Department of Internal Medicine

Endocrine-Metabolism Faculty

Mark Yorek photo

Medical School:
University of North Dakota

Postdoctoral Studies:
The University of Iowa

Mark A. Yorek, Ph.D.
Professor
Associate Chief of Staff for Research and Education, VAMC

The long range goal of my laboratory has been to determine the etiology of diabetic vascular and neural disease. The pathophysiology of diabetic neuropathy (DN) is not well understood. In a quality of life assessment, patients with DN had significantly higher scores indicating an impaired quality of life compared to diabetic patients without DN or non-diabetic controls. This assessment emphasizes the need for further research for the prevention/treatment of DN. In diabetic animal models the pathophysiology of DN can be divided into two phases. The first phase is characterized by metabolic derangements of the nerve and vascular tissue. The metabolic derangements are readily reversible and can also be prevented by a variety of interventions, which implies that the etiology of DN is multifactorial. The second phase of DN is characterized by morphological derangement of peripheral nerves thought to be caused by ischemia and/or loss of neurotrophic factors. We have little understanding of the pathogenesis responsible for the second phase of DN.

To date clinical interventions to prevent/treat DN have been disappointing. However, many of the treatments were designed to prevent the pathogenesis that occurs during the first phase of DN and failed when applied to patients with clinical symptoms. It is likely that these patients had already experienced damage to nerve and vascular tissue, consistent with the second phase of DN. In recent studies, we have determined that epineurial arterioles of the sciatic nerve are innervated by sensory nerves containing the neuropeptide calcitonin-gene related peptide (CGRP). We have also demonstrated that the innervation of epineurial arterioles by sensory nerves containing CGRP and CGRP-mediated vascular relaxation are decreased in diabetes. Neuropeptides such as CGRP are thought to regulate vascular tone and blood flow to peripheral nerves. Given this information one project in the laboratory is to test the hypothesis that compromising the function of CGRP contributes to nerve ischemia and the morphological/progressive changes that occur during the second phase of DN. The objectives of this study are: 1) Determine whether loss of CGRP-sensory nerve innervation causes diabetes-like changes in vascular and neural function, 2) Determine the sequential effect of diabetes on CGRP sensory nerve innervation and bioactivity in epineurial arterioles in relation to morphologic changes in the peripheral nerves, and 3) Determine whether the decrease in CGRP-sensory nerve innervation and CGRP bioactivity caused by diabetes can be prevented and/or reversed.

Another project in the laboratory is to examine the effect of Angiotensin converting enzyme (ACE) inhibition and/or blocking of the angiotensin receptor with angiotensin II receptor antagonists (ARBs) on DN. These drugs have become a common form of treatment for renal and cardiovascular disease in diabetes patients. However, there is little information available about the potential benefits of these drugs on DN. These drugs have been shown to have antioxidant and neuroprotective properties and, therefore, may also provide beneficial effects towards preventing and/or halting the progression of DN. The hypothesis being examined is that treating streptozotocin-induced diabetic rats, a model for type 1 diabetes, with an ACE inhibitor and/or ARB will prevent the development/progression of DN. These studies are being done using both prevention and intervention protocols. An effective treatment for DN is currently unavailable. It is the goal of these studies to provide a rationale for investigating the potential of ACE inhibitors and/or ARBs for the treatment of human DN.

Another project in the laboratory is to examine the etiology 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 will precede slowing of motor nerve conduction velocity, thereby suggesting that vascular related defects are primarily responsible for the development of DN 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 DN. Such a result would suggest that investigators should focus on correcting vascular dysfunction as a means of treating DN. 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.

Honors, Awards, and Organizations

Recent Publications

  1. Oltman, C.L, Davidson, E.P., Coppey, L.J., Kleinschmidt, T.L., Lund, D.D., and Yorek, M.A. Attenuation of Vascular/Neural Dysfunction in Zucker Rats Treated with Enalapril or Rosuvastatin. Obesity, in press.
  2. Obrosova, I.G., Drel, V.R., Oltman, C.L., Mashtalir, N., Tibrewala, J., Groves, J.T. and Yorek, M.A. Role of Nitrosative Stress in early Neuropathy and Vascular Dysfunction in Streptozotocin-Diabetic Rats. Am. J. Physiol., 293:E1645-E1655, 2007.
  3. Oltman, C.L, Kleinschmidt, T.L., Davidson, E.P., Coppey, L.J., Lund, D.D. and Yorek, M.A. Treatment of Cardiovascular Dysfunction Associated with the Metabolic Syndrome and Type 2 Diabetes. Vascular Pharmacology, in press.

PubMed publications list

Links of Interest

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