The goal of our studies is to determine whether treatment of streptozotocin-induced diabetic rats, an animal model for type 1 diabetes, Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes, or Zucker obese rats, an animal model for pre-diabetes/metabolic syndrome with Enalapril, an angiotensin converting enzyme (ACE) inhibitor, AVE7688, a vasopeptidase inhibitor, or Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, prevents/reverses the development/progression of diabetic neuropathy (DN). Treatment of diabetes patients with ACE inhibitors is a common form of treatment for renal and cardiovascular disease. However, there is a lack of knowledge about the potential benefits of ACE inhibitor treatment for DN. ACE inhibitors have been shown to have antioxidant and neuroprotective properties;whereas vasopeptidase inhibitors block both ACE and neutral endopeptidase (NEP) activity. We also have evidence that Sitagliptin, a drug used to increase insulin sensitivity and treat type 2 diabetes, may also inhibit NEP. NEP degrades natriuretic peptides as well as neuropeptides such as calcitonin gene-related peptide (CGRP) and bradykinin. Our working hypothesis is that vascular dysfunction contributes significantly to DN and that successful therapies for DN must protect the vasculature. We have shown that diabetes and obesity alters the activity of vasodilators in epineurial arterioles including nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and CGRP. This likely causes an impairment of blood flow to the nerve and contributes to DN. Based on recent studies we hypothesize the C-type natriuretic peptide (CNP) functions as EDHF in epineurial arterioles. CNP causes vasodilation of epineurial arterioles and CNP activity/expression is decreased by diabetes. Therefore, we propose that treating rat models of type 1 and type 2 diabetes as well as obesity with Enalapril, AVE7688 or Sitagliptin will attenuate the development/progression of DN by: 1) preventing oxidative stress in vascular tissue thereby protecting the activity of NO, 2) preventing the loss of CNP and protecting its bioactivity, and 3) protecting sensory nerves and the availability and function of CGRP. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of ACE and/or vasopeptidase inhibitor treatment in human DN.

Public Health Relevance

After many years of research that is not an effective treatment for diabetic neuropathy. The goal of this study is to test the efficacy in pre-clinical studies of three classes of drugs on diabetic vascular and neural disease. Our working hypothesis is that vascular dysfunction contributes significantly to diabetic neuropathy and that successful therapies must protect the vasculature. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of angiotensin converting enzyme and/or vasopeptidase inhibitor treatment in human diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073990-05
Application #
8271438
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jones, Teresa L Z
Project Start
2008-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$262,421
Indirect Cost
$54,150
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Stavniichuk, Roman; Shevalye, Hanna; Lupachyk, Sergey et al. (2014) Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy. Diabetes Metab Res Rev 30:669-78
Davidson, Eric P; Coppey, Lawrence J; Dake, Brian et al. (2011) Effect of Treatment of Sprague Dawley Rats with AVE7688, Enalapril, or Candoxatril on Diet-Induced Obesity. J Obes 2011:
Coppey, Lawrence; Davidson, Eric; Lu, Bao et al. (2011) Vasopeptidase inhibitor ilepatril (AVE7688) prevents obesity- and diabetes-induced neuropathy in C57Bl/6J mice. Neuropharmacology 60:259-66
Davidson, Eric P; Coppey, Lawrence J; Holmes, Amey et al. (2011) Effect of treatment of high fat fed/low dose streptozotocin-diabetic rats with Ilepatril on vascular and neural complications. Eur J Pharmacol 668:497-506
Oltman, Christine L; Davidson, Eric P; Coppey, Lawrence J et al. (2011) Role of the effect of inhibition of neutral endopeptidase on vascular and neural complications in streptozotocin-induced diabetic rats. Eur J Pharmacol 650:556-62
Davidson, Eric P; Coppey, Lawrence J; Calcutt, Nigel A et al. (2010) Diet-induced obesity in Sprague-Dawley rats causes microvascular and neural dysfunction. Diabetes Metab Res Rev 26:306-18
Sivitz, William I; Yorek, Mark A (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 12:537-77
Davidson, Eric P; Coppey, Lawrence J; Kleinschmidt, Travis L et al. (2009) Vascular and neural dysfunctions in obese Zucker rats: effect of AVE7688. Exp Diabetes Res 2009:912327
Davidson, Eric; Coppey, Lawrence; Lu, Bao et al. (2009) The roles of streptozotocin neurotoxicity and neutral endopeptidase in murine experimental diabetic neuropathy. Exp Diabetes Res 2009:431980
Oltman, C L; Davidson, E P; Coppey, L J et al. (2009) Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes Metab 11:223-33

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