Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes

NCT ID: NCT03014011

Last Updated: 2020-01-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-13
• Study Completion Date: 2018-07-24

Brief Summary

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.

Here, the investigators propose to provide quantitative results on cognition during an acute mild hypoglycaemic episode (target plasma glucose 3 mmol/L) in 28 subjects with type 2 diabetes. Data will be provided on executive function, attention and memory.

Detailed Description

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.

Conditions

Diabetes Mellitus, Type II; Hypoglycemia; Cognitive Change

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Hypoglycaemic clamp first, then euglyceamic clamp

First intervention with a hypoglycaemic clamp (one examination day of approximately 5 hours), there after a wash out period of 21-42 days, then second and final intervention day with an euglycaemic clamp (approximately 5 hours).

Group Type: OTHER

Hypoglycaemic clamp

Intervention Type: 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

Intervention Type: 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.

Euglycaemic clamp first, then hypoglycaemic clamp

First intervention with an euglycaemic clamp (one examination day of approximately 5 hours), there after a wash out period of 21-42 days, then second and final intervention day with a hypoglycaemic clamp (approximately 5 hours).

Group Type: OTHER

Hypoglycaemic clamp

Intervention Type: 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

Intervention Type: 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.

Interventions

Hypoglycaemic clamp

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.

Intervention Type: OTHER

Euglycaemic clamp

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.

Intervention Type: OTHER

Eligibility Criteria

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.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: collaborator

Psychiatric Centre Rigshospitalet

OTHER

Sponsor Role: collaborator

Bispebjerg Hospital

OTHER

Sponsor Role: lead

Responsible Party

Malin Nilsson

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jørgen Rungby, Professor

Role: PRINCIPAL_INVESTIGATOR

Department of Endocrinology, Bispebjerg University Hospital, Denmark

Locations

Department of Research in Endocrinology, Bispebjerg University Hospital

Copenhagen, , Denmark

Countries

Denmark

References

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.

Reference Type: DERIVED

PMID: 31367958 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MISP

Identifier Type: -

Identifier Source: org_study_id