What Emerging Research Reveals About Hyperglycemia And Vascular Imbalances

By Javier La Fontaine, DPM

      Research is an essential part of medicine when it comes to the ongoing improvement of patient care. Although podiatry is still very early into its development of consistent research contributions, research in diabetes has an impact in what we do daily. Research on topics such as diabetic neuropathy, vascular disease, wound care, the management of diabetes and offloading should be of interest.       Diabetic neuropathy has been identified as an important risk factor for foot problems in the diabetic patient. The cost of diabetic neuropathy and its consequences to the U.S. healthcare system amount to approximately $13.7 billion dollars annually. About 50 to 60 percent of patients with diabetes will develop neuropathy and 15 percent of patients with diabetes will develop an ulcer in their lifetimes.       Patients with diabetic neuropathy do not always have pain but for those who do, the Food and Drug Administration (FDA) has approved duloxetine (Cymbalta, Eli Lilly) and pregabalin (Lyrica, Pfizer) for the management of painful diabetic neuropathy. These are the only two drugs with an indication to treat this entity.       However, little is known about the epidemiology and natural history of diabetic neuropathy. Many researchers have spent their entire careers investigating the etiology of neuropathy, and have concluded that hyperglycemia is the most important factor leading to the development and severity of neuropathy.       That is not to say that other etiologies may play a role. The Rochester Neuropathy Study demonstrated that the cause of the neuropathy in 10 percent of the diabetic patients was due to other etiologies than diabetes.1 Deficiency of growth factors, advanced glycosylated end product accumulation, immune mechanisms, glucose auto-oxidation, and PKC-inhibition activation are among other etiologies advocated in the medical literature.       However, it is clear that hyperglycemia plays a central role in creating the vascular imbalances that are so unique to the diabetic process. Glucose does not directly cause adverse changes to the vascular system. These changes are accomplished indirectly through the alteration of multiple metabolic pathways. This sequence of events leads to early changes in functional flow and pressure as well as late structural changes that ultimately compromise the ability of the microvasculature, namely the endothelium, to carry out its functions in an ever changing vascular environment. These disturbances eventually may involve capillary closure, extinction, thrombosis or non-perfusion.       Peripheral vascular disease is present in approximately 15 percent of patients who have a 10-year history of diabetes and in 45 percent of patients who have a greater than 20-year history of diabetes. Vascular insufficiency accounts for 10 to 15 percent of diabetic ulcers.2 A lack of blood flow inhibits the ability to fight infection by decreasing oxygen, nutrient and antibiotic delivery to the site of the infection/ulcer.

Understanding The Impact Of Microvascular And Macrovascular Diseases In Patients With Diabetes

      Macrovascular diseases such as atherosclerosis are also common among those with diabetes. Patients with diabetes may present with a spectrum of lower extremity vascular disease in both the macrovasculature and microvasculature. This spectrum correlates with the duration and degree of diabetes, the presence of comorbid risk factors, such as dyslipidemia, obesity, hypertension and smoking, family history and anatomic location (i.e. proximal versus distal).       Over the years, techniques of lower extremity revascularization have been evolving. Distal reconstruction with synthetic materials and reverse saphenous vein has been somewhat successful. New research has shown that “excision” of plaques via the SilverHawk (FoxHollow) system in the common femoral artery, superficial femoral artery and femoral-popliteal artery is successful in treating the ischemic limb.3 This will help to preserve the saphenous vein for future intervention in the lower extremity and heart. Current research is evaluating the use of plaque excision in medium-sized vessels such as the peroneal, posterior tibial and anterior tibial arteries.       Microvascular dysfunction is a systemic disease that can lead to progressive and destructive retinopathy, nephropathy, neuropathy, impotence and gastroparesis, all of which can serve as clinical markers of disease severity. This same microvascular dysfunction can occur in the nutritional capillaries of the foot of the diabetic patient, and can affect clinical outcomes even in the absence of overt macrovascular disease. The staging of diabetic microvascular disease in other organs may prove helpful in predicting and explaining prolonged morbidity in patients with diabetic foot disease.

What Research Reveals About Wound Healing

      Many recent advances have occurred in the realm of chronic wound healing but more research is still necessary. Part of the dilemma with research into this area is the fact that the development of a chronic wound is multifactorial. For instance, research into certain growth factors and cytokines, such as insulin growth factor-1, has concluded that their deficiency may play a role in chronic wound healing.4 Other promising research in the future may give us more insights into the potential effect of bacterial load, excess metalloproteinases, nutritional deficiencies and low homocysteine, and how these factors may impact wound healing.       One of the major advances in wound healing is the role of nitric oxide, which is the most potent and abundant vasodilator. Also be aware the endothelium has the ability to produce vasoactive substances that help control the tone of the microvasculature. This process is called autoregulation. Nitrous oxide also has a role in the modulation of the wound healing process along with another vasodilator, prostacyclin, which is a potent antithrombotic agent and decreases white blood cell adhesion to the endothelium. Research has found a low level of nitric oxide in patients with diabetes.5 Therefore, autoregulation is abnormal and poor oxygenated blood diffusion occurs.

How Research Influences Diabetes Management

      The management of diabetes has evolved immensely over the years. Being able to identify patients at high risk of developing diabetes is a major advance. Hyperlipidemia, a pre-hypertensive state, obesity and family history are among some of the risk factors for diabetes that researchers have documented in the literature. New medications such as pioglitazone decrease the blood glucose produced in the liver and increase sensitivity to patient’s insulin to control hyperglycemia.       Researchers have also shown that a combination of medications with different mechanisms of action (such as rosiglitazone and metformin) are effective in patients.6 Exubera® (insulin human [rDNA origin], Pfizer) inhalation powder is the first diabetes treatment that can be inhaled. Exubera helps control high blood sugar in adults with type 1 diabetes and in people with type 2 diabetes as well.

In Conclusion

      Research continues to evolve in regard to diabetes and lower extremity complications from the disease. As podiatrists, we are in the driving seat to investigate and collaborate with those in the research arena because we treat all varieties of diabetic foot pathology. Podiatry schools are essential in this teaching and raising awareness about the importance of true research for the benefit of patient care, the healthcare economy and our profession.       Dr. La Fontaine is a Fellow of the American College of Foot and Ankle Surgeons. He is an Assistant Professor and Interim Chief of the Podiatry Division at the University of Texas Health Science Center at San Antonio. He is also the Director of the Podiatry Residency Training Program in the Department of Orthopedics in the aforementioned institution.       Dr. Steinberg (pictured) is an Associate Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C.



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