Clinical trial NCT02051504: Muscle Oxygenation, Type 1 Diabetes, and Glycated Hemoglobin
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 1 Diabetes
Keywords: Type 1 diabetes
Glycated hemoglobin
Muscle Oxygenation
Exercise
Maximal Oxygen uptake
Mitochondrial respiration
Endocannabinoid system
Oxidative stress
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
First posted: 2014-01-31
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximal oxygen uptake
timeFrame: Participants will perform the incremental maximal exercise on visit 1, one week minimum and 8 weeks maximum after their inclusion in the protocol
Secondary outcomes:
measure: Arterial oxygen content during maximal exercise
timeFrame: Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
measure: Oxyhemoglobin dissociation at active muscle during maximal exercise
timeFrame: On visit 1, continuously during the incremental maximal exercise
measure: Mitochondrial respiration capacity of vastus lateralis muscle
timeFrame: Participants will have a muscle biopsy on visit 2, performed 3 days minimum and 32 weeks maximum after their visit 1.
measure: Prefrontal cortex oxygenation during exercise
timeFrame: On visit 1, continuously during the incremental maximal exercise
Other outcomes:
measure: Other factors than hemoglobin glycation that could influence arterial oxygen content
timeFrame: Prior to the incremental maximal exercise on visit 1
measure: Other factors able to modify the oxyhemoglobin dissociation curve
timeFrame: Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
measure: Mechanisms possibly involved in muscle mitochondrial dysfunctions
timeFrame: 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.
measure: Other health markers in link with physical activity levels and aerobic fitness
timeFrame: 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.
measure: Blood metabolic and hormonal responses to exercise
timeFrame: Prior to the incremental maximal exercise on visit 1, and immediately after the incremental maximal exercise on visit 1.
measure: Body composition
timeFrame: Prior to incremental maximal exercise on visit 1
Locations:
city: Lille
country: France
facility: CHRU Lille
Study officials:
affiliation: EA4488 'Physical activity, Muscle, Health
name: Elsa HEYMAN, PHD
role: STUDY_DIRECTOR
affiliation: CHRU LILLE
name: Pierre FONTAINE, MD-PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lespagnol E, Tagougui S, Fernandez BO, Zerimech F, Matran R, Maboudou P, Berthoin S, Descat A, Kim I, Pawlak-Chaouch M, Boissiere 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.
citation: 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.
citation: 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.
citation: 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.