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

NCT02146404 | Completed

• 1 other identifier: 1H_lac_acc
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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).

Conditions

Type 1 Diabetes Mellitus; Hypoglycemia Unawareness

Keywords

Type 1 Diabetes Mellitus; Hypoglycemia unawareness; 1H MRS; Lactate

Outcome Measures

Primary Outcomes (1)

• Brain lactate concentration

  Concentration brain lactate measured with 1H-MRS

  during stable euglycemia and hypoglyemia

Secondary Outcomes (2)

• Plasma lactate levels

  during stable euglycemia and hypoglyemia

• Hormone response

  during stable euglycemia and hypoglyemia

Study Arms (2)

Euglycemia

ACTIVE COMPARATOR

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

Other: euglycemia

Hypoglycemia

EXPERIMENTAL

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

Other: hypoglycemia

Interventions

hypoglycemia OTHER

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

Also known as: Low blood glucose levels

Hypoglycemia

euglycemia OTHER

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

Also known as: Normal blood glucose levels

Euglycemia

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Dutch Diabetes Research Foundation: collaborator
• European Foundation for the Study of Diabetes: collaborator

Study Sites (1)

Radboud umc

Nijmegen, Netherlands

Location

Related Publications (9)

• 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.

  PMID: 19913052 BACKGROUND

• 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.

  PMID: 21464446 BACKGROUND

• 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.

  PMID: 22688331 BACKGROUND

• 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.

  PMID: 23298837 BACKGROUND

• 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.

  PMID: 23543056 BACKGROUND

• 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.

  PMID: 23715622 BACKGROUND

• 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.

  PMID: 22457647 BACKGROUND

• 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.

  PMID: 31001674 DERIVED

• 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.

  PMID: 26993070 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Hig1 protein, mouse

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Bastiaan de Galan, Dr.

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2014
• First Posted: May 23, 2014
• Study Start: August 1, 2014
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: November 10, 2015

Record last verified: 2015-11

Locations

NL (1)