title: Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat.
abstract: Cardiovascular disease risk and all-cause mortality are largely predicted by physical fitness. Exercise stimulates vascular mitochondrial biogenesis through endothelial nitric oxide synthase (eNOS), sirtuins, and PPARγ coactivator 1α (PGC-1α), a response absent in diabetes and hypertension. We hypothesized that an agent regulating eNOS in the context of diabetes could reconstitute exercise-mediated signaling to mitochondrial biogenesis. Glucagon-like peptide 1 (GLP-1) stimulates eNOS and blood flow; we used saxagliptin, an inhibitor of GLP-1 degradation, to test whether vascular mitochondrial adaptation to exercise in diabetes could be restored. Goto-Kakizaki (GK) rats, a nonobese, type 2 diabetes model, and Wistar controls were exposed to an 8-day exercise intervention with or without saxagliptin (10 mg·kg·d). We evaluated the impact of exercise and saxagliptin on mitochondrial proteins and signaling pathways in aorta. Mitochondrial protein expression increased with exercise in the Wistar aorta and decreased or remained unchanged in the GK animals. GK rats treated with saxagliptin plus exercise showed increased expression of mitochondrial complexes, cytochrome c, eNOS, nNOS, PGC-1α, and UCP3 proteins. Notably, a 3-week saxagliptin plus exercise intervention significantly increased running time in the GK rats. These data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a diabetic rodent model and may augment the impact of exercise on the vasculature.
authors.affiliation: *Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; †Department of Medicine, Denver VA Medical Center, Denver, CO; and ‡Division of Pulmonary Sciences and Critical Care Medicine, Cardiovascular Pulmonary Research, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Keller
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Knaub
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Miller
authors.forename: Nicholas
authors.initials: N
authors.lastname: Birdsey
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D004151:Dipeptides / Q000494:pharmacology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D001678:Organelle Biogenesis; D010805:Physical Conditioning, Animal / Q000502:physiology; D051381:Rats; D016896:Treatment Outcome
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D024101:Mitochondrial Proteins; D052216:Glucagon-Like Peptide 1; C502994:saxagliptin; D052250:Nitric Oxide Synthase Type III; D000218:Adamantane