The Impact of Diabetes on Skeletal Muscle Metabolic & Physical Capacities
Type 1 Diabetes
Type 1 Diabetes Mellitus (T1D) is a chronic auto-immune disease characterized by decreased insulin production (hypoinsulinemia) and elevated blood glucose levels (hyperglycemia). Despite treatment options like insulin therapy, persons with T1D still experience fluctuations in metabolism and insulin resistance. Over-time, this can lead to health complications including cardiovascular disease, neuropathy, retinopathy, nephropathy – and of particular interest to our lab, myopathy or damage to skeletal muscle.
Skeletal muscle is the largest organ in the human body by mass. Muscle not only gives us the ability to move, but plays a crucial role in metabolism (glucose uptake, fat metabolism, insulin sensitivity).
Surprisingly, the impact of T1D on skeletal muscle has received little clinical attention despite the importance of skeletal muscle to our physical and metabolic well-being. Though skeletal muscle is remarkably resilient and can maintain basic function in T1D, this does not equate to ‘healthy muscle’. Impairments in skeletal muscle health (decreases in mass, strength and reparative and metabolic capacity or plasticity) can be observed in very early stages of T1D onset, before other primary complications.
Areas of Interest
We have convincingly demonstrated that while T1D may begin with a state of hyperglycaemia caused by hypoinsulinemia, the disease is far more complex than this.
Currently, we are exploring how T1D impacts the following:
- Mitochondrial function
- Muscle repair
- Myostatin expression
Mitochondria are tiny organelles found inside the cells of our body and are commonly known for being the “powerhouses” of the cell. The reason being is that inside our cells, mitochondria are predominantly responsible for releasing energy from the foods we eat (metabolism). This process is known as cellular (or mitochondrial) respiration and is essential for keeping our cells alive and with full of energy.
However, a natural byproduct of mitochondrial respiration is highly reactive molecules, referred to as oxidants. While our cells are typically well equipped with antioxidants, whose job is to destroy these oxidants, under conditions of excess energy (calorie) intake, the number of oxidants produced far exceeds our antioxidant capacity. This causes “oxidative stress” within our cells, meaning that there is a strong probability for severe damage to our proteins and DNA as well as the mitochondria themselves (aka mitochondrial dysfunction). Over time, mitochondrial dysfunction and oxidative stress can cause cells to die.
You can imagine that if mitochondria were dysfunctional in a tissue such as our skeletal muscles, which requires lots of energy, then our metabolic capacity and our ability to perform activities of daily living (such as walking), physical activity, exercise, or even standing for a prolonged period of time would be severely impacted. While many studies have found that people with diabetes are at greater risk for early frailty and poor physical performance/disability, which suggests premature “problems” with their skeletal muscle system, very few studies have interrogated this in humans with Type 1 Diabetes, and in particular, at the cellular level.
We have recently discovered that the mitochondria in skeletal muscle cells of young adults (18-30 years old) with Type 1 Diabetes are dysfunctional compared to age-, sex-, BMI- and physical activity levels-matched non-diabetics. Specifically, we found that their mitochondria had decreased respiration, increased emission of oxidants and increased susceptibility to cell death. For the first time, our findings may explain the cellular mechanism behind why people with diabetes are at a greater risk for skeletal muscle complications (including frailty, reduced muscle strength, early muscle fatigue, etc.). We are currently investigating this further and across different age groups.
Skeletal muscle is highly recognized for its dynamic ability to adapt and repair in response to exercise, metabolism, and injury. Successful repair is crucial to maintaining long-term muscle health. Unfortunately, muscle repair has not been directly investigated in humans with T1D. Diabetic rodents have a reduced capacity to undergo muscle repair.Previous work from our lab suggests a similar trend in humans, with young-adults with T1D having a decreased number of muscle pre-cursor cells (satellite cells). As T1D commonly develops during adolescence, chronic reductions in muscle repair may manifest into functional impairments in early adulthood.
A portion of our research is dedicated to investigating muscle-specific factors that are disturbed in diabetes. One of our primary targets, myostatin, is a molecule that is responsible for stopping muscle growth, and high levels cause muscle atrophy (i.e. decreased size) and other abnormalities. Our preliminary findings show that there may be higher levels of myostatin in those with T1D, and that levels may worsen with age. Together our findings suggest that myostatin may be a key contributor in diabetic myopathy, especially in the later stages of life.