Skeletal muscle glucose transport and mitochondrial function in type 1 diabetes

Rationale: Type 1 diabetes mellitus (T1DM) is caused by immune-mediated destruction of the insulin-producing pancreatic β-cells, resulting in lifelong reliance on exogenous insulin (via multiple daily injections or insulin pump). During exercise, glucose disposal increases via insulin-independent means in healthy people and those living with T1DM. Some remnants of these cellular features (such as increased NOX2 signalling) have also been described in animal models of T1DM, but never for humans with T1DM. This insulin-independent glucose signalling likely comes at a price of an impaired skeletal muscle mitochondrial function. The observation that mitochondrial dysfunction and exercise intolerance also occur in young, physically active, and otherwise healthy individuals with T1DM confirms this suggestion. Since the cause of this mitochondrial dysfunction in individuals with T1DM is unknown, this limits preventive measures and effective treatment. Not only will we study the intracellular metabolism in T1DM, we also expect that myokine secretion levels are altered in T1DM, affecting inter-organ communication and whole-body glucose and fat metabolism. In this project, we hypothesise that: 1) Patients with type 1 diabetes display poorer mitochondrial function when compared to healthy controls matched for age-, sex- and physical activity. 2) Patients with type 1 diabetes display an altered reliance on skeletal muscle glucose uptake pathways such as the NOX2 pathway when compared to healthy controls matched for age-, sex- and physical activity. 3) Patients with type 1 diabetes display an altered myokine signalling profile following exercise when compared to healthy controls matched for age-, sex- and physical activity. 3) An increased reliance on the NOX2 pathway is associated with the extent of mitochondrial dysfunction in patients with type 1 diabetes 4) Exercise training will improve mitochondrial function, skeletal muscle glucose handling and myokine secretion in both patients with type 1 diabetes and healthy controls Primary Aim: We aim to determine markers for NOX2-mediated insulin-independent glucose uptake signalling pathways, mitochondrial function, myokine secretion both at rest and after a bout of acute exercise in individuals with T1DM and healthy controls, and secondly, to determine each of these variables both before and after an exercise training intervention. The secondary objective of this study is to obtain insight into the determinants of exercise intolerance in T1DM by assessing the relationships between the measures obtained from muscle biopsies (i.e. mitochondrial function) and whole-body exercise tolerance, both before and after an exercise training intervention. Study design: An exercise training intervention study in individuals with T1DM and healthy controls will be performed to assess insulin-independent glucose metabolism, mitochondrial function, and exercise tolerance by invasive as well as non-invasive measurements. Study population: 16 otherwise healthy individuals with T1D (18-65 years) and 16 healthy controls without T1D) will be matched for age, body mass index, and physical activity levels. Intervention: Both groups will undertake a 4-week moderate-intensity exercise training intervention, wherein participants will perform 30-60 minutes of continuous moderate-intensity cycle exercise (at the steady-state heart rate associated with the gas exchange threshold, GET), 3 times per week. Main study parameters: The differences in markers of insulin-independent glucose uptake, parameters of mitochondrial function and exercise tolerance between T1DM and control groups both before and after the exercise training intervention.

1) Patients with type 1 diabetes display poorer mitochondrial function when compared to healthy controls matched for age-, sex- and physical activity. 2) Patients with type 1 diabetes display an altered reliance on skeletal muscle glucose uptake pathways such as the NOX2 pathway when compared to healthy controls matched for age-, sex- and physical activity. 3) Patients with type 1 diabetes display an altered myokine signalling profile following exercise when compared to healthy controls matched for age-, sex- and physical activity. 3) An increased reliance on the NOX2 pathway is associated with the extent of mitochondrial dysfunction in patients with type 1 diabetes 4) Exercise training will improve mitochondrial function, skeletal muscle glucose handling and myokine secretion in both patients with type 1 diabetes and healthy controls

Before and after exercise training

Exercise training