MINISTRY OF EDUCATION MINISTRY OF DEFENSE AND TRAINING VIETNAM MILITARY MEDICAL UNIVERSITY NGO DUC KY REREARCH OF OSTEOCALCIN CONCENTRATION, BODY COMPOSITION, BONE MINERAL DENSITY IN TYP E DIABETES MELLITUS Specialized : Internal Medical Code : 9720107 DOCTORAL THESIS HANOI - 2019 THE WORK WAS COMPLETED AT VIETNAM MILITARY MEDICAL UNIVERSITY Science instructor: Assoc.Prof Doan Van De Assoc.Prof Dang Hong Hoa Reviewer 1:Assoc.Prof Ta Van Binh Reviewer 2:Assoc.Prof Nguyen Khoa Dieu Van Reviewer 3: Assoc.Prof Hoang Trung Vinh The thesis will be defended at the Dissertation Panel school level, meeting at the Military Medical University At: The thesis can be found at: National Library Library of Military Medical University LIST OF RESEARCH WORKS HAS BEEN DISCLOSURE OF THE AUTHOR RELATED TO THE THESIS Ngo Duc Ky, Doan Van De, Dang Hong Hoa (2018) Relationship between serum osteocalcin and glucose metabolism in patients with type diabetes Vietnam medical journal, Vol 465(1), p 136-140 Ngo Duc Ky, Doan Van De, Dang Hong Hoa (2019) Association between body mass composition and HbA1c in type diabetic patients Vietnam Journal of Medicine, Vol 474(1), p 74 - 77 INTRODUCTION As we know that type diabetes in addition to vascular complications, renal complications, eye complications, increased risk of fracture recently is also considered an important complication of type diabetes Other factors such as bone marrow fat saturation and increased accumulation of final metabolite products of glucose (AGE) may also be related to bone cell function and fracture risk in type diabetes On the other hand, disease Type diabetes mellitus often exhibits changes in body composition, which is to increase fat mass, reduce lean mass and reduce minerals Abdominal fat mass (or body fat) and total fat intake are strongly related to insulin resistance, development of type diabetes and blood glucose control in patients with type diabetes has been demonstrated Osteocalcin is a bone marrow imprint associated with bone resorption Recently, it has been found that interactions between bone metabolism and glucose metabolism are related through osteocalcin activity both in vivo and in vitro The role of osteocalcin, lean mass and lean body mass in glucose metabolism and insulin resistance has been mentioned by studies But there is little data on special clinical research in Vietnam DEXA measurements are considered an optimal method to evaluate body composition Therefore, we carried out the research: "Research of osteocalcin concentration, body composition, bone mineral density in type diabetic patients" with focus: Assessment of serum osteocalcin concentration, body composition, bone density in patients with type diabetes mellitus Analysis of the relationship between serum osteocalcin, changes in body composition, bone mineral density with characteristics of type diabetic patients CHAPTER 1: OVERVIEW 1.1 Risk factors and insulin resistance in type diabetes 1.1.1 Risk factors: Risk factors for type diabetes are classified into four major risk groups, such as genetics, anthropology, lifestyle behaviors and transitional risk groups (intermediate risk) * Genetic factors Genetic factors play a very important role in type diabetes Persons with a blood relation with people with diabetes such as a parent or sibling with diabetes often have a risk of to times higher than normal people (there is no risk in the family) muscle with diabetes) * Causes of anthropology (gender, age, race) The incidence and age of diabetes vary by ethnicity The prevalence of type diabetes is to times higher in the African-American, AsianAmerican, Hispanic, Native American and Indian populations compared to non-Western skinned people Age factor (especially age 50 and older) is ranked first among risk factors for type diabetes, older age, higher risk of disease * Risk factors related to behavior and lifestyle + Obesity Abdominal obesity is closely related to insulin resistance due to post-receptor deficiency leading to a relative lack of insulin due to reduced receptors in peripheral tissues (mainly muscle tissue, adipose tissue) Due to insulin resistance plus reduced insulin secretion, it is expected to reduce membrane permeability to glucose in muscle and fat, inhibit phosphorinization and glucose oxidation, slow down the conversion of carbohydrates into fat, reduced glycogen synthesis in the liver, increased new sugar production and diabetes appear + Less physical activity Various studies in the world have shown that regular physical exercise has the effect of rapidly reducing plasma glucose levels in patients with type diabetes, while maintaining the stability of blood lipids and blood pressure , improve insulin resistance and help improve psychology The combination of regular physical activity and diet adjustment can help reduce the incidence of type diabetes by 58% + Diet Many studies have found high rates of diabetes in people with the most saturated, high-carbohydrate diets In addition, deficiency of trace elements or vitamins contributes to the progression of disease in young people as well as the elderly + Other factors Different studies around the world show that diabetes is growing rapidly in developing countries, with rapid urbanization; these are places where there is a transition in nutrition, lifestyle, stress, * Metabolic factors and types of intermediate risks Reducing fasting glucose tolerance, reducing glucose tolerance Factors related to pregnancy (birth status, gestational diabetes, diabetes, descendants of diabetic women during pregnancy, intrauterine environment) In general, type diabetes is a consequence of the complex interaction between genetic factors and lifestyle factors Risk factors for type diabetes include unchangeable factors and modifiable factors 1.1.2 Fat tissue and insulin resistance in type diabetes 1.1.2.1 Fat and insulin resistance Insulin resistance is considered to be an inherently unrelated component of the disease in most patients Obesity is often associated with insulin resistance, because most type diabetes is obese Insulin resistance due to obesity is considered a contributing factor in insulin diseases and sensitivity As we know, obesity is a risk factor for the development of type diabetes and cardiovascular disease However, it is now recognized that a small proportion of individuals have reduced cardiovascular risk despite being obese Studies have revealed the molecular and metabolic properties of white adipose tissue associated with metabolically unhealthy normal weight (MUNW) and MHO (metabolically healthy obese) It has also been found that the function of white adipose tissue is closely related to the risk of independent cardiovascular obesity and thus contributes to the development of MUNW and MHO 1.1.2.2 Endocrine role of adipose tissue in insulin resistance Currently adipose tissue is known to produce a variety of bioactive peptides that are topical adipokines (autocrine / paracrine) as well as endocrine In terms of endocrine function, when fatty tissue is increased or obesity, especially internal fat deposition is often associated with insulin resistance, hyperglycemia, lipid disorders, hypertension, preinflammatory, pre-thromboembolism 1.2 The role of osteocalcin in type diabetes + Related to glucose metabolism Undercarboxylate osteocalcin (ucOC) is an active form that regulates glucose metabolism Osteocalcin changes to its active form by carboxylation via ESP gene Then ucOC through the target organ of the GPRC6A receptor increases insulin secretion in the pancreas to increase secretion of GLP-1 in the small intestine, increase insulin signaling in muscle tissue and increase adiponectin release in adipose tissue Figure 1.6: Mechanism of action of osteocalcin on glucose metabolism + Related to insulin The bone-pancreas axis can affect energy exchange Insulin acts on osteoblast cell receptor via an insulin receptor (IR) to produce osteocalcin Osteocalcin then transformed into an activated form of osteocalcin undercarboxylated (ucOC), perhaps due to the low pH level of the microbial environment of the bone being recovered, then the interaction with pancreatic β cells to release Insulin affects energy metabolism The molecular mechanism of undercarboxylated (ucOC) with the interaction between osteocalcin and β cells of the pancreas is unclear On the other hand, leptin derived from adipose tissue cells may act as a signal inhibiting the activity of osteocalcin in the feed transition loop of insulin activity Thus, on the bone-pancreas axis can affect energy metabolism Insulin interacts with osteoblast through an insulin receptor (IR) to produce osteocalcin Carboxylated osteocalcin turns into undercarboxylated osteocalcin (ucOc) as an active form Figure 1.7 Relationship between bone and pancreas + Associated with fat metabolism On osteoblast cells, there is a receptor of adiponectin and when adiponectin binds to the specific receptor stimulates osteocalcin expression in osteoblasts Adiponectin stimulates the expression of osteocalcin and osteoblasts cells through the activation pathway of active kinase protein AMPK (AMPK) Figure 1.8 Relationship between bone - pancreas and adipose tissue 1.3 Changes in body composition and bone mineral density in type diabetes 1.3.1 Body composition change in type diabetes: Lean mass: this is the main body component, determining the basic metabolic rate, energy demand and body nourishment Lean mass changes throughout life In any person, lean mass attracts most energy needs Fat mass: varies greatly according to the individual These differences reflect the number and size of fat cells that make up the fat organization The amount of fat varies with age, exercise and environment Normally, about half of body fat is under the skin, so measuring the thickness of the skin can estimate the fat mass 1.3.2 Changes in bone density and osteoporosis in type diabetes In patients with type diabetes, the mechanism related to mineral change is complicated due to many factors that can be summarized by the following diagram: Diagram 1.1 Diagram of mechanism to cause osteoporosis in type diabetes 1.3.3 Measure bone mineral density by double-energy X-ray adsorption method (DEXA) Advantages: High accuracy, short probe time, low beam dose of only 2-4 mrem, low cost It can be measured in high-risk locations such as the lumbar spine, femoral neck and peripheral positions such as wrist, heel bone or body measurements Disadvantages: there are errors if the patient has severe spinal degeneration with multiple bone spines, or calcification of the arteries, then the technician needs to treat bone prickectomy to ensure the correct bone density The method of measuring bone density with DXA calculates the bone density on a flat plane (2D), so the unit is g / cm2, does not calculate the height (3D) and also does not distinguish bone and bone bones sponge 1.3.4 Measure body composition by DEXA method + Advantages: Can accurately calculate each component of fat mass, lean mass, mineral block in each part, low beam dose + Disadvantages: high cost, only in big centers 1.3.5 The problems still exist Studies in the world have mentioned bone density, osteoporosis, lean mass and fat content in type diabetic patients, especially serum osteocalcin levels were also studied and published The problem of studying bone density, the rate of osteoporosis in Vietnam has also been mentioned by many studies, however, the rate of lean mass, fat mass and mineral mass of bone has not yet been mentioned in diabetic patients The type of osteocalcin has not yet been studied in a type diabetic patient, even studies of normal human concentration are not available Therefore, the study of serum osteocalcin concentration, body composition, and bone density in type diabetic patients is still necessary in Vietnam CHAPTER 2: SUBJECTS AND METHODS OF RESEARCH 2.1 Research subjects The study carried out over 218 subjects divided into groups: - Diseases: 151 patients were diagnosed with type diabetes, were treated and monitored at Nghe An General Friendship Hospital 10 Figure 2.5 HOMA2 index calculator 2.2.4 Data analysis - Using SPSS 16.0 statistical software to process and analyze data according to statistical algorithms - The data are standardly verified by Kolmogonov Smimov test If variation according to the standard rule will be calculated and presented as average and standard deviation If the variable does not follow the law of normal distribution, it will be presented as median and quartile - T - test to compare mean values between groups, analyze variance to compare mean values when there are more than groups - Compare rates (test χ2) - Compare medians by non-parametric Mann - Whitney test, many median numbers by Kruskal-Wallis test - Use linear equation with correlation coefficient r to find out the relationship between two quantitative variables If the variable is classified according to the standard distribution rule, it will verify Pearson correlation, if the variable does not follow the law of normal distribution, then check the non-Spearman parameter The correlation coefficient r is from - to + When r> 0: homologous correlation, r