Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Master of Science




Melling, Jamie

2nd Supervisor

Mottola, Michelle


In response to repetitive bouts of aerobic exercise, type I diabetes mellitus (T1DM) female rats demonstrate greater post-exercise blood glucose (BG) recovery during proestrus than T1DM males. Fuel selection differences may explain sex-related differences in the blunted counterregulatory responses to subsequent exercise and estrogen (E2) has shown to mediate fuel metabolism. Evidence of E2’s activation of AMP-kinase (AMPK) may mediate the metabolic actions of E2. This study aimed to examine sex-related differences in lipid and glucose metabolism in response to a 4-day aerobic exercise protocol in skeletal muscle and liver tissue of male and female T1DM-induced (n = 5) and non-T1DM (n = 5) rats. Western blot analysis and phenol sulphuric acid and β-oxidation activity assays were used to assess AMPK and gluconeogenic enzyme protein expression, muscle glycogen content, and lipid oxidation. T1DM and non-T1DM females demonstrated significantly greater β-oxidation activity in muscle compared to males but this fuel shift towards lipids was not associated with higher AMPK activity. No muscle glycogen content differences between the sexes were found. T1DM and non-T1DM females demonstrated higher hepatic G6Pase expression than males. Therefore, T1DM females may be less susceptible to repeated exercise-induced hypoglycemia through E2-mediated shift towards lipid oxidation during the proestrus phase.

Summary for Lay Audience

Type I diabetes mellitus (T1DM) is a chronic illness that results in disrupted blood sugar levels due to the lack of insulin a hormone which typically helps maintain blood sugar levels. A combination of insulin therapy, diet, and exercise can assist the management of T1DM. However, participating in consecutive exercise or exercise training may present a challenge for individuals with T1DM because it can lead to low blood sugar levels, or hypoglycemia onset. The typical physiological responses the body produces to maintain blood sugar levels are less effective in response to successive aerobic exercise. Interestingly, T1DM females are less affected by these blunted responses to successive bouts of exercise and normalize blood glucose during and following exercise more efficiently than T1DM males. During aerobic exercise of moderate intensity, the body uses a combination of sugars or fats for fuel; however, it has been suggested females use more fats which in turn conserves other energy sources such as sugars for more efficient post-exercise recovery. The sex hormone estrogen has been noted to explain this sex-related difference in fuel selection during exercise. Our laboratory recently demonstrated in response to repetitive bouts of aerobic exercise during elevated levels of estrogen blood glucose levels in T1DM females post-exercise normalised more quickly than T1DM males. Estrogen has shown to activate a major energy sensor AMP-kinase (AMPK), a known initiator of fat metabolism, and through this enzyme may create a shift towards using fats as fuel during exercise. Additionally, estrogen has shown to decrease gluconeogenesis through expression of key enzymes PEPCK and G6Pase. If this pathway is decreased it may indicate a shift toward fat utilization, however it is unclear how this may influence T1DM as gluconeogenesis is the primary supply of glucose (sugars) during exercise. This thesis investigates sex-related differences in activation of key metabolic regulatory enzymes involved in fat and glucose metabolism in liver and muscle tissue of male and female T1DM rats following repetitive exercise. We aimed to investigate if differences in fuel selection between sexes and diseased states were attributed to the presence of estrogen. Skeletal muscle and liver tissues were taken on the fourth day of a repetitive exercise protocol which coincided with the phase of high estrogen levels (proestrus). The primary findings of this study were that T1DM female rats indeed demonstrated higher β-oxidation activity than T1DM males suggesting increased use of fats as fuel. We did not find that the heightened activation of fat metabolism led to the conservation of glycogen stores in muscle and liver tissues. In addition, higher β-oxidation activity was not associated with greater AMPK activation in T1DM females. A greater expression of gluconeogenic enzyme G6Pase in T1DM and non-T1DM females suggests that exercise during higher estrogen did not negatively impact T1DM fuel metabolism, rather an increase in fat availability likely alleviated the challenge to balance blood glucose levels. In conclusion, in response to successive aerobic exercise during proestrus T1DM females may be at less risk for hypoglycemia development due to a shift towards fats as fuel, however this was not due to an increase in AMPK, nor did it spare muscle glycogen stores.