Neurovascular Dysfunction of Diabetes

The Role of Eicosanoids in the Neurovascular Dysfunction of Diabetes
CONTACT: Henri Parson, PhD PHONE: 757-446-7976

ABSTRACT OF RESEARCH INTERESTS:

Introduction:

The research work that we carry out involves the study of the neurovascular defect in skin blood flow in diabetes. Our lab has demonstrated that there is compromised cutaneous blood supply in diabetes (1) which has been corroborated by several other investigators(2), (3), (4). Our present research endeavors are directed towards the study of the role of prostanoids (arachidonic acid metabolites) in the compromised microvascular blood flow. The levels of inflammatory cytokines, IL-6 and TNF-a are raised in sera of patients with type 2 diabetes with impaired blood flow and there is evidence of oxidative stress with increased 8ketoPGF2a and increased TBARS(5). There is also an increased arachidonic acid vs. eicosapentaenoic acid ( AA/EPA) ratio in the sera of patients with diabetic neuropathy (6). We therefore hypothesize that prostanoids may have a significant impact on neurovascular function. AA from omega-6 fatty acids is the precursor for many pro-inflammatory and vasoconstrictive prostanoids, whereas EPA, an omega- 3-derived fatty acid, is the precursor of anti-inflammatory and vasodilative prostanoids. Prostanoids mediate vasodilation through a cAMP mediated pathway. Our preliminary data suggest that prostanoids are major regulators of skin blood flow and that the cyclo-oxygenase enzyme pathway for generating prostaglandins may be defective in diabetes or that the actions on generating cAMP are defective.

Aims and objectives:

The aim of this proposed study is to measure the levels of prostanoids in the interstitial fluid in microdialysate samples. Microdialysis is a technique for both drug delivery and sampling the chemistry of the individual tissues and organs of the body (7). The principle is to mimic the function of capillaries by perfusing a thin dialysis tube implanted into the tissue with a physiologic fluid. The perfusate reflects the composition of the extracellular fluid due to the diffusion of substances back and forth over the membrane. We propose to measure the levels of cAMP in the microdialysate samples, as a we believe that there might well be a defect in the pathway involving cAMP mediated smooth muscle relaxation in microvascular blood vessels.

The aim of the study is therefore to compare levels of these vasoactive molecules and their intermediates in the skin of normal healthy controls and diabetic patients. This study does not involve interaction with human research subjects but rather samples that have been collected from such subject with consent to use these for different purposes rather than proposed initially. We intend to use an ELISA technique to analyze samples of the interstitial fluid. Therefore students who wish to be involved with this project should be proficient in lab methods such as pipetting, preparation of reagents, use of plate readers and use of software like Excel® to analyze data. Students will be required to have proper training on handling of blood and body fluids, blood borne pathogens and biosafety training. It is mandated that students be HIPAA trained as this project may involve confidential patient information.

Duration:

The duration of this project is estimated to be about 8 to 10 weeks. We anticipate that the outcome of this project will be presented on EVMS Research Day and will also be worthy of publication. This project will yield results that could potentially be used to support future grant proposals and possibly facilitate us to seek funding from agencies such as NIH to carry out larger prospective studies.

Reference List

1. Vinik, A., Erbas, T., Park, T., Stansberry, K., Scanelli, J., and Pittenger, G. Dermal Neurovascular Dysfunction in Type 2 Diabetes. Diabetes Care 24(8), 1468-1475. 2001.

2. Wilson SB, Jennings PE, Belch JJF: Detection of microvascular impairment in type I diabetics by laser Doppler flowmetry. Clinical Physiology 12:195-208, 1992

3. Rendell M, Bamisedun O: Diabetic cutaneous microangiopathy. Am.J.Med. 93:611-618, 1992

4. McDaid EA, Monaghan B, Parker AI, Hayes JR, Allen JA: Peripheral autonomic impairment in patients newly diagnosed with type II diabetes. Diabetes Care 17:1422-1427, 1994

5. Pittenger, G., Erbas, T., Burcus, N., and Vinik, A. Serum Laminin and IL-6 Levels in Proapoptotic Sera Correlate with specific clinical nerve fiber. Peripheral Nerve Society Abstract. 2001.

6. Bell, S. J., Sears, B., Pittenger, G. L., and Vinik, A. I. Increased arachidonic acid to eicosapentaenoic acid ratio (AA/EPA) correlates with increased severity of neuropathy. Abstract. 2003.

7. Ungerstedt U: Microdialysis-principles and applications for studies in animals and man. Journal of Internal Medicine 230:365-373, 1991