Impact of Physical Activity on Blood Glucose Stability and Energy Stores in Individuals With Type 1 Diabetes

Study Overview
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Brief Summary
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Whereas physical activity clearly results in improvements in glycemic control in type 2 diabetes, in individuals with type 1 diabetes (T1DM) the impact of exercise on blood sugar control is more complex. In type 1 diabetes T1DM the inability to reduce exogenous insulin levels during exercise is a key factor that contributes to an increased risk of exercise-induced hypoglycemia. Since rapid adaptation of insulin dosage may be especially difficult in patients on a multiple daily injection regimen, alternative strategies are required to improve exercise-associated glucose stability. There is increasing evidence that the combination of steady state continuous low to moderate intensity exercise with short bursts of high intensity exertion (eg in the form of sprints) is an effective, well tolerated, novel strategy to prevent exercise-related hypoglycemia. A further promising option to stabilize blood sugar levels during and after exercise may be the ingestion of fructose in addition to glucose in form of a sport drink.

Detailed Description
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Background Regular physical activity enhances insulin sensitivity in both healthy subjects and patients with diabetes mellitus. However, while the effects of physical activity on glucose control are undoubtedly beneficial in patients with type 2 diabetes, exercise can cause major disturbances in blood glucose levels in type 1 diabetic individuals. Hypoglycemia is a common complication in patients with T1DM engaging in endurance activities such as running and cycling. So far there are limited strategies suggested to improve exercise-related blood sugar self-management. Current recommendations focus on variation in timing and dosage of insulin administration and adjustments in carbohydrate intake. Since rapid adaptation of insulin dosage may be difficult, alternative strategies to improve exercise-related glucose stability are required. Increasing evidence suggests that intermittent high intensity exercise (IHE), by triggering a counterregulatory hormone response, may counter-balance the risk of exercise-associated hypoglycemia. However, previous studies investigating IHE in T1DM were limited by heterogeneous study populations, comparably short exercise protocols, and deficits in standardization procedures. In addition, a comprehensive assessment of the underlying fuel metabolism has not been performed so far. As a consequence, the results remain controversial and their interpretation as well as applicability are restricted. A further alternative strategy to maintain stable glycemia during exercise may be deduced from recent studies in non-diabetic individuals suggesting that the combined ingestion of fructose and glucose during exercise provides the liver with an increased amount of gluconeogenic precursors, thereby reducing consumption of endogenous glycogen stores.Moreover, conversion of fructose into glucose and lactate may provide constant and efficient fuel for working muscles. However, studies assessing the impact of fructose ingestion during exercise in patients with T1DM have not been performed so far. Objective The investigators aim to assess the impact of two novel non-pharmaceutical and easily feasible approaches on exercise-related blood glucose stability and its underlying exercise-related fuel metabolism in patients with T1DM. Substudy A will assess the influence on exercise-related glycemia and fuel metabolism of an IHE protocol compared to an iso-energetic continuous exercise (CONT). It will be investigated whether individuals reach more stable blood glucose levels when engaging in IHE compared to CONT. Substudy B will investigate whether fueling the patients with a mixed oral 1:1 glucose-fructose carbohydrate solution will maintain glucose values within a more stable range when compared to carbohydrate supplementation by glucose alone. Methods Blood glucose levels, counterregulatory hormones, metabolites such as lactate and free fatty acids as well as inflammatory biomarkers will be assessed by regular blood samplings. By means of oral and intravenously given stable isotopes (U-13 C glucose and 2H glucose) exercise-related glucose kinetics will be investigated. Exercise-induced glycogen consumption will be measured using magnetic resonance spectroscopy technology. Late glycemic excursions will be recorded by continuous glucose monitoring systems. In order to validate 13C magnetic resonance spectroscopy (MRS) measurement of hepatic and myocellular glycogen content a pre-study involving 10 patients and an equal number of matched healthy controls will be performed (validation and reproducibility study).

Official Title
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Exercise-related Fuel Metabolism and Glucose Stability in Individuals With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus, Exercise, Hypoglycemia, Carbohydrate Metabolism

Intervention / Treatment
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* Procedure: IHE first, CONT second
* Procedure: CONT first, IHE second
* Procedure: GLU first, GLU-FRU second
* Procedure: GLU-FRU first, GLU second


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Aged 18 to 35 years Diabetes mellitus duration for at least 5 years No change in insulin regimen for at least 3 months prior to the study Under acceptable to good metabolic control Normal insulin sensitivity Regular physical activity BMI in the range of 18-25 kg/m2 Written informed consent Exclusion Criteria Diabetes-related complications (macro and microvascular) Anemia (hemoglobin concentration <130g/l) Abnormal thyroid function Dyslipidemia Major depression, psychosis and other severe personality disorders, claustrophobia Active neoplasia Contraindications to exposure to a 3 T magnetic field Abnormal liver or renal function Smoking, drug abuse, or daily alcohol consumption >60g Participation in another study Medication other than insulin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IHE first, CONT second, CSII and MDI therapy<br>IHE: intermittent high intensity exercise: integration of 10 s maximal sprints every 10 minutes in a continuous low to moderate intensity exercise of 90 minutes CONT (occurring after a washout period of 2-8 weeks): continuous moderate intensity exercise of 90 minutes | Procedure: IHE first, CONT second<br>* IHE: intermittent high intensity exercise: integration of 10 s maximal sprints every 10 minutes in a continuous low to moderate intensity exercise of 90 minutes. CONT (occurring after a washout period of 2-8 weeks): continuous moderate intensity exercise of 90 minutes<br>|
| Experimental: CONT first, IHE second,CSII and MDI therapy<br>CONT: continuous moderate intensity exercise of 90 minutes. IHE (occurring after a washout period of 2-8 weeks): intermittent high intensity exercise: integration of 10 s maximal sprints every 10 minutes in a continuous low to moderate intensity exercise of 90 minutes | Procedure: CONT first, IHE second<br>* CONT: continuous moderate intensity exercise of 90 minutes. IHE (occurring after a washout period of 2-8 weeks): intermittent high intensity exercise: integration of 10 s maximal sprints every 10 minutes in a continuous low to moderate intensity exercise of 90 minutes<br>|
| Experimental: GLU first, GLUFRU second, CSII and MDI therapy<br>GLU: ingestion of a 6% carbohydrate solution (consisting of 100 g glucose dissolved in 1000 ml tap water) over a continuous moderate exercise of 90 minutes. GLU FRU (occurring after a washout period of 2-8 weeks): ingestion of a 20% carbohydrate solution (consisting of 100 g glucose + 100 g fructose dissolved in 1000 ml tap water) over a continuous moderate exercise of 90 minutes. CSII = continuous subcutaneous insulin infusion. MDI=multiple daily injections. | Procedure: GLU first, GLU-FRU second<br>* : ingestion of a 6% carbohydrate solution (consisting of 90 g glucose dissolved in 1500 ml tap water) over a continuous moderate exercise of 90 minutes. GLU FRU (occurring after a washout period of 2-8 weeks): ingestion of a 12% carbohydrate solution (consisting of 90 g glucose + 90 g fructose dissolved in 1500 ml tap water) over a continuous moderate exercise of 90 minutes<br>|
| Experimental: GLU-FRU first, GLU second, CSII therapy<br>GLU-FRU : ingestion of a 20% carbohydrate solution (consisting of 100 g glucose + 100 g fructose dissolved in 1000 ml tap water) over a continuous moderate exercise of 90 minutes. GLU (occurring after a washout period of 2-8 weeks): ingestion of a 10% carbohydrate solution (consisting of 100 g glucose dissolved in 1000 ml tap water) over a continuous moderate exercise of 90 minutes. CSII = continuous subcutaneous insulin infusion. MDI=multiple daily injections. | Procedure: GLU-FRU first, GLU second<br>* GLU-FRU : ingestion of a 12% carbohydrate solution (consisting of 90 g glucose + 90 g fructose dissolved in 1500 ml tap water) over a continuous moderate exercise of 90 minutes. GLU (occurring after a washout period of 2-8 weeks): : ingestion of a 6% carbohydrate solution (consisting of 90 g glucose dissolved in 1500 ml tap water) over a continuous moderate exercise of 90 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of exogenous glucose required to maintain glycemia within a range between 7-10mM |  | 30 minutes (last 30 minutes of 90 min exercise period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise - related glycogen consumption |  | 90 minutes | 
| Glucose kinetics | Rate of glucose appearance and disappearance | 180 minutes | 
| Counterregulatory hormones, metabolites, and inflammatory response |  | 300 minutes | 
| Spiroergometric parameters | CO2 and O2 production, RER | 180 minutes | 
| Pre- and post-exercise glycemic excursions |  | 72 h pre-exercise and 72 h post-exercise respectively | 
| Heart rate variability |  | 90 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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exercise, isotope labeling, stable, spectroscopy, magnetic resonance, monitoring, home blood glucose, hormones