Research and Development - Iowa City VA Health Care System
Research in Progress
Principal Investigator:
- Mark A. Yorek, Ph.D.
Project Title:
Pathology of Type 2 Diabetes
Summary:
The goal of this project is to determine the cause of vascular and neural dysfunction in Type 2 diabetes. Obesity and many years of escalating insulin resistance, chronic hyperinsulinaemia and an ultimate failure of pancreatic islet b -cells to cope with the progressive demand for insulin characterize the pathology of Type 2 diabetes. The insidious nature of this process usually means that Type 2 diabetes often remains undiagnosed until the patient presents with chronic complications. The natural history of diabetic complications in Type 2 diabetes is less well known than in Type 1 diabetes in part because of the difficulty in identifying the precise onset of the disease. To address this issue we are examining the sequential development of vascular and neural dysfunction and potential treatment of vascular and neural complications in the male Zucker diabetic obese rat (ZDF/Drt-fa), an animal model for Type 2 diabetes. We hypothesize that vascular dysfunction and reduction in endoneurial blood flow precedes slowing of motor nerve conduction velocity, thereby suggesting that vascular related defects are primarily responsible for the development of diabetic neuropathy in Type 2 diabetes. In addition, we propose that hyperglycemia combined with hyperlipidemia via formation of advanced glycation end products and/or an increase in oxidative stress contribute to the development and progression of vascular and neural dysfunction in ZDF-obese diabetic rats. To test our hypotheses we are addressing the following two objectives: 1) Determine the sequential development and progression of vascular and neural dysfunction in ZDF-obese diabetic rats, and 2) Determine whether treatment of ZDF-obese diabetic rats with rosiglitazone, aminoguanidine, pyridoxamine, a -lipoic acid or M40403 improves vascular and neural dysfunction. Our previous studies have demonstrated that vascular and neural dysfunction is apparent in ZDF-obese diabetic rats following 4 weeks of hyperglycemia. We have not determined whether slowing of motor nerve conduction velocity (neural dysfunction) in Type 2 diabetes is preceded by vascular dysfunction as in streptozotocin-induced diabetic rats, an animal model for Type 1 diabetes. If vascular dysfunction precedes neural deficits in Type 2 diabetes it would suggest that abnormal vascular activity is responsible for early diabetic neuropathy. Such a result would suggest that investigators should focus on correcting vascular dysfunction as a means of treating diabetic neuropathy. In this regard, our studies we will determine the efficacy of treating ZDF-obese diabetic rats with rosiglitazone, aminoguanidine, pyridoxamine, a -lipoic acid or M40403, on vascular and neural function. Combined, these studies will provide us with a better understanding and insight for potential treatment of diabetic vascular and neural disease in Type 2 diabetes.
MeSH Terms: diabetes mellitus Type 2, obesity, oxidative stress, peripheral nerve, antioxidants
