people assessing the outcomes were blinded to group assignment.


Cognitive performance was impaired during hypoglycaemia with a mean score in the primary outcome test, Symbol Digit Modalities Test measuring psychomotor speed, of 48.7 ± 9.8 (hypoglycaemia) vs 56.6 ± 12.0 (euglycaemia); i.e. a change of −7.9 points (95% CI −10.9, −4.9; p < 0.0001). In addition, hypoglycaemia reduced global cognitive score by −0.7 (95% CI −0.9, −0.6; p < 0.0001). A stable glucose plateau was achieved during both experimental visits. For the hypoglycaemic clamp, mean plasma glucose concentration (± SD) during neurocognitive testing was 3.1 (± 0.3) mmol/l. Age, sex, fasting C-peptide, counter-regulatory hormones and the severity of hypoglycaemic symptoms did not influence cognitive function.


Acute non-severe hypoglycaemia (mean plasma glucose 3.1 mmol/l) has a substantial negative impact on cognitive function in individuals with type 2 diabetes.

Trial registration NCT03014011.


The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation.


Cognitive function Hypoglycaemia Type 2 diabetes 



Estimated treatment difference


Rey Auditory Verbal Learning Test


Rapid Visual Processing


Symbol Digit Modalities Test


Trail Making Test


Wechsler Adult Intelligence Scale III



The authors would like to thank all of the study participants. They also thank H. Wodschow (University of Copenhagen, Denmark) and the research assistants from the Neurocognition and Emotion in Affective Disorders (NEAD) Group, Psychiatric Centre Copenhagen, Denmark, for assistance during the experimental visits. Thank to I. Brandslund and D. Olsen (Department of Biochemistry and Immunology, University Hospital of Southern Denmark) for performing the ELISA for glucagon. Finally, thanks to B. Della Valle (GLX Analytix, Copenhagen, Denmark) for proofreading the manuscript.

Contribution statement

MN contributed to trial design, collected the data, performed the data analyses and wrote the manuscript. NJ contributed to the statistical analyses, and review and editing of the manuscript. MG, HS and MZ contributed to the study design and interpretation of data and critically reviewed the manuscript. MLB was involved in data analysis and revision of the manuscript. KM adapted the neurocognitive test battery, trained and supervised the research assistants who performed the neurocognitive testing, contributed to the statistical analysis plan and interpretation of results, and revised the manuscript. JR (study sponsor) was responsible for the overall supervision and design of the study, interpretation of data, and review and editing of the manuscript, and made the decision to submit it for publication. All authors approved the final version. JR is responsible for the integrity of the work as a whole.


The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation. The funding sources were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4964_MOESM1_ESM.pdf (242 kb)
ESM (PDF 241 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyBispebjerg University HospitalCopenhagenDenmark
  2. 2.Department of EndocrinologyAarhus University HospitalAarhusDenmark
  3. 3.Department of Biochemistry and ImmunologyUniversity Hospital of Southern DenmarkVejleDenmark
  4. 4.Clinical Metabolic Physiology, Steno Diabetes Center CopenhagenGentofte HospitalHellerupDenmark
  5. 5.Department of Psychology and Mental Health ServicesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Psychiatric Centre CopenhagenRigshospitaletDenmark
  7. 7.Copenhagen Center for Translational ResearchBispebjerg University HospitalCopenhagenDenmark

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