Type 2 diabetes continues to negatively impact the health of millions. The inability to respond to insulin to clear blood glucose (insulin resistance) is a key pathogenic driver of the disease. Skeletal muscle is the primary tissue for maintaining glucose homeostasis through glucose uptake via insulin-dependent and -independent mechanisms. Skeletal muscle is also responsive to exercise-meditated glucose transport, and as such, exercise is a cornerstone for glucose management in people with type 2 diabetes. Skeletal muscle glucose uptake requires a concert of events. First, the glucose-rich blood must be transported to the skeletal muscle. Next, the glucose must traverse the endothelium, extracellular matrix, and skeletal muscle membrane. Lastly, intracellular metabolic processes must be activated to maintain the diffusion gradient to facilitate glucose transport into the cell. This review aims to examine the physiology at each of these steps in healthy individuals, analyze the dysregulation affecting these pathways associated with type 2 diabetes, and describe the mechanisms by which exercise acts to increase glucose uptake.

Type 2 diabetes (T2D) has been rising in prevalence in the United States and worldwide over the past few decades and contributes to significant morbidity and premature mortality, primarily due to cardiovascular disease (CVD). Cardiorespiratory fitness (CRF) is a modifiable cardiovascular (CV) risk factor in the general population and in people with T2D. Young people and adults with T2D have reduced CRF when compared with their peers without T2D who are similarly active and of similar body mass index. Furthermore, the impairment in CRF conferred by T2D is greater in women than in men. Various factors may contribute to this abnormality in people with T2D, including insulin resistance and mitochondrial, vascular, and cardiac dysfunction. As proof of concept that understanding the mediators of impaired CRF in T2D can inform intervention, we previously demonstrated that an insulin sensitizer improved CRF in adults with T2D. This review focuses on how contributing factors influence CRF and why they may be compromised in T2D. Functional exercise capacity is a measure of interrelated systems biology; as such, the contribution of derangement in each of these factors to T2D-mediated impairment in CRF is complex and varied. Therefore, successful approaches to improve CRF in T2D should be multifaceted and individually designed. The current status of this research and future directions are outlined.

Background: People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. Methods: Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m²) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m²) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO₂peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. Results: Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E’ (P < 0.01), but did not change RH (P = 0.92), or VO₂peak (P = 0.33) in any participants. Conclusion: Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets. Trial registration NCT00786019. Prospectively registered May 2008

Cardiorespiratory fitness (CRF) inversely predicts cardiovascular (CV) mortality and CRF is impaired in people with type 2 diabetes (T2D). Aerobic exercise training (ET) improves CRF and is associated with decreased risk of premature death in healthy and diseased populations. Understanding the mechanisms contributing to ET adaptation may identify targets for reducing CV mortality of relevance to people with T2D. The antihyperglycemic hormone glucagon‐like peptide‐1 (GLP‐1) influences many of the same pathways as exercise and may contribute to CV adaptation to ET. We hypothesized that GLP‐1 is necessary for adaptation to ET. Twelve‐week‐old male Wistar rats were randomized (n = 8–12/group) to receive PBS or GLP‐1 receptor antagonist (exendin 9‐39 (Ex(9‐39)) via osmotic pump for 4 weeks ± ET. CRF was greater with ET (P < 0.01). Ex(9‐39) treatment blunted CRF in both sedentary and ET rats (P < 0.001). Ex(9‐39) attenuated acetylcholine‐mediated vasodilation, while this response was maintained with Ex(9‐39)+ET (P = 0.04). Aortic stiffness was greater with Ex(9‐39) (P = 0.057) and was made worse when Ex(9‐39) was combined with ET (P = 0.004). Ex vivo aortic vasoconstriction with potassium and phenylephrine was lower with Ex(9‐39) (P < 0.0001). Carotid strain improved with PBS + ET but did not change in the Ex(9‐39) rats with ET (P < 0.0001). Left ventricular mitochondrial respiration was elevated with Ex(9‐39) (P < 0.02). GLP‐1 receptor antagonism impairs CRF with and without ET, attenuates the vascular adaptation to ET, and elevates cardiac mitochondrial respiration. These data suggest that GLP‐1 is integral to the adaptive vascular response to ET.