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

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  • Malin Nilsson, Department of Endocrinology, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400, Copenhagen, NV, Denmark. malin.sofia.desiree.nilsson@regionh.dk.
  • ,
  • Nicole Jensen, Department of Endocrinology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark. mads.gustav.juul.skytte@regionh.dk.
  • ,
  • Michael Gejl
  • Marianne L Bergmann, Syddansk Universitet
  • ,
  • Heidi Storgaard, Københavns Universitet
  • ,
  • Mette Zander, Department of Endocrinology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark. mads.gustav.juul.skytte@regionh.dk.
  • ,
  • Kamilla Miskowiak, Psychiatric Centre Copenhagen, Rigshospitalet, Denmark.
  • ,
  • Jørgen Rungby

AIMS/HYPOTHESIS: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS/INTERPRETATION: 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: ClinicalTrials.gov NCT03014011.

FUNDING: 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.

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind62
Nummer10
Sider (fra-til)1948-1958
Antal sider11
ISSN0012-186X
DOI
StatusUdgivet - okt. 2019

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