bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time to Glucose Peak during Oral Glucose Tolerance Test (OGTT) and Pathophysiological Biomarkers of Type 2 Diabetes in Obese Youth
Authors: KIM JOON YOUNG , TFAYLI HALA , BACHA FIDA , MICHALISZYN SARA , ARSLANIAN SILVA A. 
Published: June 2018

The time to glucose peak occurring at or after 30 min. during an OGTT identifies physiologically distinct groups of adults with differences in insulin sensitivity (IS) and secretion and risk of prediabetes and type 2 diabetes. We stratified 102 obese nondiabetic youth (age 15.0 ± 0.2 years; 49 M/53 F; 42 black/60 white) to Early-peak (EP) vs. Late-peak (LP) according to time to reach peak glucose (at 30 min. vs. &gt;30 min.) during an OGTT and assessed the relationship to clamp-derived biomarkers of youth type 2 diabetes risk. Hepatic [[6,6-2H2]glucose] and peripheral IS [3-hour hyperinsulinemic (80 mu/m2/min)-euglycemic clamp], insulin secretion [2-hour hyperglycemic (225 mg/dL) clamp], β-cell function (BCF) relative to IS and body composition were compared. The LP group had lower hepatic and peripheral IS, lack of compensatory increase in 1st and 2nd phase insulin secretion and impaired BCF relative to IS compared with the EP group (Table), with similar fasting glucose and insulin, BMI percentiles and % body fat. In obese nondiabetic youth, the time to glucose peak during an OGTT reflects pathophysiological alterations associated with risk of type 2 diabetes. The risk imparted by a Late-peak glucose, independent of fasting glucose and insulin level, is mirrored in lower in vivo insulin sensitivity and impaired β-cell function, two major pathophysiologic biomarkers of youth type 2 diabetes.Variables, mean ± SEMEarly-peak (n=49)Late-peak (n=53)PGlycemic status (NGT/IGT), n (%)40 (82%) / 9 (18%)28 (53%) / 25 (47%)0.003Hepatic insulin sensitivity (mg/kg/min per µU/mL)-120.1 ± 1.714.5 ± 1.10.004Peripheral insulin sensitivity (mg/kg/min per µU/mL)2.55 ± 0.182.03 ± 0.150.0111st-phase insulin secretion (µU/mL)244.3 ± 26.7231.9 ± 26.7NSβ-cell function relative to insulin sensitivity (mg/kg/min)509.9 ± 45.3393.0 ± 33.40.026OGTT 2-hr glucose concentration (mg/dL)120.1 ± 2.8135.5 ± 3.40.001OGTT 2-hr insulin concentration (µU/mL)168.3 ± 22.0226.9 ± 21.80.010

Disclosure
J. Kim: None. H. Tfayli: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. S. Michaliszyn: None. S.A. Arslanian: None.
Valine Metabolism Is Altered in Obese Adolescents with Polycystic Ovary Syndrome and Relates to Insulin Sensitivity
Authors: CARREAU ANNE-MARIE , RAHAT HASEEB , REYES YESENIA GARCIA , PYLE LAURA , NADEAU KRISTEN J. , CREE-GREEN MELANIE 
Published: June 2018

Polycystic Ovarian Syndrome (PCOS) is common and associated with insulin resistance (IR). The mechanism of IR in PCOS is unclear, likely multifactorial, and may relate to branched-chain amino acids (BCAA) and mitochondrial metabolism. We quantitated differences in BCAA and BCAA breakdown product short chain (C3-C5) acylcarnitines in response to hyperinsulinemia in obese girls with and without PCOS, and assessed the relationship to IR and hyperandrogenism. Obese girls with PCOS [n=15, 14.5 ± 1.6 years, BMI %ile 98.5 ± 1.0] and without PCOS [n=6; 13.2 ± 1.2 years, BMI %ile 98.0 ± 1.1] were studied. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp and a testosterone panel obtained. Nontargeted metabolomics were performed in plasma samples obtained before and after the clamp. T-tests were used for group comparisons, with the Benjamini-Hochberg procedure (false discovery rate (FDR) set to 0.05) to control for multiple testing. Spearman’s correlation coefficient was calculated for BCAA vs. glucose infusion rate (GIR) and free androgen index (FAI). The groups had similar demographic, physical activity, diet attributes, HbA1c and lipids. Girls with PCOS had higher FAI and worse IR than controls. FAI related negatively to short chain acylcarnitines C4 (r = -0.74, p=0.0002) and C3 (r=-0.60, p =0.007). During hyperinsulinemia, girls with PCOS had higher valine (FDR-adjusted p=0.04) and lower valine breakdown product C4 butyrylcarnitine (FDR-adjusted p=0.01). End-clamp valine correlated with GIR (r= -0.59, p= 0.006) as did C4 butyrylcarnitine (r=0.44, p=0.04). Under hyperinsulinemia, a metabolomic signature was revealed in obese girls with PCOS, distinct from that in uncomplicated obesity. Valine was higher in girls with PCOS, while C4 acylcarnitine, its direct mitochondrial metabolite, was lower. Further work is needed to determine if BCAA metabolism is a modifiable target to improve insulin sensitivity or simply a useful biomarker.

Disclosure
A. Carreau: None. H. Rahat: None. Y. Garcia Reyes: None. L. Pyle: None. K.J. Nadeau: None. M. Cree-Green: None.
Maternal Gestational Diabetes and Childhood Obesity—A Large Observational Study
Authors: WANG JING , WANG LEISHEN , ZHANG SHUANG , LIU HUIKUN , LENG JUNHONG , LI WEIQIN , ZHANG TAO , LI NAN , LI WEI , BACCARELLI ANDREA , HOU LIFANG , HU GANG 
Published: June 2018

Previous studies found conflicting results about the associations between the exposure to maternal hyperglycemia in utero and the later risks of childhood overweight and obesity. The aim of the present study was to compare the children’s body mass index (BMI) growth between offspring exposed to maternal gestational diabetes mellitus (GDM) and those not exposed, and assess the associations between maternal GDM and their offspring’s overweight and obesity risk. We performed a large observational study in 1156 women and their offspring (578 GDM and 578 non-GDM mother-child pairs, matched by their offspring’s gender and age). The mean values of children were 5.86 years (range 3-9 years old). After adjustment for maternal and children’s characteristics, children born to mothers with GDM during pregnancy had higher mean values of Z scores for BMI-for-age, Z-scores for weight-for-age, waist circumferences, body fat, subscapular skinfold, and suprailiac skinfold, in comparison with their counterparts born to mothers with normal glucose (all P values &lt;0.05). Moreover, maternal GDM was associated with a higher risk of childhood overweight and obesity with multivariate-adjusted odds ratios of 1.42 (95% confidence interval [CI]: 1.02-1.97) and 1.18 (95% CI: 1.11-1.24), respectively, compared with the children of mothers without GDM during pregnancy. Maternal GDM is an independent risk factor of childhood overweight and obesity, and it is associated with children’s faster growth of BMI.

Disclosure
J. Wang: None. L. Wang: None. S. Zhang: Employee; Self; American Diabetes Association. Advisory Panel; Self; Company/ABC. H. Liu: None. J. Leng: None. W. Li: None. T. Zhang: None. N. Li: None. W. Li: None. A. Baccarelli: None. L. Hou: None. G. Hu: None.
Genotype–Phenotype Correlations and Structural Basis of INSR and IGF1R Mutations Causing Severe Insulin/IGF-1 Resistance
Authors: HOSOE JUN , KADOWAKI HIROKO , MIYA FUYUKI , TAKAKURA MINAKA , TSUNODA TATSUHIKO , SHOJIMA NOBUHIRO , YAMAUCHI TOSHIMASA , KADOWAKI TAKASHI 
Published: June 2018

Mutations of the insulin receptor (INSR) gene cause severe insulin resistance, resulting in several syndromes with various abnormal phenotypes associated with variable severity of INSR dysfunction. As a member of the insulin receptor family, the IGF-I receptor (IGF1R) shows the same domain structure as INSR containing the fibronectin type III (FnIII) domains where there are an α-β cleavage site and a part of the ligand binding site. Mutations of IGF1R can cause intrauterine and postnatal growth retardation. We compiled 3 mutations of the FnIII-2 and FnIII-3 domains in IGF1R registered in HGMD, ClinVar and UniProt databases as causing growth retardation as well as the SNP with &gt;1% allele frequency in IGF1R from the 1000 Genomes Project data, ESP6500, HGVD and 3.5KJPN, a reference panel of Japanese individuals. We conducted in silico structural analysis of the mutations of the FnIII domains in IGF1R which revealed that the pathogenic mutations were predicted to severely impair stability of the FnIII domains and hydrophobic core formation or affect processing site, while the SNP was predicted not to affect folding of the domains. In addition, IGF-1 proreceptor processing was impaired in cells expressing mutations of FnIII compared to cells expressing WT form. Previously, we performed structural analysis of mutations of the FnIII domains in INSR, which revealed that missense mutations causing the most severe Donohue syndrome were predicted to severely impair hydrophobic core formation and stability of the FnIII domains, while those causing less severe Rabson-Mendenhall syndrome were predicted to lead to localized destabilization and not to affect folding of the FnIII domains. Genotype-structure-phenotype correlations of variants of the FnIII domains in INSR and IGF1R identified in these analyses will enable early diagnosis of pathogenic mutations in INSR and IGF1R and provide a valuable insight into the molecular mechanism of severe insulin or IGF-1 resistance.

Disclosure
J. Hosoe: None. H. Kadowaki: None. F. Miya: None. M. Takakura: None. T. Tsunoda: None. N. Shojima: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
Variation in Phenotypic Features of Two Siblings with PC1/3 Deficiency—Obesity and Hyperproinsulinemia
Authors: DAVIS ELISABETH K. , BROADNEY MIRANDA , PERSKY REBECCA , TORKY AHMED , YANOVSKI JACK A. 
Published: June 2018

Background: Inactivating mutations in the PCSK1 gene encoding prohormone convertase 1/3 (PC1/3) are associated with failure to thrive (FTT) and diarrhea during infancy, a tendency toward childhood obesity, and the potential for development of endocrinopathies throughout life, including hyperproinsulinemia. We describe two siblings with the same inactivating compound heterozygous mutations (c.625G&gt;A and c.473G&gt;A) in PCSK1, but with phenotypes of differing severity affecting both body composition and glucose homeostasis.
Methods: After sequencing confirmed inactivating PCSK1 mutations, we assessed the siblings for resultant endocrinopathies of PC1/3 deficiency.
Results: The siblings, a 9y male (M) and an 11y female (F), had severe early onset FTT with diarrhea. Currently, M has extreme obesity (BMI=38.2 kg/m2, &gt;99%), diabetes insipidus, central hypothyroidism (FT4 0.7 ng/dL; TSH 4.9 mIU/L with little diurnal variation), and adrenal insufficiency (peak cortisol post-ACTH 10.8 ug/dL). After an overnight fast, glucose was 64 mg/dL and he had dramatic hyperproinsulinemia (5030 pmol/L, normal &lt;8), far exceeding his fasting insulin concentration (360 pmol/L). Glucose tolerance was better than predicted for his degree of obesity (OGTT 2h glucose 79 mg/dL) and proinsulin remained markedly elevated during the OGTT (6610 pmol/L; normal &lt;200).
F was in the 86th percentile for BMI. She had central hypothyroidism (FT4 0.7 ng/dL; TSH 4.7 mIU/L with little diurnal variation) and diabetes insipidus, but had normal adrenal function (peak cortisol post-ACTH 20.3 ug/dL). F also had high fasting proinsulin (1340 pmol/L), out of proportion to fasting insulin (70 pmol/L) and glucose (87 mg/dL) and good glucose tolerance (OGTT 2h glucose 89 mg/dL).
Discussion: PC1/3 deficiency reduces processing of proinsulin to insulin and may thus predispose to fasting or post-prandial hypoglycemia. There is substantial heterogeneity in PC1/3 deficiency even within families.

Disclosure
E.K. Davis: None. M. Broadney: None. R. Persky: None. A. Torky: None. J.A. Yanovski: Research Support; Self; Rhythm Pharmaceuticals Inc., Zafgen.
KIAA2022, a Candidate Gene for Syndromic Diabetes
Authors: STEKELENBURG CAROLINE , BLOUIN JEAN-LOUIS , SANTONI FRED , O'HARE ELIZABETH A. , ZAGHLOUL NORANN A. , SCHWITZGEBEL VALERIE 
Published: June 2018

Background/Introduction: Using whole exome sequencing we identified a truncating mutation in the KIAA2022 gene in a child with mental retardation and antibody-negative diabetes. The KIAA2022 gene encodes a large protein of 1516 amino acids, which has no significant homology with other known proteins. KIAA2022 has already been associated to X-linked mental retardation. In this study we analyze the potential contribution of KIAA2022 to diabetes.
Methods: Whole exome capture sequencing was performed using the Illumina HiSeq instrument. We performed qRT-PCR and immunohistochemistry. We used the INS-1E cell line for in vitro and zebrafish and mice for in vivo knock down studies.
Results: We confirmed mRNA and protein expression of KIAA2022 in murine and human islets by qRT-PCR and immunohistochemistry. KIAA2022 partially co-stained with insulin in pancreatic sections. In vitro experiments with INS-1E cells showed that KIAA2022 is highly expressed during cell division and after stress induction by H202. To characterize KIAA2022 function in vivo, we performed knock down studies in zebrafish and found a decrease of the beta cell mass by 40% compared to wild type. The beta cell expansion rate, assessed by culturing zebrafish embryos with and without glucose, lead to a 30% decrease of the expansion rate in the knock-down animals in comparison to the control group. We further used the CRISPR Cas9 technology to disrupt the KIAA2022 gene in mice. The knockout mice showed smaller islets and DNA damage signals in islets in comparison to the control mice. The i.p. glucose tolerance tests at twelve weeks of age showed glucose intolerance in mutant in comparison to wild type mice.
Conclusion: In vitro experiments using INS-1E cells suggest that KIAA2022 may play a role in cell division and in DNA damage signaling or repair. The KIAA2022 knock down experiments lead to a decrease of the beta cell mass and glucose-induced expansion rate in zebrafish and DNA damage signals in beta cells of mutant mice as well as glucose intolerance.

Disclosure
C. Stekelenburg: None. J. Blouin: None. F. Santoni: None. E.A. O'Hare: None. N.A. Zaghloul: None. V. Schwitzgebel: None.
Gluten Intake and Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in Children at Increased Risk of Disease
Authors: LUND-BLIX NICOLAI A. , DONG FRAN , MARILD KARL , BARON ANNA E. , SEIFERT JENNIFER A. , WAUGH KATHLEEN , JONER GEIR , STORDAL KETIL , TAPIA GERMAN , STENE LARS C. , JOHNSON RANDI K. , REWERS MARIAN , NORRIS JILL 
Published: June 2018

Background: Few studies have examined gluten intake as a risk factor for islet autoimmunity (IA) and type 1 diabetes (T1D). Our aim was to study the association of gluten intake with development of IA and progression to T1D, accounting for HLA genotype.
Methods: The Diabetes Autoimmunity Study in the Young (DAISY) follows children with an increased risk of T1D based on presence of a first-degree relative with T1D, or HLA genotype. HLA genotypes were categorized in three groups as DR3/4 (DR3/4-DQ2/8), DR3 (DR3/3 or 3/X), and DR4 (DR4/4, 4/X or X/X, where X was neither 3 nor 4). Blood samples were collected at age 9, 15 and 24 months, and annually thereafter. IA was defined by the appearance of at least one autoantibody against insulin, IA-2, GAD or ZnT8 in at least two consecutive blood samples; T1D was defined using ADA criteria. Using FFQs we estimated the gluten intake (g/d) annually from 1 year of age. Cox regression was used to estimate hazard ratios adjusted for potential confounders.
Results: This report includes 1,916 subjects followed from birth to the median age 13.5 y; 178 developed IA and 56 of these progressed to T1D. At the first assessment (median age 1.4 y) the average daily gluten intake was 11.4 g (SD: 5.6). The amount of gluten intake did not predict risk of IA (HR per 4 g 0.93; 95% CI 0.78-1.11) or progression from IA to T1D (HR 1.30; 95% CI 0.94-1.78). Four grams of gluten equal to a slice of bread. However, we found a significant interaction with HLA (p=0.02), where the association between gluten and IA were significantly different between all groups. Moreover, we found a significant interaction for progression to T1D (p=0.04) where in children with IA, gluten intake was associated with T1D among children with DR3/4 (HR 1.66 95% CI 1.10-2.51), but not in children with the other HLA groups.
Conclusion: Gluten intake may have different effects on development of IA and progression from IA to T1D depending on HLA genotype.

Disclosure
N.A. Lund-Blix: None. F. Dong: None. K. Marild: None. A.E. Baron: None. J.A. Seifert: None. K. Waugh: None. G. Joner: None. K. Stordal: None. G. Tapia: None. L.C. Stene: None. R.K. Johnson: None. M. Rewers: None. J. Norris: None.
Novel, Culturally Sensitive Shared Group Appointment Program for Hispanic Pediatric Type 1 Diabetes Patients Is Feasible, Improves Technology Uptake, and Has Promising Results on Better Diabetes Outcomes
Authors: GONZALEZ ANDREA GERARD , BRADY ANDREA CAROLINA , KLINGENSMITH GEORGEANNA J. , PYLE LAURA , THURSTON JESSICA 
Published: June 2018

Objective: Hispanic patients with type 1 diabetes (T1D) face cultural and language barriers in care that contribute to a high A1c, infrequent use of diabetes technology and risk of complications. Culturally sensitive programs and shared medical appointments (SMAs) have been recognized as effective models of care. Our aim is to develop a culturally sensitive, cost effective SMA model for pediatric Hispanic T1D patients.
Methods: Hispanic patients, ages 1-20, with T1D (n= 88), and their families were recruited to participate in the SMAs. They received routine care appointments alternating with SMAs that included group diabetes education. Teens, ages 12 to 18 attended a separate educational session from parents. Younger children and parents were seen together. A1c, behavioral tools, and use of diabetes technology were measured at baseline and every 3 months for two years. Satisfaction questionnaires were obtained.
Results: 62% of young children and 48% of teens completed the first 2 years of the SMA model of care. Results showed that there was a significant association between age and change in A1c for SMA participants from baseline to year 1 (p =.001) and baseline to year 2 (p = &lt;.0001). Participants &lt; 12 years old, there was a significant improvement in A1c from baseline to year 1 (p = 0.014) and from year 1 to year 2 (p = 0.007). Participants ≥ 12 years old, also had a change in A1c from year 1 to year 2 (p = 0.008). Technology use increased significantly from baseline to year 2 for participants who were less than 12 years of age (17% to 40% p =.014) and marginally significant for participants who were &gt;11 years of age (10% to 18% p = .083). Participants had a 90% satisfaction rate.
Conclusions: The culturally sensitive SMA proved to be an appreciated, feasible and effective alternative to care for Hispanics with T1D. It may prove to be cost-effective and more effective over the long-term if begun shortly after diagnosis.

Disclosure
A. Gerard Gonzalez: None. A. Brady: None. G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. L. Pyle: None. J. Thurston: None.
Comparison of E-Consults and Face-to-Face Care on Costs and Glycemic Control among Veterans with Type 2 Diabetes Mellitus
Authors: KARAJGIKAR NEHA , DETOYA KARLA B. , BEATTIE JANICE N. , LUTZ-MCCAIN STACEY J. , BOUDREAUX-KELLY MONIQUE Y. , BANDI ARCHANA 
Published: June 2018

Electronic Consults (EC) offer enhanced access to endocrinologists for patients with type 2 diabetes mellitus (T2DM). The effects of EC on costs of care and glycemic control compared to Face-to-Face (F2F) visits are unknown. A retrospective chart review was conducted for Veterans who received EC (n=440) or F2F (n=397) care for T2DM through the VA Pittsburgh Healthcare System (VAPHS) from 2010 to 2015. Data on demographics, rurality, days to consult completion, and percent (%) A1C at baseline and post-consult at 3-6, and 12 months were collected. A web-based tool calculated the average round-trip distance in miles and travel time in hours from patient’s residential zip code to VAPHS. Annual travel costs for recommended 3 visits per year were estimated at a reimbursement rate of $0.415 per mile. Continuous measures (mean ± standard deviation) were compared using Wilcoxon rank-sum tests. Categorical measures (sex, rurality) were presented as percentages and compared between groups by time point using chi-square tests. Veterans who received EC were predominantly male (98.4%), younger (64.2±8.5 years) and rural (15.8%) than those who received F2F care (95.3% male, p=0.01; 68.1±8.7 years, p&lt;0.0001; 3.7% rural, p&lt;0.0001). The EC cohort had shorter consult completion time than the F2F cohort (EC: 10±10 days, F2F: 37±33; p&lt;0.0001). Mean annual travel-related savings per Veteran in the EC cohort were 431±297 miles, 9.4±7 hours, and $179±123. Mean annual travel burden per Veteran in the F2F cohort were 159±171 miles, 3.5±4 hours and $66±71. EC and F2F cohorts had similar baseline A1C values (10%±1.6). Both cohorts had decline in baseline percent A1C to 3- 6 months (EC: 8.98%±1.54, F2F: 8.75%±1.77, p=0.03) and from baseline percent A1C to 12 months (EC: 8.80%±1.61, F2F: 8.57%±1.72, p=0.002). Electronic consults deliver effective and expedient care by saving money and travel time, and offer long-term, sustainable glycemic control comparable to F2F care for patients in remote areas with T2DM.

Disclosure
N. Karajgikar: None. K.B. Detoya: None. J.N. Beattie: None. S.J. Lutz-McCain: None. M.Y. Boudreaux-Kelly: None. A. Bandi: None.