HbA1c Test as a Tool in the Diagnosis of Gestational Diabetes Mellitus

Aims

Gestational diabetes mellitus (GDM) is a prevalent and potentially serious condition which may put both mothers and neonates at risk. The current recommendation for diagnosis is the oral glucose tolerance test (OGTT). This study aimed to determine the usefulness of HbA1c test as a diagnostic tool for GDM as compared to the traditional criteria based on the OGTT.

Methods

This was a diagnostic test accuracy study. We performed OGTT and HbA1c test in women attending prenatal visits at a tertiary hospital. GDM was defined according to WHO1999 or ADA/WHO 2013 criteria. ROC curve was used to evaluate the diagnostic performance of HbA1c. Sensitivity, specificity and likelihood ratios for different HbA1c cut-off points were calculated.

Results

Of the 262 women in the third trimester of gestation enrolled in the study, 86 (33%) were diagnosed with GDM. Only five of these women presented HbA1c ≥48 mmol/mol (6.5%). This cut-off point presented 100% specificity but very low sensitivity (7%). Based on ROC curve, and considering OGTT as the reference criterion, HbA1c ≥40 mmol/mol (5.8%) showed adequate specificity in diagnosing GDM (94.9%) but low sensitivity (26.4%). Unlike, HbA1c values of 31 mmol/mol (5.0%) presented adequate sensitivity (89.7%) but low specificity (32.6%) to detect GDM. For women with HbA1c ≥40 mmol/mol (5.8%), the positive and negative likelihood ratios were 5.14 (95%CI 2.49–10.63) and 0.78 (0.68–0.88), respectively. The post-test probability of GDM was about 40%, representing a 4.0-fold increase in the mean pre-test probability. This cut-off point could eliminate the need for the unpleasant and laborious OGTT tests in almost one third of cases, as 38% of patients with GDM may be diagnosable by HbA1c test alone.

Conclusions

Our results show that combined HbA1c and OGTT measurements may be useful in diagnosing GDM.     

Secular Trends of Gestational Diabetes Mellitus and Changes in Its Risk Factors

Objective

The aim of this study was to evaluate the secular trends of incidence of gestational diabetes mellitus (GDM) and insulin treatment for GDM in a Korean population and to determine the factors that contribute to the trends in the incidence of GDM.

Study Design

We used data collected by the Health Insurance Review & Assessment Service of Korea and analyzed data from women who had given birth from 2006 to 2010. We evaluated the trends in the incidence of GDM and GDM requiring insulin treatment and the changes in risk factors.

Results

There were 1,824,913 births during the study period, which included 129,666 cases of GDM, an incidence of 7.11% over this period. The incidence of GDM increased from 3.86% in 2007 to 11.83% in 2010, with a continuous increase after adjustment for age. However, the number of GDM cases that required insulin treatment decreased significantly from 13.87% in 2007 to 5.94% in 2010. The proportion of patients who were at an older age and multiparity, 2 GDM risk factors, increased during the study period.

Conclusions

In Korea, the incidence of GDM, especially mild GDM, increased dramatically during the period from 2006 to 2010. Further efforts are needed to monitor this trend and to identify associated factors.     

Prevalence of Gestational Diabetes Mellitus and Its Risk Factors in Chinese Pregnant Women: A Prospective Population-Based Study in Tianjin,China

Objective

We compared the increases in the prevalence of gestational diabetes mellitus (GDM) based on the 1999 World Health Organization (WHO) criteria and its risk factors in Tianjin, China, over a 12-year period. We also examined the changes in the prevalence using the criteria of International Association of Diabetes and Pregnancy Study Group (IADPSG).

Methods

In 2010-2012, 18589 women who registered within 12 weeks of gestation underwent a glucose challenge test (GCT) at 24-28 gestational weeks. Amongst them, 2953 women with 1-hour plasma glucose ≥7.8 mmol/L underwent a 75-gram 2-hour oral glucose tolerance test (OGTT) and 781 women had a positive GCT but absented from the standard OGTT. An adjusted prevalence of GDM was calculated for the whole cohort of women by including an estimate of the proportion of women with positive GCTs who did not have OGTTs but would have been expected to have GDM. Logistic regression was used to obtain odds ratios and 95% confidence intervals using the IADPSG criteria. The prevalence of GDM risk factors was compared to the 1999 survey.

Results

The adjusted prevalence of GDM by the 1999 WHO criteria was 8.1%, a 3.5-fold increase as in 1999. Using the IADPSG criteria increased the adjusted prevalence further to 9.3%. Advanced age, higher pre-pregnancy body mass index, Han-nationality, higher systolic blood pressure (BP), a family history of diabetes, weight gain during pregnancy and habitual smoking were risk factors for GDM. Compared to the 1999 survey, the prevalence of overweight plus obesity had increased by 1.8 folds, age≥30 years by 2.3 folds, systolic BP by 2.3 mmHg over the 12-year period.

Conclusions

Increasing prevalence of overweight/obesity and older age at pregnancy were accompanied by increasing prevalence of GDM, further increased by change in diagnostic criteria.     

Serum LBP Is Associated with Insulin Resistance in Women with PCOS

Introduction

Lipopolysaccharide-binding protein (LBP) is closely associated with many metabolic disorders. However, no study has been done to explore the relationship between LBP and polycystic ovary syndrome (PCOS). The objective of this study was to investigate whether the serum LBP level is elevated and associated with insulin resistance (IR) in PCOS.

Participants and Design

In this cross-sectional study, 117 PCOS patients and 121 age-matched controls were recruited. Hyperinsulinemic-euglycemic clamp was performed with an expression of M value for insulin sensitivity. Fasting serum samples were collected to detect LBP, lipids, insulin, sex hormones and high sensitive C reactive protein (hs-CRP). Pearson’s correlation and multiple linear regression was used to analyze the associations between M value and LBP level.

Settings

The study was performed in a clinical research center.

Results

Compared with controls, PCOS subjects had a significantly higher LBP concentration (33.03±14.59 vs. 24.35±10.31 μg/ml, p<0.001), and lower M value (8.21±3.06 vs. 12.31±1.72 mg/min/kg, p<0.001). Both in lean and overweight/obese individuals, serum LBP level was higher in PCOS subjects than that in controls. M value was negatively correlated with body mass index (BMI), fasting serum insulin, triglycerides, low-density lipoprotein cholesterol (LDL-c), free testosterone, high sensitive C reactive protein (hs-CRP) and LBP, whereas positively correlated with high-density lipoprotein cholesterol (HDL-c) and sex hormone binding globulin (SHBG). Serum LBP level was associated with M value after adjusting for BMI, fasting serum insulin, SHBG, as well as hs-CRP.

Conclusion

Serum LBP level significantly is elevated in PCOS, and is independently associated with IR in PCOS.     

The rs2237892 Polymorphism in KCNQ1 Influences Gestational Diabetes Mellitus and Glucose Levels: A Case-Control Study and Meta-Analysis

Objective

Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians.

Methods

A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted.

Results

The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)).

Conclusion

The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.     

Circulating Betatrophin Is Strongly Increased in Pregnancy and Gestational Diabetes Mellitus

Aims/hypothesis

Betatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear.

Methods

Circulating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results.

Results

Betatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight.

Conclusions/interpretation

Circulating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease.     

Relationship between High Serum Cystatin C Levels and the Risk of Gestational Diabetes Mellitus

Aims

Serum cystatin C (CysC) has recently been shown to be associated with the incidence of type 2 diabetes mellitus (T2DM) and progression to the pre-diabetic state. The aim of this study was to explore the relationship between serum CysC and the risk of gestational diabetes mellitus (GDM) in Chinese pregnant women.

Methods

This cross-sectional study consisted of 400 pregnant women including111 with GDM and 289 with normal glucose tolerance at 24–28 weeks of gestation. The subjects were further divided into four groups according to the CysC quartiles, and their clinical characteristics were compared. The serum CysC concentration was measured using immunoturbidimetry and the degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR).

Results

Serum CysC levels were significantly higher in pregnant women with GDM than in the healthy pregnant women[1.0(0.8–1.8) vs 0.7(0.6–1.0), P<0.01). The Spearman’s correlation analysis showed that serum CysC was positively associated with HOMA-IR(r = 0.118, P<0.05) and the occurrence of GDM(r = 0.348, P<0.01). The pregnant women were divided into quartiles according to their serum CysC concentrations. Compared to the first quartile, pregnant women in Q2 (OR, 2.441; P = 0.025), Q3 (OR, 3.383; P = 0.001) and Q4 (OR, 5.516; P<0.001) had higher risk of GDM after adjusted for age, BMI, HbA1c and HOMA-IR. Further, with a rise in the serum CysC, there was an increasing trend in the HOMA-IR levels (P<0.05). A binary logistic regression analysis after adjusting for other confounding variables revealed a significant and independent association between serum CysC and GDM [OR = 14.269; 95% confidence interval, 4.977–40.908, P<0.01].The receiver operating characteristic curve analysis revealed that the optimal cutoff point for serum CysC to indicate GDM was 0.95mg/L.

Conclusions

Serum CysC is significantly and independently associated with insulin resistance and GDM. It may be a helpful biomarker to identify the risk of GDM in Chinese pregnant women.     

Risk Factors for Hyperglycaemia in Pregnancy in Tamil Nadu,India

Introduction

Hyperglycaemia in pregnancy (HIP), i.e. gestational diabetes mellitus (GDM) and diabetes in pregnancy (DIP), increases the risk of various short- and long-term adverse outcomes. However, much remains to be understood about the role of different risk factors in development of HIP.

Objective

The aims of this observational study were to examine the role of potential risk factors for HIP, and to investigate whether any single or accumulated risk factor(s) could be used to predict HIP among women attending GDM screening at three centres in urban, semi-urban and rural Tamil Nadu, India.

Methodology

Pregnant women underwent a 75 g oral glucose tolerance test. Data on potential risk factors was collected and analysed using logistical regression analysis. Receiver operating characteristic (ROC) curves, sensitivity, specificity and predictive values were calculated for significant risk factors and a risk factor scoring variable was constructed.

Results

HIP was prevalent in 18.9% of the study population (16.3% GDM; 2.6% DIP). Increasing age and BMI as well as having a mother only or both parents with diabetes were significant independent risk factors for HIP. Among women attending the rural health centre a doubling of income corresponded to an 80% increased risk of HIP (OR 1.80, 95%CI 1.10–2.93; p = 0.019), whereas it was not significantly associated with HIP among women attending the other health centres. The performance of the individual risk factors and the constructed scoring variable differed substantially between the three health centres, but none of them were good enough to discriminate between those with and without HIP.

Conclusions

The findings highlight the importance of socio-economic circumstances and intergenerational risk transmission in the occurrence of HIP as well as the need for universal screening.     

Polyunsaturated Fatty Acids Attenuate Diet Induced Obesity and Insulin Resistance,Modulating Mitochondrial Respiratory Uncoupling in Rat Skeletal Muscle

Objectives

Omega (ω)-3 polyunsaturated fatty acids (PUFA) are dietary compounds able to attenuate insulin resistance. Anyway, the precise actions of ω-3PUFAs in skeletal muscle are overlooked. We hypothesized that PUFAs, modulating mitochondrial function and efficiency, would ameliorate pro-inflammatory and pro-oxidant signs of nutritionally induced obesity.

Study Design

To this aim, rats were fed a control diet (CD) or isocaloric high fat diets containing either ω-3 PUFA (FD) or lard (LD) for 6 weeks.

Results

FD rats showed lower weight, lipid gain and energy efficiency compared to LD-fed animals, showing higher energy expenditure and O₂ consumption/CO₂ production. Serum lipid profile and pro-inflammatory parameters in FD-fed animals were reduced compared to LD. Accordingly, FD rats exhibited a higher glucose tolerance revealed by an improved glucose and insulin tolerance tests compared to LD, accompanied by a restoration of insulin signalling in skeletal muscle. PUFAs increased lipid oxidation and reduced energy efficiency in subsarcolemmal mitochondria, and increase AMPK activation, reducing both endoplasmic reticulum and oxidative stress. Increased mitochondrial respiration was related to an increased mitochondriogenesis in FD skeletal muscle, as shown by the increase in PGC1-α and -β.

Conclusions

our data strengthened the association of high dietary ω3-PUFA intake with reduced mitochondrial energy efficiency in the skeletal muscle.     

Pulsatile Hyperglycaemia Induces Vascular Oxidative Stress and GLUT 1 Expression More Potently than Sustained Hyperglycaemia in Rats on High Fat Diet

Introduction

Pulsatile hyperglycaemia resulting in oxidative stress may play an important role in the development of macrovascular complications. We investigated the effects of sustained vs. pulsatile hyperglycaemia in insulin resistant rats on markers of oxidative stress, enzyme expression and glucose metabolism in liver and aorta. We hypothesized that liver’s ability to regulate the glucose homeostasis under varying states of hyperglycaemia may indirectly affect oxidative stress status in aorta despite the amount of glucose challenged with.

Methods

Animals were infused with sustained high (SHG), low (SLG), pulsatile (PLG) glucose or saline (VEH) for 96 h. Oxidative stress status and key regulators of glucose metabolism in liver and aorta were investigated.

Results

Similar response in plasma lipid oxidation was observed in PLG as in SHG. Likewise, in aorta, PLG and SHG displayed increased expression of glucose transporter 1 (GLUT1), gp-91^PHOX and super oxide dismutase (SOD), while only the PLG group showed increased accumulation of oxidative stress and oxidised low density lipoprotein (oxLDL) in aorta.

Conclusion

Pulsatile hyperglycaemia induced relatively higher levels of oxidative stress systemically and in aorta in particular than overt sustained hyperglycaemia thus supporting the clinical observations that pulsatile hyperglycaemia is an independent risk factor for diabetes related macrovascular complications.     

Insulin Resistance Is Associated with Prevalence of Physician-Diagnosed Urinary Incontinence in Postmenopausal Non-Diabetic Adult Women: Data from the Fourth Korea National Health and Nutrition Examination Survey

Objective

To investigate the association between insulin resistance (IR) and urinary incontinence in Korean adult women by analyzing the data from the Korea National Health and Nutrition Examination Survey IV (KNHANES) 2007–2009

Methods

A nationally representative sample of 5318 non-diabetic Korean women ≥19-years-of-age (3043 premenopausal and 2275 postmenopausal women) was included from KNHANES 2008–2010. IR was measured using the homeostasis model assessment of IR (HOMA-IR). Participants in the highest and lowest quartile of HOMA-IR were defined as insulin-resistant and insulin-sensitive respectively. Women who have current physician-diagnosed urinary incontinence were classified as having urinary incontinence.

Results

Incontinence was found in 9.18% of the total population, 8.51% of the premenopausal population, and 10.86% of the postmenopausal population. The prevalence of incontinence increased with age, reaching a peak at 60-69-years-of-age. The prevalence of urinary incontinence increased significantly with higher HOMA-IR quartiles in pre- and post-menopausal women (p for linear association = 0.0458 and 0.0009 respectively). Among post-menopausal women, those in the highest quartile of HOMA-IR were significantly more likely to have urinary incontinence compared to those in the lowest quartile [adjusted odds ratio, 1.72; 95% confidence interval, 1.07–2.77]. However premenopausal population exhibited no association between incontinence and HOMA-IR quartiles

Conclusion

Our results suggest that the prevalence of incontinence increased across HOMA-IR in non-diabetic adult women, and especially, IR might be a risk factor for incontinence in postmenopausal non-diabetic women.     

Dual Opposing Roles of Metallothionein Overexpression in C57BL/6J Mouse Pancreatic β-Cells

Background

Growing evidence indicates that oxidative stress (OS), a persistent state of excess amounts of reactive oxygen species (ROS) along with reactive nitrogen species (RNS), plays an important role in insulin resistance, diabetic complications, and dysfunction of pancreatic β-cells. Pancreatic β-cells contain exceptionally low levels of antioxidant enzymes, rendering them susceptible to ROS-induced damage. Induction of antioxidants has been proposed to be a way for protecting β-cells against oxidative stress. Compared to other antioxidants that act against particular β-cell damages, metallothionein (MT) is the most effective in protecting β-cells from several oxidative stressors including nitric oxide, peroxynitrite, hydrogen peroxide, superoxide and streptozotocin (STZ). We hypothesized that MT overexpression in pancreatic β-cells would preserve β-cell function in C57BL/6J mice, an animal model susceptible to high fat diet-induced obesity and type 2 diabetes.

Research Design and Methods

The pancreatic β-cell specific MT overexpression was transferred to C57BL/6J background by backcrossing. We studied transgenic MT (MT-tg) mice and wild-type (WT) littermates at 8 weeks and 18 weeks of age. Several tests were performed to evaluate the function of islets, including STZ in vivo treatment, intraperitoneal glucose tolerance tests (IPGTT) and plasma insulin levels during IPGTT, pancreatic and islet insulin content measurement, insulin secretion, and islet morphology assessment. Gene expression in islets was performed by quantitative real-time PCR and PCR array analysis. Protein levels in pancreatic sections were evaluated by using immunohistochemistry.

Results

The transgenic MT protein was highly expressed in pancreatic islets. MT-tg overexpression significantly protected mice from acute STZ-induced ROS at 8 weeks of age; unexpectedly, however, MT-tg impaired glucose stimulated insulin secretion (GSIS) and promoted the development of diabetes. Pancreatic β-cell function was significantly impaired, and islet morphology was also abnormal in MT-tg mice, and more severe damage was detected in males. The unique gene expression pattern and abnormal protein levels were observed in MT-tg islets.

Conclusions

MT overexpression protected β-cells from acute STZ-induced ROS damages at young age, whereas it impaired GSIS and promoted the development of diabetes in adult C57BL/6J mice, and more severe damage was found in males.     

Relationship between Polycystic Ovarian Syndrome and Subsequent Gestational Diabetes Mellitus: A Nationwide Population-Based Study

Objective

This nationwide population-based study aims to explore the relationship between polycystic ovarian syndrome (PCOS) and subsequent gestational diabetes mellitus (GDM).

Methods

Data from 1998–2012 Taiwan National Health Insurance Research Database were used for this study. ICD9-CM codes 256.4X and 648.X were used separately for the diagnoses of PCOS and GDM, which were further confirmed by records of blood tests or ultrasonography to ensure the accuracy of the diagnoses. Women diagnosed at < 15 or > 45 years of age, and those diagnosed with overt diabetes mellitus or GDM prior to PCOS were excluded. During pregnancy, each woman with a previous diagnosis of PCOS was age-matched to 10 women without PCOS. Odds ratios (ORs) for risk of GDM were calculated by logistic regression analysis with adjustment for economic status and co-morbidities.

Results

Among 7,629 eligible women with a valid PCOS diagnosis, 3,109 (42.87%) had subsequent pregnancies. GDM occurred frequently among women with a history of PCOS as compared to those without PCOS (20.46% vs. 10.54%, p<0.0001). Logistic regression analysis revealed that PCOS was associated with GDM (adjusted OR = 2.15; 95% CI:1.96–2.37). Among 3,109 affected patients, 1,160 (37.31%) had used medications for PCOS and 261 (8.39%) were treated with an oral hypoglycemic agent (OHA). There was no significant difference in development of GDM between the medication and no medication sub-groups (p>0.05). If not used after conception, OHAs did not reduce the risk of GDM (adjusted OR = 1.20; 95% CI:0.88–1.62).

Conclusions

A history of PCOS is a significant and independent risk factor for development of GDM. Medication for PCOS or pre-pregnancy use of OHAs does not reduce the risk of GDM. When at-risk women become pregnant, they require closer surveillance for maternal and fetal well-being, and should follow a strict diet and adhere to weight gain control to avoid obstetric complications due to GDM.     

Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men

Context

Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified.

Objective

To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal.

Design

Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5–40.2 kg/m²) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL₁ and VLDL₂) were measured after the fat-rich meal.

Main Outcome Measures

Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.

Results

The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.

Conclusions

In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.     

Increased Maternal and Cord Blood Betatrophin in Gestational Diabetes

Aim

The aim of the study was to compare maternal and cord blood levels of betatrophin – a new peptide potentially controlling beta cell growth - as well as in its mRNA expression in subcutaneous adipose tissue, visceral adipose tissue and placental tissue obtained from pregnant women with normal glucose tolerance (NGT) and gestational diabetes (GDM).

Methods

Serum betatrophin and irisin concentrations were measured by ELISA in 93 patients with GDM and 97 women with NGT between 24 and 28 week of gestation. Additionally, maternal and cord blood betatrophin and irisin, as well as their genes (C19orf80 and Fndc5) expression were evaluated in 20 patients with GDM and 20 women with NGT at term.

Results

In both groups, serum betatrophin concentrations were significantly higher in the patients with GDM than in the controls (1.91 [1.40-2.60] ng/ml vs 1.63 [1.21-2.22] ng/ml, p=0.03 and 3.45 [2.77-6.53] ng/ml vs 2.78 [2.16-3.65] ng/ml, p=0.03, respectively). Cord blood betatrophin levels were also higher in the GDM than in the NGT group (20.43 [12.97-28.80] ng/ml vs 15.06 [10.11-21.36] ng/ml, p=0.03). In both groups betatrophin concentrations in arterial cord blood were significantly higher than in maternal serum (p=0.0001). Serum irisin levels were significantly lower in the patients with GDM (1679 [1308-2171] ng/ml) than in the healthy women between 24 and 28 week of pregnancy (1880 [1519-2312] ng/ml, p=0.03). Both C19orf80 and Fndc5 mRNA expression in fat and placental tissue did not differ significantly between the groups studied.

Conclusions

Our results suggest that an increase in maternal and cord blood betatrophin might be a compensatory mechanism for enhanced insulin demand in GDM.     

Endothelial-Derived Oxidative Stress Drives Myofibroblastic Activation and Calcification of the Aortic Valve

Aims

Oxidative stress is present in and contributes to calcification of the aortic valve, but the driving factors behind the initiation of valve oxidative stress are not well understood. We tested whether the valve endothelium acts as an initiator and propagator of oxidative stress in aortic valve disease.

Methods and Results

Calcified human aortic valves showed side-specific elevation of superoxide in the endothelium, co-localized with high VCAM1 expression, linking oxidative stress, inflammation, and valve degeneration. Treatment with inflammatory cytokine TNFα increased superoxide and oxidative stress and decreased eNOS and VE-cadherin acutely over 48 hours in aortic valve endothelial cells (VEC) and chronically over 21 days in ex vivo AV leaflets. Co-treatment of VEC with tetrahydrobiopterin (BH₄) but not apocynin mitigated TNFα-driven VEC oxidative stress. Co-treatment of ex vivo AV leaflets with TNFα+BH₄ or TNFα+peg-SOD rescued endothelial function and mitigated inflammatory responses. Both BH₄ and peg-SOD rescued valve leaflets from the pro-osteogenic effects of TNFα treatment, but only peg-SOD was able to mitigate the fibrogenic effects, including increased collagen and αSMA expression.

Conclusions

Aortic valve endothelial cells are a novel source of oxidative stress in aortic valve disease. TNFα-driven VEC oxidative stress causes loss of endothelial protective function, chronic inflammation, and fibrogenic and osteogenic activation, mitigated differentially by BH₄ and peg-SOD. These mechanisms identify new targets for tailored antioxidant therapy focused on mitigation of oxidative stress and restoration of endothelial protection.     

Association of Insulin Resistance,Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases

Background

Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV).

Methods

The study group included 303 subjects, mean age 51.8 ±13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis.

Results

Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL.

Conclusions

These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.     

Association of Maternal Vitamin D Status with Glucose Tolerance and Caesarean Section in a Multi-Ethnic Asian Cohort: The Growing Up in Singapore Towards Healthy Outcomes Study

Objective

Epidemiological studies relating maternal 25-hydroxyvitamin D (25OHD) with gestational diabetes mellitus (GDM) and mode of delivery have shown controversial results. We examined if maternal 25OHD status was associated with plasma glucose concentrations, risks of GDM and caesarean section in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study.

Methods

Plasma 25OHD concentrations, fasting glucose (FG) and 2-hour postprandial glucose (2HPPG) concentrations were measured in 940 women from a Singapore mother-offspring cohort study at 26–28 weeks’ gestation. 25OHD inadequacy and adequacy were defined based on concentrations of 25OHD ≤75nmol/l and >75nmol/l respectively. Mode of delivery was obtained from hospital records. Multiple linear regression was performed to examine the association between 25OHD status and glucose concentrations, while multiple logistic regression was performed to examine the association of 25OHD status with risks of GDM and caesarean section.

Results

In total, 388 (41.3%) women had 25OHD inadequacy. Of these, 131 (33.8%), 155 (39.9%) and 102 (26.3%) were Chinese, Malay and Indian respectively. After adjustment for confounders, maternal 25OHD inadequacy was associated with higher FG concentrations (β = 0.08mmol/l, 95% Confidence Interval (CI) = 0.01, 0.14), but not 2HPPG concentrations and risk of GDM. A trend between 25OHD inadequacy and higher likelihood of emergency caesarean section (Odds Ratio (OR) = 1.39, 95% CI = 0.95, 2.05) was observed. On stratification by ethnicity, the association with higher FG concentrations was significant in Malay women (β = 0.19mmol/l, 95% CI = 0.04, 0.33), while risk of emergency caesarean section was greater in Chinese (OR = 1.90, 95% CI = 1.06, 3.43) and Indian women (OR = 2.41, 95% CI = 1.01, 5.73).

Conclusions

25OHD inadequacy is prevalent in pregnant Singaporean women, particularly among the Malay and Indian women. This is associated with higher FG concentrations in Malay women, and increased risk of emergency caesarean section in Chinese and Indian women.     

Effect of Oral Glucose Administration on Rebound Growth Hormone Release in Normal and Obese Women: The Role of Adiposity,Insulin Sensitivity and Ghrelin

Context

Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue.

Objective

The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity.

Participants and Methods

We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed.

Results

The AUC of GH (μg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.     

Trend of Cardio-Metabolic Risk Factors in Polycystic Ovary Syndrome: A Population-Based Prospective Cohort Study

Objective

To see the changes of cardio-metabolic risk factors overtime in polycystic ovary syndrome vs. control women.

Methods

This study was conducted on 637 participants (85 PCOS and 552 control reproductive aged, 18–45 years) of Tehran Lipid and Glucose Study (TLGS), an ongoing population-based cohort study with 12 years of follow-up. The cardiovascular risk factors of these groups were assessed in three-year intervals using standard questionnaires, history taking, anthropometric measures, and metabolic/endocrine evaluation. Generalized estimating equation was used to analyze the data.

Results

Overall mean of insulin (3.55, CI: 0.66–6.45), HOMA-IR (0.63, CI: 0.08–1.18), and HOMA-β (45.90, CI: 0.86–90.93) were significantly higher in PCOS than in healthy women after adjustment for age, BMI, and baseline levels. However, the negative interaction (follow-up years × PCOS status) of PCOS and normal women converged overtime. Comparing third follow-up with first, insulin and HOMA-IR decreased 10.6% and 5%, respectively in PCOS women; and increased 6.7% and 14.6%, respectively in controls (P<0.05). The results did not show any significant result for other cardio-metabolic variables including WC, lipid profile, FPG, 2-h PG, SBP, and DBP.

Conclusion

While the insulin level and insulin resistance rate were higher in reproductive aged PCOS than in healthy women, the difference of these risk factors decreased overtime. Thus, the metabolic consequences of PCOS women in later life may be lower than those initially anticipated.