Conducting the study: Research on insulin resistance, pancreatic alpha and beta cell function in patients with type 2 diabetes mellitus treated with suppressive DPP-4i therapy at the Nat
Trang 1Diabetes is a group of metabolic diseases, characterized bychronic hyperglycemia due to deficiency in insulin secretion,defective effect of insulin or a combination of both Chronichyperglycemia of diabetes causes long-term harm, dysfunction andmultiple organ failure, particularly eye, kidney, nervous, cardiac andvascular diseases
The declination of beta-cell function and insulin resistanceare the main mechanisms of type 2 diabetes The role of insulinresistance or beta-cell dysfunction in each patient is variable.Through the effects of endogenous incretin, DPP4 inhibitorsstimulate beta-cell growth, insulin secretion and glucose-dependentglucose-dependent glucose blockers, DPP4 inhibitors in the second-line drug recommendation for Met, when Met mono-therapy failed toachieve 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 2 diabetes mellitus treated with suppressive DPP-4i therapy at the National Endocrinology Hospital with two goals:
1 Determination of insulin resistance, alpha and beta pancreaticcell function and its theirs association with some parameters
in patients with type 2 diabetes mellitus
2 Evaluation of blood glucose control and alteration of insulinresistance, pancreatic alpha and beta-cell function aftersupplementation with DPP-4i in patients with type 2 diabeteswho are taking other diabetes oral medications
Scientific significance
Trang 2This study showed that when supplemented with sitagliptin,patients treated with diabetes with other pills oral medicationsimproved blood glucose, improved insulin resistance, improved beta-cell function and glucagon concentration, and showed the role ofglucagon 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 aftersupplementation with DPP-4i in patients with type 2 diabetesmellitus treated with other blood and some related factors
New contributions of the thesis
CFollowing combination therapy with DPP-4i, type 2 diabetesmellitus patients who were receiving other glucose lowering drugshad reduced FPG, PPG2h, HbA1C and altered insulin resistanceindex, fasting plasma C peptide, beta -betaine phosphate, fastingplasma glucagon and the role of glucagon in blood sugar variability
The composition of the thesis
The dissertation is 127 pages (excluding the annexes andreferences), which consists of 6 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 6 appendices, 40 tables, 19 charts and 132references, of which 28 in Vietnamese and 104 in English
Trang 3CHAPTER 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 onone of four criteria:
a) Blood glucose (venous blood) ≥ 126 mg / dl (7mmol/l) (after
8 hours intolerance) (measured 2 different times different)b) Any blood glucose level ≥ 200mg / dl (11.1mmol/l) andsigns of hyperglycaemia (excessive drinking, frequenturination, unresolved weight loss)
c) Blood glucose (glucose tolerance test)≥200mg/dl (11.1mmol/l) after 2 hours oral 75g glucose (glucose tolerance test)d) HbA1C ≥6.5%, performed in a laboratory-tested, calibratedand normalized manner
1.1.2 Mechanism of pathogenesis of type 2 diabetes mellitus
Beta-cell function and insulin resistance are the mainmechanisms of type 2 diabetes At present, at least eight factorscontribute 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 2 diabetes mellitus Insulin resistance is a decrease in the biological effects of insulin Characteristics of type 2 diabetes: insulin resistance and known
major motor insulin resistance, hepatotoxic and fatty insulinresistance
Main mechanism of insulin resistance: Deficiency of insulin or
receptor signaling pathways in type 2 diabetes
Trang 4Insulin 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 insulinsensitivity / resistance with different strengths and weaknesses.HOMA: evaluation method of homeostasis equation, assessment ofcorrelation between G and I in the steady state
* Model Homa 2 (Assessment of the equilibrium model of
homeostasis 2) Computer method, HOMA 2 is a model oftransmission
- HOMA2 calculate accurately
- HOMA 2 is an experimental model used for non-specific insulin
and insulin-specific insulin; used for C-peptide replacement forinsulin; Taking into account the fact that glucose tolerance in theliver and muscles, it can be used even if blood glucose > 10 mmol/l
1.2.4 Physiological and abnormal glucagon roles in type 2 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 oninsulin secretion
Glucose Disorder in Type 2 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
Trang 5method for the widespread use of alpha-cell function assessments intype 2 diabetes
1.3 Treatment of type 2 diabetes
*Treatment goal: according to recommends current ADA 2015treatment goals
*Drug therapy: Most patients with type 2 diabetes mellitus arerequired to achieve optimal glycemic control
*Dipeptidyl Peptidase-4 (DPP-4) Inhibitor: acts to prevent thebreakdown 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 toinhibits the breakdown of GLP-1 by inhibiting the enzyme thatdisrupts GLP-1 Sitagliptin increases the endogenous GLP-1 effect
by prolonging the survival time of this hormone
+ Dose: Sitagliptin fFor type 2 diabetes mellitus with normal renalfunction, sitagliptin is given at 100 mg / day of monotherapy, or incombination with Met, thiazolidinedione, SU or Met combined withSU
- There are also saxagliptin, alogliptin, vildagliptin
* ADA guidelines from 2012 up to date DPP-4i have been added as athird drug and a fourth drug when HbA1C did not reach its goal after
3 months
1.4 A number of sStudies on endocrine pancreatic function and use of DPP-4i in type 2 diabetic patients
Trang 61.4.1 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 mgsitagliptin, the A1C decreased 0.67% than the original A1C, theaverage blood glucose decreased 0.9 mmol/l compared to the initialfasting blood glucose level C-peptide increased from 0.83 nmol / l to0.93 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 2 diabetic patients
In the year 2012, Nguyen Thi Thu Thao noted: Rate of insulinresistance: HOMA2-IR-Cp 84.7%; Beta-cell function decline:HOMA2-% B-Cp was 76.9% Recognition of pathogenesis includinginsulin resistance and beta-cell function decline (C-peptide 84.7%insulin resistance, 76.9% reduction in beta-cell function)
Trang 7CHAPTER 2 OBJECTIVES AND RESEARCH METHODS
2.1 Research subjects
Subjects: 166 people devided into 2 groupConsisted of 166 people (screening on 300 subjects), obtained 101+ Group 1: : 65 healthysubjects
+ Group 2: and 101 patients with type 2 diabetesdiabetes Thesepatients were treated with oral hypoglycemic agents other than DPP-
4 enzyme inhibitor with a stable dose for 3 months but has not yetachieved the goal of blood glucose control Prior study 3 months oftreatment with oral hypoglycemic drug, after 3 months have notachieved 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 2 diabetes
+ Type 2 diabetes patients diagnosed according to ADA
2015 standards based on 1 of the following 4 criteria:
1) Fasting blood sugar (venipuncture) ≥ 126 mg / dl (7mmol /l) (after 8 hours of calorie intolerance) (measured twicedifferently)
2) Any blood sugar ≥ 200mg / dl (11.1mmol / l) andmanifestations of hyperglycemia (heavy drinking, excessiveurination, unexplained weight loss)
3) Blood sugar after 2 hours of taking 75g glucose (glucosetolerance test) ≥ 200mg / dl (11.1mmol / l)
4) HbA1C ≥ 6.5%, performed at the correct laboratory andstandardized method
Trang 8In the absence of clinical symptoms of hyperglycemia and amarkedly low blood glucose level, one of the four criteria should berepeated on another day to confirm the diagnosis.
+ HbA1C from 7.0% to ≤ 10% and GML from 7mmol / l to ≤ 16 mmol / l
+ From 30 years or older; Agree to join NC +Patients Type 2 diabetic patients who were treated for diabetesmellitus by oral hypoglycaemic or combination non-DPP-4combination therapy were given stable doses over 3 months andfailed to achieve glycemic control
+ The standard has not met the target based on GM from 7mmol /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 2 diabetes
+ Patients with a history of erythrocyte anemia have been identified,hemolytic anemia (female hemoglobin <120 g / l and male <130 g /l), the test has abnormal stimulation of red blood cells and canHemoglobin hemoglobin
+ Liver enzymes increase ≥ 3 times the high value of normal
Trang 9+ Being suffering from other acute diseases that requirehospitalization.
+ Patients with unstable angina, myocardial infarction, cerebralvascular accident, coagulopathy, severe exhaustion, mental disorders.+ Type 2 diabetic patients being treated with DPP4 inhibitors andGLP1 receptor agonists
+ Do not use thyroid hormone drugs
+ Do not have thyroid disease
+ Do not collect enough study information
+ Do not agree to participate in research.Group 2 diabetic patients+ Have glomerular filtration rate <45 ml/min+ Liver enzyme increased ≥ 3 times the highvalue of normal
+ Being admitted to other acute carehospitals
+Patients with unstable angina, myocardial
coagulopathy, severe exacerbation, mentaldisorders
+ Patients with type 2 diabetes are beingtreated with DPP4 inhibitors and /or GLP1receptor agonists
+ Do not use thyroid hormone
+ There is no thyroid disease
+ Patients do not collect enough researchindicators
2.1.2.2 Healthy controls group
Trang 10In history or at present there are chronic diseases, especially cardiovascular and metabolic diseases: hypertension, type 2 diabetes (based on basic biochemical tests).
+ Pregnant women.
+ Are suffering from acute infections.
+ Have been taking or have taken some medicines in the last 3 months such as corticosteroids, birth control pills.
2.1.3 Time and place of study
- Study Period: April 2014 to February 2017
-Location: Outpatient Department, Central Hospital ofEndocrinology
2.2 Research Methods
2.2.1 Sampling: Random, convenient.
2.2.2 Study design: Describe, evaluate and intervene before and
2.2.4 Research content (Diagram 2.1)
2.2.4.1 For patients with type 2 diabetes mellitus
- Patients were evaluated clinically and subclinically at baseline and
12, 24 weeks after DPP4i combination:
- Clinical indicators
- Subclinical indicators: fasting plasma glucose, 2-hour postprandialblood glucose, HbA1C, fasting plasma C-peptide (nmol / l),calculation of HOMA2 indices
Trang 11- Fasting Glucagon in 30 patients randomly selected in each group.
- Urea (mmol/l), creatinine (µmol/l), SGOT, SGPT fasting plasma
- Cholesterol TP, Triglyceride, HDL-C, LDL-C in fasting plasma.+ Drug treatment
* The oral hypoglycemic drugs that patients used before the studywere continued to be used and kept the same dose throughout thestudy including: metformin and gliclazide
* All patients were given DPP-4i: an initial dose of 50 mg or 100 mg
Sitagliptin daily during the first 12 weeks After 12 weeks, the dosewas adjusted to suit each patient: if HbA1C <7.5% and currenlytaking the dose of 50mg/day, then increase sitagliptin dose to 100mg/day during the next 12 weeks If HbA1C <6.5%, and currentlytaking a dose of 100mg/day, reduce the dose to 50mg/day during thenext 12 weeks
Evaluation of patients is done twice: after 12 weeks - 24 weeksEvaluation of clinical and subclinical indicators according to auniform medical record: - Height, weight, BMI calculation, BPmeasurement and heart rate
- Subclinical: GMLA, GMSA2h, urea, creatinine, SGOT, SGPT,Cholesterol, Triglyceride, HDL-C, LDL-C, C-peptide, serumglucagon at fasting (only at 12 weeks in 30 patients)
- Monitor side effects: Headache, rhinitis,urticaria, sinusitis; stomachache Control
Trang 12.Triglyceride (mmol/l), HDL-C (mmol/l), LDL-C (mmol/l) Fast plasma plasma C-peptide assay (nmol /l).
+ Serum glucose serum indices (T0) and after 12 weeks (T3) in 30patients after combination therapy with DPP-4i
+ Drug treatment
* Blood pressure medications used by patients prior to study werecontinued and remained unchanged throughout the study period: Metand gliclazide
* All patients were given DPP-4i: Sitagliptin suit each patient,individualize treatment 101 patients with type 2 diabetes mellituswho in a median follow-up of 24 consecutive weeks, to meet ADA
2015 target without causing hypoglycemia
Patients monitoring method in 12-24 weeks
These patients were the test is done on a sample Patients are guidedproper diet and exercise and use of hypoglycemic drugs Guidepatients to check PPG 2h at home
2.2.4.2 Control group: The clinical and subclinical examinations
collect the standardized research indicators (Appendix 4) as for thesickthe same way as the sick group
Fasting plasma glucagon was measured in 30 patients at baseline(healthy controls)
- Assessment of insulin resistance, beta-cell function: The insulinresistance was defined by HOMA2-IR-CP It is caculated by fastingplasma glucose levels and fasting plasma C-peptide levels
- C-peptide plasma: considered normal within ± SD, increased when
X > + SD and decreased when X <- SD value of NC
Trang 13- Diagnosis of insulin resistance: Based on the HOMA2-IR index, thequartile cut-off value in HOMA2-IR index of control group wascalculated following the WHO recommendation in 1999
- Diagnosis of beta-cell function reduction: based on HOMA2-% B,cut-off point < X - SD value of control group
- Diagnosis of alpha-cell function: based on glucagon concentration,cut-off point > X + SD value of control group
2.2.2.3: Research diagnostic, assessment and classification criteria
- Diagnostic criteria of diabetes mellitus: ADA 2015
- Assessment criteria for FPG and PPG 2h control: HbA1c: ADA2015
- Classification criteria for Body Mass Index (BMI): Based on BMI
of the Vietnamese Association of Diabetes and EndocrinologyGuideline in 2016
- Classification criteria for dyslipidemia: in 2016 of the VietnameseAssociation of Diabetes and Endocrinology guideline, in 2016
- Classification criteria for hypertension: Ministry of Health (2010)
2.2.2.4: Data processing: Using SPSS software 22.0
2.3 Trial design
Insulin resistance, Alpha-cell function, beta-cell function Screening
Insulin resistance, Alpha-cell function, beta-cell function Screening
Compare
Patients with T2DM using hypoglycemic medications ( n= 101)
Healthy controls
(n= 65)
Patients enrolled (n=166)
Combination therapy with
Trang 14CHAPTER 3 STUDY RESULT 3.1: General characteristics of the study subjects
3.1.1: Gender, age , BMI and Diabetes detection time
Table 3.1, 3.2, 3.3 Gender, age and Diabetes detection timeBMI in control group and treatment group
- The ratio of male and female in 2 groups is not statisticallysignificant
- Age average 54,13 ± 10,11 (years).
- The Diabetes diagnosis time less than 5 years had the highestrate (83.1%) Diabetes diagnosis time over 10 years is the lowest(5%)
- BMI in the treatmet group is 23.49 kg/m2, which is higher thancontrol group of 21.53 kg/m2 The proportion of overweight andobesity patients higher than normal
3.1.2 Subclinical characteristics
Table 3.4 Baseline Plasma glucose index FPG , PPG 2h, HbA1C
sequence 8,62 ± 1,67 (mmol/l); 12,36 ± 2,36 (mmol/l); 7,93 ±0,83(%)
Table 3.5 Proportion of baseline patients who meet and do not meet blood glucose target
Only a few patients achieved FPG, PPG 2h was 18.8%, 11.9%All patients failed to achieve HbA1C goal at baseline
3.1.3 Pre-study Anti-diabetes drugs characteristics
Table 3.6: Pre-study anti-diabetes drugs
Trang 15Anti-diabetes drugs Number
(n)
Proportion (%)
Before the study, all patients had only oral anti-diabetes drugs
3.2 Insulin resistance, pancreatic alpha-cell and beta-cell function in Patients with T2DM
3.2.1 Insulin resistance Index in Patients with T2DM
Table 3.7 HOMA2-IR comparison
Index Control group
(>1,650) 17 (26,2%) 92 (91,1%) <0,001**
* Independent – Samples T-test accrediation; ** χ2 accrediation;
Treament group had a lower non-insulin resistance proportionthan control group Treatment group have higher rates of insulinresistance (91,1%) than control group (26,2%)
3.2.2 Beta-cell function in Patients with T2DM
Table 3.8 HOMA2-%B-CP comparision
Index Control group (n=65) Treatment group
( X ± SD) 112,82 ± 28,34 73,51 ±
25,14
< 0,001*
Trang 16* Independent – Samples T-test accrediation; ** χ2 accrediation;
The reduction in HOMA2-% B in treatment group is higher than
in the control group
3.2.3 Alpha-cell function in Patient with T2DM
Table 3.9 Fasting plasma glucagon concentration comparison
Index Control group
(n=30)
Treatment group
* Independent – Samples T-test accrediation; ** χ2 accrediation
Figure 3.2, 3.3, 3.4, 3.5: Correlation between glucagon and FPG, PPG2h, HbA1C, HOMA2-%B-Cp in patients at baseline with no combination of DPP4-inhibitors (n=300)
Fasting plasma glucagon concentration at baseline without inhibitor combination correlates posotively, strictly and