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

Type 1 Diabetes Mellitus Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02146404
• Other study ID #: 1H_lac_acc
• Status: Completed
• Phase: N/A
• First received: May 21, 2014
• Last updated: November 9, 2015
• Start date: August 2014
• Est. completion date: October 2015

Study information

• Verified date: November 2015
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical 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 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hypoglycemia
• Hypoglycemia Unawareness
• Type 1 Diabetes Mellitus
• Unconsciousness

Intervention

Other:
• hypoglycemia
Blood glucose levels will be kept at ~3.0 mmol/l
• euglycemia
Blood glucose levels will be kept at ~5.0 mmol/l

Locations

Country	Name	City	State
Netherlands	Radboud umc	Nijmegen

Sponsors (3)

Lead Sponsor	Collaborator
Radboud University	Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes

Country where clinical trial is conducted

Netherlands, 

References & Publications (7)

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. — View 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. — View 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. — View 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 ¹³C magnetic resonance spectroscopy. Diabetes. 2011 May;60(5):1467-73. doi: 10.2337/db10-1592. Epub 2011 Apr 4. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Brain lactate concentration	Concentration brain lactate measured with 1H-MRS	during stable euglycemia and hypoglyemia	No
Secondary	Plasma lactate levels	Concentration arterial plasma lactate	during stable euglycemia and hypoglyemia	No
Secondary	Hormone response		during stable euglycemia and hypoglyemia	No