Obesity, insulin resistance and associated metabolic abnormalities leading to increased risk of development of type 2 diabetes is best known by the term metabolic syndrome. Obesity and type 2 diabetes have reached epidemic levels in the United States and patients served by the Veterans Affairs Health Care System. These conditions are responsible for increased morbidity, reduced quality of life, and increased health care costs. Currently, there is no effective treatmen for the complications associated with obesity and type 2 diabetes. Even though studies have led to new therapies to improve insulin sensitivity this approach only delays the onset of complications. Since complications are ultimately responsible for the increased morbidity and poor quality of life in patients with type 2 diabetes there is an urgent need for development of therapies that can prevent or reduce their impact. Our proposed studies will provide preclinical evidence of efficacy and insight to mechanisms of Ilepatril, a vasopeptidase inhibitor that simultaneously blocks angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activities, treatment for insulin resistance and vascular complications associated with obesity and type 2 diabetes. In the last 5 years we made significant progress in determining the role of ACE and NEP in the development of vascular and neural complications associated with obesity and diabetes. We have also characterized the vascular and neural complications in the high fat diet/low dose streptozotocin treated rat, an interesting model for type 2 diabetes. In the present proposal we will extend these studies and examine the ability of Ilepatril to act as a treatment fo obesity and/or reverse insulin resistance and vascular complications caused by obesity and type 2 diabetes in vivo. The central hypothesis to be explored is that obesity and type 2 diabetes up-regulate ACE and NEP expression/activity in tissues sensitive to insulin resistance and prone for complications related to obesity and diabetes leading to impaired glucose tolerance and vascular dysfunction. We propose that by targeting preservation of vascular function Ilepatril treatment of diet induced obese rats will: 1) reduce oxidative stress in vascular tissue and protect vasoactive peptides from degradation leading to improved vascular function, 2) improve glucose utilization in the whole animal, and 3) improve blood flow in skeletal muscle thereby improving insulin action and glucose uptake. We believe that treatment of obese rats after the onset of hyperglycemia (type 2 diabetes) will be less effective and may require a more comprehensive and aggressive treatment strategy to reduce the impact of complications. Specific Objectives: Objective 1: Determine whether treatment of diet induced obese rats with Ilepatril improves insulin sensitivity and vascular dysfunction in feed arteries of gastrocnemius and soleus muscle by reducing oxidative stress and protecting vasoactive peptides to a greater extent than monotherapies that block ACE or NEP alone. Objective 2: Determine whether type 2 diabetes reduces the benefits of Ilepatril treatment due to higher levels of oxidative stress and/o degradation of vasoactive peptides.

Public Health Relevance

Obesity and metabolic syndrome are approaching epidemic levels and along with type 2 diabetes are creating a large burden on the financial capabilities of the VA health care system. Moreover, treatments for obesity and metabolic syndrome have been disappointing. Current therapies have not prevented the progression of disease, which often results with patients developing type 2 diabetes and severe complications leading to amputations and increased mortality. These poor outcomes impact the quality of life of these patients and also affect their families. From our studies we will identify mechanism(s) responsible for complications associated with obesity and type 2 diabetes. We also intend to provide a rationale for moving forward with clinical studies using Ilepatril as a treatment for obesity and type 2 diabetes. Developing an effective treatment will improve the quality of life of these patients while reducing health care costs to the VA health care system.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001680-04
Application #
8795694
Study Section
Endocriniology A (ENDA)
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita et al. (2016) Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep 6:26933
Messingham, Kelly A N; Aust, Samantha; Helfenberger, Joseph et al. (2016) Autoantibodies to Collagen XVII Are Present in Parkinson's Disease and Localize to Tyrosine-Hydroxylase Positive Neurons. J Invest Dermatol 136:721-723
Messingham, Kelly N; Wang, Jeffrey W; Holahan, Heather M et al. (2016) Eosinophil localization to the basement membrane zone is autoantibody- and complement-dependent in a human cryosection model of bullous pemphigoid. Exp Dermatol 25:50-5
Holmes, Amey; Coppey, Lawrence J; Davidson, Eric P et al. (2015) Rat Models of Diet-Induced Obesity and High Fat/Low Dose Streptozotocin Type 2 Diabetes: Effect of Reversal of High Fat Diet Compared to Treatment with Enalapril or Menhaden Oil on Glucose Utilization and Neuropathic Endpoints. J Diabetes Res 2015:307285
Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna et al. (2015) Effect of diet-induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice. J Peripher Nerv Syst 20:24-31
Dominguez 2nd, James M; Yorek, Mark A; Grant, Maria B (2015) Combination therapies prevent the neuropathic, proinflammatory characteristics of bone marrow in streptozotocin-induced diabetic rats. Diabetes 64:643-53
Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna et al. (2014) Effect of glycemic control on corneal nerves and peripheral neuropathy in streptozotocin-induced diabetic C57Bl/6J mice. J Peripher Nerv Syst 19:205-17
Davidson, Eric P; Coppey, Lawrence J; Holmes, Amey et al. (2014) Characterization of diabetic neuropathy in the Zucker diabetic Sprague-Dawley rat: a new animal model for type 2 diabetes. J Diabetes Res 2014:714273
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
Lamping, K G; Nuno, D W; Coppey, L J et al. (2013) Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction. Diabetes Obes Metab 15:144-52

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