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Type 1 Diabetes MellitusNCT02146404

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

A study testing hypoglycemia and euglycemia in people with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness, run by Radboud University Medical Center at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 50 yearsHealthy volunteers can take part
What is being tested?
hypoglycemia and euglycemia
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
1 siteNetherlands
Study dates
Aug 2014to Oct 2015
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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
Show all 17Show fewer
  • 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

Who cannot join

  • 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)
  • 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)

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Radboud umc

    Nijmegen

Other trials in Netherlands

About this study

Official title: 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).

Being tested
hypoglycemia, euglycemia
Keywords
Type 1 Diabetes Mellitus, Hypoglycemia unawareness, 1H MRS, Lactate
Medical subject headings
Diabetes Mellitus, Type 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • hypoglycemiaOther

    Also called Low blood glucose levels

    Blood glucose levels will be kept at ~3.0 mmol/l

  • euglycemiaOther

    Also called Normal blood glucose levels

    Blood glucose levels will be kept at ~5.0 mmol/l

Study groups in NCT02146404
Study groupRoleWhat they receive
EuglycemiaActive comparatorPlasma glucose levels will be clamped at a constant value of ~5.0 mmol/l
Receives: Other: euglycemia
HypoglycemiaExperimentalPlasma glucose levels will be clamped at a stable value of ~3.0 mmol/l
Receives: Other: hypoglycemia

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Brain lactate concentration

    Concentration brain lactate measured with 1H-MRS

    Measured: during stable euglycemia and hypoglyemia

Secondary outcomes (2)

  1. Plasma lactate levels

    Concentration arterial plasma lactate

    Measured: during stable euglycemia and hypoglyemia

  2. Hormone response

    Measured: during stable euglycemia and hypoglyemia

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 May 2014 (estimated)
  2. Study startAug 2014
  3. Primary completionOct 2015
  4. Study completionOct 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02146404
Sponsor's protocol ID
1H_lac_acc
Status last verified
Nov 2015
First submitted
21 May 2014
Last updated
10 Nov 2015
Results posted
No
Data monitoring committee
No

Publications

  • van de Ven KC, van der Graaf M, Tack CJ, Klomp DW, Heerschap A, de Galan BE. Optimized [1-(13)C]glucose infusion protocol for 13C magnetic resonance spectroscopy at 3T of human brain glucose metabolism under euglycemic and hypoglycemic conditions. J Neurosci Methods. 2010 Jan 30;186(1):68-71. doi: 10.1016/j.jneumeth.2009.10.025. Epub 2009 Nov 11.

    PubMed 19913052

  • van de Ven KC, de Galan BE, van der Graaf M, Shestov AA, Henry PG, Tack CJ, Heerschap A. Effect of acute hypoglycemia on human cerebral glucose metabolism measured by (1)(3)C magnetic resonance spectroscopy. Diabetes. 2011 May;60(5):1467-73. doi: 10.2337/db10-1592. Epub 2011 Apr 4.

    PubMed 21464446

  • van de Ven KC, van der Graaf M, Tack CJ, Heerschap A, de Galan BE. Steady-state brain glucose concentrations during hypoglycemia in healthy humans and patients with type 1 diabetes. Diabetes. 2012 Aug;61(8):1974-7. doi: 10.2337/db11-1778. Epub 2012 Jun 11.

    PubMed 22688331

  • van de Ven KC, Tack CJ, Heerschap A, van der Graaf M, de Galan BE. Patients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia. J Clin Invest. 2013 Feb;123(2):623-9. doi: 10.1172/JCI62742. Epub 2013 Jan 9.

    PubMed 23298837

  • Herzog RI, Jiang L, Herman P, Zhao C, Sanganahalli BG, Mason GF, Hyder F, Rothman DL, Sherwin RS, Behar KL. Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. J Clin Invest. 2013 May;123(5):1988-98. doi: 10.1172/JCI65105. Epub 2013 Apr 1.

    PubMed 23543056

  • De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.

    PubMed 23715622

  • Bergersen LH, Gjedde A. Is lactate a volume transmitter of metabolic states of the brain? Front Neuroenergetics. 2012 Mar 19;4:5. doi: 10.3389/fnene.2012.00005. eCollection 2012.

    PubMed 22457647

  • Wiegers EC, Rooijackers HM, van Asten JJA, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. Diabetologia. 2019 Jun;62(6):1065-1073. doi: 10.1007/s00125-019-4862-9. Epub 2019 Apr 19.

    PubMed 31001674

  • Wiegers EC, Rooijackers HM, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2016 Jun;65(6):1601-5. doi: 10.2337/db16-0068. Epub 2016 Mar 18.

    PubMed 26993070

Questions about this trial

What is this clinical trial studying?

A study testing hypoglycemia and euglycemia in people with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness, run by Radboud University Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Brain lactate concentration (time frame: during stable euglycemia and hypoglyemia). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02146404, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2015.

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