Impact of obesity on microvascular insulin action and cardiorespiratory fitness in Type 1 Diabetes - Project Summary/Abstract The overall relative risk of cardiovascular disease (CVD) remains 3- to 10-fold higher in individuals with type 1 diabetes (T1D), despite intensive glycemic control and traditional CVD risk management. Epidemiologic studies indicate that more than 60% of individuals with T1D are either overweight or obese, which confer significant additional CVD risk. A better understanding of CVD pathophysiology and the development of additional effective interventions are urgently needed, particularly in the context of the global obesity epidemic, to reduce CVD-related morbidity and mortality in T1D. In the proposed studies we will test an overarching hypothesis that in T1D, endothelial oxidative stress and microvascular insulin resistance lead to reduced skeletal and cardiac muscle microvascular perfusion and cardiorespiratory fitness (CRF), with obesity exacerbating while exercise training mitigating these abnormalities. Specifically, we will test in individuals with T1D whether skeletal and cardiac muscle microvascular insulin resistance predicts CRF reduction and whether obesity worsens both microvascular insulin resistance and CRF decline (Aims 1 and Aim 2). Additionally, we will investigate whether 14 weeks of high-intensity intermittent exercise training attenuates microvascular insulin resistance and improves CRF in humans with either T1D or obesity, with more pronounced improvements in those with both conditions (Aim 3). We will analyze the interrelationships among microvascular insulin responses, microvascular endothelial cell oxidative stress, cardiac function, muscle function, and vascular function before and after exercise training. Results from the proposed studies should define 1) the critical role of microvascular insulin resistance in CRF reduction in T1D, 2) the impact of obesity on microvascular insulin resistance and CRF in T1D, and 3) the potential underlying mechanisms. These will open new avenues for future mechanistic and therapeutic studies in T1D and obesity research.
