Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat.

Diabetes is a leading cause of death worldwide, imparting a 3- to 5-fold excess cardiovascular disease (CVD) mortality, despite optimal control of traditional CVD risk factors.1 Epidemiological and cohort studies demonstrate that lower CVD and all-cause mortality are predicted by increased physical fitness or increased quantity of physical activity.2–4 We and others have demonstrated that adults and children with type 1 and type 2 diabetes (T1DM and T2DM) have impairments in functional exercise capacity, or fitness, at maximal and submaximal workloads.5–8 Understanding the mechanism of this functional limitation has high clinical relevance. The importance of mitochondrial function for vascular contractile function was established by Taggart and Wray and Sward et al.9,10 More recent studies have confirmed the importance of mitochondrial function for maintenance of blood pressure in a model of sepsis-mediated hypotension11 and a genetic model of Huntington's disease with mitochondrial dysfunction.12 Mitochondrial calcium handling in the vascular smooth muscle cell is a postulated mechanism for the mitochondrial regulation of vascular contractile function (reviewed in Ref. 13). In diabetes, studies demonstrate changes in vascular mitochondrial structure and function including fragmentation of mitochondria in cardiac endothelial cells, increased mitochondrial reactive oxygen species production in the vasculature, and impaired contractile function.14–16 The impact of exercise on mitochondrial regulation in the vasculature has only recently been examined in disease states.17,18 We and others have also shown abnormal mitochondrial responses to exercise in the vasculature of animal models of diabetes and hypertension and after manipulation of nitric oxide synthase (NOS).19,20 Mitochondrial protein expression failed to increase with exercise in spontaneous hypertension and heart failure (SHHF) animals as compared with a significant increase in complexes I, II, and III in exercised control animals.19 We recently reported that endothelial NOS (eNOS)/NOS enzyme activity is essential for the maintenance of basal and adaptive mitochondrial regulation in the vasculature.21 The mechanisms contributing to impaired vascular mitochondrial exercise response in T2DM have not been fully characterized in the vasculature but may in part be explained by dysregulation of eNOS in the diabetic vasculature.22 NOS and nitric oxide (NO) are established regulators of mitochondrial biogenesis, and they are a critical component of the vascular response to a bout of exercise.23–25 eNOS null mice have reductions in mitochondrial biogenesis in the muscle and the vasculature,21,24,26 and deletion of eNOS in brown adipocytes interferes with cyclic guanosine monophosphate induction of PGC-1α and mitochondrial biogenesis.24 An agent capable of stimulating eNOS in the diabetic environment could be used to test the importance of eNOS for vascular mitochondrial adaptation in diabetes. Food and Drug Administration–approved drugs for the management of diabetes that could be repurposed to target eNOS include agents that regulate the gut hormone, glucagon-like peptide 1 (GLP-1). GLP-1 is an insulin secretagogue, and for the purpose of this investigation, GLP-1 also regulates mitochondrial function by stimulating cyclic adenosine monophosphate (cAMP), eNOS, and cAMP response element-binding protein and decreasing mitochondrial reactive oxygen species.27–30 GLP-1 receptors are highly expressed in vascular tissues, and GLP-1 improves muscle blood flow through a NOS-/NO-dependent mechanism.31 Endogenously, GLP-1 has a brief half-life and is cleaved by dipeptidyl peptidase 4 (DPP-4), an enzyme both freely circulating and located on endothelial cells. Inhibitors of DPP-4 increase circulation of endogenous GLP-1. In this study, we hypothesized that blunted mitochondrial adaptation to exercise in the diabetic vasculature would be restored by saxagliptin, a Food and Drug Administration–approved DPP-4 inhibitor that increases circulating GLP-1, in turn activating eNOS. After initial baseline mitochondrial comparisons between a control (Wistar) and nonobese insulin-resistant [Goto-Kakizaki (GK)] rat model exposed to a bout of exercise, we administered saxagliptin in combination with an acute 8-day exercise intervention in the GK rats and measured the effects of this intervention on mitochondrial profiles. In a second 3-week exercise training intervention, we evaluated the impact of saxagliptin on running time in these animals. Our primary aim was to characterize responses to a short-term exercise exposure (low intensity, nonvoluntary treadmill exercise), concurrent with saxagliptin administration, with a focus on mitochondria adaptation in the aorta.