Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure, a heightened risk of postoperative respiratory complications, and a greater need for prolonged mechanical ventilation. However, it is not known how diabetes produces these problems. One potential explanation is that uncontrolled diabetes alters respiratory muscle function, reducing the capacity of the respiratory pump. The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlled diabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in the following groups of studies.
Aim I studies will characterize the effects of uncontrolled diabetes on diaphragm specific force generation, changes in muscle mass, and diaphragm endurance, testing the hypothesis diabetes induced alterations in diaphragm performance are related to increases in free radical generation.
Aim II studies will interrogate a number of free radical generating pathways in muscle (including the cell surface NADPH oxidase) and determine which pathways are responsible for increased free radical generation in the diaphragm in diabetes.
Aim III studies will determine if iNOS is upregulated in the diaphragm in diabetes, and will test the hypothesis that iNOS acts as an upstream modulator of free radical generation.
Aim I V studies will examine several downstream targets of diabetes induced free radical generation in the diaphragm that are responsible for reductions in diaphragm performance, including contractile protein alterations, calpain mediated reductions in muscle mass, and alterations in mitochondrial ATP generating capacity. A variety of physiologic, biochemical, proteomic, fluorogenic, pharmacologic and genetic techniques will be used to test these hypotheses. Our preliminary data represent the first demonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease process, and suggest that iNOS regulates NADPH oxidase activity and free radical generation in the diaphragm in diabetes. These new data should provide important information regarding the pathogenesis of diabetes induced diaphragm dysfunction, and uncover pathways which could provide novel therapeutic targets for treatment of respiratory muscle weakness in this condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080609-04
Application #
7582346
Study Section
Special Emphasis Panel (ZRG1-MOSS-E (02))
Program Officer
Croxton, Thomas
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$355,629
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Callahan, Leigh A; Supinski, Gerald S (2014) Hyperglycemia-induced diaphragm weakness is mediated by oxidative stress. Crit Care 18:R88
Supinski, Gerald S; Callahan, Leigh Ann (2010) Calpain activation contributes to endotoxin-induced diaphragmatic dysfunction. Am J Respir Cell Mol Biol 42:80-7
Baker-Herman, T L; Bavis, R W; Dahlberg, J M et al. (2010) Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol 170:260-7
Callahan, Leigh Ann; Supinski, Gerald S (2010) Diaphragm weakness and mechanical ventilation--what's the critical issue? Crit Care 14:187
Supinski, G S; Vanags, J; Callahan, L A (2009) Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol 296:L994-L1001
Supinski, G S; Murphy, M P; Callahan, L A (2009) MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 297:R1095-102
Callahan, Leigh Ann; Supinski, Gerald S (2009) Sepsis-induced myopathy. Crit Care Med 37:S354-67
Supinski, Gerald S; Ji, Xinying; Callahan, Leigh Ann (2009) The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation. Am J Physiol Regul Integr Comp Physiol 297:R825-34
Callahan, Leigh Ann; Supinski, Gerald S (2009) Hyperglycemia and acquired weakness in critically ill patients: potential mechanisms. Crit Care 13:125
Baker-Herman, Tracy L; Mitchell, Gordon S (2008) Determinants of frequency long-term facilitation following acute intermittent hypoxia in vagotomized rats. Respir Physiol Neurobiol 162:8-17

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