JOURNAL OF MILITARY PHARMACO MEDICINE N 0 4 2022 193 ASSESSMENT OF INSULIN RESISTANCE AND SERUM CONCENTRATION OF HUMAN PLACENTAL LACTOGENIC HORMONE IN GESTATIONAL DIABETES MELLITUS Vu Thi Hien Trinh 1[.]
JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 ASSESSMENT OF INSULIN RESISTANCE AND SERUM CONCENTRATION OF HUMAN PLACENTAL LACTOGENIC HORMONE IN GESTATIONAL DIABETES MELLITUS Vu Thi Hien Trinh1,2, Nguyen Thi Phi Nga2 Summary Objectives: To assess insulin resistance by HOMA-IR and serum human placental lactogen (hPL) level and the relationship between these factors and risk factors of gestational diabetes mellitus (GDM) Subjects and methods: A descriptive, cross-sectional study on 252 pregnant women with GDM and 48 pregnant women without GDM (non-GDM) from 7/2018 to 1/2022 at the National Hospital of Endocrinology Results: Insulin resistance index (HOMA2IR) in GDM group (1.48 (0.93 - 2.15) was higher than that in non-GDM (1.06 (0.64 - 1.45) (p < 0.01) The rate of increasing HOMA2-IR index in the GDM women (48.4%) was higher than that in non-GDM women (22.9%) (p < 0.01) The concentrations of hPL in GDM group (6.02 mg/L) was higher than in nonGDM group (5.3 mg/L) (p < 0.01) The rate of elevated hPL levels in GDM women (61.2%) was higher than in non-GDM women (22.9%) (p < 0.01) HOMA2-IR was positively correlated with serum hPL levels (r = 0.23), prepregnancy BMI (r = 0.3), BMI at diagnosis of GMD (r = 0.42), maternal weight gain (r = 0.32), mean weight gain per week (r = 0.3) and fasting plasma glucose (FPG) (r = 0.32) hPL concentration correlated positively with maternal weight gain (r = 0.14) and FPG (r = 0,32), but it was not associated with age, pregestational BMI, BMI at diagnosis of GDM and maternal weight gain Conclusion: Insulin resistance index (HOMA2-IR) was higher in GDM group and correlates positively with BMI prior to pregnancy, BMI at diagnosis of GDM, gestational weight gain and FPG Serum hPL level was higher in GDM than that in non-GDM, and there was a positive correlation between HOMA2-IR, maternal weight gain, and FPG * Keywords: HOMA-IR; Serum human placental lactogen level; Gestational diabetes mellitus National Hospital of Endocrinology Military Hospital 103, Vietnam Military Medical University Corresponding author: Vu Thi Hien Trinh (vuhientrinh@gmail.com) Date received: 05/5/2022 Date accepted: 20/5/2022 193 JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 INTRODUCTION Gestational diabetes is a highly prevalent metabolic disorder among pregnant women, and the incidence of GDM has increased rapidly in recent years Short-term and long-term complications of GDM impose great burdens on patients, their families and the society [12] The most significant metabolic change during pregnancy is insulin resistance Available literature demonstrates that there are numerous factors contributing to insulin resistance in pregnancy, including the role of the placenta The extent of insulin resistance in pregnancy corresponds to the growth of the placenta and the increase of placental hormone levels, including human placental lactogen (hPL) [4] hPL is a peptide hormone secreted throughout pregnancy and present only during pregnancy hPL can promotes synthesize and secrete insulin in the first half of pregnancy [13] hPL also promotes beta cell regeneration, growth, and increased beta cell mass In the catabolic phase of the third trimester, hPL causes increased lipolysis and fat mobilization, especially during fasting periods hPL causes insulin resistance and sensitivity to various extents In late pregnancy, hPL reduces glucose 194 transport while increasing ketone, glycerol, and free fatty acid levels, thereby mainly contributing to the insulin-resistant state [14] In order to elucidate the role of insulin resistance and the impact of hPL on GMD, this study was conducted: To assess insulin resistance by HOMA-IR and serum hPL levels and the relationship between these factors and risk factors of GDM SUBJECTS AND METHODS Subjects The subjects included 300 pregnant women, divided into groups: - GDM group: 252 pregnant women diagnosed with GDM were treated at the ational Hospital of Endocrinology from July 2018 to July 2019 - Non-GDM group: 48 pregnant women without GDM had maternal age and gestational age matching with GDM group * Selection criteria: - GDM group: + The diagnosis of GDM is made by a 75g oral glucose tolerance test (OGTT) according to the World Health Organization (WHO) criteria (2013); GDM patients received no specific intervention JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 + Diagnose GDM if one or more values equals or exceed the following thresholds [4]: 75g OGTT FPG level (mmol/L) A one-hour plasma glucose level (mmol/L) A two-hour plasma glucose level (mmol/L) GDM 5.1 - 6.9 ≥ 10 8.5 - 11.0 + Patients agreed to participate in the study - Non-GDM group: + Pregnant women without GDM and patients with OGTT data were excluded + Patients agreed to participate in the study * Exclusion criteria: - Pregnant women with acute diseases, threatened preterm labor, pre-eclampsia and on corticosteroid therapy - Patients refused to participate in the study Methods * Study design: Cross-sectional study * Sample size: - GDM group: The sample size was calculated according to the formula: n= Of which: n: minimum sample size required, α: statistically significant; when α = 0.05, = 1.96, p = 0.203 (the prevalence of GDM in Ho Chi Minh City in a study by Jane E Hirst (2012) was 20.3%) [5]; q = 0.797; d = 0.05 We calculated n = 249, and the total number of patients in this study was 252 * Content of study: - Clinical examination: + Age, height, weight, BMI + Measurement of hypertension, comprehensive physical examination of cardiovascular, respiratory, digestive, thyroid, and other organ systems - Subclinical examination: + Procedures for OGTT: patients fast for - 12 hours prior to the OGTT; collect ml venous blood to measure the FPG; drink a 75g solution of glucose (sugar) in 200 ml of water within five minutes; collect mL of venous blood and measure venous plasma glucose at hour and hours after oral intake of 75g of glucose + Determination of insulin, C-peptide, HbA1c, ure, creatinin, GOT, GPT + Quantitative determination of hPL: Using ELISA technique based on the specific reaction between antibody 195 JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 binding to the bottom of the well and hPL antigen in patient’s serum in combination with the color change of specific substrate Use a spectrophotometer at a wavelength of 450 nm It was performed at the Department of Pathophysiology, Military Medical University Evaluate the increase or reduction of hPL based on the interquartile range (IQR) of the control group: Increased hPL: value greater than the third quartile of the control group No increased hPL: value equal to or less than the first quartile of the control group HOMA was calculated based on FPG and fasting insulin levels The data was entered and calculated by software version 2.2.3 (2013) on Excel provided by Oxford University [15] The elevation and reduction of variables were assessed based on the IQR of the control group Increase: value greater than the third quartile of the control group Non-increase: value equal to or less than the first quartile of the control group Statistical analysis Data are expressed as mean (SD) or, if skewed, as median (interquartile range) for the continuous variables and as a percentage for categorical variables (Q1-Q3) Statistical analyses were performed using SPSS 26.0 RESULTS Table 1: Characteristics of age, pre-pregnancy BMI, glucose, and HbA1c GDM (n = 252) 30.8 ± 4.68 Non-GDM (n = 48) 28.9 ± 1.9 > 0.05 21.8 ± 3.0 20.5 ± 1.6 < 0.05 4.94 ± 0.61 4.24 ± 0.34 3.6 - 6.78 3.4 - 4.99 10.45 ±1.32 7.73 ± 1.2 4.67 - 14.5 4.46 - 9.97 9.19 ± 1.11 6.72 ± 1.02 Min - Max ± SD 5.38 ± 11.08 4.23 - 8.42 5.36 ± 0.36 5.05 ± 0.19 Min - Max 4.6 - 6.4 4.7 - 5.6 Variables Age (years) Pre-pregnancy BMI (kg/m2) FPG (mmol/L) 1-hour plasma glucose (OGTT) (mmol/L) 2-hour plasma glucose (OGTT) (mmol/L) HbA1c (%) ± SD Min - Max ± SD Min - Max ± SD P < 0.001 < 0.001 < 0.001 < 0.001 - Pre-pregnancy BMI, blood glucose levels at various timepoints of OGTT, and HbA1c in the GDM group were higher than that in the non-GDM group 196 JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 GDM (n = 252) Non-GDM (n = 48) p Insulin (pmol/L) 80.4 (50.6 - 115) 59.6 (36.1 - 80.7) < 0.01 Cpeptid (nmol/L) 0.99 (0.68 - 1.31) 0.74 (0.48 - 1.0) < 0.001 Median (Q1-Q3) 67.2 (46.7 - 107.1) 93 (60.8 - 150.1) < 0.01 Reductio (< 60.8) 104 (41.3%) 11 (22.9%) < 0.05 HOMA2-IR insulin Median (Q1-Q3) 1.48 (0.93 - 2.15) 1.06 (0.64 - 1.45) < 0.01 Increase (> 1.45) 122 (48.4%) 11 (22.9%) < 0.01 HOMA2-B insulin Table 2: Characteristics of concentration of insulin, C-peptide and HOMA2 index in two groups Median (Q1-Q3) 134 (97.6 - 168.2) 141.7 (107.4 177.6) > 0.05 Decrease ( 5.61 mg/L) 169 (61.2%) 11 (22.9%) Non-increase (≤ 5.61 mg/L) 107 (38.8%) 37 (77.1%) < 0.01 The median hPL level in the GDM group was higher than that in the non-GDM, with a statistically significant difference (p < 0.01) 197 JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 Table 4: The correlation between hPL concentrations, HOMA2-IR, and some factors in GDM HOMA2-IR hPL (mg/L) R p r P -0.01 > 0.05 0.015 > 0.05 Pre-pregnancy BMI (kg/m2) 0.3 < 0.001 0.04 > 0.05 BMI at diagnosis of GDM (kg/m2) 0.42 < 0.001 0.03 > 0.05 Maternal weight gain (kg) 0.32 < 0.001 0.14 < 0.05 Mean weight gain /week (kg) 0.3 < 0.001 0.1 > 0.05 FPG (mmol/L) 0.32 < 0.001 0.32 < 0.05 Patients’ characteristics Age (years) There was a significantly positive correlation between BMI, maternal weight gain, FPG, and HOMA2-IR; hPL correlated positively with increased maternal gestational weight gain and FPG Table 5: Correlation between hPL and insulin and HOMA2 in GDM group hPL Index R p Insulin 0,21 < 0.01 HOMA2-IR 0,23 < 0.001 HOMA2-S -0,23 < 0.001 HOMA2-%B 0,02 > 0.05 There was a weak positive correlation between hPL levels and insulin (r = 0,21; p < 0.01), HOMA2-IR (r = 0,23, p < 0.001) Serum hPL level correlated negatively with HOMA2-S (r = -0.23, p < 0.001) 198 JOURNAL OF MILITARY PHARMACO - MEDICINE N04 - 2022 DISCUSSION Insulin resistance in GMD In some pregnancies, GDM develops as a consequence of either unusually high insulin resistance, perhaps because of the contribution of pre-existing insulin resistance in overweight women, or because of inadequate beta cell expansion and concomitant insulin insufficiency [6] In Asians, pancreatic beta cell mass is relatively smaller than in the European population Asian individuals have lower insulin secretory capacity Moreover, beta cell adaptation in pregnancy is significantly lower in South Asian women compared with Western European counterparts Fasting C-peptide and insulin allows estimation of insulin secretion The best noninvasive approach to the assessment of insulin secretion is to measure insulin levels and fasting C-peptide The HOMA model is the most widely used surrogate measure for assessing insulin sensitivity/resistance In our study, insulin level and fasting C-peptide in GDM group were significantly higher than in the controls (80.4 vs 59.6 pmol/L, p < 0.01; 0.99 vs 0.74 nmol/L, p < 0.001 In GDM group, HOMA2-S and HOMA2-B were lower, whereas HOMA2-IR was higher compared to the control group Insulin levels and C-peptide in GDM group was reported in a study by Le Dinh Tuan was 115.9 ± 79.7 pmol/L and 1.15 ± 0.66 nmol/L [1] Research by Nguyen Thu Hien et al demonstrated that insulin levels and fasting C-peptide in GDM group were significantly higher than in non-GDM women and that GDM women have greater insulin resistance and beta cell dysfunction (difference with p < 0.001) This finding is in line with Tania Tofail’s research: fasting insulin, HOMA-IR in GDM group is significantly higher than in non-GDM, HOMA2-B and HOMA2-%S are lower than non-GDM group (p < 0.01) Overweight, pre-pregnancy obesity, and excessive gestational weight gain are the main contributors to GDM and emerge as risk factors for maternofetal complications Women who have GDM are at higher risk of overweight and obesity at diagnosis of GDM than the general population There is a significant decrease in insulin sensitivity in late gestation, especially for obese women with GDM In obesity, there is an inverse relationship between decreased insulin sensitivity and fat accumulation from pre-pregnancy to late pregnancy Pregnancy is characterized by alterations in insulin sensitivity, which leads to metabolic change Pre-pregnancy BMI and gestational weight gain are positively associated with maternal insulin resistance and increased risks of adverse maternal and fetal outcomes 199 ... contributing to insulin resistance in pregnancy, including the role of the placenta The extent of insulin resistance in pregnancy corresponds to the growth of the placenta and the increase of placental. .. consequence of either unusually high insulin resistance, perhaps because of the contribution of pre-existing insulin resistance in overweight women, or because of inadequate beta cell expansion and concomitant... the assessment of insulin secretion is to measure insulin levels and fasting C-peptide The HOMA model is the most widely used surrogate measure for assessing insulin sensitivity /resistance In