DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study

Background The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia. Results Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7–9 years) and 698 Indian (5–7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes. Conclusion This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences.

Parameters of Glucose Homeostasis in the Recognition of the Metabolic Syndrome in Young Adults with Prader–Willi Syndrome

To verify the accuracy of different indices of glucose homeostasis in recognizing the metabolic syndrome in a group of adult patients with Prader–Willi syndrome (PWS), 102 PWS patients (53 females/49 males), age ±SD 26.9 ± 7.6 yrs, Body Mass Index (BMI) 35.7 ± 10.7, were studied. The following indices were assessed in each subject during an oral glucose tolerance test (OGTT): 1 h (>155 mg/dL) and 2 h (140–199 mg/dL) glucose levels, the oral disposition index (ODI), the insulinogenic index (IGI), the insulin resistance (HOMA-IR) were evaluated at baseline, 1 h and 2 h. Although minor differences among indices were found, according to the ROC analysis, no index performed better in recognizing MetS. Furthermore, the diagnostic threshold levels changed over the years and therefore the age-related thresholds were calculated. The easily calculated HOMA-IR at baseline may be used to accurately diagnose MetS, thus avoiding more complicated procedures.

Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We set out to examine the genetics of variation in concentrations of postprandial metabolites (t=150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity study (N=5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta (SE): -0.23 (0.03), P-value: 2.15×10^-19). In addition, <i>ANKRD55</i> locus led by rs458741:C showed strong associations to extremely large VLDL particle (XXLVLDL) response (with XXLVLDLC: beta (SE): 0.17 (0.03) P-value: 5.76×10^-10and with XXLVLDLCE: beta (SE): 0.17 (0.03), P-value: 9.74×10^-10), which also revealed strong associations to body composition and diabetes in the UK Biobank (p-values<5×10^-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, ISI matsuda index and HbA1c in the NEO study further implied the role of chylomicron synthesis in diabetes (with FDR corrected q-value<0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of <i>ANKRD55</i> locus underlying diabetes.

Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We set out to examine the genetics of variation in concentrations of postprandial metabolites (t=150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity study (N=5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta (SE): -0.23 (0.03), P-value: 2.15×10^-19). In addition, <i>ANKRD55</i> locus led by rs458741:C showed strong associations to extremely large VLDL particle (XXLVLDL) response (with XXLVLDLC: beta (SE): 0.17 (0.03) P-value: 5.76×10^-10and with XXLVLDLCE: beta (SE): 0.17 (0.03), P-value: 9.74×10^-10), which also revealed strong associations to body composition and diabetes in the UK Biobank (p-values<5×10^-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, ISI matsuda index and HbA1c in the NEO study further implied the role of chylomicron synthesis in diabetes (with FDR corrected q-value<0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of <i>ANKRD55</i> locus underlying diabetes.

245Comparison of methods for classifying heterogeneity in gestational diabetes (GDM) and association with outcomes

Background Clinical experience suggests that diverse clinical subtypes exist within the broader diagnosis of GDM. Analysis from a single centre recently outlined heterogeneity in GDM with respect to insulin secretion and sensitivity, defining four GDM subtypes: 1) GDMsecr (&lt;25th centile HOMA-β (Hb) for non-GDM); 2) GDMsens (&lt;25th centile Matsuda Index for non-GDM); 3) GDMmixed (both GDMsecr and GDMsens); 4) GDMND, no defect (neither GDMsecr and GDMsens). Classification using these subtypes is associated with adverse outcomes. Methods Following similar methodology, women with GDM were classified into four subtypes including comparison of Hb, insulinogenic index (II) and Stumvoll first-phase estimate (SV) for defining GDMsecr. Analyses compared neonatal outcomes with non-GDM women and between GDM groups using c2 tests and regression analyses adjusted for multiple confounders including maternal age, BMI and HAPO study centre. Results Hb, II and SV gave divergent results for GDMsecr, with only 19% concordance. In all analyses, GDMND (10% by Hb, 6% by II, 6% by SV) showed outcome frequencies similar to those of non-GDM women; groups 1-3 showed higher risks (p &lt; 0.01 vs non GDM). These results persisted in the fully adjusted model (aOR generally &gt;2.0). Conclusions Different clinical subtypes in GDM are associated with differing risks of adverse outcome. Key messages Determination of GDM subtype can assist in assessing GDM women at higher risk of adverse clinical outcome and help guide clinical practice.

GLUCOSE METABOLISM AND INSULIN RESPONSE TO ORAL GLUCOSE TOLERANCE TEST (OGTT) IN PREPUBERTAL PATIENTS WITH TRANSFUSION DEPENDENT Β-THALASSEMIA (TDT): A LONG-TERM RETROSPECTIVE ANALYSIS

Background: Glucose dysregulation (GD), including prediabetes and diabetes mellitus (DM), is a common complication of transfusion dependent β-thalassemia (TDT) patients. The prevalence increases with age and magnitude of iron overload, affecting a significant proportion of patients. The development of GD is frequently asymptomatic and therefore an early diagnosis, according to the international guidelines, requires an annual oral glucose tolerance test (OGTT) in all TDT patients aged ten years or older. Purpose: This retrospective study aims to evaluate the prevalence of GD in a homogenous population of prepubertal TDT patients and to enhance understanding of the pathogenesis and progression of glucose homeostasis in this group of patients. Methods: A selected group of 28 TDT patients was followed for at least 10.3 years (range: 10.3 - 28.10 years) from prepubertal age (mean 11.0 ± standard deviation 1.1 years) to adulthood (28.7 ± 3.7 years). Glucose tolerance and insulin response to OGTT were assessed, and indices of β-cell function, insulin sensitivity and insulin secretion were calculated. Results: At baseline, 18 TDT patients had normal glucose tolerance (NGT) and 10 isolated impaired fasting glycaemia (IFG), according to the American Diabetes Association (ADA) criteria. Compared to 18 prepubertal healthy controls (mean ± SD age: 10.9 ± 1.1 years), the fasting plasma glucose (FPG), basal insulin level and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were significantly higher in the group of TDT patients (p= 0.001, 0.01 and 0.012, respectively). At the last observation, 7/18 patients (38.8%) with NGT and 9/10 (90%) with IFG at baseline deteriorated; 3 female patients developed type 2 DM (1 from the NGT group and 2 from the IFG group). Compared to adult controls, TDT patients with NGT had a reduced oral disposition index (DI) (p= 0.006), but no significant difference in HOMA-IR and Matsuda index. Conversely, all insulin indices (HOMA-IR, MI and DI) but one [insulinogenic index (IGI)] were statistically different in TDT patients with GD compared to controls. Conclusion: This study shows a spectrum of disturbances in glucose homeostasis among TDT patients and that prepubertal patients with IFG are at higher risk for developing a deterioration of glucose metabolism.

Early postpartum abnormal glucose metabolism subtype differs according to mid-trimester lipid profile in women with gestational diabetes mellitus

Background It is unknown whether early postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) is related to their mid-trimester lipid profile. The aim of this study was to characterize the mid-trimester lipid profile of women who experienced GDM and developed into different pathophysiologic subtypes of early postpartum AGM. Methods A retrospective cohort study of 498 women with history of GDM was conducted. A 75-g oral glucose tolerance test (OGTT) and plasma lipid measurements were performed at 24–28 weeks of gestation and 6–12 weeks of postpartum. Insulin secretion and sensitivity were estimated using early postpartum OGTT-based indices. Results Women in the mid-trimester dyslipidemia group had higher postpartum 30-min and 2-h plasma glucose, higher postpartum 2-h plasma insulin, higher postpartum triglyceride (TG), higher postpartum low density lipoprotein cholesterol (LDL-c) concentrations, lower postpartum 30-min insulinogenic index (IGI30), lower postpartum insulin sensitivity index (ISI), and lower postpartum disposition index than those in the normal lipid group (all P < 0.05). Abnormal mid-trimester TG and LDL-c concentrations were associated with postpartum AGM (adjusted odds ratio [OR] = 1.786, 95 % confidence interval [CI] = 1.142–2.425; and adjusted OR = 1.621, 95 % CI = 1.323–2.051, respectively; both P < 0.05). AGM women with low IGI30 and low ISI had higher mid-trimester total cholesterol and LDL-c concentrations, and AGM women with low ISI had higher mid-trimester TG concentrations than women with NGT or other subtypes of AGM (all P < 0.05). Conclusions GDM women with abnormal mid-trimester TG and LDL-c were predisposed to early postpartum AGM. Postpartum AGM women who experienced GDM had heterogeneous mid-trimester lipid profile when classified according to their pathophysiologic subtype.

Association between insulin resistance and cardinal rheological parameters in young healthy Japanese individuals during 75 g oral glucose tolerance test

Background: Insulin resistance is a well-known predictor and risk factor for Type 2 Diabetes Mellitus (T2DM). Higher hematocrit induced by higher insulin resistance affects blood rheology. Objective: This study intended to reveal the association between indices of insulin resistance and hemorheological parameters during a 75 g oral glucose tolerance test (75-g OGTT). Methods: A total of 575 healthy young Japanese participants took 75-g OGTT. We then analyzed the association between insulin resistance indices and hematological parameters. Results: The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly correlated with hematocrit (Ht), hemoglobin (Hb), Red Blood Cell (RBC), White Blood Cell (WBC), platelet count, lipid parameters, and Body Mass Index (BMI). The Matsuda index was negatively correlated with RBC count, WBC count, platelet count, Total Cholesterol (TC), Low-Density Lipoprotein-Cholesterol (LDL-C), triglyceride (TG), and positively correlated with High-Density Lipoprotein-Cholesterol (HDL-C). The disposition index was negatively correlated with Hb, RBC count, LDL-C, and BMI, while remaining positively correlated with HDL-C. The Homeostasis Model Assessment of beta cell (HOMA- IR ) was positively correlated with WBC count, platelet count, TC, LDL-C, and TG. The insulinogenic index was positively correlated with WBC count, platelet count, and TC. Multiple regression analysis revealed that HOMA-IR was independently associated with TG, and the Matsuda index was independently associated with TG, WBC count, and platelet count. The insulinogenic index was independently associated with WBC count. Conclusion: Cardinal rheological parameters reflected insulin resistance and were released even in the young, healthy Japanese individuals within the physiological range of glycemic control.

Genetic Risk Score for Type 2 Diabetes and Traits Related to Glucose-Insulin Homeostasis in Youth: The Exploring Perinatal Outcomes Among Children (EPOCH) Study

<em>Objective</em>: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. <em>Research Design and Methods</em>: We used data from 356 youth (mean age 16.7 years, 50% female) in the EPOCH cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms (SNPs) associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-hour glucose, homeostasis model of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, body mass index (BMI) z-score, <i>in utero</i> exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z-score,<i> in utero </i>exposure to maternal diabetes and ethnicity. <em>Results</em>: Higher weighted GRS was associated with lower oral disposition index (b=-0.11; 95% CI: -0.19, -0.02) and insulinogenic index (b=-0.08; 95% CI: -0.17, -0.001), but not with fasting glucose (b=0.01; 95% CI: -0.01, 0.02), 2-hour glucose (b=0.03; 95% CI: -0.0004, 0.06), or HOMA-IR (b=0.02; 95% CI: -0.04, 0.07). BMI z-score and <i>in utero</i> exposure to maternal diabetes increased the effect of the GRS on glucose levels. <em>Conclusions</em>: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk for T2D. <br> <p> </p>