The Effect of Hypoglycaemia on Brain Lactate Accumulation and Cerebral Blood Flow

November 9, 2015 updated by: Radboud University Medical Center

The Effect of Insulin-induced Hypoglycemia on Brain Lactate Accumulation and Regional Cerebral Blood Flow in Patients With Type 1 Diabetes Mellitus With and Without Hypoglycemia Unawareness and Non-diabetic Controls

Iatrogenic hypoglycemia is the most frequent acute complication of insulin therapy in people with type 1 diabetes (T1DM). Recurrent hypoglycemic events initiate a process of habituation, characterized by suppression of hypoglycemic symptoms and lead to hypoglycemia unawareness, which in itself defines a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for increased brain lactate transport capacity in the pathogenesis of hypoglycemia unawareness. However, there is uncertainty about the magnitude of this effect and whether such excess brain lactate is oxidizes as a glucose-sparing alternative energy source or acts as a metabolic regulator controlling brain glucose metabolism, oxygen consumption and cerebral blood flow.

Objective: The primary objective of this study is to investigate the effect of hypoglycemia on brain lactate accumulation and regional cerebral blood perfusion in humans. The secondary objective is to assess whether this effect is a related to hypoglycemia unawareness or a consequence of T1DM per se.

Hypothesis: The investigators hypothesize that hypoglycemia stimulates lactate transport over the blood-brain barrier leading to cerebral lactate accumulation and that this lactate accumulation is a function of prior hypoglycemic exposure frequency contributing to clinical hypoglycemia unawareness. Furthermore, the investigators expect that this effect of hypoglycemia on brain lactate accumulation is related to changes in cerebral blood flow (CBF).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria for healthy subjects

  • Age: 18-50 years
  • Body-Mass Index: 18-30 kg/m2
  • Blood pressure: <160/90 mmHg

Inclusion criteria T1DM patients with normal hypoglycemic awareness

  • Diabetes duration ≥ 1 year
  • Age: 18-50 years
  • Body-Mass Index: 18-30 kg/m2
  • HbA1c: 42-75 mmol/mol (6-9%)
  • Outcome Clarke questionnaire: 0-1
  • Blood pressure: <160/90 mmHg

Inclusion criteria T1DM patients with hypoglycemia unawareness

  • Diabetes duration ≥ 1 year
  • Age: 18-50 years
  • Body-Mass Index: 18-30 kg/m2
  • HbA1c: 42-75 mmol/mol (6-9%)
  • Outcome Clarke questionnaire: >3
  • Blood pressure: <160/90 mmHg

Exclusion criteria for healthy subjects

  • Inability to provide informed consent
  • Presence of any medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event or anxiety disorders
  • Use of any medication, except for oral contraceptives
  • MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)

Exclusion criteria for all T1DM patients

  • Inability to provide informed consent
  • Presence of any other medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event, anxiety disorders, or complications of T1DM (including neuropathy and retinopathy)
  • Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy
  • MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Euglycemia
Plasma glucose levels will be clamped at a constant value of ~5.0 mmol/l
Other: euglycemia
Blood glucose levels will be kept at ~5.0 mmol/l
Other Names:
  • Normal blood glucose levels
Experimental: Hypoglycemia
Plasma glucose levels will be clamped at a stable value of ~3.0 mmol/l
Other: hypoglycemia
Blood glucose levels will be kept at ~3.0 mmol/l
Other Names:
  • Low blood glucose levels

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain lactate concentration
Time Frame: during stable euglycemia and hypoglyemia
Concentration brain lactate measured with 1H-MRS
during stable euglycemia and hypoglyemia

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma lactate levels
Time Frame: during stable euglycemia and hypoglyemia
Concentration arterial plasma lactate
during stable euglycemia and hypoglyemia
Hormone response
Time Frame: during stable euglycemia and hypoglyemia
during stable euglycemia and hypoglyemia

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Collaborators

European Foundation for the Study of Diabetes
Dutch Diabetes Research Foundation

Investigators

  • Principal Investigator: Bastiaan de Galan, Dr., Radboud UMC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2014

Primary Completion (Actual)

October 1, 2015

Study Completion (Actual)

October 1, 2015

Study Registration Dates

First Submitted

May 21, 2014

First Submitted That Met QC Criteria

May 22, 2014

First Posted (Estimate)

May 23, 2014

Study Record Updates

Last Update Posted (Estimate)

November 10, 2015

Last Update Submitted That Met QC Criteria

November 9, 2015

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1H_lac_acc

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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