Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes

Hypoglycaemia in subjects suffering from type 2 diabetes may have substantial consequences including a significant negative impact on quality of life. Further, repeated minor hypoglycaemias may result in significant productivity losses. In healthy subjects a number of studies show that during a hypoglycaemic episode with plasma levels of 2.2 - 2.5 mmol/L (40-45 mg/dl) brain areas responsible for cognition have an altered neuronal function when measuring cerebral blood flow. This is accompanied by severely impaired cognitive function with a reduced ability to solve simple cognitive tasks. At higher levels of glucose (above 3 mmol/L (54 mg/dl)), it remains to be settled whether cognitive functions are also affected negatively and whether this may be accompanied by changes in brain metabolism. Apart from raising the blood glucose directly or indirectly via glucagon, no treatment for hypoglycaemia exists, but since Glucagon-like peptide-1 (GLP-1) based therapies used in type 2 diabetes may affect brain glucose consumption, therapeutic interventions to prevent negative results of hypoglycaemia may eventually become clinically possible.

Here, the investigators propose to provide quantitative results on cognition during an acute mild hypoglycaemic episode (target plasma glucose 3 mmol/L). Data will be provided on executive function, attention and memory.

• Hypoglycaemic clamp (Other): The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to lower and keep plasma blood glucose levels at 3 mmol/L for outcome measurements.
• Euglycaemic clamp (Other): The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to keep plasma blood glucose levels at 6 mmol/L for outcome measurements.

Primary outcomes

• Psychomotor Speed [All neurocognitive testing was assessed at each intervention when glucose levels had been stabile for 40 minutes, an average of 2 hours after clamp procedure start. The duration of neurocognitive testing was approximately 40 min.]: Symbol Digit Modalities Test was used as a measurement of psychomotor speed. For the Symbol Digit Modalities Test, participants were required to use a coded key to match nine abstract symbols paired with numerical digits. The final score is the correct number of substitutions in 120 s, and scores range between 0 and 110. Higher values represent a better outcome.

Sex: All, ages: 35 Years to 70 Years

Inclusion Criteria:

* Informed and written consent
* Clinically diagnosed type 2 diabetes mellitus for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO)).
* Normal haemoglobin ≥ 8.0 mmol/L (male) or ≥ 6.4 mmol/L (female)
* Male or female participants aged 35-70 years, both inclusive.
* Treated with diet or any antidiabetic medication except sulfonylureas, meglitinides or insulin.
* HbA1c ≤ 9.0 % by local laboratory analysis.
* BMI >23 kg/m2 and <35 kg/m2

Exclusion Criteria:

* Receipt of any investigational medicinal product within 3 months before screening in this trial.
* Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary disorder.
* Nephropathy (serum creatinine levels ≥ 126 μmol/L (male) or ≥ 111 μmol/L (female)).
* Cardiac problems defined as decompensated heart failure (New York Heart Association (NYHA) class III and IV) at any time and/or angina pectoris within the last 12 months and/or acute myocardial infarction at any time.
* Active or recent malignant disease.
* Treatment with drugs that cannot be paused for 12 hours.
* Repeated resting blood pressure at screening outside the range 90-140 mmHg for systolic or 50-90 mmHg for diastolic. This exclusion criterion also pertains to subjects taking antihypertensives.
* Visual impairment or auditory impairment.
* Known abnormalities of the central nervous system or any endocrinological (with the exception of diabetes mellitus and euthyroid goiter), haematological, neurological, psychiatric diseases or other major disorders that in the opinion of the investigator precludes compliance with the protocol, evaluation of the results or represent an unacceptable risk for the participant's safety.
* Proliferative retinopathy (funduscopy performed within 3 months before the screening is acceptable) and/or severe neuropathy.
* Current treatment with systemic drugs, which may interfere with glucose metabolism.
* Significant history of alcoholism or drug/chemical abuse as per investigator's judgement.
* Current tobacco user (smoking or nicotinic product use 3 months prior to screening).
* Severe hypoglycaemic event during the past 6 months.
* Known hypoglycaemia unawareness.
* Participants with mental incapacity or language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator or their general practitioner, should not participate in the trial.
* For females only: Pregnancy, breast-feeding status or intention of becoming pregnant during the trial.
* Any chronic disorder or severe disease that in the opinion of the investigator might endanger participant's safety or compliance with the protocol.

Participant flow

Outcome results

• Psychomotor Speed (Primary), Mean, score on a scale: Hypoglycaemia 48.7 +/- 9.8; Euglycaemia 56.6 +/- 12

Adverse events

Time frame: For each participant, adverse event data was collected from the day they were included, until the day after their second (and final) intervention visit, an average of 2 months.

• Results publication: Nilsson M, Jensen N, Gejl M, Bergmann ML, Storgaard H, Zander M, Miskowiak K, Rungby J. Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial. Diabetologia. 2019 Oct;62(10):1948-1958. doi: 10.1007/s00125-019-4964-4. Epub 2019 Jul 31. PMID 31367958

• Study Protocol and Statistical Analysis Plan (PDF, 2016-12-15)

• Jørgen Rungby, Professor, Principal investigator, Department of Endocrinology, Bispebjerg University Hospital, Denmark