Cardiovascular disease is the most lethal complication for the more than 10 million patients in the United States who suffer from diabetes mellitus. In experimental models of type 1 diabetes, hypoinsulinemia has profound effects on myocardial perfusion, fatty acid metabolism, and function. It is unknown if these observations are applicable to the human condition our hypothesis is that in patients with type 1 diabetes 1) hypoinsulinemia impairs myocardial perfusion, and increases the reliance on fatty acid utilization to support overall oxidative metabolism which impairs systolic function particularly when myocardial work in increased; and 2) interventions that decrease the reliance on fatty acid utilization will have salutary effects on myocardial mechanical function, particularly when myocardial work in increased. We will prove or disprove this hypothesis by addressing the following specific aims: 1. To verify whether myocardial glucose utilization can be determined more accurately from the myocardial kinetics of 1-/11C-glucose or 18F- fluorodeoxyglucose measured by PET in a well-controlled canine model: 2. To determine in humans with type 1 diabetes in myocardial perfusion reserve is impaired which leads to an impairment in myocardial mechanical function at rest and during pharmacological stress and to assess the relative contributions of hyperglycemia and hypoinsulinemia to this phenomena. 3. To determine in humans with type 1 diabetes the importance of plasma fatty acid levels on the proportional contribution of myocardial fatty acid to overall oxidative metabolism and its impact on mechanical function at rest and during pharmacological stress. 4. To determine in humans with type 1 diabetes the importance of plasma insulin levels on the proportional contribution of myocardial fatty acid to overall oxidative metabolism and its impact on mechanical function at rest and during pharmacological stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL013851-35A1
Application #
6109360
Study Section
Project Start
1998-07-01
Project End
1999-06-30
Budget Start
Budget End
Support Year
35
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Peterson, Linda R; Herrero, Pilar; Coggan, Andrew R et al. (2015) Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart. Am J Physiol Heart Circ Physiol 308:H1510-6
Zhou, Dong; Chu, Wenhua; Xu, Jinbin et al. (2014) Synthesis, [¹?F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography. Bioorg Med Chem 22:1700-7
Gropler, Robert J (2014) Trying to prevent diabetic cardiovascular autonomic neuropathy: more questions than answers. J Nucl Cardiol 21:842-4
Lyons, Matthew R; Peterson, Linda R; McGill, Janet B et al. (2013) Impact of sex on the heart's metabolic and functional responses to diabetic therapies. Am J Physiol Heart Circ Physiol 305:H1584-91
Herrero, Pilar; Laforest, Richard; Shoghi, Kooresh et al. (2012) Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. J Nucl Med 53:994-1001
Gropler, Robert J (2012) The road connecting obesity and coronary vasomotor function: straight line or U-turn? JACC Cardiovasc Imaging 5:816-8
Solingapuram Sai, Kiran Kumar; Kil, Kun-Eek; Tu, Zhude et al. (2012) Synthesis, radiolabeling and initial in vivo evaluation of [(11)C]KSM-01 for imaging PPAR-? receptors. Bioorg Med Chem Lett 22:6233-6
Cheng, Ju-Chieh Kevin; Shoghi, Kooresh; Laforest, Richard (2012) Quantitative accuracy of MAP reconstruction for dynamic PET imaging in small animals. Med Phys 39:1029-41
Peterson, Linda R; Saeed, Ibrahim M; McGill, Janet B et al. (2012) Sex and type 2 diabetes: obesity-independent effects on left ventricular substrate metabolism and relaxation in humans. Obesity (Silver Spring) 20:802-10
Zhou, Dong; Chu, Wenhua; Dence, Carmen S et al. (2012) Highly efficient click labeling using 2-[¹?F]fluoroethyl azide and synthesis of an ¹?FN-hydroxysuccinimide ester as conjugation agent. Nucl Med Biol 39:1175-81

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