Ignite Creation Date:
2025-12-25 @ 1:23 AM
Ignite Modification Date:
2026-04-11 @ 5:57 PM
Study NCT ID:
NCT02308293
Status:
COMPLETED
Last Update Posted:
2016-11-25
First Post:
2014-11-14
Is Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D003922', 'term': 'Diabetes Mellitus, Type 1'}], 'ancestors': [{'id': 'D003920', 'term': 'Diabetes Mellitus'}, {'id': 'D044882', 'term': 'Glucose Metabolism Disorders'}, {'id': 'D008659', 'term': 'Metabolic Diseases'}, {'id': 'D009750', 'term': 'Nutritional and Metabolic Diseases'}, {'id': 'D004700', 'term': 'Endocrine System Diseases'}, {'id': 'D001327', 'term': 'Autoimmune Diseases'}, {'id': 'D007154', 'term': 'Immune System Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000072696', 'term': 'High-Intensity Interval Training'}], 'ancestors': [{'id': 'D064797', 'term': 'Physical Conditioning, Human'}, {'id': 'D015444', 'term': 'Exercise'}, {'id': 'D009043', 'term': 'Motor Activity'}, {'id': 'D009068', 'term': 'Movement'}, {'id': 'D009142', 'term': 'Musculoskeletal Physiological Phenomena'}, {'id': 'D055687', 'term': 'Musculoskeletal and Neural Physiological Phenomena'}]}}, 'protocolSection': {'designModule': {'phases': ['NA'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'BASIC_SCIENCE', 'interventionModel': 'CROSSOVER'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 30}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2015-01'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2016-04', 'completionDateStruct': {'date': '2016-07', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2016-11-23', 'studyFirstSubmitDate': '2014-11-14', 'studyFirstSubmitQcDate': '2014-12-03', 'lastUpdatePostDateStruct': {'date': '2016-11-25', 'type': 'ESTIMATED'}, 'studyFirstPostDateStruct': {'date': '2014-12-04', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2016-05', 'type': 'ACTUAL'}}, 'outcomesModule': {'otherOutcomes': [{'measure': 'Plasma glucose concentration', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Plasma glucose concentration, necessary to adjust glucose infusion rate'}, {'measure': 'Plasma insulin concentration (Insulin levels, measured in arterial plasma)', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Insulin levels, measured in arterial plasma'}], 'primaryOutcomes': [{'measure': 'Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)', 'timeFrame': 'during 60 m of hypoglycemia'}], 'secondaryOutcomes': [{'measure': 'Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma)', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Levels of counter-regulatory hormones measured in arterial plasma'}, {'measure': 'Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values)', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Amount of glucose 20% necessary to maintain plasma glucose at steady state values'}, {'measure': 'Plasma lactate levels (Lactate levels measured in arterial plasma)', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Lactate levels measured in arterial plasma'}, {'measure': 'Cognitive functioning, as measured by cognitive tests', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat'}, {'measure': 'Plasma levels of inflammatory markers (levels of cytokines)', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'levels of cytokines'}, {'measure': 'Brain perfusion measured with ASL-MRI', 'timeFrame': 'During 60 min hypoglycemia', 'description': 'Brain perfusion measured with ASL-MRI'}, {'measure': 'Brain lactate accumulation measured with 1H-MRS', 'timeFrame': 'During 60 min of hypoglycemia', 'description': 'Brain lactate levels measured with 1H-MRS'}]}, 'oversightModule': {'oversightHasDmc': False}, 'conditionsModule': {'keywords': ['Type 1 Diabetes Mellitus', 'Hypoglycemia unawareness', 'Lactate', 'high intensity interval exercise', 'MRS'], 'conditions': ['Type 1 Diabetes Mellitus', 'Hypoglycemia Unawareness']}, 'referencesModule': {'references': [{'pmid': '19913052', 'type': 'BACKGROUND', '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.'}, {'pmid': '21464446', 'type': 'BACKGROUND', '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.'}, {'pmid': '22688331', 'type': 'BACKGROUND', '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.'}, {'pmid': '23715622', 'type': 'BACKGROUND', '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.'}, {'pmid': '21640838', 'type': 'BACKGROUND', 'citation': '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': '31001674', 'type': 'DERIVED', '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.'}, {'pmid': '28935628', 'type': 'DERIVED', 'citation': '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': '28420673', 'type': 'DERIVED', 'citation': '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.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nObjective: 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.\n\nHypothesis: 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT'], 'maximumAge': '40 Years', 'minimumAge': '18 Years', 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion criteria for healthy subjects\n\n* Age: 18-40 years\n* Body-Mass Index: 18-30 kg/m2\n* Blood pressure: \\<160/90 mmHg\n* Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week.\n\nInclusion criteria T1DM patients with normal hypoglycemic awareness\n\n* Diabetes duration ≥ 1 year\n* Age: 18-40 years\n* Body-Mass Index: 18-30 kg/m2\n* HbA1c: 42-75 mmol/mol (6-9%)\n* Outcome Clarke questionnaire: 0-1\n* Blood pressure: \\<160/90 mmHg\n* Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week\n\nInclusion criteria T1DM patients with hypoglycemia unawareness\n\n* Diabetes duration ≥ 1 year\n* Age: 18-40 years\n* Body-Mass Index: 18-30 kg/m2\n* HbA1c: 42-75 mmol/mol (6-9%)\n* Outcome Clarke questionnaire: =\\>3\n* Blood pressure: \\<160/90 mmHg\n* Recreationally active\n\nExclusion criteria:\n\n* Inability to provide informed consent\n* 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\n* Use of any medication, except for oral contraceptives\n* MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)\n* Orthopedic and/or neurological diseases that impair exercise\n* Cardiopulmonary disease as stated in the 2001 American heart association and 2002 American college of cardiology/American heart association guidelines\n\nAdditional exclusion criteria for all T1DM patients:\n\n* Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy\n* complications of T1DM, including proliferative retinopathy, neuropathy or nephropathy'}, 'identificationModule': {'nctId': 'NCT02308293', 'briefTitle': 'The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia', 'organization': {'class': 'OTHER', 'fullName': 'Radboud University Medical Center'}, 'officialTitle': 'The Effect of Exercise-induced Hyperlacticacidemia on Counterregulatory Responses, Symptoms, Cognitive Function and Brain Lactate Accumulation During Hypoglycemia in (Hypoglycemic Unaware)Type I Diabetes Patients and Normal Controls', 'orgStudyIdInfo': {'id': 'End_lac_sympt'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'High intensity exercise', 'description': 'Subjects will preform a high intensity training exercise (3\\* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels', 'interventionNames': ['Behavioral: High intensity exercise']}, {'type': 'SHAM_COMPARATOR', 'label': 'Lay down comfortably', 'description': 'As a control conditions, subjects wil lay down comfortably and rest', 'interventionNames': ['Behavioral: Lay down comfortably']}], 'interventions': [{'name': 'High intensity exercise', 'type': 'BEHAVIORAL', 'description': "3x30 seconds 'all out' sprints", 'armGroupLabels': ['High intensity exercise']}, {'name': 'Lay down comfortably', 'type': 'BEHAVIORAL', 'description': 'rest', 'armGroupLabels': ['Lay down comfortably']}]}, 'contactsLocationsModule': {'locations': [{'city': 'Nijmegen', 'country': 'Netherlands', 'facility': 'Radboud umc', 'geoPoint': {'lat': 51.8425, 'lon': 5.85278}}], 'overallOfficials': [{'name': 'Bastiaan de Galan, Dr.', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Radboud University Medical Center'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Radboud University Medical Center', 'class': 'OTHER'}, 'collaborators': [{'name': 'Dutch Diabetes Research Foundation', 'class': 'OTHER'}, {'name': 'European Foundation for the Study of Diabetes', 'class': 'OTHER'}], 'responsibleParty': {'type': 'SPONSOR'}}}}