title: Targeting mitochondria to restore failed adaptation to exercise in diabetes.
abstract: Our translational research group focuses on addressing the problem of exercise defects in diabetes with basic research efforts in cell and rodent models and clinical research efforts in subjects with diabetes mellitus. CREB (cAMP-response-element-binding protein) regulates cellular differentiation of neurons, β-cells, adipocytes and smooth muscle cells; it is also a potent survival factor and an upstream regulator of mitochondrial biogenesis. In diabetes and cardiovascular disease, CREB protein content is decreased in the vascular media, and its regulation in aberrant in β-cells, neurons and cardiomyocytes. Loss of CREB content and function leads to decreased vascular target tissue resilience when exposed to stressors such as metabolic, oxidative or sheer stress. This basic research programme set the stage for our central hypothesis that diabetes-mediated CREB dysfunction predisposes the diabetes disease progression and cardiovascular complications. Our clinical research programme revealed that diabetes mellitus leads to defects in functional exercise capacity. Our group has determined that the defects in exercise correlate with insulin resistance, endothelial dysfunction, decreased cardiac perfusion and diastolic dysfunction, slowed muscle perfusion kinetics, decreased muscle perfusion and slowed oxidative phosphorylation. Combined basic and clinical research has defined the relationship between exercise and vascular function with particular emphasis on how the signalling to CREB and eNOS [endothelial NOS (nitric oxide synthase)] regulates tissue perfusion, mitochondrial dynamics, vascular function and exercise capacity. The present review summarizes our current working hypothesis that restoration of eNOS/NOS dysfunction will restore cellular homoeostasis and permit an optimal tissue response to an exercise training intervention.
authors.affiliation: *Anschutz Medical Campus, University of Colorado, 13001 E 17th Place, Aurora, CO 80045, U.S.A.
authors.forename: Kate
authors.initials: K
authors.lastname: Geary
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Knaub
authors.forename: Irene E
authors.initials: IE
authors.lastname: Schauer
authors.forename: Amy C
authors.initials: AC
authors.lastname: Keller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Watson
authors.affiliation: *Anschutz Medical Campus, University of Colorado, 13001 E 17th Place, Aurora, CO 80045, U.S.A.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Miller
authors.affiliation: *Anschutz Medical Campus, University of Colorado, 13001 E 17th Place, Aurora, CO 80045, U.S.A.
authors.forename: Chrystelle V
authors.initials: CV
authors.lastname: Garat
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nadeau
authors.forename: Melanie
authors.initials: M
authors.lastname: Cree-Green
authors.forename: Subbiah
authors.initials: S
authors.lastname: Pugazhenthi
authors.affiliation: *Anschutz Medical Campus, University of Colorado, 13001 E 17th Place, Aurora, CO 80045, U.S.A.
authors.forename: Judith G
authors.initials: JG
authors.lastname: Regensteiner
authors.affiliation: *Anschutz Medical Campus, University of Colorado, 13001 E 17th Place, Aurora, CO 80045, U.S.A.
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D002318:Cardiovascular Diseases / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D015444:Exercise / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D052250:Nitric Oxide Synthase Type III