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

NCT ID: NCT02146404

Last Updated: 2015-11-10

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

21 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-08-31

Study Completion Date

2015-10-31

Brief Summary

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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).

Detailed Description

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Conditions

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Type 1 Diabetes Mellitus Hypoglycemia Unawareness

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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Euglycemia

Plasma glucose levels will be clamped at a constant value of \~5.0 mmol/l

Group Type ACTIVE_COMPARATOR

euglycemia

Intervention Type OTHER

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

Hypoglycemia

Plasma glucose levels will be clamped at a stable value of \~3.0 mmol/l

Group Type EXPERIMENTAL

hypoglycemia

Intervention Type OTHER

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

Interventions

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hypoglycemia

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

Intervention Type OTHER

euglycemia

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

Intervention Type OTHER

Other Intervention Names

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Low blood glucose levels Normal blood glucose levels

Eligibility Criteria

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Inclusion Criteria

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


* 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


* 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

* 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)
Minimum Eligible Age

18 Years

Maximum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Dutch Diabetes Research Foundation

OTHER

Sponsor Role collaborator

European Foundation for the Study of Diabetes

OTHER

Sponsor Role collaborator

Radboud University Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Bastiaan de Galan, Dr.

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

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Radboud umc

Nijmegen, , Netherlands

Site Status

Countries

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Netherlands

References

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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.

Reference Type BACKGROUND
PMID: 19913052 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21464446 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22688331 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23298837 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23543056 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23715622 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22457647 (View on PubMed)

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.

Reference Type DERIVED
PMID: 31001674 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26993070 (View on PubMed)

Other Identifiers

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1H_lac_acc

Identifier Type: -

Identifier Source: org_study_id

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