Neurovascular Dysfunction

Neurovascular dysfunction refers to the impaired blood flow in the small blood vessels that provide nutrition to the skin and the nerves within the skin. In a series of studies funded by the American Diabetes Association, the Strelitz Diabetes Institutes has sought to determine the cause of the predisposition to foot ulceration, infection and amputations that are so prevalent amongst people with diabetes.

There are 85,000 amputations in the US each year, one every 10 minutes, and 87% of the contributory factor is diabetic nerve damage or, "neuropathy." It has been estimated that the cost of this complication is approaching $37 Billion; once one leg has been amputated, then there is a 50% chance that the other will be amputated within 5 years. After the second amputation, the 5-year mortality approximates 50%.

Indeed, neurovascular dysfunction can cause severe life-spoiling complications that profoundly affect health, quality of life and economic status. Few amputees return to gainful employment or activity, creating a huge unemployment economic burden over and above the costs of health care. An objective of "Healthy People 2010" was to reduce the rate of amputations by 50%.

Fundamental to achieving this ambitious goal requires an understanding of the underlying causes embedded in the now widespread recognition that Type 2 diabetes is one manifestation of a constellation of conditions comprising: insulin resistance,dyslipidemia; obesity, hypertension, and increased blood clotting (hypercoagulability). This constellation of conditions is referred to as either the "metabolic syndrome" or by a variety of synonyms including the "dysmetabolic syndrome."

Recently, yet another component has been added: altered blood flow in a variety of organs including skin, muscle, gut, pancreas, corpora cavernosa, etc. There is even the suggestion that disturbed blood flow may be a major contributor to apparent resistance to the action of insulin. Furthermore, there has been more direct evidence that disturbed blood flow in skin precedes the development of diabetes and is part of an "inflammatory syndrome." However, the precise mechanisms of disturbance in blood flow in the inflammatory syndrome has not been resolved.

The inflammatory syndrome can be recognized by elevations in circulating levels of "cytokines" such as C reactive protein, TNFa, interleukin 6 (amongst others) but more importantly, by changes in the vasodilatory prostaglandins, or eicosanoids, products of fatty acid metabolism, that can be influenced by dietary manipulation. Arachidonic acid (AA) is a precursor of vasoconstrictor and prothrombotic prostaglandins and eicosapentaenoic acid (EPA), a vasodilator anti thrombotic eicosanoid. Scientists at the Strelitz Diabetes Institutes hypothesized that inflammation was an important component of the disturbed blood flow in diabetes.

To test this hypothesis, they examined the relationship between the AA/EPA ratio, inflammatory cytokines in serum and quantitative measures of neurovascular function. They found that a healthy AA/EPA ratio is between 1.5 and 3. In contrast, their neuropathic subjects had significantly elevated AA/EPA ratios between 20 and 40. The serum AA/EPA ratio was significantly and positively related to blood flow and nerve function.

Researchers concluded that an elevated AA/EPA ratio reflects a proinflammatory state in diabetic neuropathy, which may exert effects either directly by affecting the peripheral neurons, or indirectly by impairing neurovascular perfusion. The condition may be secondary to increased levels of visceral (abdominal) fat in type 2 diabetics. This increased visceral fat is known to generate increased production of pro-inflammatory cytokines such as IL-6 and TNFa, which in turn will increase the production of C-reactive protein that is associated with greater incidence of cardiovascular disease.

In newly funded studies, they will determine if feeding fish oil can correct this inflammatory state. There is promise from preliminary data generated by Dr. Barry Sears (author of the "ZONE Diet") who is collaborating with the SDI, that this can influence the AA/EPA ratio and potentially become a means whereby we can reduce the inflammation in Type 2 diabetes.

Not only is inflammation important but features of the metabolic syndrome. Significant inverse correlations between systolic blood pressure, LDL-cholesterol, triglycerides, C-peptide and skin blood flow were found. Thus, there is a disorder of the whole neurovascular unit in Type 2 diabetes that co-segregates with elements of the metabolic syndrome particularly insulin resistance.

SDI researchers propose a model in which they will seek to determine whether the major defect is a consequence of these metabolic abnormalities. They are currently engaged in clinical trials of agents that enhance the sensitivity to insulin such as the glitazones and lipid lowering agents such as Rosuvastatin. Thus, they are making a comprehensive attempt to establish all the facets that are conducive to impairment of microvascular function in Type 2 diabetes which appear to be familial and precede the onset of diabetes. Only with an approach that addresses all the underlying abnormalities is it likely that inroads will be made into achieving the Healthy People 2010 objective.

SDI researchers believe that it is a combination of reduced thermal and pain perception of neuropathy combined with a reduction in the ability to increase blood flow to the skin and nerves, upon demand, that conspire in the development of neuro-ischemia culminating in foot ulceration and gangrene. A better understanding of these processes will lead to better therapeutic and preventative options for people at risk of these complications of diabetes.

Click Here to View Abstract