Remarkable Improvement in Diabetic Neuropathy with Systemic Medicine

Remarkable Improvement in Diabetic Neuropathy with Systemic Medicine
Sánchez N. (a), Atencio M. (*), Mavare M. (*), Apóstol N. (*), Mora N. (*), Parra N. (*), Portal N. (*), Falcón P. (*), Sequera R. (*), Pire W. (*).
(a) Director of the Adaptógeno Educational Medical Center of Barquisimeto, State of Lara, Venezuela.
(*) Assistant Doctors of the Adaptógeno Educational Medical Center of Barquisimeto.

Summary

A prospective, multicentric and descriptive study was carried out in the city of Barquisimeto with the purpose of evaluating clinical changes and changes in the quality of life of patients with Diabetic Peripheral Neuropathy, coming from the 8 Adaptógenos Educational Medical Centers in Venezuela. 126 patients were evaluated of whom 77% demonstrated improvement in their Quality of Life and clinical improvement in the typical symptoms of diabetic neuropathy mentioned by them. With the data obtained in this study, besides avoiding in diabetic patients the severe side effects that are usually produced by the extended use of conventional medicines (anti-inflammatories and antidepressants, among others) for the treatment of this neurological complication, we consider that the outline proposed by Systemic Medicine must be prescribed as treatment for patients with Diabetic Neuropathy.

I. Introduction

Diabetes mellitus is one of the most frequent and better documented endocrine diseases in the history of medicine, and it is defined as a chronic disorder where there is an absolute or relative insufficiency of insulin, insensibility or resistance to its metabolic action by the target tissues (1).
Diabetes is a growing threat to the world’s health. In 2003, the International Federation of Diabetes calculated that 194 million people suffer from diabetes in the whole world. It is estimated that by the year 2025, this number will increase to 333 million, which means that 6.3% of the world population will suffer from diabetes. Today, diabetes is the fourth cause of death in the majority of developed countries.
The clinical symptoms of this disease include polydipsia, polyphagia and polyuria, and it progresses with hyperglycemia, glucosuria and alterations of the metabolism of lipids and proteins, micro and macroangiopathy that affect virtually all organs (2).
Diabetes mellitus includes three categories: Insulin-dependant diabetes mellitus, non-insulin-dependant diabetes mellitus, gestational diabetes mellitus and other types of diabetes that, including the previous categories, can be the result of another clinical condition (3).
Diabetic ketoacidosis, hyperosmolar coma, lactic acidosis and hypoglycemia are among the acute complications. Most frequent later complications are vascular alterations such as diabetic nephropathy and retinopathy, ulcer in the feet and diabetic neuropathy.
“Diabetic neuropathy can affect any part of the nervous system, with a probable exception of the encephalon” (4). The pathogenesis of this type of lesion still is not clear, although it is considered that hyperglycemia is mainly responsible for this complication.
The mechanism by which an insulin deficit induces neurological lesions is unknown, although there are three proposed theories: 1. The accumulation of sorbitol, which concentration in the peripheral nerves of a diabetic patient is 2-10 times higher than average; based on the fact that, in said patients, the excess of glucose that cannot be metabolized by way of glucose-6-phosphate chooses the way of sorbitol, which does not require insulin. 2. The alternative hypothesis of meso-inositol is based on the fact that concentrations of this substance are reduced in experimental diabetes and that the alteration of the speed of nervous transmission that is observed in these cases becomes normal through the addition of mesoinositol in the diet. 3. Other researchers theorize that a reduced synthesis of myelin is the primary alteration of diabetic neuropathy (2).
Another theory states that the dysfunction observed in the nervous trunks of diabetic patients is the result of the infarction of one or more ramifications of the vasa vasorum or vasa nervorum. On the other hand, it states that the progressive deterioration leads to the death of cells, which contributes to the sensory anesthesia that is observed in these patients (2).
From a clinical perspective, it is useful to consider separately the peripheral diabetic neuropathy, which can be: Symmetric Distal Neuropathy, Symmetric Proximal Neuropathy and Asymmetric Diabetic Neuropathy.
Symmetric distal neuropathy is the most common form of neuropathy; as indicated by its name, it is usually symmetric and affects the lower extremities, with a distribution called “in glove or sock”. Its symptoms are paresthesias, cramps, pain, muscular atrophy and fasciculations.
Symmetric proximal neuropathy (diabetic amyotrophy) is characterized by an asymmetric motor deficit of the psoas and of the quadriceps, sometimes associated with pain, muscular atrophy and fasciculations.
Isolated motor neuropathy consists in the isolated condition of any cranial or peripheral nerve. The cranial pairs (CP) affected more often are the II, IV and V cranial pairs. However, other CPs such as the VII, VIII and XII can be involved. Besides, some distal nerves (median, cubital, peroneal or sciatic) can be affected.
The lesion of the autonomous nervous system is frequent (autonomic diabetic neuropathy). The most common signs are alterations in the sweating function, sexual impotence, orthostatic hypotension, diabetic arteriopathies, gastroparesis and neurogenic bladder.
Many research studies have been carried out worldwide with the purpose of determining diabetic neuropathy from the epidemiologic point of view.
For example, in 1993, AJ-Boulton and MJ-Young determined, through a multicentric study, the prevalence of peripheral neuropathy in patients treated in diabetes specialized hospitals in the United Kingdom. The prevalence of diabetic neuropathy was of 28.5%, with the conclusion that diabetic neuropathy is a common complication associated with diabetes (5).
In 1994, JA-O’Hare and F-Abauisha determined the prevalence of neuropathy in a group of 800 diabetic patients, obtaining the following results: Pain and paresthesia were present in 13%, loss of sensibility in 7%. The prevalence of diabetic amyotrophy was of 0.8%. Erectile impotence was present in 20%, postural hypotension in 1% and diarrhea in 1%. 22.9% of the group was affected by one or more neurological alterations (6).
In Venezuela, only a few research studies have been carried out to determine the frequency of the neurological alterations, and said studies differ in their results.
The struggle against diabetes in Venezuela started in 1975, when the National Program to Fight Diabetes was decreed and delegated to the Direction of Public Health of the Ministry of Health and Social Assistance. The positive effects of this public health measure are undeniable, however, diabetes continues to be a public health problem that results in significant morbidity and mortality rates, as well as high economic and social costs.

II. Theoretical Framework

The handling of a diabetic patient and his/her complications is extremely complex because diabetes is a chronic, progressive and degenerative disease that affects practically all the human biological system. Most of the conventional treatments that are currently prescribed, in many cases do not guarantee the stoppage of the degenerative process and therefore the quality of life of the patient. Hence the importance of finding alternative and complementary treatments that allow to achieve these objectives.
From a clinical point of view, neuropathy can be classified in peripheral neuropathy and autonomic neuropathy, although both conditions frequently develop jointly (diabetic polyneuropathy).
With respect to diabetic autonomic neuropathy, we can find the following clinical signs:
• Genital-urinary alterations: neurogenic bladder, impotence, retrograde ejaculation, defective vaginal lubrication, loss of testicular sensitivity.
• Alterations in sweat functions: anhidrosis, hyperhidrosis, gustatory hyperhidrosis.
• Metabolic alterations: hypoglycemia (inadvertent/lack of response to hypoglycemia/autonomic dysfunction).
• Alterations in the gastrointestinal tract: esophageal dysfunction (dysphagia), gastroparesis, constipation, diarrhea and fetal incontinence, vesicle hypotonia.
• Genital-urinary alterations.
• Respiratory alterations.

The most frequent symptoms in diabetic peripheral neuropathy are:

Paresthesia, tingling, cramps, numbness, itching sensation, acute or sharp pain in the extremities, loss of balance.
Diabetic neuropathy is the most frequent chronic, progressively incapacitating complication in diabetic patients and, although isolated neuropathic changes rarely end in death, most of the morbidity and decrease in the quality of life can be attributed to this complication. For this reason, and with the purpose of complementing conventional therapeutics and providing solutions, this work is intended to demonstrate that with the use of medicinal plants, under the principles of Systemic Medicine, an improvement can be reached in the quality of life of diabetic patients.
According to Systemic Medicine (8,7), the potential of survival of any living system depends on the correction of three elements that coexist in a triangular relationship. These factors are: Energy, Intelligence and Organization. Energy is defined as the physiological mechanisms associated to the synthesis of ATP (such as the oxidative phosphorylation, tricarboxylic acid cycle, beta-oxidation, etc.). Biological intelligence is the element responsible for the regulation of the neuroendocrine, biochemical, immunological and cellular processes. Lastly, Organization refers to the structure and function of the organs. Under these concepts, survival (or health) of a human being can be improved by increasing any of the three components of that triangle, due to their interdependence. The systemic treatment includes the combination of superior plants that modulate the three axes of the triangle of survival or health, maximizing the benefits in health and contributing to improve the clinical evolution of the patient, as well as his/her quality of life.
Explanation of the Systemic Protocol summarized and applied to the treatment of Diabetic Peripheral Neuropathy.
The formulation of this protocol (9) is based on the systemic triangle of health and on the triangle of Biological Intelligence. (Fig. 1). This combination of superior plants modulates the three axes of the survival (health) triangle, contributing to improve the clinical evolution of patients, as well as their quality of life.

Fig. 1

Figure 1: Systemic Protocol summarized for diabetic peripheral neuropathy.

Stimulation of Energy, Organization and Intelligence in the triangle of Health.

a) Stimulation of the Energy Axis.

Panax ginseng: its active principles bind to the beta-adrenoreceptors of the cellular membrane, releasing the system of messages of the second transmitter (AMPc). The signal travels to the mitochondria, to increase the activity of malate dehydrogenase, citrate synthetase and succinate dehydrogenase, enzymes of the tricarboxylic acid cycle. This makes the production of ATP go up, increasing the levels of energy, utilizing glucose as fuel (10). Fig. 2.

Figure 2: Energizing Mechanism of Ginsenosides

As energy is increased, a larger triangle of health is obtained, because the biological Intelligence of the system has more capacity to organize. However, Panax ginseng is a phytomedicine capable of simultaneously increasing Energy, Intelligence and Organization, in each cell of the living system, as shown further on.

b) Stimulation of the Organization Axis.

Vaccinum myrtillus: the antocyanosides of this plant reduce the deposits of arterial plaque, stimulate the release of vasodilator substances such as prostacyclin (PGI2), which protect the endothelium, inhibit platelet aggregation and prevent the synthesis of pro-inflammatory compounds. These mechanisms increase the blood flow and the supply of nutrients and oxygen, which are vital in the treatment of microangiopathy and of diabetic peripheral neuropathy. (11,12).

c) Stimulation of the Intelligence (Cellular) Axis.

Panax ginseng: its ginsenosides improve cellular Intelligence by stimulating the beta pancreatic cells, and this stimulates the production of insulin and the number of insulin receptors (13). Ginsenosides contribute to the reduction of glucose levels, which is helpful to diabetic patients (10).
The mitochondrial metabolism generates ATP and increases the intracellular relation of ATP/ADP, which results in the closure of ATP-sensitive channels of potassium of the cellular membrane. The closure of these channels depolarizes the membrane and produces the opening of voltage-sensitive channels of calcium, which leads to the quick entry of calcium in the cell. The increase of intracellular calcium stimulates the translocation of granules that contain insulin to the plasmatic membrane and the release of insulin by exocytosis (14). (Fig. 3).

Figure 3: Insulinogenic Mechanism of Ginsenosides.

Diabetic neuropathy corresponds to a complication of hyperglycemia, related to the glycosylation of myelin and to the activation of Aldose Reductase (an enzyme that is present in peripheral nerves, and which catalyzes the reduction of glucose to sorbitol). Hyperglycemia activates the Aldose Reductase of the peripheral nerves, producing an increase in sorbitol and a blocking of the Na+/K bomb of the cellular membrane, and this leads to the entry of Na+, water, axonal edema and a drop in the speed of nervous transmission, which are characteristics of diabetic neuropathy.
Ginsenosides block the channels of Na+ of the cellular membrane, which prevents the entry of Na+ and water, decreasing the axonal edema and increasing the speed of nervous transmission (15,17). In addition, they offer an activity that inhibits protein glycosylation, which benefits neuropathy and other diabetic complications (16).

d) Stimulation of the Intelligence (Biochemical) Axis.

Rhodiola rosea: its main active principles are: phenylpropanoids and flavonoids. These substances explain its adaptogenic, cardiopulmonary protective properties and activity on the Central Nervous System, mainly attributed to its capacity to modulate the levels and activities of biogenic amines such as: serotonin, dopamine and norepinephrine in the cerebral cortex, brain stem and hypothalamus. The changes of these amines are due to the inhibition of the activity of the enzymes responsible for their degradation, and to the facilitation of the transportation of neurotransmitters at brain level. (18).
In addition, Rhodiola prevents the release of catecholamines and the subsequent increase of cyclic AMP, as well as the depletion of adrenal catecholamines induced by acute stress. (19).
The adaptogenic activity of Rhodiola can also be due to the induction of the biosynthesis of opioid peptides and to the activation of the central and peripheral opioid receptors. (20-23).

III. General and Specific Objectives.

General Objectives.
• To evaluate the clinical changes in patients with Diabetic Neuropathy who receive treatment with medicinal plants under the principles of Systemic Medicine.
Specific Objectives.
• To know the symptoms described by patients with Diabetic Neuropathy.
• To evaluate the changes shown by patients with Diabetic Peripheral Neuropathy before and after the treatment with superior plants under the principles of Systemic Medicine.
• To evaluate the changes in glycemia that patients showed during the treatment with Systemic Medicine.
• To evaluate the changes in quality of life showed by patients before and after the treatment with Systemic Medicine.
• To evaluate the tolerance to treatment described by patients.

IV. Materials and Methods.

This investigation consisted in a prospective, descriptive and multicentric study, which sample was constituted by diabetic patients with Diabetic Neuropathy of any sex, age and type of Diabetes mellitus, who attended the Adaptógenos Medical Centers all over the country, during the period between August-November 2004.
• Patients diagnosed with diabetes Mellitus complicated with Diabetic Neuropathy, independently of the treatment they may be receiving.

V. Criteria for exclusion

• Patients with acute complications such as diabetic ketoacidosis and hyperosmolar coma, diabetic foot, peripheral vasculopathy, etc.
• Patients with demyelinizating diseases.
• Patients with a background of ischemic or hemorrhagic CVA who show after-effects such as pareses or paresthesias in the extremities.
The information was obtained from the clinical histories of each one of the medical center. Said information was entered into a database previously designed for the purpose of evaluating certain variables of clinical-therapeutical interest.
All those clinical histories of patients who did not go back for subsequent appointments or who did not stick to the treatment were excluded. All the patients were prescribed a lab routine that included full hematology, glycemia, glycosylated Hb., urea, creatinine, cholesterol, triglycerides, feces and urine, as part of their general evaluation; however, for the purpose of this study, only the results of glycemia in the first and last appointments were considered. Glycosilated Hb. was not taken into consideration, because for its assessment a minimum of two to three months is required to notice any changes, and the majority of patients did not fulfill the requirement in consecutive appointments. In addition, those diabetic patients with a diabetic foot complication were excluded from the study.
A protocol previously assessed by experts was applied. Said protocol collected data related to the identification, symptomatology and its evolution, lab data, fulfillment of the systemic treatment and quality of life.
For the assessment of the evolution of the symptoms in the period of three months in which the sample of patients was considered, the following rating system was applied in the protocol: Absent Symptom = 0, Mild Symptom = 1, Moderate Symptom = 2, Severe Symptom = 3.
The changes in the quality of life were evaluated in accordance with the scale of measurement of quality of life by Grogono-Woodgate (24).

VI. Results

The full sample was constituted by 126 patients with Diabetic Neuropathy, whose ages ranged between 20 and 81 years old, 46.8% of whom were between 40 and 59 years old. Most of the patients were males (53.8%). From all the patients from the study, 92.06% had type 2 Diabetes.

Evolution of typical symptoms of diabetic neuropathy:

The predominant neurological symptoms and their evolution were:

The statistical tests(1) performed allow to state that Systemic Medicine produces significant results in relation to an improvement of the symptoms associated to:
• Peripheral Neuropathy, for p<0.00006.
• Autonomic Neuropathy: Hyperhidrosis, for p<0.0009; Sexual Dysfunction and Micturition Disorders, for p<0.00001.
• Other symptoms referred by patients with diabetic neuropathy: Hyporexia, for p<0.0003; Sleep Disorders; Physical Strain, for p<0.00001; and Migraine, for p<0.000013.

Quality of Life:

It was determined that from the 126 patients that were evaluated, 77% (97 patients, c 2 = 73.75)(2) improved their Quality of Life, going from a “poor” quality to a “good” quality of life, which confirms with 99.99% certainty (p<0.0001), that the therapeutic principles of Systemic Medicine improve the quality of life of patients with Diabetic Neuropathy.

Tolerance to treatment.

None of the patients reported any type of intolerance to the treatment during the time of the study. None of the cases reported symptoms that would require suspension of the treatment.

VII. Conclusions

The study evidenced an improvement in the Quality of Life in 77% of the patients and a clinical improvement of at least one of the signs or symptoms associated with diabetic neuropathy in many of these patients, which is an element of good prognosis linked to the prevention and treatment of one of the most frequent complications in these patients.
The improvement of the typical symptoms of diabetic neuropathy described by the patients, the improvement in the quality of life and the excellent tolerance to the treatment, totally justify the use of this formulation.
The World Health Organization recommends all the Health National Systems to incorporate, in accordance with their respective health regulations, complementary therapies and medicines, in order to achieve an extension of the therapeutic range of a large number of acute and chronic diseases which are difficult to cure by means of conventional methods and procedures. This study proves that Systemic Medicine achieves a remarkable improvement in the neurological symptoms, other symptoms and in the Quality of Life of patients with Diabetic Peripheral Neuropathy, with an excellent tolerance to this treatment.
The systemic formula used in this study is in the procedure of registration of intellectual property. For this reason, Adaptógeno Educational Medical Center has only mentioned 3 plants from the ones used in this disease, together with their scientific references. Any person who wants to know the complete systemic formula may formally request it to the institution.

(1) Mc Nemar’s Test with correction for continuity. With 1 Degree of Freedom.

H0 Null Hypothesis: for any of the patients who changed, the probability of the symptom disappearing after the treatment (P A) is equal to the probability of the symptom appearing after the treatment (P D) (P A=P D).

(2) Mc Nemar’s Test with correction of continuity.

H0 Null Hypothesis: for any of the patients who changed, the probability of the quality of life improving after the treatment (P A) is equal to the probability of the quality of life being affected after the treatment (P D) (P A=P D).
Alternate Hypothesis: H1: P A >P D.