1 FOREWORDS Type 2 diabetes is a chronic disease characterized by insulin resistance, dysfunction of β cells (cells are responsible for insulin secretion) leading to hyperglycemia Insulin resistance is the most importance mechanism of type 2 diabetes Evaluation of insulin resistance is performed based on one or more signs such as: elevated blood insulin levels, increased insulin resistance indices and decreased insulin sensitivity Among small vascular complications, chronic kidney disease is an early occurring complication, gradually progresses to severe conditions and becomes one of the leading causes of disability or death in type 2 diabetic patients Nephropathy due to type 2 diabetes clinically exhibits with 3 successive levels, including the occurrence of microalbuminuria (MAU), urinary protein excretion or macroalbuminuria (MAC) with or without nephrotic syndrome and ultimately, chronic renal failure (CRF), wherein, with end-stage chronic renal failure the patient must be applied renal replacement therapy In treatment of type 2 diabetic patients with renal complication, drugs for controlling blood glucose including insulin are commonly used Therefore, determination of insulin resistance indices based on the relation between glucose and C-peptide eliminates the influence factors, using HOMA2 model we can estimate the insulin resistance indices in type 2 diabetic patients being treated with any method Insulin resistance, nephropathy and efficacy on controlling indices in type 2 diabetic patients are scientific and practical significance in the treatment and prognosis of the disease, the investigation is objected to: 1 Investigate the variation and the relation between insulin resistance and nephropathy degree in type 2 diabetic patients with renal complication 2 Evaluate the efficacy on controlling some indices, the variation of insulin resistance and nephropathy degree 6 months after start treatment NEW CONTRIBUTION OF THE THESIS + The thesis has used a computer model based on the HOMA 2 pairs of glucose - C-peptide to determine the index of insulin resistance, insulin sensitivity and β-cell function in patients with type 2 diabetes in 2 general and kidney damage in particular, to avoid the influence of drugs are used to control blood glucose, including insulin + Identify the significant association between insulin resistance index with the degree of kidney damage, additional indicators related to the pathogenesis, prognosis and treatment of diabetic nephropathy + Have an effective application of the content in the clinical practice recommendations for patients with type 2 diabetes and nephropathy by KDOQI in 2007 and updated in 2012 to treat patients studied + Due to the application of the treatment of diabetic nephropathy patients as recommended by the KDOQI should have achieved effective control of several key indicators such as glucose , blood pressure , blood lipid effects and improve insulin resistance as well as significantly reduce the level of kidney damage Treatment results are also evidence of an effect to slow the progression of chronic kidney disease in patients with type 2 diabetes STRUCTURE OF THE THESIS The thesis includes 125 pages (references and appendix not included), with 4 chapters, 53 tables, 7 charts, 2 diagram, 36 Vietnamese references and 110 English references 2 pages forewords, 33 pages overview, 21 pages subjects and methods, 33 pages results, 33 pages discussion, 2 pages conclusion, 1 pages recommendations CHAPTER 1 - OVERVIEW 1.1 Insulin resistance in type 2 diabetic patients with nephropathy 1.1.1 Concept of insulin resistance Insulin resistance is a condition in which the biological effect of insulin is lowered, which is showed by the increased levels of insulin in the blood Conditions contribute in insulin resitance include: Blood sugar disorder (fasting blood sugar disorder, glucose tolerance disorder or type 2 diabetes) Hypertension Blood lipid disorder in which most clearly is the decrease in HDL-c level and the increase in triglyceride levels Insulin resistance causes atherosclerosis Overweight, obesity, in particularly, men obesity are considered as triggering conditions of insulin resistance Glomerular damage with the appearance of proteinuria In addition, some risk factors that facilitate the development and progression of insulin resistance include: age over 40, sedentary lifestyle, little activity, consumption of too much 3 protein, animal fat, sugar, starch, alcohol, family history with type 2 diabetes, hypertension, history of glucose tolerance disorder or gestational diabetes, BMI ≥ 25.0 kg/m2, waist circumference in men >102 cm, in women > 88 cm, increased triglyceride level and/ or decreased HDL-c level, coronary artery disease, acanthosis nigricans or polycystic ovary syndrome 1.1.2 Methods used to evaluate insulin resistance There are some methods for evaluation of insulin resistance as follows: + Evaluate endogenous insulin activity + Evaluate exogenous insulin activity + Indirectly determine insulin resistance: Based on the relation between fasting insulin index (or C-peptidee) and fasting blood glucose index to determine HOMA-Homeostasis Model Assessment (includes HOMA 1 and HOMA 2) Quantitative insulin sensitivity check index (QUICKI) Determine ß cell function or some other nonspecific indices such as: Mc Auley index, Bennett index, ISI (insulin sensitivity index) 1.2 Objectives for controlling indices in type 2 diabetic patients with nephropathy Multi-factor management is a goal introduced by the International Diabetes Committee There are many recommendations on controlling indices such as the recommendations of IDF 2005; Asia-Pacific Diabetes Assocication 2005; ADA 2013 In Vietnam, there are some recommendations from 2009, things need to be managed include: blood glucose, HbA1C, blood pressure, BMI and blood lipids 1.3 Effect of treatment on controlling indices and on the variation of insulin resistance and nephropathy degree in type 2 diabetic patients with nephropathy 1.3.1 Recommendations for treatment of type 2 diabetic patients with nephropathy All type 2 diabetic patients with nephropathy are recommeded using insulin to control blood glucose In addition to controlling recommended indices, nephropathy treatment is necessary: + Patients with MAC (+) and MAU (+): to control proteinuria and reduce proteinuria excretion by low doses of angiotensin converting 4 enzyme inhibitors alone or in combination with angiotensin II AT1 receptors block + Patients with nephrotic syndrome: combination treatment of edema, hyperlipidemia, proteinuria Patients can be used corticoid or medium doses of short time immunosuppresive drugs to reduce renal tubular damage caused by the invasion of inflammatory cells + Patients with chronic renal failure: low lipid dietary, dialysis when glomerular filtration rate < 15 mL/min 1.3.2 Variation of insulin resistance indices post treatment Objectives for controlling indices: no dyslipidemia, normal BMI, blood pressure ≤ 130/80 mmHg, HbA1C < 6.5% and fasting blood glucose 4.4 – 6.1 mmol/L So that the nephropathy condition will be controlled and the insulin resistance level will reduce significantly CHAPTER 2- SUBJECTS AND METHODS OF THE INVESTIGATION 2.1 Subjects From December 2009 to December 2012, we investigated 288 subjects, wherein: 51 healthy people as controls (N1 group), 113 diabetic patients without nephropathy (N2 group) ND 124 diabetic patients with nephropathy (N3 group) Among N3 group, there were 22 patients with MAU (+), 39 patients with MAC (+) and 63 patients with CFR All patients were examined and treated in Nguyen Trai Hospital of Ho Chi Minh city 2.1.1 Inclusion criteria of type 2 diabetic patients:: According to the criteria of World Health Organization (WHO) in 1998: + Fasting blood glucose (after the latest meal 8-12 hours) ≥ 7mmol/L (tested at least 2 times) or + Optional blood glucose ≥ 11.1 mmol/L associated with increasing blood glucose symtom (tested 2 times) or + Blood glucose in the 2nd hour of the glucose tolerance test ≥ 11.1 mmol/L 2.1.2 Inclusion criteria of N1 group: + Healthy people with fasting blood glucose < 6.1 mmol/L + All people were tested by fasting glucose tolerance test, they would be selected if their blood glucose < 7.8 mmol/L after 2 hours 2.1.3 Inclusion criteria of N2 group: 5 + First time diagnosed or being treated diabetes + Similar age and sex with N1 and N3 groups + No acute or malignant diseases + Being treated at the department in the investigational time + Consent to paticipate in the investigation 2.1.4 Inclusion criteria of N3 group: + Includes criteria of N2 group + Had one of the renal complications: MAU (+); MAC (+); CRF with glomerular filtration rate < 60 mL/min 2.1.5 Exclusion criteria of N2, N3 groups: + Type 1 diabetes, Diabetes with specific causes or gestational diabetes + Experiencing serious complications such as infection, diabetic coma, acute myocardial infarction, acute cerebral stroke + Had other diseases such as acromegaly, Basedow, adrenal medulla tumor… + Diabetes with nephrotic syndrome + End-stage CRF patients being cycling dialysis + Used corticoids within 1 month before start the investigation + Did not complete all required tests + Patients with fasting blood glucose 25mmol/L + Patients did not abide the treament 2.2 Methods of the investigation 2.2.1 Investigation design We used a prospective, cross-sectional descriptive method with the comparison between normal control group, patient control group and patient group in combination with tracking post treatment 2.2.2 Calculating sample size Sample size was calculated as follows: 2 1  96  n = , p (   × ×1 −p )  m  Wherein: n is sample size m is error p: 0.5 when n is maximum (p: the ratio of insulin resistance in type 2 diabetic patients with nephropathy) 6 Estimated error was about 0.1 (m = 0.1) So that the sample size required for the investigation was n= 96 The minimum number of patients required for the investigation was 96 patients, this investigation used 124 patients 2.2.3 Duration and site of the investigation Site: The investigation was conducted in the Endocrinology department of Nguyen Trai Hospital, Ho Chi Minh City Duration of investigation: from December 2009 to December 2012 2.2.4 Contents of the investigation General characteristics of the subjects of investigation + Age, sex, time of diabetes detection, calculated BMI + Explored combining diseases, syndromes, complications such as: hypertension, TMTCBMT, eye damage… + Haematological indices: HC, Hb, Hct + Blood biochemical indices: glucose, HbA1C, ure, creatinine, blood fat… + The ratio of used drugs + Nephropathy characteristics of diabetic patients with nephropathy Investigated the variation and the relation between insulin resistance and nephropathy degree in type 2 diabetic patients with nephropathy + Variation of insulin resistance indices such as: insulin, C-peptide, HOMA2-IR, HOMA2-%S and HOMA2-%B + Relation between insulin resistance indices and nephropathy degree, indices relating to insulin resistance like: blood lipids, blood pressure, BMI… Evaluated the effect in controlling some indices, the variation of insulin resistance and nephropathy degree 6 months after start treatment + Effect in controlling blood glucose, HbA1C, blood pressure and blood lipids indices was evaluated following 3 levels: good, acceptable, bad + Evaluated the variation of insulin resistance indices, includes: Cpeptide, HOMA2-IR, HOMA2-%S and HOMA2-%B 6 months after start treatment + The variation of nephropathy degree 6 months after start treatment, includes: calculated again the ratio of patients with MAU(+), MAC (+), CRF and calculated again glomerular filtration rate of diabetic patients with nephropathy 7 * Time marks of the investigation: We designed a cross-sectional investigation to survey the insulin resistance indices and their relation with nephropathy degree To know such relation, patients were consulted personal dietary, exercise, treatment regime Each month, patients were re-examined, retested and adjusted treatment regime if necessary, after 6 months data was collected and analysed and compared to evaluate the treatment effect 2.2.5 Evaluation criteria used in the investigation + Diagnosis of type 2 diabetes: according to WHO 1998 + Diagnosis of hypertension according to JNC 7 (2003) + Diagnosis of dyslipidemia according to guideline of the Vietnam Cardiovascular Association 2008 + Diagnosis of overweight, obesity according to WHO for Asians + Evaluation of effect according to the recommendations of the Vietnam Endocrinology – Diabetes Society + Diagnosis of renal complications: MAU (+), MAC (+), CRF according to the International nephrology Society 2007 + Evaluated the increasing or decreasing degree of insulin resistance indices according to quartiles of results from healthy control group + Evaluated haematological and biochemical indices according to the Vietnamese biological constants 2.2.6 Data processing methods + Data was collected into Excel sheets + Processed data using SPSS 15.0 + Automatically drawn charts on Excel CHAPTER 3 – RESULTS OF THE INVESTIGATION 3.1 General characteristics of the subjects of investigation 3.1.1 Characteristics of age, sex, BMI and some biochemical and haematological indices, complications of investigation groups Mean ages by sex, male/female ratios of investigation groups were not significantly different, p > 0.05 The diabetic detection time of group with nephropathy was 9.3 ± 6.3 years, significantly higher than that of the group without nephropathy (6.6 ± 5.8 years), p< 0.01 There was no difference between groups about the ratio of patients with different BMI, mean values of BMI were not significantly different between groups, p> 0.05 When comparing some biochemical and haematological indices of patients with and 8 without nephropathy, we recognized that: in group with nephropathy the mean values of HC, Hb, Hct, protein and albumin levels were lower and the mean values of urea, creatinine, uric acid levels were significantly higher than in group without nephropathy, with p < 0.05 and p < 0.01, respectively The rate of occurring hypertensive complication, ischemic heart disease, retinopathy and chronic heart failure in diabetic patients with nephropathy was higher than in diabetic patients without nephropathy, with p < 0.05 and p < 0.01, respectively 3.1.1 Nephropathy charateristics of investigation group Table 3.9: Distribution of patients according to chronic renal disease stages based on the NKF/KDOQI classification N3 (n=124) Stage of nephropathy Number (n) Percent (%) 1 12 9.6 2 49 39.5 3 34 27.4 4 17 13.7 5 12 9.7 Patients with 2nd and 3rd stages of chronic nephropathy occupied large numbers Chart 3.5: Percent of patients with chronic nephropathy Comment: The percent of patients with CRF was highest, and patients with MAU (+) was smallest 9 3.2 Insulin resistance in diabetic patienst with nephropathy 3.2.1 Variation of insulin resistance indices Table 3.14: Comparing mean indices between 3 groups N1 (n =51) (1) N2 (n=113) (2) N3 (n=124) (3) 6.99 ± 3.3 10.42 ± 6.13 15.8 ± 9.2 < 0.01 0.77 ± 0.41 1.05 ± 0.6 1.44 ± 0.77 < 0.01 1.43 ± 0.49 2.83 ± 1.81 3.76 ± 2.08 HOMA2-%S 75.78 ± 33.36 48.78±30.13 49.26±38.03 HOMA2-%B 151.56±62.51 78.91±47.54 80.32±48.69 < 0.01 1-2 1-3 < 0.01 2-3 > 0.05 1-2 1-3 < 0.01 2.3 > 0.05 Index Insulin (μmol/mL) C-peptide (nmol/L) HOMA2-IR pANOVA + The mean values of insulin, C-peptide levels, insulin resistance indices of diabetic patients were significantly higher than healthy controls, in which these values of diabetic patients with nephropathy were highest + The insulin sensitivity and β cell function of type 2 diabetic patients decreased as compared to healthy controls but the difference was not statistically significant Table 3.16: Comparing the percent of patients between 2 groups based on levels of indices Index Insulin (> 10.29 Increase (μmol/mL) C-peptide (> 1.18 nmol/L) HOMA2-IR (> 1.92) Decreas HOMA2-%S (< 45.5) e HOMA2-%B (< 89.1) N2 (n=113) n (%) N3 (n=124) n P (%) 46 40.7 101 81.5 39 86 49 51 34.5 76.1 43.4 45.1 77 99 97 100 62.1 79.8 78.2 80.6 < 0.01 < 0.01 > 0.05 < 0.01 < 0.01 + Percent of nephropathic patients with increased insulin, C-peptide, HOMA2-IR indices was higher than percent of type 2 diabetic patients without nephropathy + Percent of nephropathic patients with decreased insulin sensitivity index and decreased insluin secretion function of β cells was higher than percent of type 2 diabetic patients without nephropathy 3.2.2 Relation between insulin resistance and nephropathy 10 Table 3.17: Comparing mean values of insulin resistance indices in patients with nephropathy Index MAU (+) (n=22) MAC (+) (n=39) CRF (n=63) p ANOVA Insulin < 0.01 12.15 ± 7.04 15.51 ± 8.86 18.54 ± 11.28 (μmol/mL) C-peptide < 0.05 1.12 ± 0.45 1.53 ± 0.61 1.86 ± 1.33 (nmol/L) HOMA2-IR 2.96 ± 1.11 3.61±1.74 4.43 ± 2.42 < 0.01 HOMA2-%S 54.74 ± 29.9 48.7 ± 24.12 42.3 ± 24.26 < 0.05 HOMA2-%B 88.7 ± 45.78 81.4 ± 57.52 73.3 ± 34.76 < 0.05 When the nephropathy level increased: Levels of insulin, C-peptide, HOMA2-IR statistically significantly increased Mean value of insulin sensitivity index and insulin secretion function of β cells decreased (p< 0,05) Table 3.18: Comparing the percent of patients with abnormal insulin resistance indices according to clinical renal damage states MAU (+) MAC (+) CRF Characteristic P (n=22),(1) (n=39),(2) (n=63),(3) n % n % n % Increased insulin 1-3 < 0.05 (> 10.29 55 87 2-3 < 0.05 17 77.3 29 74.4 (μmol/mL) 3 1-2 > 0.05 (n= 101) Increased C1-3 < 0.05 peptide 43 68 2-3 < 0.05 12 54.5 22 56.4 (> 1.18 nmol/L) 3 1-2 > 0.05 (n= 77) Increased 1-3 < 0.05 HOMA2-IR 53 84 2-3 < 0.05 16 72.7 30 76.9 (> 1.92) 1 1-2 > 0.05 (n= 99) Decreased 1-3 < 0.05 HOMA2-%S 51 80 2-3 < 0.05 17 77.3 29 74.4 (< 42.42) 9 1-2 > 0.05 (n= 97) Decreased 15 68.2 27 69.2 1-3 < 0.05 HOMA2-%B 58 92 2-3 < 0.05 (< 89.05) 1 1-2 > 0.05 11 (n= 100) When the nephropathy level increased: Percent of patients with increased C-peptide level increased Among CRF patients, the percent of patients with increased insulin level and increased HOMA2-IR was highest while such percent of MAU(+) patients was equivalent with MAC(+) patients Among CRF patients, percent of patients with decreased insulin sensitivity or decreased β cell function was highest while such percent of MAU(+) patients was equivalent with MAC(+) patients Table 3.22: Correlation between insulin resistance indices and glomerular filtration rate Glomerular filtration rate (ml/min/1.73m 2) Index R p Equation HOMA2-IR - 0.39 < 0.05 y = -0.0262x + 4.3803 HOMA2-%S 0.41 < 0.05 y = 0.5066x + 25.029 HOMA2-%B 0.43 < 0.05 y = 0.7246x + 33.555 - Insulin resistance indices moderately inversely correlated with glomerular filtration rate Insulin sensitivity, β cell function moderately correlated with glomerular filtration rate Table 3.23: Multivariable logistic regression model of the relation between the occurence of microalbuminuria-macroalbuminuria and insulin resistance, glomerular filtration rate, hypertension, BMI, RLLM, detection time of diabetes Factor Insulin resistance Glomerular filtration rate Hypertension BMI ≥23 RLLM TGPH- Diabetes ≥ 10 years β coefficient - 0.12 2.322 1.77 0.204 0.092 OR 95%CI 0.89 10.2 5.88 1.23 1.1 0.37 - 2.15 4.04 – 25.74 0.88 – 39.39 0.51 – 2.96 0.33 – 3.66 0.437 1.55 0.66 – 3.63 p 0.79 < 0.0001 0.068 0.65 0.88 0.315 GLOMERULAR FILTRATION RATE 12 Forecasting equation= - 6.446 - 0.12 x KI+ 2.322 x glomerular filtration rate + 1.77 x hypertension + 0.204 x BMI + 0.092 x RLLM + 0.437 x diabetes duration>10 năm If type 2 diabetic patients had got microalbuminuria, risk of increasing glomerular filtration rate 10.2 folds Table 3.24: Multivariable logistic regression model of the relation between the occurence of nephropathy and insulin resistance, glomerular filtration rate, hypertension, BMI, RLLM, detection time of diabetes Factor β coefficient -0.292 1.288 - 0.15 0.154 OR 95%CI p Insulin resistance 0.75 0.43 - 1.3 0.302 Hypertension 3.62 1.53 – 8.56 0.003 BMI ≥23 0.86 0.5 – 1.48 0.586 RLLM 1.17 0.56 – 2.4 0.678 TGPH- Diabetes 0.889 2.43 1.36 – 4.36 0.003 ≥10 years Forecasting equation = - 2,572 - 0,292 x KI + 1,288 x hypertension – 0,15 x BMI + 0,154 x RLLM + 0,889 x diabetes duration >10 years If type 2 diabetic patients had hypertension and diabetes duration ≥ 10 years then their risk of occurrence of nephropathy increased 3.3 Effect in controlling some indices, variation of insulin resistance and nephropathy degree 6 months after start treatment 3.3.1 Effect in controlling some indices of diabetic patients 13 Chart 3.6: Percent of patients with some abnormal indices in the treatment duration (n= 124) Percent of patient with hypertension, HbA1c > 7%, RLLM 6 months after start treatment decreased significantly as compared to baseline Table 3.26: Comparing mean values of some indices before and after start treatment (n = 124) Before After Index P treatment treatment Glucose (mmol/L) 8.9 ± 3.6 6.59 ± 1.33 < 0.01 HbA1C (%) 8.4 ± 2.2 7.22 ± 0.96 < 0.01 HATT (mmHg) 136.9 ± 19.1 130.3 ± 14.2 < 0.05 HATTr (mmHg) 77.2 ± 7.6 73.2 ± 8.1 < 0.05 4.92 ± 1.59 4.36 ± 1.43 < 0.05 Cholesterol (mmol/L) 2.79 ± 2.01 2.31 ± 2.05 < 0.05 Triglyceride (mmol/L) 0.99 ± 0.34 1.04 ± 0.37 > 0.05 HDL-c (mmol/L) 3.21 ± 1.11 3.12 ± 1.09 > 0.05 LDL-c (mmol/L) Mean values of fasting glucose, HbA1c, systolic blood pressure (HATT), diastolic blood pressure (HATTr), cholesterol, triglyceride after treatment decreased significantly as compared to before treatment The variation of HDL-c, LDL-c before and after treatment was not statistically significant 14 3.3.2 Variation of insulin resistance indices 6 months after start treatment Table 3.35: Comparing mean values of aome insulin resistance indices, beta cell function, insulin sensitivity before and after treatment (n=124) Percent of Before After Index variation p treatment treatment (%) C-peptide 1.44 ± 0.77 1.17 ± 0.94 0.18 < 0.05 (nmol/mL) HOMA2-IR 3.76 ± 2.08 2.86 ± 0.83 -23.9 < 0.05 HOMA2-%S 49.3 ± 38.03 64.68 ± 18.76 31.2 < 0.01 HOMA2-%B 80.3 ± 48.69 113.13 ± 41.3 < 0.05 56.63 - Mean values of C-peptide, insulin resistance indices decreased, insulin sensitivity, beta cell function increased significantly 6 months after start treatment (p < 0.05 and p < 0.01, respectively) - The increasing degree of beta cell function after treatment was highest - The decreasing degree of insulin resistance after treatment was smallest Table 3.36: Percent of patients with abnormal insulin resistance indices before and after treatment (n=124) Before treatment After treatment Index n (%) n (%) C-peptide > 1.18 nmol/L 59 (47.6) 30 (24.2) HOMA2-IR > 1.92 99 (79.8) 47 (37.9) HOMA2-%S < 45.5 97 (78.2) 33 (26.6) HOMA2-%B < 89.1 100 (80.6%) 34 (27.4%) - 6 months after start treatment, the percent of increased insulin resistance indices decreased - Percent of patients with decreased insulin sensitivity or decreased beta cell function also decreased 3.3.3 Variation of nephropathy degree 6 months after start treatment 15 Table 3.37: Comparing mean value of glomerular filtration rate before and after treatment (n=124) Glomerular filtration rate (ml/min/173m2) Highest Smallest Before treatment After treatment 104.8 12.4 106.4 11.8 61.2 ± 23.16 74.3 ± 24.48 P < 0.01 After treatment, the mean value of glomerular filtration rate increased significantly 16 Table 3.38: Distribution of patients according to stages of chronic renal disease before and after treatment (n=124) Before Variation After treatment Stage treatment in pairs % n % n % 1 12 9.6 19 15.3 59.4 2 49 39.5 35 28.3 -28.4 3 34 27.4 41 33.1 20.8 4 17 13.7 16 12.9 -5.8 5 12 9.7 13 10.4 7.2 - The percents of patients before and after treatment according to stages of chronic renal disease changed differently and unevenly Table 3.39: Distribution of patients according to clinical states of chronic renal disease before and after treatment (n=124) Before After Variation Clinical state treatment treatment in pairs (%) Number (n) Number(n) MAU (-) 0 7 5.8 MAU (+) 22 29 63.8 MAC (+) 39 24 -38.4 CRF 63 64 1.6 - After treatment, the percent of patients with MAC (+) decreased but the percent of patients with MAU increased, in particularly, there were 5.8% cases of MAU(-) disappeared nephropathy when tested - Percent of patients with chronic renal failure slightly increased CHAPTER 4- DISCUSSION 4.1 General characteristics of the subjects of investigation 4.1.1 Age, sex, detection time of diabetes Advanced age is not a disease but it facilitates the occurence and development of diseases With type 2 diabetes, age is always considered as an unchangeable risk factor The percents of female 17 patients in both groups were higher than the percents of male patients (73.4% - 73.5%) Because the percents of patients in sex were as stated then we had to select equivalent ratio of male/female in healthy control group to prevent the significant difference in sex with others groups and to eliminate the factors affecting investigation indices from sex aspect The detection time of type 2 diabetes is an impacting and influencing factor The detection time relates to target organ complications Diabetic patients with nephropathy had longer detection time, so, with prolonged detection time, the risk of nephropathy complications also increased 4.1.2 Some clinical, sub-clinical characteristics of patients Type 2 diabetes is a disease that appears and progresses silently About 50% of cases are not diagnosed in time, in many cases the disease is detected based on complications occurring before the patients know that they have diabetes Diabetic patients with complications had all rick factors such as high BMI, dyslipidemia, heart, eye and kidney complications higher than patients without complications Especially patients with complications had less ability to control factors than patients without complications 4.1.3 Ratio, characteristics of nephropathy in investigation patients Nephropathy in diabetic patients is classified as small vascular complication If classify nephropathy according to BTM stage or based on glomerular filtration rate we obtained results with different percents, in which 2nd and 3rd stages nephropathy accounted higher percents, 37.9% and 31.4%, respectively If match with glomerular filtration rate then the 3 first stages of BTM are counted as mild conditions in which the 1st and 2nd stages haven’t had renal failure, and the 3rd stage has had reduced glomerular filtration rate The 4th and 5th stages of BTM are accounted as serious renal failure stages, among these subjects, there are 23.4% of cases belong to the 3rd and 4th stages If analyse according to clinical 18 states of nephropathy then we will see the difference in patient percent, wherein the highest percent is CRF patients with 50.8% of cases - a haft of patients have nephropathy Two other clinical states also have different percents, where percent of MAC(+) patients without CRF counted 31.5%, higher than percent of MAC(+) patients with normal glomerular filtration rate The investigation on complications and nephropathy characteristics of type 2 diabetic patients with nephropathy of Nguyen Van Quynh showed that in the first year of type 2 diabetes there are only 18.3% of cases can be diagnosed 4.2 Variation of insulin resistance and the relation between insulin resistance and nephropathy degree in type 2 diabetic patients with nephropathy 4.2.1 Variation of insulin resistance indices Results from comparison of mean values of insulin resistance indices from 3 groups showed that insulin and C-petide levels of type 2 diabetic patients with nephropathy were higher than such indices of healthy controls and type 2 diabetic patients without nephropathy with p 90 ml/min/1.73 m2 The variations of patient percents in next stages were different, wherein, the percents of 2 nd and 4th patients after treatment decreased 28.4% and 5.8%, respectively; while the percents of 3rd and 5th patients increased 20.8% and 7.2%, respectively The transfer of subjects between stages leaded to the variation of patient percents in each stage before and after treatment CONCLUSION Our investigation on insulin resistance and controlling degree of some indices in 124 type 2 diabetic patients with nephropathy as compared to healthy controls and patient controls obtained the following conclusions: 1 Variation of insulin resistance and relation between insulin resistance and nephropathy degree in type 2 diabetic patients + Increase in mean values of insulin, C-peptide, HOMA2-IR indices, decrease in mean values of HOMA2-%S, HOMA2-%B as compared to corresponding indices in healthy controls and patient controls 24 + Percent of CRF patients with increased insulin, C-peptide, HOMA2-IR indices, reduced HOMA2-%S, HOMA2-%B as compared to patients with MAU or MAC Percent of patients had the variation of such indices when they got microalbuminuria and macroalbuminuria were equal + Mean values of insulin, C-peptide, HOMA2-IR indices increased, mean values of HOMA2-%S, HOMA2-%B reduced following BMT stages + HOMA2-IR index inversely correlated in a moderate degree and HOMA2-%S, HOMA2-%B indices positively correlated in a thick degree with glomerular filtration rate 2 Effect in controlling some indices, variation of insulin resistance, nephropathy degree after 6 months of treatment + Both indices of blood glucose, HbA1c, blood pressure, blood lipids reduced when counted in mean values and patient percents Percent of patients with good and acceptable ability to control blood glucose, HbA1c, blood pressure, blood lipids indices increased while percent of patient wit less ability to control such indices reduced + Variation of indices after treatment: HOMA2-IR reduced 23.9%, HOMA2-%S, HOMA2-%B increased 31.2% and 41.3%, respectively Percent of patients with increased HOMA2-IR, decreased HOMA2-%S, HOMA2-%B reduced after treatment + Mean value of glomerular filtration rate increased Percent of patients following nephropathy degrees improved significantly 25 RECOMMENDATIONS Through these investigation results, we have the following recommendations: + There is a need to better control risk factors promoting nephropathy according to the recommended targets to eliminate the rate and severity of nephropathy in type 2 diabetic patients + There is a need for other investigations on the relation between insulin resistance and the degree and stages of chronic nephropathy in type 2 diabetic patients using a large number of patients and a prolonged duration for avaluation after treatment to be able to understant the progression of nephropathy under the effect of treatment methods  ... 0.05 1. 12 ± 0.45 1.53 ± 0.61 1.86 ± 1.33 (nmol/L) HOMA2-IR 2. 96 ± 1.11 3.61±1.74 4.43 ± 2. 42 < 0.01 HOMA2-%S 54.74 ± 29 .9 48.7 ± 24 . 12 42. 3 ± 24 .26 < 0.05 HOMA2-%B 88.7 ± 45.78 81.4 ± 57. 52 73.3... 84 2- 3 < 0.05 16 72. 7 30 76.9 (> 1. 92) 1 -2 > 0.05 (n= 99) Decreased 1-3 < 0.05 HOMA2-%S 51 80 2- 3 < 0.05 17 77.3 29 74.4 (< 42. 42) 1 -2 > 0.05 (n= 97) Decreased 15 68 .2 27 69 .2 1-3 < 0.05 HOMA2-%B... Factor Insulin resistance Glomerular filtration rate Hypertension BMI ? ?23 RLLM TGPH- Diabetes ≥ 10 years β coefficient - 0. 12 2. 322 1.77 0 .20 4 0.0 92 OR 95%CI 0.89 10 .2 5.88 1 .23 1.1 0.37 - 2. 15