Ethnic differences in gestational diabetes : impact on South Asians

Background: GDM is a state of glucose intolerance first diagnosed in pregnancy. It is a pre-diabetes state, predisposing both the mother and offspring to future risk of diabetes. GDM is associated with increased risk to macrosomia, adiposity, Caesarean Section (CS) delivery, shoulder dystocia, and neonatal hypoglycaemia. SA have a greater than two fold risk of both GDM and future diabetes risk compared to WC. However, despite having higher levels of hyperglycaemia in pregnancy, SA babies are amongst the smallest babies in the world. The mechanism behind this increased glycaemic risk in SA is complex, multifactorial and unclear. Disordered hypothalamic-pituitary-adrenal axis (HPA) has been linked to adult diabetes, obesity and metabolic syndrome in WC but has not been studied in SA. The current management of GDM is largely based on evidence from studies in WC and has been extrapolated to other ethnic groups such as SA. This includes: diagnostic criteria to define GDM, postnatal screening methods for postpartum glucose abnormalities, effect of GDM on offspring birth weight (BW) and fetal growth in GDM. Through this research we aim to explore the ethnic differences between SA and WC in the applicability of diagnostic criteria, post partum screening methods, effect of GDM on BW, fetal growth patterns in GDM and also examine ethnic differences in HPA activity as a potential mechanism underlying the increased glycaemic risk in SA in pregnancy. Methods: i. Retrospective analysis of a routinely collected multicentre data (n=14477) over a 3-year period was used to study the applicability of various GDM diagnostic criteria and post partum screening methods. A subgroup analysis of the above data set was used to compare fetal growth between SA and WC (177 WC and 160 SA). ii. A retrospective analysis of a large birth weight cohort (n=53,128) from Leicestershire between 1994 and 2006 was used to compare the effect of maternal diabetes and GDM on BW in SA and WC. iii. To examine fetal growth in SA, a retrospective case control analysis of serial fetal biometry was performed between GDM and control population from India. (178 controls and 153 GDM) iv. To explore underlying HPA dysfunction as a potential mechanism for increased glycemia in SA and ethnic differences in HPA behaviour a prospective cohort study comprising of high risk pregnant SA and WC women was performed. Diurnal salivary and urinary cortisol excretion was studied in relation to glycaemia in SA and WC (n=100, 50 SA, 50WC) Results: i. The newer IADPSG detects obese women with mild fasting hyperglycaemia. The benefits of treatment of hyperglycemia are not well established. The increase in detection rates of GDM with the new NICE and IADPSG criteria were uniform across ethnic groups in a selectively screened population. ii. Postnatal screening with oral glucose tolerance test (OGTT) is associated with poor uptake in all ethnic groups, which improves substantially with using HbA1c. SA were more likely to attend postnatal screening with HbA1c compared to WC. Screening for postnatal diabetes using FPG is more likely to miss women of non-WC ethnicity owing to the larger proportion of post-load glucose abnormalities. iii. The BW increase associated with maternal diabetes was lower in SA by 139g compared to WC. iv. Important ethnic differences in fetal growth were noted. SA fetuses had overall smaller measures of head and abdomen circumferences, but with disproportionately smaller abdominal circumference compared to WC, signifying early evidence of a head sparing growth restricted pattern. v. SA fetuses of GDM mothers showed early evidence of increased abdominal adiposity at 20 weeks with smaller measures of other fat free mass and skeletal growth compared to non-GDM controls vi. SA had higher cortisol awakening responses compared to WC. First trimester waking cortisol was an independent predictor of glycaemia in the third trimester. Despite significantly lower BMI, SA had similar glucocorticoid (GC) excretion to WC. Urinary GC excretion was independently predicted by maternal adiposity and not BMI in SA. Conclusion: This research addresses important gaps in the literature in gestational diabetes in SA. There are important ethnic differences in the impact of maternal diabetes and gestational diabetes on BW and fetal growth, and evidence of early increase in adiposity at the expense of lean body mass in SA. This research provides novel evidence to support the argument for ethnicity tailored management of GDM. Our research also provides novel evidence for disordered HPA activity as a possible mechanism for the increased glycemic risk in SA. Larger randomized prospective studies incorporating offspring outcomes in relation to HPA are needed

Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians : more evidence for the ‘thin–fat’ baby

Aims/hypothesis Gestational diabetes mellitus (GDM) is associated with an increased future risk of obesity in the offspring. Increased adiposity has been observed in the newborns of women with GDM. Our aim was to examine early fetal adiposity in women with GDM. Methods Obstetric and sonographic data was collated for 153 women with GDM and 178 controls from a single centre in Chennai, India. Fetal head circumference (HC), abdominal circumference (AC), femur length (FL) and biparietal diameter (BPD) were recorded at 11, 20 and 32 weeks. Anterior abdominal wall thickness (AAWT) as a marker of abdominal adiposity at 20 and 32 weeks was compared between groups. Adjustments were made for maternal age, BMI, parity, gestational weight gain, fetal sex and gestational age. Results Fetuses of women with GDM had significantly higher AAWT at 20 weeks (β 0.26 [95% CI 0.15, 0.37] mm, p < 0.0001) despite lower measures of HC, FL, BPD and AC. AAWT remained higher in the fetuses of women with GDM at 32 weeks (β 0.48 [0.30, 0.65] mm, p < 0.0001) despite similar measures for HC, FL, BPD and AC between groups. Both groups had similar birthweights at term. There was an independent relationship between fasting plasma glucose levels and AAWT after adjustment as described above. Conclusions/interpretation A ‘thin but fat’ phenotype signifying a disproportionate increase in adiposity despite smaller or similar lean body mass was observed in the fetuses of mothers with GDM, even at 20 weeks, thus pre-dating the biochemical diagnosis of GDM. Increased AAWT may serve as an early marker of GDM

Vitamin B12 status among pregnant women in the UK and its association with obesity and gestational diabetes

Background To evaluate vitamin B12 and folate status in pregnancy and their relationship with maternal obesity, gestational diabetes mellitus (GDM), and offspring birthweight. Methods A retrospective case-control study of 344 women (143 GDM, 201 no-GDM) attending a district general hospital and that had B12 and folate levels measured in the early 3rd trimester was performed. Maternal history including early pregnancy body mass index (BMI) and neonatal data (birthweight, sex, and gestational age) was recorded for all subjects. Results: 26% of the cohort had B12 levels <150 pmol/L (32% vs. 22% in the two groups respectively, p < 0.05) while 1.5% were folate deficient. After adjusting for confounders, 1st trimester BMI was negatively associated with 3rd trimester B12 levels. Women with B12 insufficiency had higher odds of obesity and GDM (aOR (95% CI) 2.40 (1.31, 4.40), p = 0.004, and 2.59 (1.35, 4.98), p = 0.004, respectively), although the latter was partly mediated by BMI. In women without GDM, the lowest quartile of B12 and highest quartile of folate had significantly higher adjusted risk of fetal macrosomia (RR 5.3 (1.26, 21.91), p = 0.02 and 4.99 (1.15, 21.62), p = 0.03 respectively). Conclusion This is the first study from the UK to show that maternal B12 levels are associated with BMI, risk of GDM, and additionally may have an independent effect on macrosomia. Due to the increasing burden of maternal obesity and GDM, longitudinal studies with B12 measurements in early pregnancy are needed to explore this link

Development of a Selective Inhibitor of Protein Arginine Deiminase 2.

Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in \u3e100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated

The effects of somatostatin analogues on glycaemia in the treatment of neuroendocrine tumours.

Long-acting somatostatin analogues (SSAs) are the most commonly used drugs in the management of neuroendocrine tumours (NETs) because of their ability to control symptoms and prolong survival. SSA use is associated with changes in glucose metabolism. However, the impacts on glycaemic control and body mass index (BMI) caused by SSAs in NETs are largely unknown. In the present study, we evaluated the effects of SSA treatment on BMI and glycated haemoglobin (HbA1c) in our cohort of patients with NETs. We also assessed changes in glycaemic control and BMI before and after SSA treatment. In addition, we assessed the incidence of new diabetes or whether there was worsening of glycaemic control for patients with pre-existing diabetes. The study comprised a retrospective study of 279 patients with NETs who were treated with SSAs between January 2014 and January 2019. Glycaemic control was assessed by measuring changes in Hba1c. A number needed to harm analysis was used to look at new cases of diabetes within the study population. Treatment with SSAs was associated with a mean increase in HbA1c of 3.35 ± 6.30 mmol mol despite a mean decrease in BMI of -1.04 ± 2.79 kg m . There were 19 new cases of type 2 diabetes mellitus (T2DM) in the population of 209 with a number needed to harm of 12.5. Of the 34 patients with pre-existing T2DM, five had worsening of their mean HbA1c. Treatment with SSAs for NETs is associated with an increase in HbA1c, despite a reduction in BMI and, importantly, a risk of developing T2DM with a number needed to harm of 12.5. This project was registered with the National Health Service Clinical Audit and Registries. It has a CARMS number - 17666

Surgical Correction of Carcinoid Heart Disease Improves Liver Function and 5-Hydroxyindoleacetic Acid Levels.

Introduction Carcinoid heart disease (CHD) is a consequence of neuroendocrine tumors releasing 5-hydroxytryptamine (5-HT) into the systemic circulation, affecting right heart valves, causing fibrosis, and eventually right heart failure. The aim of this study was to determine the effect of valve-replacement on kidney function, liver function, and 5-hydroxyindoleacetic acid (5-HIAA) levels. Methods A Retrospective study of 17 patients with CHD who had undergone heart-valve replacement surgery between 2010 and 2019, from the Queen Elizabeth Hospital Birmingham. 5-HIAA levels, liver, and kidney function were measured in addition to hepatic inferior vena cava (IVC) diameter and its relationship to carcinoid symptoms. Results Eleven patients were male and six were female. At time of surgery, average age was 66.6 ± 8.1 years and average BMI was 25.8 ± 5.5 Kg/cm. Three out of 17 patients had one valve replaced, 13/17 had two replaced (tricuspid and pulmonary), and 1/17 had three replaced (tricuspid, pulmonary and aortic). There was a 31% average decline in 5-HIAA [799.8 (343.6-1078.0) to 555.3 (275.8-817.9), = 0.011], a 35% decline in bilirubin [20 (16-29) to 13 (10-19), = < 0.001], and a 15% reduction in the short and long axes of the IVC after valve-replacement surgery [20.0 (18.0-25.0) and 36.5 (29.0-39.8) to 17.0 (14.5-19.3) and 31.0 (26.5-34.3) respectively, = < 0.001 and 0.002 respectively]. Conclusion Valve replacement surgery improves 5-HIAA levels alongside improved liver function and hepatic IVC diameter. These findings are consistent with resolution of congestive hepatopathy, and therefore enhanced clearance of 5-HIAA. This suggests that valve-replacement surgery can indirectly have beneficial outcomes on hepatic function and is also associated with a drop in the circulating levels of tumor derived serotonin

Multidisciplinary team management of carcinoid heart disease.

Carcinoid heart disease (CHD) is a consequence of valvular fibrosis triggered by vasoactive substances released from neuroendocrine tumours, classically in those with metastatic disease and resulting in tricuspid and pulmonary valve failure. CHD affects 1 in 5 patients who have carcinoid syndrome (CS). Valve leaflets become thickened, retracted and immobile, resulting most often in regurgitation that causes right ventricular dilatation and ultimately, right heart failure. The development of CHD heralds a significantly worse prognosis than those patients with CS who do not develop valvular disease. Diagnosis requires a low threshold of suspicion in all patients with CS, since symptoms occur late in the disease process and clinical signs are difficult to elicit. As a result, routine screening is recommended using the biomarker, N-terminal pro-natriuretic peptide, and regular echocardiography is then required for diagnosis and follow-up. There is no direct medical therapy for CHD, but the focus of non-surgical care is to control CS symptoms, reduce tumour load and decrease hormone levels. Valve surgery improves long-term outcome for those with severe disease compared to medical management, although peri-operative mortality remains at between 10-20% in experienced centres. Therefore, care needs to be multidisciplinary at all stages, with clear discussion with the patient and between teams to ensure optimum outcome for these often-complex patients