The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia

NCT02308293 | Completed

• 1 other identifier: End_lac_sympt
• Study Type: interventional
• Target: 30
• 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, eventually leading to hypoglycemia unawareness, which creates a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for (brain) lactate in the pathogenesis of hypoglycemia unawareness. Indeed, exogenous lactate administration may preserve brain function and attenuate counterregulatory responses to and symptomatic awareness of hypoglycemia. It is unknown whether endogenous elevation of plasma lactate produces the same effects and whether such effects differ between patients with T1DM with and without hypoglycemia unawareness and healthy controls. Objective: To investigate the effect of elevated levels of endogenous lactate on brain lactate accumulation and on counterregulatory responses to, symptomatic awareness of and cognitive function during hypoglycemia in patients with T1DM with and without hypoglycemia unawareness and normal controls. Hypothesis: The investigators hypothesize first that endogenous lactate, when raised through high intensity exercise, preserves neuronal metabolism during subsequent hypoglycemia, which in turn will attenuate counterregulatory hormone responses, appearance of symptoms and deterioration of cognitive function. Second, the investigators posit that these effects will be augmented in patients with hypoglycemia unawareness compared to healthy subjects and T1DM patients with normal awareness as a consequence of greater transport capacity of lactate into the brain.

Conditions

Type 1 Diabetes Mellitus; Hypoglycemia Unawareness

Keywords

Type 1 Diabetes Mellitus; Hypoglycemia unawareness; Lactate; high intensity interval exercise; MRS

Outcome Measures

Primary Outcomes (1)

• Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)

  during 60 m of hypoglycemia

Secondary Outcomes (7)

• Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma)

  During 60 min hypoglycemia

• Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values)

  During 60 min hypoglycemia

• Plasma lactate levels (Lactate levels measured in arterial plasma)

  During 60 min hypoglycemia

• Cognitive functioning, as measured by cognitive tests

  During 60 min hypoglycemia

• Plasma levels of inflammatory markers (levels of cytokines)

  During 60 min hypoglycemia

Other Outcomes (2)

• Plasma glucose concentration

  During 60 min hypoglycemia

• Plasma insulin concentration (Insulin levels, measured in arterial plasma)

  During 60 min hypoglycemia

Study Arms (2)

High intensity exercise

EXPERIMENTAL

Subjects will preform a high intensity training exercise (3\* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels

Behavioral: High intensity exercise

Lay down comfortably

SHAM COMPARATOR

As a control conditions, subjects wil lay down comfortably and rest

Behavioral: Lay down comfortably

Interventions

High intensity exercise BEHAVIORAL

3x30 seconds 'all out' sprints

High intensity exercise

Lay down comfortably BEHAVIORAL

rest

Lay down comfortably

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: 18-40 years
• Body-Mass Index: 18-30 kg/m2
• Blood pressure: \<160/90 mmHg
• Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week.
• Diabetes duration ≥ 1 year
• Age: 18-40 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
• Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week
• Diabetes duration ≥ 1 year
• Age: 18-40 years
• Body-Mass Index: 18-30 kg/m2
• HbA1c: 42-75 mmol/mol (6-9%)

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)
• Orthopedic and/or neurological diseases that impair exercise
• Cardiopulmonary disease as stated in the 2001 American heart association and 2002 American college of cardiology/American heart association guidelines
• Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy
• complications of T1DM, including proliferative retinopathy, neuropathy or nephropathy

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 (8)

• 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

• 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

• Maddock RJ, Casazza GA, Buonocore MH, Tanase C. Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): a dynamic 1H-MRS study. Neuroimage. 2011 Aug 15;57(4):1324-30. doi: 10.1016/j.neuroimage.2011.05.048. Epub 2011 May 27.

  PMID: 21640838 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, Groenewoud HJMM, Heerschap A, de Galan BE, van der Graaf M. Effect of Exercise-Induced Lactate Elevation on Brain Lactate Levels During Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2017 Dec;66(12):3105-3110. doi: 10.2337/db17-0794. Epub 2017 Sep 21.

  PMID: 28935628 DERIVED

• Rooijackers HM, Wiegers EC, van der Graaf M, Thijssen DH, Kessels RPC, Tack CJ, de Galan BE. A Single Bout of High-Intensity Interval Training Reduces Awareness of Subsequent Hypoglycemia in Patients With Type 1 Diabetes. Diabetes. 2017 Jul;66(7):1990-1998. doi: 10.2337/db16-1535. Epub 2017 Apr 18.

  PMID: 28420673 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

High-Intensity Interval Training

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Physical Conditioning, Human; Exercise; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Bastiaan de Galan, Dr.

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: November 14, 2014
• First Posted: December 4, 2014
• Study Start: January 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: July 1, 2016
• Last Updated: November 25, 2016

Record last verified: 2016-04

Locations

NL (1)