Nghiên cứu kháng insulin, chức năng tế bào tụy alpha, bêta ở bệnh nhân đái tháo đường týp 2 được điều trị bổ sung thuốc ức chế enzyme DPP 4 tại bệnh viện nội tiết trung ương tt tiếng anh

1 PREFACE Diabetes is a group of metabolic diseases, characterized by chronic hyperglycemia due to deficiency in insulin secretion, defective effect of insulin or a combination of both Chronic hyperglycemia of diabetes causes long-term harm, dysfunction and multiple organ failure, particularly eye, kidney, nervous, cardiac and vascular diseases The declination of beta-cell function and insulin resistance are the main mechanisms of type diabetes The role of insulin resistance or beta-cell dysfunction in each patient is variable Through the effects of endogenous incretin, DPP4 inhibitors stimulate beta-cell growth, insulin secretion and glucose-dependent glucose-dependent glucose blockers, DPP4 inhibitors in the secondline drug recommendation for Met, when Met mono-therapy failed to achieve KSGM goal The DPP-4i group has not been studied extensively in Vietnam Conducting the study: Research on insulin resistance, pancreatic alpha and beta cell function in patients with type diabetes mellitus treated with suppressive DPP-4i therapy at the National Endocrinology Hospital with two goals: Determination of insulin resistance, alpha and beta pancreatic cell function and its theirs association with some parameters in patients with type diabetes mellitus Evaluation of blood glucose control and alteration of insulin resistance, pancreatic alpha and beta-cell function after supplementation with DPP-4i in patients with type diabetes who are taking other diabetes oral medications  Scientific significance This study showed that when supplemented with sitagliptin, patients treated with diabetes with other pills oral medications improved blood glucose, improved insulin resistance, improved betacell function and glucagon concentration, and showed the role of glucagon in the variation in blood glucose including the pathogenesis of diabetes  Practical significance Determining tThe results of blood glucose control and alteration of insulin resistance, pancreatic alpha and beta-cell function after supplementation with DPP-4i in patients with type diabetes mellitus treated with other blood and some related factors  New contributions of the thesis CFollowing combination therapy with DPP-4i, type diabetes mellitus patients who were receiving other glucose lowering drugs had reduced FPG, PPG2h, HbA1C and altered insulin resistance index, fasting plasma C peptide, beta -betaine phosphate, fasting plasma glucagon and the role of glucagon in blood sugar variability  The composition of the thesis The dissertation is 127 pages (excluding the annexes and references), which consists of parts: preface (2 pages), overview (34 pages), subjects and methods (19 pages), research (32 pages), discussion (38 pages), conclusions (2 pages), and recommendations (1 page) The thesis has appendices, 40 tables, 19 charts and 132 references, of which 28 in Vietnamese and 104 in English CHAPTER 1: OVERVIEW OF DOCUMENTS 1.1 Diagnosis criteria and mechanism of diabetes mellitus 1.1.1 Diagnostic criteria for diabetes mellitus According to the Diabetes Association of America in 2015: based on one of four criteria: a) Blood glucose (venous blood) ≥ 126 mg / dl (7mmol/l) (after hours intolerance) (measured different times different) b) Any blood glucose level ≥ 200mg / dl (11.1mmol/l) and signs of hyperglycaemia (excessive drinking, frequent urination, unresolved weight loss) c) Blood glucose (glucose tolerance test)≥200mg/dl (11.1mmol/l) after hours oral 75g glucose (glucose tolerance test) d) HbA1C ≥6.5%, performed in a laboratory-tested, calibrated and normalized manner 1.1.2 Mechanism of pathogenesis of type diabetes mellitus Beta-cell function and insulin resistance are the main mechanisms of type diabetes At present, at least eight factors contribute to hyper-glycaemia 1.2 Insulin resistance and beta-cell function decline, glucagon secretion disorders and incretin related defects in diabetes mellitus 1.2.1 Insulin resistance in patients with type diabetes mellitus Insulin resistance is a decrease in the biological effects of insulin Characteristics of type diabetes: insulin resistance and known major motor insulin resistance, hepatotoxic and fatty insulin resistance Main mechanism of insulin resistance: Deficiency of insulin or receptor signaling pathways in type diabetes Insulin resistance factors: related to genetic factors, acquired factors, overweight obesity and decreased physical activity 1.2.2 Decreased beta cell function Causes: Genetic and environmental effects, effects of fetal and adolescent development, hyper-glycaemia, "Lipotoxicity" 1.2.3 Methods for evaluating insulin resistance, beta-cell function There are many different methods of assessing insulin sensitivity / resistance with different strengths and weaknesses HOMA: evaluation method of homeostasis equation, assessment of correlation between G and I in the steady state * Model Homa (Assessment of the equilibrium model of homeostasis 2) Computer method, HOMA is a model of transmission - HOMA2 calculate accurately - HOMA is an experimental model used for non-specific insulin and insulin-specific insulin; used for C-peptide replacement for insulin; Taking into account the fact that glucose tolerance in the liver and muscles, it can be used even if blood glucose > 10 mmol/l 1.2.4 Physiological and abnormal glucagon roles in type diabetes Physiological role of glucagon: increases blood glucose levels through increased glucose production in the liver Regulation of glucose secretion: Glucagon secretion by regulating blood glucose levels in contrast to the effect of blood glucose on insulin secretion Glucose Disorder in Type Diabetes: Glucagon increased in both postprandial and postprandial conditions, leading to hyperglycemia Other methods of evaluating alpha cell function: Up to now there have been noare not many studies and there is no standardized method for the widespread use of alpha-cell function assessments in type diabetes 1.3 Treatment of type diabetes *Treatment goal: according to recommends current ADA 2015 treatment goals *Drug therapy: Most patients with type diabetes mellitus are required to achieve optimal glycemic control *Dipeptidyl Peptidase-4 (DPP-4) Inhibitor: acts to prevent the breakdown of the protein of the endogenous incretin molecule, prolonging the activity of the endogenous incretin molecule *Sitagliptin: The mechanism of action of the drug sitagliptin is to inhibits the breakdown of GLP-1 by inhibiting the enzyme that disrupts GLP-1 Sitagliptin increases the endogenous GLP-1 effect by prolonging the survival time of this hormone + Dose: Sitagliptin fFor type diabetes mellitus with normal renal function, sitagliptin is given at 100 mg / day of monotherapy, or in combination with Met, thiazolidinedione, SU or Met combined with SU - There are also saxagliptin, alogliptin, vildagliptin * ADA guidelines from 2012 up to date DPP-4i have been added as a third drug and a fourth drug when HbA1C did not reach its goal after months 1.4 A number of sStudies on endocrine pancreatic function and use of DPP-4i in type diabetic patients 1.4.1 International studdyy on the efficacy of DPP-4i for blood glucose control, insulin resistance, beta-cell function, and plasma glucagon concentration In 2006, in the study of Charbonnels B and CS, after adding 100 mg sitagliptin, the A1C decreased 0.67% than the original A1C, the average blood glucose decreased 0.9 mmol/l compared to the initial fasting blood glucose level C-peptide increased from 0.83 nmol / l to 0.93 nmol/l, HOMA-B increased from 46.4% to 65.2% 1.4.2 Domestic study of insulin resistance, alpha cell function alpha cell function, beta cell function in type diabetic patients In the year 2012, Nguyen Thi Thu Thao noted: Rate of insulin resistance: HOMA2-IR-Cp 84.7%; Beta-cell function decline: HOMA2-% B-Cp was 76.9% Recognition of pathogenesis including insulin resistance and beta-cell function decline (C-peptide 84.7% insulin resistance, 76.9% reduction in beta-cell function) CHAPTER OBJECTIVES AND RESEARCH METHODS 2.1 Research subjects Subjects: 166 people devided into groupConsisted of 166 people (screening on 300 subjects), obtained 101+ Group 1: : 65 healthy subjects + Group 2: and 101 patients with type diabetesdiabetes These patients were treated with oral hypoglycemic agents other than DPP4 enzyme inhibitor with a stable dose for months but has not yet achieved the goal of blood glucose control Prior study months of treatment with oral hypoglycemic drug, after months have not achieved the target of cyanosis are included in the study 2.1.1 Subject Selection Criteria Standard selection object 2.1.1.1 Criteria for selection of patients with type diabetes + Type diabetes patients diagnosed according to ADA 2015 standards based on of the following criteria: 1) Fasting blood sugar (venipuncture) ≥ 126 mg / dl (7mmol / l) (after hours of calorie intolerance) (measured twice differently) 2) Any blood sugar ≥ 200mg / dl (11.1mmol / l) and manifestations of hyperglycemia (heavy drinking, excessive urination, unexplained weight loss) 3) Blood sugar after hours of taking 75g glucose (glucose tolerance test) ≥ 200mg / dl (11.1mmol / l) 4) HbA1C ≥ 6.5%, performed at the correct laboratory and standardized method In the absence of clinical symptoms of hyperglycemia and a markedly low blood glucose level, one of the four criteria should be repeated on another day to confirm the diagnosis + HbA1C from 7.0% to ≤ 10% and GML from mmol / l to ≤ 16 mmol / l + From 30 years or older; Agree to join NC + Patients Type diabetic patients who were treated for diabetes mellitus by oral hypoglycaemic or combination non-DPP-4 combination therapy were given stable doses over months and failed to achieve glycemic control + The standard has not met the target based on GM from mmol /l to ≤ 16 mmol / l and has HbA1C from 7.0% to ≤ 10% + No anemia; age of 30 years or above; Agree to participate in research 2.1.1.2 Criteria for selecting control subjects + Over 30 years old + Currently identified as healthy people based on histry, physical examination and basic biochemical tess + No risk factors; FPG, HbA1C normal + Agree to participate in research 2.1.2 Exclusion criteria 2.1.2.1 Group of patients with type diabetes + Patients with a history of erythrocyte anemia have been identified, hemolytic anemia (female hemoglobin