Arterial hypertension and diabetes mellitus: modeling of the interrelationship, new approaches to diagnosis and combination therapy

The dissertation is devoted to the study of the interrelation between arterial hypertension and diabetes mellitus as two closely connected non-communicable diseases that form the basis of the metabolic syndrome and determine a high risk of cardiovascular complications. The work combines an epidemiological, pathogenetic, and clinical analysis of these pathologies with mathematical modelling of the correlations between blood pressure level and blood glucose concentration in healthy persons, patients with arterial hypertension, and patients with diabetes mellitus.

On the basis of the constructed regression models, a new non-invasive method for determining blood glucose concentration from haemodynamic parameters has been proposed and patented, and computer programmes as well as a portable device, the "Glucotonometer", have been developed for the express diagnosis of glycaemia. In addition, original methods of reflexodiagnosis and complex therapy of arterial hypertension and diabetes mellitus have been developed, using reflexotherapy, acupuncture, and homeopathy, and are protected by RF patents. A clinical evaluation of the effectiveness of the proposed approaches and of the stability of the mathematical models against the background of treatment has been carried out.

Relevance of the topic. Arterial hypertension and diabetes mellitus are among the three most common non-communicable diseases and constitute risk factors for cardiovascular complications, which lead worldwide in the frequency of fatal outcomes [91, 238, 263, 271]. The development of adequate measures for the diagnosis, prevention, and treatment of these socially significant pathologies is one of the most pressing problems of modern medicine [249, 302, 376].

Despite the considerable volume of research in cardiology and endocrinology, the epidemiological picture of both arterial hypertension (AH) and diabetes mellitus (DM) is worsening every year [56, 57, 128, 181, 296]. At present, up to 50% of the adult population of Europe, Asia, and America suffer from arterial hypertension, especially in economically developed countries [229, 234, 241, 282, 352]. In the Russian Federation, arterial hypertension affects more than 40% of the adult population [5, 126, 165, 346]. The prevalence of diabetes mellitus ranges from 2 to 6% of the population in different countries [56, 243, 315, 371]. The number of registered DM patients worldwide reached 160 million in 2000 (more than 4% of the population), and by 2025 an almost twofold increase in morbidity is forecast [291]. In Russia, more than 8 million people suffer from diabetes mellitus, with an annual increase of 150,000 cases [51, 52]. Of the total number of cases, type II DM accounts for 85–90%, while type I DM accounts for 10–15% [53, 148, 296].

Epidemiological studies consider AH and DM as interrelated pathologies: more than half of DM patients simultaneously suffer from AH, while disorders of carbohydrate metabolism are detected in 20–30% of AH patients [181, 211, 212, 245, 358]. DM is a significant risk factor for cardiovascular diseases and their complications [45, 64, 249], while AH is among the four main components of the metabolic syndrome that contribute to the development of diabetes mellitus [55, 288, 329, 332, 364]. With the combination of diabetes mellitus and AH, the risk of cardiovascular complications increases two- to threefold, and mortality from coronary insufficiency and strokes increases twenty- to thirtyfold [100, 144, 167, 258].

The role of insulin resistance is actively considered as a connecting link between elevated blood pressure and metabolic disorders in arterial hypertension and diabetes mellitus [10, 72, 81, 112, 223, 233, 262, 283, 310]. The presence of a correlation between blood insulin concentration and blood pressure level is noted by many authors [43, 44, 84, 112, 269, 356]. However, in the available literature we have found no data on the study of the correlation between glycaemia and blood pressure parameters, although such research, in our view, may contribute to the solution of diagnostic problems.

Researchers note the low awareness of the population regarding both AH and DM [196, 296]. Often, verification of AH and DM is carried out 5–10 years later, already in the presence of complications [10, 119, 256, 315]. At the same time, it has been established that careful control of blood pressure and blood glucose concentration, and their maintenance within physiological limits, appreciably reduce the probability of complications and fatal outcomes in patients with AH and DM [214, 310, 342, 374]. Therefore, considerable importance is attached worldwide to improving methods and means for the early diagnosis of AH and diabetes mellitus [241, 296].

One of the most important tasks in diabetology is the development of non-invasive methods for measuring blood glucose, since modern glucometers perform blood analysis with test strips, which cause considerable inconvenience to patients and carry the risk of injury and infection [198]. The proposed developments of non-invasive methods based, for example, on measurements of electrical, thermal, and chemical parameters of the skin [39, 67, 68, 81] are imperfect for practical implementation, do not provide the required accuracy, and involve the use of special, expensive equipment [197]. The problem of developing non-invasive devices for the operational monitoring of glycaemia remains relevant for modern medicine and requires new solutions [81, 180].

Successful prevention of AH and diabetes mellitus also causes considerable difficulties, especially when these pathologies are combined [16, 17, 48, 98, 117, 191, 207, 295, 314]. Achieving positive results is complicated by the fact that antihypertensive and hypoglycaemic drugs have a number of contraindications [54, 61, 64, 131, 186, 247, 266, 273, 275]. Antihypertensive drugs may exert side effects on carbohydrate and lipid metabolism and aggravate the course of vascular and non-vascular complications of diabetes [16, 98, 186, 289]. The use of high doses of antihypertensive and hypoglycaemic drugs is accompanied by the danger of hypoglycaemic states [282, 289, 293].

The low adherence of patients to drug therapy, noted in a number of studies [127, 128], indicates that the problem of adequate reduction of blood pressure in diabetes mellitus requires close attention and new approaches, since it cannot be solved by medication alone. In this regard, methods of traditional medicine, in particular reflexotherapy and homeopathy, are of interest [37, 40, 106, 109, 150, 154, 159]. However, the widespread introduction of new methods of therapy into clinical practice is held back by the absence in some cases of scientific substantiation, and by the limited availability of methodological materials, recommendations, and experience in treating complex functional diseases.

Overall, a comprehensive approach to the diagnosis and therapy of AH and diabetes mellitus requires the study of patterns of interrelation between these pathologies as components of the metabolic syndrome, and the improvement of methods and means for their early diagnosis and prevention.

Based on the foregoing, the aim of this work was to establish the dynamics and patterns of the interrelation between arterial hypertension and diabetes mellitus, and to develop new approaches to the diagnosis and complex therapy of these diseases.

To achieve this aim, the following tasks were to be accomplished:

1. To study the pathogenetic interrelation between arterial hypertension and diabetes mellitus, and to substantiate the presence of a correlation between blood pressure and glycaemia.

2. To construct mathematical models characterising the dynamics of the correlation between blood pressure and glycaemia in arterial hypertension, diabetes mellitus, and in healthy persons, to evaluate their adequacy, and to select optimal models.

3. To develop a new method of express diagnosis of glycaemia based on mathematical models of the relationship between blood pressure and glycaemia, and to prepare the hardware and software for its implementation.

4. To propose new methods of reflexodiagnosis of diseases and complex therapy of arterial hypertension and diabetes mellitus using reflexotherapy and homeopathy techniques, and to evaluate their clinical effect.

5. To trace changes in the dynamics of the correlation between glycaemia and blood pressure parameters against the background of correction of the diseases in order to assess the stability of the mathematical models.

6. To determine the practical significance and possible fields of application of the new methods of glycaemia diagnosis, reflexodiagnosis, and complex therapy of arterial hypertension and diabetes mellitus.

The work was carried out in accordance with the main directions of research of the International Centre for Astronomical and Medical-Ecological Research under the Presidium of the Russian Academy of Sciences and with the Federal Target Scientific Programme of the Presidium of the Russian Academy of Sciences "Fundamental Sciences for Medicine", state registration of the VNTI Centre No. 030242614.0379.

Main propositions submitted for the defence of the dissertation

1. The pathogenetic relationship between arterial hypertension and diabetes mellitus determines the presence of a correlation between the level of blood pressure and the concentration of glucose in the blood.

2. The dynamics of the correlation between blood pressure and blood glucose concentration in patients with arterial hypertension and diabetes mellitus, as well as in healthy persons, can be described by means of mathematical models representing a system of linear and non-linear regression equations.

3. Optimal mathematical models that characterise the relationship between glycaemia and blood pressure parameters with a high adequacy of description of statistical data can be used for non-invasive determination of blood glucose concentration.

4. Methods of traditional medicine (reflexotherapy and homeopathy) can serve as a substantial and reliable supplement to the therapy of arterial hypertension and diabetes mellitus, increasing the clinical effect and reducing the side reactions of medications.

5. The stability of the obtained mathematical models of the relationship between glycaemia and blood pressure parameters is preserved against the background of correction of the diseases and is confirmed by an assessment of representativeness.

6. Computer software tools provide the possibility of practical implementation of the new methods of diagnosis and complex therapy of arterial hypertension and diabetes mellitus.

Scientific novelty

For the first time, patterns of the correlation between blood pressure and blood glucose level have been established in arterial hypertension, diabetes mellitus, and in healthy persons. It has been proved that the dynamics of the relationship between blood pressure parameters and blood glucose level can be described by means of mathematical models representing a system of regression equations.

For the first time, it has been established that optimal mathematical models linking glycaemia and blood pressure parameters can be used to calculate blood glucose content with high accuracy.

For the first time, a non-invasive method for determining blood glucose concentration, based on the measurement of haemodynamic parameters, has been developed, and computer software tools for its implementation have been created. An RF patent for the invention "Method for Determining Blood Glucose Concentration" (No. 2198586, priority 21.11.2000) has been obtained. Applications have been filed for a US patent: "Noninvasive Glucose Meter" (22151 U.S. P&TO 60/5507812004) and for an RF patent "Portable Device for Determining Blood Glucose Concentration" (No. 2004136942, priority 16.12.2004).

For the first time, a new method of diagnosing the functional state of internal organs in reflexotherapy has been proposed, based on blood pressure parameters, allowing the effective selection of points of action and the scientifically grounded development of a plan for correction of diseases. An RF patent for the invention "Method of Diagnosis in Reflexotherapy" (No. 2175521, priority 10.03.99) has been obtained.

For the first time, new methods of treating arterial hypertension and diabetes mellitus have been developed using techniques of reflexotherapy and homeopathy. RF patents have been obtained for the inventions: "Method of Treatment of Patients with Arterial Hypertension" (No. 2218146, priority 07.02.2001), "Method of Treatment of Patients with Type II Diabetes Mellitus" (No. 2193875, priority 21.11.2000); "Homeopathic Preparation for the Treatment of Type II Diabetes Mellitus" (No. 2217149, priority 08.01.2002). It has been shown that methods of traditional medicine can be effectively applied in the complex treatment of arterial hypertension and diabetes mellitus, without causing additional complications or allergic reactions.

It has been established that the patterns of the relationship between glycaemia and blood pressure parameters are preserved against the background of treatment of the diseases, which confirms the stability of the mathematical models and the possibility of their use in monitoring the diseases.

Practical significance of the work

The studies performed have served as the basis for the development of a new method of non-invasive diagnosis of glycaemia, which is protected by an RF patent for the invention. For the implementation of the method, reference tables, diagrams, and a computer programme "Diagnosis of Glycaemia" have been developed; their practical use is recommended for physicians of all specialties at the level of primary and secondary prevention in order to carry out preliminary diagnosis of glycaemia and to identify persons with risk factors.

The portable device "Glucotonometer", designed for the automatic measurement of blood pressure and the calculation of blood glucose concentration, can be used for self-monitoring and in automated systems in both clinical and large-scale epidemiological studies.

The new method of reflexodiagnosis of diseases using the computer programme "Meridians", protected by an RF patent for the invention, can be recommended to practicing physicians for the diagnosis of the state of internal organs and the selection of acupuncture points, which considerably reduces the time of examination and allows a well-grounded treatment plan to be drawn up.

The methods of complex therapy of AH and diabetes mellitus using techniques of traditional medicine are protected by RF patents for inventions, contain the necessary list of instructions for conducting acupuncture and homeopathy procedures, and therefore can be recommended in clinical practice, especially in the presence of objective contraindications to medications. Procedures of reflexotherapy and homeopathy are psychologically acceptable, substantially increase the clinical effect, and stabilise blood pressure and carbohydrate metabolism.

In the presence in patients of obesity or alcohol dependence, which frequently accompany the underlying disease, preliminary sessions of reflexotherapy are recommended to increase the effectiveness of treatment, the description of which is contained in the RF patents for inventions: "Method of Treatment of Patients with Obesity" (No. 2163478, priority 20.06.2000) and "Method of Treatment of Alcohol Dependence" (No. 2125436, priority 27.01.99).

Implementation in practice

The main propositions and practical recommendations of these studies are used in the work of the International Centre for Astronomical and Medical-Ecological Research under the Presidium of the Russian Academy of Sciences. An automated system for the diagnosis of diabetes mellitus has been implemented, operating in conjunction with the computer programme "Diagnosis of Glycaemia" for the non-invasive determination of blood glucose concentration. Reflexodiagnosis using the computer programme "Meridians" is applied in the examination of patients. The implementation of the new developments has made it possible to improve the methodology of examination of patients, to organise high-quality diagnosis of diseases using computers, and to expand the possibilities of non-pharmacological therapy.

In accordance with State Contract No. 10002-251/P-11/159-017/010403-580 dated 01.01.03 under the programme of the Presidium of the Russian Academy of Sciences "Fundamental Sciences for Medicine", the research work "Non-invasive Method for Determining Glycaemia and an Automated System for the Early Diagnosis of Diabetes Mellitus" was carried out. The scientific output in the form of the computer programme "Diagnosis of Glycaemia" and recommendations for the creation of an automated system for the diagnosis of AH and diabetes mellitus has been accepted for implementation by the Centre for Medical-Ecological Research — a branch of the State Scientific Centre of the Russian Federation — Institute of Medical-Biological Problems of the Russian Academy of Sciences.

Into the practice of clinical and scientific work of the medical company-polyclinic "Albina" LLC of the city of Kursk (State licence A671645 No. 0686 of 15.04.02), methods of non-invasive express diagnosis of glycaemia have been introduced using the computer programme "Diagnosis of Glycaemia" in the initial examination of patients, as well as methods of acupuncture diagnosis and reflexotherapy using the computer programme "Meridians" in the treatment of patients suffering from diabetes mellitus, arterial hypertension, obesity, and alcoholism. For practical application and the carrying out of acupuncture, methodological recommendations "Selection of Acupuncture Points" have been developed. The practical implementation of the developments has made it possible to considerably reduce the time required for the examination of patients, to increase the effectiveness of diagnosis of diseases, and to improve the quality of their treatment.

The methodological materials and recommendations contained in the monograph "Diabetes Mellitus and Arterial Hypertension: Mechanisms of Interrelation and Ways of Correction" (Moscow–Stavropol, 2003) /Elbayev A.D., Kurdanov Kh.A./, are used in the research work and educational process of the Department of Normal and Pathological Physiology and the Department of Faculty Therapy of the Medical Faculty of the Kabardino-Balkarian State University in studying the sections "Diabetes Mellitus" and "Arterial Hypertension". The scientific and practical significance of the methodological materials lies in the substantiation of the correlation between the pathologies under consideration and in the application of new methods of diagnosis and treatment.

Publications

On the topic of the dissertation, 47 works have been published, including 2 monographs (print runs of 3,000 and 2,000 copies), articles in peer-reviewed scientific journals, and in collections of scientific works and materials of Russian and international scientific conferences. Seven RF patents for inventions have been obtained. The results of the research are most fully presented in the monograph "Diabetes Mellitus and Arterial Hypertension: Mechanisms of Interrelation and Ways of Correction". — Moscow — Stavropol, 2003. — 136 p.

Approbation of the dissertation work

The results of the research were reported:

— at the II Russian Congress on Pathophysiology with international participation (Moscow, 2000); at the VII International Congress on Immunorehabilitation (New York, 2000);

— at the XVIII Congress of the I.P. Pavlov Physiological Society (Kazan, 2001); at the X International Symposium "Ecological-Physiological Problems of Adaptation" (Moscow, RUDN, 2001);

— at the international conference "Natural Science at the Turn of the Centuries" (Moscow, 2001);

— at the republican scientific-practical conference "Actual Problems of Medicine" (Nalchik, 2001);

— at the 2nd Russian Conference with international participation on Neuroimmunology (Moscow, RAMS, 2002); at the international conference ASTROECO-2002 (KBR, Prielbrusye, 2002);

— at the scientific conference dedicated to the 70th anniversary of the Kabardino-Balkarian State University "Achievements of Medical Science for Practical Public Health" (Nalchik, 2002);

— at the 3rd and 4th scientific-practical conferences "Health and Education in the XXI Century" with international participation (Moscow, RUDN, 2002, 2003);

— at the II Russian National Congress of Cardiologists (Moscow, 2003);

— at the international scientific conference "Actual Problems of Morphology and Clinical Medicine" (Nalchik, 2003);

— at the scientific-practical conferences of the Medical Faculty of the Kabardino-Balkarian State University (Nalchik, 1994–2003); at the scientific conferences of the Russian Academy of Sciences "Fundamental Sciences for Medicine" (Moscow, 2003, 2004, 2005);

— at the All-Russian scientific conferences of students, postgraduates, and young scientists "Perspective-2003", "Perspective-2004", "Perspective-2005" (Nalchik, 2003, 2004, 2005); at the III All-Russian Conference on Pathophysiology with international participation (Moscow, 2004);

— at the international congress "High Technologies" (Paris, 2004).

The dissertation work was approbated at a joint scientific conference of the Department of High-Mountain Physiology and Pathology of the International Centre for Astronomical and Medical-Ecological Research under the Presidium of the Russian Academy of Sciences; the Department of Faculty Therapy, the Department of Hospital Therapy, and the Department of Propaedeutics of Internal Diseases of the Medical Faculty of the Kabardino-Balkarian State University; the State Healthcare Institution "Cardiological Centre" of the Ministry of Health and Social Development of the Kabardino-Balkarian Republic (Nalchik, 2004).

Scope and structure of the dissertation.

The dissertation is set out on 230 pages of typewritten text and includes an introduction, a review of the literature, material and methods of research, four chapters of the author's own research, a conclusion, conclusions, practical recommendations, and a bibliographic reference list of 200 domestic and 184 foreign sources. The work is illustrated with 29 tables and 86 figures.