Muscle Oxygenation, Type 1 Diabetes, and Glycated Hemoglobin (OXYDIAB)

Impact of Type 1 Diabetes and Glycated Haemoglobin Levels on Oxygen Delivery and Release to Active Muscle During Exercise and on Muscle Oxidation Capacity - Possible Impact on Aerobic Fitness

Most of the studies concerning aerobic fitness in Type 1 diabetic patients noted a relationship between impaired aerobic fitness and high glycated haemoglobin (HbA1c) levels, reflecting poor long term glycaemic control. To explain this relationship, the indirect effect of chronically high blood glucose levels on cardiovascular complications - and hence on exercise cardiovascular adaptations - are often mentioned. However, one could wonder if HbA1c could also have a direct impact on aerobic fitness patients with Type 1 diabetes. Haemoglobin glycation may increase its O2 affinity, thus limiting the O2 availability at the muscular level and impairing maximal aerobic power. Moreover, chronic hyperglycaemia might have deleterious effect on muscle mitochondrial capacity to use O2. The aim of this study is to assess the effect of Type 1 diabetes and of HbA1c level on muscular oxygen delivery and use and hence on aerobic fitness.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Behavioral: Incremental maximal exercise; Procedure: Muscle biopsy; Procedure: Combined DLCO-DLNO; Procedure: Dual energy X-ray absorptiometry; Procedure: Accelerometry over one week; Other: Questionnaires; Dietary supplement: Oral Glucose Tolerance Test

Detailed Description

The current study aims at assessing the impact of Type 1 diabetes and HbA1c on muscle oxygen delivery and on muscle mitochondrial capacity. Our hypothesis is that these both steps of the oxygen cascade might be involved in the aerobic fitness impairment usually observed in poor-controlled patients.

Adults with Type 1 diabetes, aged 18-40 years, without microvascular and macrovascular diabetic complications, will be recruited among patients that regularly attend the unit of diabetology of the University Hospital of Lille and the regional hospital of Roubaix. They will be separated into 2 groups according to their glycaemic control at entrance in the study (HbA1c < 7%, HbA1c > 8%). Subsequently, two healthy control groups (checked by an OGTT) will be selected to strictly match the patients with Type 1 diabetes (age, sex, BMI, number of hours of physical activity per week, tobacco smoking). This is a cross-sectional study including 4 groups.

On their first visit, after the determination of HbA1c, all the subjects will perform at rest a DLCO/DLNO. Then they will realise an incremental exercise test to exhaustion on an electromagnetic cycle ergometer. Non-invasive measures will be performed throughout the exercise test, including gas exchange parameters (and maximal oxygen uptake), muscular and brain oxygenation (Near Infra Red Spectroscopy at vastus lateralis muscle and at prefrontal cortex). A blood sample from an arterialised ear-lobe will be taken at rest and exhaustion to determine O2 haemoglobin saturation, arterial partial pressure in O2 and CO2, haemoglobin concentration, hematocrit, and bicarbonates. Blood, from a catheter in a superficial cubital vein, will also be taken at rest, at a precise time during the exercise and immediately after the exercise to measure potential of hydrogen, bicarbonates, haemoglobin concentration, hematocrit, erythrocyte 2,3-diphosphoglycerate, and other blood markers of metabolic and hormonal adaptations to exercise. The subjects will also fill in questionnaires.

On a second visit, in a fasting state, the subjects will have a muscle biopsy at vastus lateralis using a specific needle (less than 150mg) in order to assess mitochondrial respiration capacity and endocannabinoid system activity. A venous blood sampling will allow analysing other health markers (lipid profile, insulin resistance...).

On another visit, the subjects will have a measure of body composition by Dual energy X-ray Absorptiometry and skinfold thickness.

They will also wear an accelerometer over one week and fill in a diet questionnaire over 3 days.

• Study Type: Observational
• Enrollment (Actual): 79

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037
    • CHRU Lille

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The two groups of patients with Type 1 diabetes are recruited from primary care clinics (university hospital of Lille and hospital of Roubaix, France) among patients with Type 1 diabetes for more than 1 year and free from micro and macrovascular complications.

Healthy participants are selected from a list (n=250) drawn up from patients' friends and contacts. Each healthy control is chosen to strictly match a patient with type 1 diabetes according to gender, age, physical activity levels, and tobacco status.

Description

Inclusion Criteria:

• Patients with Type 1 diabetes (duration of Type 1 diabetes > 1 year and < 20 years)
• Healthy subjects

Exclusion Criteria:

Exclusion Criteria for patients with Type 1 diabetes:

• Maturity onset diabetes of the young, mitochondrial diabetes, Type 2 diabetes
• Macro or microvascular complications of diabetes

Exclusion Criteria for healthy controls :

• Diabetes (Glycaemia > 11 mmol/L two hours after the OGTT)

Exclusion Criteria for all subjects :

• Obesity (Body Mass Index > 30 kg/m2)
• Contra-indication to maximal exercise
• Pregnant or breast-feeding women
• Other chronic disease than diabetes
• Muscle or articular problems

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Type 1 diabetes, HbA1c <7%; Patients with Type 1 diabetes and adequate glycemic control: HbA1c <7% at the entrance in the study. Intervention: Incremental maximal exercise Near-Infra Red-Spectroscopy at vastus lateralis and pre-frontal cortex (during exercise) Gas exchanges (VO2, VCO2) during exercise Combined DLCO/DLNO (at rest) Venous and arterialised blood sampling (rest and exercise) Muscle biopsy at the vastus lateralis (rest) Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires Accelerometry over one week Dual energy X-ray Absorptiometry	Behavioral: Incremental maximal exercise; The exercise test starts 2-4h after a standardised breakfast. After a 2-min resting period sitting on the cycle ergometer (Excalibur Sport, Lode B.V, Medical Technology, Groningen, Netherlands), the test starts at 30 watts with a 20 watts increment every 2min until exhaustion.; Procedure: Muscle biopsy; A sample of vastus lateralis (less than 150mg) is taken with a specific needle under local anesthesia.; Procedure: Combined DLCO-DLNO; Lung carbon monoxide and nitric oxide diffusion capacities are assessed at rest in a sitting position.; Procedure: Dual energy X-ray absorptiometry; Body composition is measured using dual energy X-ray absorptiometry at rest.; Procedure: Accelerometry over one week; The subjects wear an uniaxial accelerometer over one week to assess their usual physical activity level; Other: Questionnaires; Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires
Type 1 diabetes, HbA1c >8%; Patients with Type 1 diabetes and inadequate glycemic control: HbA1c >8% at the entrance in the study. Intervention: Incremental maximal exercise Near-Infra Red-Spectroscopy at vastus lateralis and pre-frontal cortex (during exercise) Gas exchanges (VO2, VCO2) during exercise Combined DLCO/DLNO (at rest) Venous and arterialised blood sampling (rest and exercise) Muscle biopsy at the vastus lateralis (rest) Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires Accelerometry over one week Dual energy X-ray Absorptiometry	Behavioral: Incremental maximal exercise; The exercise test starts 2-4h after a standardised breakfast. After a 2-min resting period sitting on the cycle ergometer (Excalibur Sport, Lode B.V, Medical Technology, Groningen, Netherlands), the test starts at 30 watts with a 20 watts increment every 2min until exhaustion.; Procedure: Muscle biopsy; A sample of vastus lateralis (less than 150mg) is taken with a specific needle under local anesthesia.; Procedure: Combined DLCO-DLNO; Lung carbon monoxide and nitric oxide diffusion capacities are assessed at rest in a sitting position.; Procedure: Dual energy X-ray absorptiometry; Body composition is measured using dual energy X-ray absorptiometry at rest.; Procedure: Accelerometry over one week; The subjects wear an uniaxial accelerometer over one week to assess their usual physical activity level; Other: Questionnaires; Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires
Healthy controls, Groupe 1; Healthy controls for patients with Type 1 diabetes and adequate glycemic control matched on age, sex, body composition and physical activity level. Intervention: Oral Glucose Tolerance Test Incremental maximal exercise Near-Infra Red-Spectroscopy at vastus lateralis and pre-frontal cortex (during exercise) Gas exchanges (VO2, VCO2) during exercise Combined DLCO/DLNO (at rest) Venous and arterialised blood sampling (rest and exercise) Muscle biopsy at the vastus lateralis (rest) Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires Accelerometry over one week Dual energy X-ray Absorptiometry	Behavioral: Incremental maximal exercise; The exercise test starts 2-4h after a standardised breakfast. After a 2-min resting period sitting on the cycle ergometer (Excalibur Sport, Lode B.V, Medical Technology, Groningen, Netherlands), the test starts at 30 watts with a 20 watts increment every 2min until exhaustion.; Procedure: Muscle biopsy; A sample of vastus lateralis (less than 150mg) is taken with a specific needle under local anesthesia.; Procedure: Combined DLCO-DLNO; Lung carbon monoxide and nitric oxide diffusion capacities are assessed at rest in a sitting position.; Procedure: Dual energy X-ray absorptiometry; Body composition is measured using dual energy X-ray absorptiometry at rest.; Procedure: Accelerometry over one week; The subjects wear an uniaxial accelerometer over one week to assess their usual physical activity level; Other: Questionnaires; Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires; Dietary supplement: Oral Glucose Tolerance Test; The subjects arrive after an overnight fast and have a 75g Glucose Oral Charge.
Healthy controls, Group 2; Healthy controls for patients with Type 1 diabetes and inadequate glycemic control matched on age, sex, body composition and physical activity level. Intervention: Oral Glucose Tolerance Test Incremental maximal exercise Near-Infra Red-Spectroscopy at vastus lateralis and pre-frontal cortex (during exercise) Gas exchanges (VO2, VCO2) during exercise Combined DLCO/DLNO (at rest) Venous and arterialised blood sampling (rest and exercise) Muscle biopsy at the vastus lateralis (rest) Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires Accelerometry over one week Dual energy X-ray Absorptiometry	Behavioral: Incremental maximal exercise; The exercise test starts 2-4h after a standardised breakfast. After a 2-min resting period sitting on the cycle ergometer (Excalibur Sport, Lode B.V, Medical Technology, Groningen, Netherlands), the test starts at 30 watts with a 20 watts increment every 2min until exhaustion.; Procedure: Muscle biopsy; A sample of vastus lateralis (less than 150mg) is taken with a specific needle under local anesthesia.; Procedure: Combined DLCO-DLNO; Lung carbon monoxide and nitric oxide diffusion capacities are assessed at rest in a sitting position.; Procedure: Dual energy X-ray absorptiometry; Body composition is measured using dual energy X-ray absorptiometry at rest.; Procedure: Accelerometry over one week; The subjects wear an uniaxial accelerometer over one week to assess their usual physical activity level; Other: Questionnaires; Diet questionnaire, quality-of-life questionnaires, physical activity questionnaires; Dietary supplement: Oral Glucose Tolerance Test; The subjects arrive after an overnight fast and have a 75g Glucose Oral Charge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal oxygen uptake	Incremental maximal exercise with gas exchange measure	Participants will perform the incremental maximal exercise on visit 1, one week minimum and 8 weeks maximum after their inclusion in the protocol

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial oxygen content during maximal exercise	measured in ear-lobe arterialised capillary samples	Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
Oxyhemoglobin dissociation at active muscle during maximal exercise	Deoxyhemoglobin and total hemoglobin assessed at vastus lateralis by Near Infrared Spectroscopy	On visit 1, continuously during the incremental maximal exercise
Mitochondrial respiration capacity of vastus lateralis muscle	Vastus lateralis muscle sample is obtained by the percutaneous technique after local anesthesia. The mitochondrial respiration is then studied in situ in saponin-skinned fibers.	Participants will have a muscle biopsy on visit 2, performed 3 days minimum and 32 weeks maximum after their visit 1.
Prefrontal cortex oxygenation during exercise	Total hemoglobin and oxyhemoglobin are assessed at the left prefrontal cortex using Near-Infrared Spectroscopy.	On visit 1, continuously during the incremental maximal exercise

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other factors than hemoglobin glycation that could influence arterial oxygen content	Lung capillary carbon monoxide and nitric oxide diffusion capacities (DLCO, DLNO)	Prior to the incremental maximal exercise on visit 1
Other factors able to modify the oxyhemoglobin dissociation curve	venous erythrocyte 2,3-diphosphoglycerate, arterialised capillary potential of hydrogen oxygen partial pressure, carbon dioxide partial pressure	Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
Mechanisms possibly involved in muscle mitochondrial dysfunctions	oxidative stress (blood oxidative and antioxidant markers at rest and in response to maximal exercise), endocannabinoid system activity	Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1. Prior to the muscle biopsy on visit 2.
Other health markers in link with physical activity levels and aerobic fitness	Lipid profile (HDL-C, LDL-C, apolipoprotein A1, apolipoprotein B, lipoprotein a, ...) Insulin resistance markers (blood ghrelin, adiponectin, leptin...)	Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1. Prior to the muscle biopsy on visit 2.
Blood metabolic and hormonal responses to exercise	Free fatty acids, glycerol, glucose, insulin, catecholamines, glucagon, cortisol, insulin-like growth factor 1, brain-derived neurotrophic factor...	Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
Body composition	Dual energy X-ray Absorptiometry, skinfold thickness, waist and hip circumferences	Prior to incremental maximal exercise on visit 1

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Investigators: Study Director: Elsa HEYMAN, PHD, EA4488 'Physical activity, Muscle, Health; Principal Investigator: Pierre FONTAINE, MD-PHD, CHRU Lille

Publications and helpful links

General Publications

• Lespagnol E, Tagougui S, Fernandez BO, Zerimech F, Matran R, Maboudou P, Berthoin S, Descat A, Kim I, Pawlak-Chaouch M, Boissière J, Boulanger E, Feelisch M, Fontaine P, Heyman E. Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes. Diabetologia. 2021 Feb;64(2):325-338. doi: 10.1007/s00125-020-05329-8. Epub 2020 Nov 21.
• Heyman E, Daussin F, Wieczorek V, Caiazzo R, Matran R, Berthon P, Aucouturier J, Berthoin S, Descatoire A, Leclair E, Marais G, Combes A, Fontaine P, Tagougui S. Muscle Oxygen Supply and Use in Type 1 Diabetes, From Ambient Air to the Mitochondrial Respiratory Chain: Is There a Limiting Step? Diabetes Care. 2020 Jan;43(1):209-218. doi: 10.2337/dc19-1125. Epub 2019 Oct 21.
• Tagougui S, Fontaine P, Leclair E, Aucouturier J, Matran R, Oussaidene K, Descatoire A, Prieur F, Mucci P, Vambergue A, Baquet G, Heyman E. Regional cerebral hemodynamic response to incremental exercise is blunted in poorly controlled patients with uncomplicated type 1 diabetes. Diabetes Care. 2015 May;38(5):858-67. doi: 10.2337/dc14-1792. Epub 2015 Feb 9.
• Tagougui S, Leclair E, Fontaine P, Matran R, Marais G, Aucouturier J, Descatoire A, Vambergue A, Oussaidene K, Baquet G, Heyman E. Muscle oxygen supply impairment during exercise in poorly controlled type 1 diabetes. Med Sci Sports Exerc. 2015 Feb;47(2):231-9. doi: 10.1249/MSS.0000000000000424.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: December 20, 2013
• First Submitted That Met QC Criteria: January 30, 2014
• First Posted (Estimate): January 31, 2014

Study Record Updates

• Last Update Posted (Estimate): September 13, 2016
• Last Update Submitted That Met QC Criteria: September 12, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Oxidative stress; Exercise; Type 1 diabetes; Glycated hemoglobin; Muscle Oxygenation; Maximal Oxygen uptake; Mitochondrial respiration; Endocannabinoid system
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 2009_12; 2009-A00746-51. (Other Identifier: ID-RCB number, AFSSAPS)