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

Primary Purpose

Type 1 Diabetes Mellitus, Hypoglycemia Unawareness

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
hypoglycemia
euglycemia
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Type 1 Diabetes Mellitus focused on measuring Type 1 Diabetes Mellitus, Hypoglycemia unawareness, 1H MRS, Lactate

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

  • Radboud umc

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Euglycemia

Hypoglycemia

Arm Description

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

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

Outcomes

Primary Outcome Measures

Brain lactate concentration
Concentration brain lactate measured with 1H-MRS

Secondary Outcome Measures

Plasma lactate levels
Concentration arterial plasma lactate
Hormone response

Full Information

First Posted
May 21, 2014
Last Updated
November 9, 2015
Sponsor
Radboud University Medical Center
Collaborators
Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes
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1. Study Identification

Unique Protocol Identification Number
NCT02146404
Brief Title
The Effect of Hypoglycaemia on Brain Lactate Accumulation and Cerebral Blood Flow
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2015
Overall Recruitment Status
Completed
Study Start Date
August 2014 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus, Hypoglycemia Unawareness
Keywords
Type 1 Diabetes Mellitus, Hypoglycemia unawareness, 1H MRS, Lactate

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Euglycemia
Arm Type
Active Comparator
Arm Description
Plasma glucose levels will be clamped at a constant value of ~5.0 mmol/l
Arm Title
Hypoglycemia
Arm Type
Experimental
Arm Description
Plasma glucose levels will be clamped at a stable value of ~3.0 mmol/l
Intervention Type
Other
Intervention Name(s)
hypoglycemia
Other Intervention Name(s)
Low blood glucose levels
Intervention Description
Blood glucose levels will be kept at ~3.0 mmol/l
Intervention Type
Other
Intervention Name(s)
euglycemia
Other Intervention Name(s)
Normal blood glucose levels
Intervention Description
Blood glucose levels will be kept at ~5.0 mmol/l
Primary Outcome Measure Information:
Title
Brain lactate concentration
Description
Concentration brain lactate measured with 1H-MRS
Time Frame
during stable euglycemia and hypoglyemia
Secondary Outcome Measure Information:
Title
Plasma lactate levels
Description
Concentration arterial plasma lactate
Time Frame
during stable euglycemia and hypoglyemia
Title
Hormone response
Time Frame
during stable euglycemia and hypoglyemia

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bastiaan de Galan, Dr.
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Radboud umc
City
Nijmegen
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
19913052
Citation
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.
Results Reference
background
PubMed Identifier
21464446
Citation
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.
Results Reference
background
PubMed Identifier
22688331
Citation
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.
Results Reference
background
PubMed Identifier
23298837
Citation
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.
Results Reference
background
PubMed Identifier
23543056
Citation
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.
Results Reference
background
PubMed Identifier
23715622
Citation
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.
Results Reference
background
PubMed Identifier
22457647
Citation
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.
Results Reference
background
PubMed Identifier
31001674
Citation
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.
Results Reference
derived
PubMed Identifier
26993070
Citation
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.
Results Reference
derived

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

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