DIABETES AND METABOLIC POLYNEUROPATHY: FROM STUDIES TO CLINICAL PRACTICE

Diabetes Mellitus (DM) is estimated by WHO in 2000 has a prevalence of 150 million, and in 2030 is expected to increase by 366 million (Wild et al., 2004). Neuropathy is a very common complication characterized by symptoms characteristic of the loss of peripheral nerve fibers in a progressive (Boulton et al., 2004). There are several clinical manifestations including mononeuropati neuropathy or polyneuropathy. In DM patients the common people with diabetic foot is the distal sensory polyneuropathy. Even so often accompanied by disturbances of motor and autonomic nerve fibers. The occurrence of neuropathy associated with poor glycemic control, and the incidence generally increased with increasing age and longer duration of DM.

DM clinic descriptive research profile on Installation Diabetes Outpatient Clinic at Hospital Dr.Soetomo of 51% (1333 of 2609 people) DM patients have complaints incidence of peripheral neuropathy and / or parastesia. In patients in the Inpatient Ward Hospital Medicine Section Dr.Soetomo recorded 90.03% of neuropathy in diabetic patients with diabetic foot complications (Soegiarto et al, 1998).
Data epidemiology and course of the disease Diabetic neuropathy showed varying numbers, and is a common medical problem faced by patients. Several studies neuropathy prevalence in outpatients is estimated that 30% (Young et al., 1993), while the prevalence in the general population is estimated to 20 (Kumar et al., 1994; Cabesas, 1998; Abbot et al., 2002; Walters et al., 1992; Dyck et al., 1993; Boyko 1998). In old age the prevalence could reach 50% (Boulton et al., 2004; Kumar et al., 1994). In a variety of population prevalence rate ranging from 14% to 63% depending on the criteria of neuropathy dipergunskan (Walters et al., 1992). In EURODIABIDDM Complications Study (Tesfaye et al., 1996) with a total sample of 3250 patients, the mean prevalence rate of neuropathy in 16 European countries reached 16%. In the Rochester Diabetic Neuropathy Study Study (Dyck et al., 1993), reported a 60% neuropathy patients, although only 15% are symptomatic.
This paper briefly discussed the development of pain management and treatment of symptoms associated with Diabetic Neuropathy.


Pathogenesis

The actual pathophysiology is still not completely revealed, although it has a lot of intensive research that has been done. Fundamental theory is the presence of microvascular complications that would lead to neuronal hypoxia, and besides that due to the direct effects of hyperglycemia on neuronal metabolism. Most of the data that describes the basic mechanisms of diabetic polyneuropathy are from experimental studies with experimental animals such as streptozotocin (STZ) induced diabetic rat and DMT1 BB / Wor-rat. In experimental conditions it can be proven that diabetic polyneuropathy caused by various factors which interact with each other and travel clinics vary widely followed than the two types of DM (Figure 1). Pathogenesis is very complex factors and extrapolation in humans often cause very difficult to make effective therapy planning framework, so that human clinical trials did not show satisfactory results.
Metabolic disorders Nitric oxide (NO) is believed to play a role through a combination of hyperglycemia and hypoxia resulting in nerve damage and changes in blood flow. The presence of chronic hyperglycemia will lead to increased reactive Oxigen Species, which then will join with NO to form peroxynitrite compounds. All properties of NO as a vasodilator would be lost with the formation of peroxynitrite and subsequent peroxynitrite have vasoconstrictor effects that would cover the food supply to the skin and nerve fibers. This situation will have the potential C nervous fibers in the skin is damaged and reduced in number, and can also cause severe pain and foot ulcers that can end in amputation. Currently thought to peroxynitrite is the major cause of amputation role. Data in the United States there are 85,000 amputations each year, which is estimated every 10 minutes there is an amputation (Vinik, 2007; https: / / www.dif.org / d_topics / gbu.html)

Data from the Rochester Longitudinal Study (Dyck et al., 1993) supports that the duration and degree of hyperglycemia influence the degree of severe neuropathy. These studies focus on oxidative stress, advanced glycation-end products (AGE), protein kinase C and the polyol pathway that has the potential to play a role in neuropathy and (Boulton et al., 2004).
Line polyol. Glucose uptake in peripheral sraf fiber does not depend on insulin. Thus, the increase in blood glucose will cause the blood glucose concentration increases in nerve fibers. These circumstances will lead to changes in glucose to sorbitol through the polyol with an intermediary series of chemical reactions by the enzyme aldose reductase dikatalisa. Levels of fructose in the nerves is also increased. Excessive accumulation of sorbitol and fructose levels will reduce the expression of the sodium / myoinositol cotransporter, which will lead to decreased levels of myoinositol. This situation will cause a decrease in phosphoinositide, which in turn will affect the activation of Na pump activity and lower Na / K ATPase. Activation of aldose reductase will reduce kofaktornya namely NADPH, which resulted in a decline in levels of nitric oxide and glutathione, which has the function of a buffer against damage from oxidative injury. NO deficiency also resulted in lowering the capacity of vascular relaxation, which will lead to chronic ischemia (Oates, 2002).
Changes in microvascular ischemia. Changes in nerve fiber pathology in diabetic patients include thickening of capillary basement membrane, hyperplasia of endothelial cells, neurons and myocardial ischemia neurons (Cameron et al, 2001).

Advanced Glycosylation End Products (AGE). Chronic hyperglycemia will lead to the formation of intracellular family glycation agent which is known by the name of AGE, which would accumulate around and within the peripheral nerve. AGE may interfere with axonal transport, which causes nerve conduction velocity to decrease. AGE can also reduce the activation of NADPH oxidase that decreased NADPH, which this situation can contribute to the formation of hydrogen peroxide and increase the process of oxidative stress (Thornalley, 2002).
Mikrovaskulopati inflammation. The evidence shows that various forms of diabetic neuropathy in the form of asymmetric neuropathy, diabetic amiotropi, and mononeuritis multiplex was associated with the inflammatory process vaskulopati or vasculitis (Kelkar et al, 2000; Dyck and Windebank, 2002; Kelkar and Parry. 2003). Diabetic neuropathy also appears to have increased susceptibility cellular and humoral immune factors, including lymphocyte activation, immunoglobulin deposition, and activation system Complemen (Kelkar et al, 2000; Graham and Johnson, 1985; Krendel et al, 1997).
Growth Factor and Insulin deficiency. Neurotrophic factors are essential for the maintenance of nerve srtuktur and functions as well as system repair after injury. Low levels of nerve growth factor and insulin-like growth factors first shown to be associated with the degree of severity of diabetic neuropathy in animal models. Insulin has a neurotrophic effect and insulin deficiency contribute to the occurrence of neuropathy (Pittenger and Vinik, 2003).
The function of neuronal membrane ion channels. Abnormal calcium channel has an important role in the process of injury and death of various disorders. Increased activity of voltage-dependent calcium channels can be proven occur in diabetic neuropathy, and allow the tissue injury (Hall et al, 2001). Sodium channel dysfunction plays an important role in the occurrence of painful neuropathy, which generally obtained pasa DM patients (Craner et al, 2002).
Essential fatty acids. Disruption of essential fatty acids path starting from linolenic acid into the formation of prostaglandins and tromboxan, will cause fluid membrane abnormalities, changes in red blood cell membrane, namely a strong reduction in vasodilator prostaglandin E2 (Jamal, 1994; Cameron et al, 1998).