Browsing by Author "Arslanian, Silva"

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    Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes
    (BMC, 2020-07-31) Syed, Farooq; Tersey, Sarah A.; Turatsinze, Jean-Valery; Felton, Jamie L.; Kang, Nicole Jiyun; Nelson, Jennifer B.; Sims, Emily K.; Defrance, Mathieu; Bizet, Martin; Fuks, Francois; Cnop, Miriam; Bugliani, Marco; Marchetti, Piero; Ziegler, Anette-Gabriele; Bonifacio, Ezio; Webb-Robertson, Bobbie-Jo; Balamurugan, Appakalai N.; Evans-Molina, Carmella; Eizirik, Decio L.; Mather, Kieren J.; Arslanian, Silva; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Background Identification of islet β cell death prior to the onset of type 1 diabetes (T1D) or type 2 diabetes (T2D) might allow for interventions to protect β cells and reduce diabetes risk. Circulating unmethylated DNA fragments arising from the human INS gene have been proposed as biomarkers of β cell death, but this gene alone may not be sufficiently specific to report β cell death. Results To identify new candidate genes whose CpG sites may show greater specificity for β cells, we performed unbiased DNA methylation analysis using the Infinium HumanMethylation 450 array on 64 human islet preparations and 27 non-islet human tissues. For verification of array results, bisulfite DNA sequencing of human β cells and 11 non-β cell tissues was performed on 5 of the top 10 CpG sites that were found to be differentially methylated. We identified the CHTOP gene as a candidate whose CpGs show a greater frequency of unmethylation in human islets. A digital PCR strategy was used to determine the methylation pattern of CHTOP and INS CpG sites in primary human tissues. Although both INS and CHTOP contained unmethylated CpG sites in non-islet tissues, they occurred in a non-overlapping pattern. Based on Naïve Bayes classifier analysis, the two genes together report 100% specificity for islet damage. Digital PCR was then performed on cell-free DNA from serum from human subjects. Compared to healthy controls (N = 10), differentially methylated CHTOP and INS levels were higher in youth with new onset T1D (N = 43) and, unexpectedly, in healthy autoantibody-negative youth who have first-degree relatives with T1D (N = 23). When tested in lean (N = 32) and obese (N = 118) youth, increased levels of unmethylated INS and CHTOP were observed in obese individuals. Conclusion Our data suggest that concurrent measurement of circulating unmethylated INS and CHTOP has the potential to detect islet death in youth at risk for both T1D and T2D. Our data also support the use of multiple parameters to increase the confidence of detecting islet damage in individuals at risk for developing diabetes.
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    Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study
    (Frontiers Media, 2021-04-26) Brooks-Worrell, Barbara M.; Tjaden, Ashley H.; Edelstein, Sharon L.; Palomino, Brenda; Utzschneider, Kristina M.; Arslanian, Silva; Mather, Kieren J.; Buchanan, Thomas A.; Nadeau, Kristen J.; Atkinson, Karen; Barengolts, Elena; Kahn, Steven E.; Palmer, Jerry P.; RISE Consortium; Medicine, School of Medicine
    The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(-) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(-) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(-), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(-) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(-) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.
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    Morning Blood Pressure is Associated with Sleep Quality in Obese Adolescents
    (Elsevier, 2014-02) Hannon, Tamara S.; Tu, Wanzhu; Watson, Sara E.; Jalou, Hasnaa; Chakravorty, Sangeeta; Arslanian, Silva; Department of Pediatrics, IU School of Medicine
    Objective To examine relationships between blood pressure (BP), adiposity, and sleep quality using overnight polysomnography (PSG) in obese adolescents. Study design Overnight PSG and morning BP measurements were performed in obese (BMI >97th %ile) non-diabetic adolescents (eligible age range 12-18 years, n=49). Subjects were stratified into two groups, one with normal BP, and one with elevated BP, and demographic and clinical characteristics compared between the groups. Multiple linear regression analysis was used to assess the BP effects of sleep quality measures. Results Participants (n=27) had normal morning BP, and 22 (44.9%) had elevated morning BP. There were no differences in age (p=0.53), sex (p=0.44), race (p=0.58) or BMI (p=0.56) between the two BP groups. The group with elevated BP spent shorter percentages of time in rapid eye movement (REM; p=0.006) and slow-wave sleep (SWS; p=0.024). Multiple linear regression analysis showed a lower percent of both REM and SWS were associated with increased morning BP, after adjusting for pubertal stage, sex, race, and BMI. Conclusion Lack of deeper stages of sleep, REM sleep and SWS, is associated with higher morning BP in obese adolescents, independent of BMI. Poor sleep quality should be considered in the work-up of obese youth with hypertension. Intervention studies are needed to evaluate whether improving the quality of sleep will reduce blood pressure elevation.
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    Reproducibility of Glycemic Measures Among Dysglycemic Youth and Adults in the RISE Study
    (The Endocrine Society, 2023) Tjaden, Ashley H.; Edelstein, Sharon L.; Arslanian, Silva; Barengolts, Elena; Caprio, Sonia; Cree-Green, Melanie; Lteif, Amale; Mather, Kieren J.; Savoye, Mary; Xiang, Anny H.; Kahn, Steven E.; Medicine, School of Medicine
    Aims: Previous work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs). Methods: HbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared. Results: Mean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth. Conclusions: Poor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important.
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    Treatment of Gestational Diabetes Mellitus and Offspring Early Childhood Growth
    (Endocrine Society, 2021-04) Feghali, Maisa; Atlass, Jacqueline; Abebe, Kaleab Z.; Comer, Diane; Catov, Janet; Caritis, Steve; Arslanian, Silva; Scifres, Christina; Obstetrics and Gynecology, School of Medicine
    Background: Gestational diabetes mellitus (GDM) is associated with fetal overgrowth, and certain treatments are associated with an increased risk of macrosomia. However, there are limited data about the long-term effect of GDM treatment on childhood growth. Methods: Cohort study of 816 women with GDM and their offspring delivered between 2009 and 2012. Childhood height and weight through age 3 were collected from the medical record and z-scores and body mass index (BMI) were calculated. We assessed the association between GDM treatment and childhood growth using linear mixed modeling. Results: Treatment was divided into medical nutritional therapy (MNT) (n = 293), glyburide (n = 421), and insulin (n = 102). At delivery, birthweight, z-score, and BMI were higher in the offspring of women treated with either glyburide or insulin compared to MNT. However, weight, z-score, and BMI were similar among all offspring at 6 months and 1, 2, and 3 years of age. After controlling for covariates, there were differences in the weight z-score (P = 0.01) over the 3-year period by treatment group, but no differences in weight (P = 0.06) or change in BMI (P = 0.28). Pairwise comparisons indicated that insulin was associated with more weight gain compared with MNT (0.69 kg; 95% CI, 0.10-1.28; P = 0.02) and glyburide was associated with a trend toward lower weight z-score compared with MNT (-0.24; 95% CI, -0.47 to 0.003; P = 0.05). Conclusion: Despite growth differences detected at birth, we observed no meaningful differences in childhood growth from 6 months to 3 years among treatment groups, including in the offspring of women with GDM treated with glyburide.