bluuebunny/crossref_metadata_2025_split huggingface dataset:
1639-P: Correlates and Prevalence of Hypogonadism in Male Patients with Latent Autoimmune Diabetes, Classic Type 1 Diabetes, and Classic Type 2 Diabetes
Authors: CAI MEILI , GAO JINGYANG , SHENG CHUNJUN , LI HONG , SHENG HUI , QU SHEN , ZHANG MANNA 
Published: June 2020

Objectives: The study aims to compare the prevalence of hypogonadism in male patients with latent autoimmune diabetes (LADA) and classic type 1 diabetes (T1DM) and type 2 diabetes (T2DM), and explore risk factors for hypogonadism in those patients.
Methods: Form 1 January 2016 and 9 October 2019, a total of 399 male patients with LADA(n=71), T1DM (n=72) and T2DM (n=256) respectively were recruited from the endocrinology department in Shanghai Tenth People’s Hospital for this cross-sectional study. Serum FSH, LH, testosterone, lipid profile, uric acid, HbA1c, and beta-cell function were determined in blood samples. The diagnosis of hypogonadism was based on the levels of LH, FSH, and total testosterone.
Results: The mean age of male patients with LADA, T1DM and T2DM was 54.44 ± 1.54, 47.50±1.83 and 56.55±0.74 years old, respectively. The serum total testosterone concentration in the LADA group was similar to the T1DM group, but higher than those in the T2DM group. The rate of hypogonadism in the LADA group, T1DM group, T2DM group were 1.6%, 2.4% and 20.8%, respectively (p &lt;0.05). Total testosterone was positively correlated with SHBG and HDL-c, and negatively correlated with uric acid, HbA1c, BMI, SBP, DBP and TG in all, LADA, T1DM and T2DM groups. Logistic regression indicate that after adjusting for age, duration of diabetes, smoking, drinking and family history of diabetes, the independent risk factors for developing hypogonadism in male with diabetes were BMI (OR=1.31, P&lt;0.05), C-peptide (OR=1.88, P&lt;0.05), HDL-c (OR=0.41,P&lt;0.05) and SBP (OR=1.01,P&lt;0.05).
Conclusion: Our results indicate that in a population of admission to a large urban hospital in China, the rate of hypogonadism was lower in LADA patients and T1DM patients than T2DM patients. High levels of BMI, C-peptide, SBP and low level of HDL-c are risk factors for developing hypogonadism in male with diabetes.

Disclosure
M. Cai: None. J. Gao: None. C. Sheng: None. H. Li: None. S. Qu: None. M. Zhang: None.

Funding
National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
164-LB: Lower Pediatric HbA1c in Sweden during Recent Years Is Associated with a Lower HbA1c Nadir during the First Year after Onset
Authors: HANAS RAGNAR , STEINECK ISABELLE I. , ANDERZÉN JOHAN , EEG-OLOFSSON KATARINA , EKELUND JAN , GUDBJ ÖRNSDOTTIR SOFFIA , HANBERGER LENA , NÅTMAN JONATAN , LYCKÅ AUSTE PUNDZIUTE , SVENSSON ANN-MARIE , SÄRNBLAD STEFAN , AKESSON KARIN 
Published: June 2020

Background: There is a large variation in mean HbA1c levels even between high-income countries, with a decrease over time in HbA1c in some countries but an increase in others. Sweden has experienced a steady decrease in HbA1c over the past 10 years. The aim of this study was to illustrate how changes in HbA1c during the first two years after diagnosis in children and adolescents is related to calendar year for diagnosis of type 1 diabetes from 2010 to 2017.
Methods:The Swedish SWEDIABKIDS registry collects data every ~3 months and has &gt; 95% coverage up to age 18 years. We plotted all available HbA1c data vs. diabetes duration, presented as separate Loess curves per 2 consecutive year groups.
Results: In total, 5,102 patients contributed with 51,550 HbA1c values over 8 years. HbA1c at onset has slightly increased from 93.9 to 95.0 mmol/mol (10.7 to 10.8 %) between 2010 and 2017. The HbA1c nadir (lowest level during first year) is around 4 months, and has become lower over the years. Early HbA1c tracking is apparent and is established with a difference between the groups from 1 year’s diabetes duration.
Conclusions: Intensification of early diabetes treatment, resulting in a lower HbA1c nadir at 4 months and lower HbA1c from 1 year onwards is related to HbA1c two years after diagnosis. Thus, a modifiable factor for a long-term improvement in metabolic control has been identified.

Disclosure
R. Hanas: Advisory Panel; Self; Abbott, Novo Nordisk A/S. Speaker’s Bureau; Self; Sanofi. Other Relationship; Self; AstraZeneca. I.I. Steineck: None. J. Anderzén: None. K. Eeg-Olofsson: None. J. Ekelund: Employee; Spouse/Partner; AstraZeneca. S. Gudbjörnsdottir: None. L. Hanberger: None. J. Nåtman: None. A. Pundziute Lyckå: None. A. Svensson: None. S. Särnblad: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. K. Akesson: None.
1643-P: A Recessive Genome-Wide Meta-analysis of Type 2 Diabetes in 300,000 Individuals of European Ancestry Identifies Multiple Novel Variants of Large Effect Size
Authors: O’CONNOR MARK J. , CORTES-SANCHEZ PAULA , BONÀS-GUARCH SÍLVIA , COLE JOANNE B. , TORRENTS DAVID , LEONG AARON , FLOREZ JOSE C. , MERCADER JOSEP M. 
Published: June 2020

Introduction: Most genome-wide association studies (GWAS) of polygenic traits are based on the assumption that allelic effects are additive. Hundreds of loci associated with type 2 diabetes (T2D) have been identified using this approach, but a significant proportion of heritability remains unexplained. Many genetic variants behave in a recessive fashion, and rare variants of this type can be missed by additive analyses.
Methods: We used a recessive model to conduct a GWAS of T2D in unrelated individuals of European ancestry in the UK Biobank and then meta-analyzed the results with publicly available data from five European-ancestry cohorts known collectively as 70KforT2D. We used approximate conditional analysis to identify distinct secondary signals within genome-wide significant loci.
Results: In total, there were 30,661 cases and 267,948 controls. We identified 54 associated loci and 15 other conditionally independent signals. Six associations were distinct from the set of previously reported signals, including results from larger additive analyses, and three were over a million base pairs away from the closest known locus. Five of the novel variants - located near the genes PELO, ADAMTS6, JAZF1, IL7, and FCHSD2 - were rare, with allele frequencies under 5%, and had large effect sizes, with odds ratios for homozygous carriers ranging from 2.7 to 7.9.
Conclusions: Our results demonstrate that recessive analysis identifies loci missed by additive GWAS, confirming the value of recessive analyses. Some of the variants we detected have large effect sizes and could be useful for patient risk stratification. Collectively they add to our knowledge of the genetic architecture of T2D.

Disclosure
M.J. O’Connor: None. P. Cortes-Sanchez: None. S. Bonàs-Guarch: None. J.B. Cole: None. D. Torrents: None. A. Leong: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. J.M. Mercader: None.
1647-P: Rare Disruptive Loss of Function Mutations in the Cluster of Differentiation 36 (CD36) Gene Overwhelmingly Cause a Metabolic Syndrome in Multiple Members of an Inbred Pedigree from One Village in Northern Israel
Authors: LEVIN NEHAMA ZUCKERMAN , BERCOVICH DANI , PASTERNAK IDIT , GERSHONI-BARUCH RUTH , SHEHADEH NAIM 
Published: June 2020

The metabolic syndrome consisting of type 2 diabetes (T2DM), obesity, dyslipidemia and arterial hypertension, is a complex disorder whose molecular basis is largely unknown. The cluster of differentiation 36 (CD36), a multifunctional class B scavenger receptor, has been acknowledged as a promising candidate for T2DM and its complications. More than a decade ago, a rare nonsense mutation, namely c.1079T&gt;G (p.L360X) was identified in one Caucasian pedigree presenting with autosomal dominant diabetes (Hum mutation 2004). Recent studies however, have disputed the contribution of rare coding mutations in CD36 to T2DM and additional metabolic complications (Scientific Reports 2019). In an extended pedigree of Israeli Muslim Arab ancestry from a single village in northern Israel multiple members (n=33) with T2DM, obesity, dyslipidemia and arterial hypertension were investigated. Three affected individuals from three nuclear inbred families, originating from an extended Arab Muslim clan, underwent whole-exome sequencing that displayed several disruptive rare mutations in CD36 namely c.1011_1014delins26; p.(Arg337Serfs*23); c.1079T&gt;G; p.(Leu360*); and c.1202_1205delTATT; p.(Val401Glufs*4). Sanger sequencing was thereafter employed to show that these mutations segregated in 30 additional affected individuals from the same clan. Our findings substantiate that CD36 plays a pivotal role in glucose homeostasis and lipid metabolism. Mutations in this gene prompt insulin resistance, obesity and dyslipidemia in humans. A rare nonsense mutation (p.L360X) in CD36 was previously found in a French pedigree presenting with autosomal dominant diabetes. Here we provide evidence that other than the p.L360X mutation, rare loss-of-function coding mutations in CD36 evoke impaired fatty acid metabolism, glucose intolerance, type 2 diabetes and arterial hypertension.

Disclosure
N. Zuckerman Levin: None. D. Bercovich: None. I. Pasternak: None. R. Gershoni-Baruch: None. N. Shehadeh: None.
166-OR: Lower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle
Authors: BUSTOS ROCIO ZAPATA , LANGLAIS PAUL R. , COLETTA DAWN K. , DE FILIPPIS ELENA A. , GRANDJEAN DANIELLE , MANDARINO LAWRENCE 
Published: June 2020

This study was undertaken to identify transcription factors that differentially respond to exercise in insulin resistance. Candidate transcription factors were identified from analysis of 5’-untranslated regions (5’-UTRs) of exercise responsive genes and from analysis of the 5’-UTRs of genes coding for proteins that differ in abundance in insulin resistance. Muscle biopsies were obtained from lean and obese subjects before, 30 min and 240 h. after a single exercise bout. Insulin sensitivity was assessed through glucose clamps. Obese subjects (n=8) were insulin resistant compared to lean (n=12) (7.0 ± 0.95 vs. 11.3 ± 0.8 mg∙kg FFM-1∙min-1, P&lt;0.05) but performed exercise at the same intensity (VO2peak 35.0 ± 1.9 vs. 35.2 ± 3.9 ml∙min-1∙kg FFM-1, NS). Statistical over-representation analyses showed that proteins differing in abundance between healthy and insulin resistant resting muscle included those involved in mitochondrial function, protein targeting and translation, and metabolism. Transcription factor enrichment analysis of genes coding for these proteins revealed new candidate transcription factors. Q-rt-PCR analysis from pre and post-exercise muscle biopsies revealed several transcription and growth factors had altered responses to exercise in insulin resistant subjects, including EGR3, RELA, ATF2 and SP1. We previously showed that higher CTGF abundance and expression were associated with insulin resistance induced by a lipid emulsion infusion, along with extracellular matrix reorganization and tissue remodeling. Here, CTGF mRNA responded briskly 30 min after exercise in insulin sensitive but not insulin resistant subjects (4.7 ± 1.0 vs. 1.0 ± 0.22), returning to near-basal levels in both groups after 24 h. The lower response of CTGF expression to exercise in insulin resistance suggests that it may mediate the capacity of muscle to remodel itself following exercise, and partially explain the exercise resistance associated with insulin resistance.

Disclosure
R. Zapata Bustos: None. P.R. Langlais: None. D.K. Coletta: None. E.A. De Filippis: None. D. Grandjean: None. L. Mandarino: None.

Funding
National Institutes of Health (R01DK047936, DK066483, R01DK094013)
1667-P: Diabetes Incidence following Adoptive Transfer of Splenocytes Correlates with Increased Generation of Proinflammatory Lipids
Authors: WHITE TAYLEUR , CHALFANT CHARLES , RAMANADHAM SASANKA 
Published: June 2020

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic islet β-cells. An understudied area is the role of lipid signaling. We find that the Ca2+-independent phospholipase A2β (iPLA2β) is induced under a diabetic milieu and that mitigation of iPLA2β activity attenuates β-cell death. iPLA2β hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid. When the fatty acid is arachidonic acid, it can be metabolized to bioactive eicosanoids, many of which are pro-inflammatory. To address our overarching hypothesis that iPLA2β-derived lipids (iDLs) contribute to T1D development, we investigated the role of immune cell-iDLs in this process by utilizing a splenocyte adoptive transfer protocol. Splenocytes were prepared from 12-week-old female spontaneous diabetes prone non-obese diabetic (NOD, WT) and NOD.iPLA2β+/- (HET) donor mice and transferred into 5-week-old female immunodeficient (NOD.scid) recipient mice. Our overall findings revealed that: (1) splenocyte-iPLA2β mRNA in HET donor mice was ca. 40% of that in WT donor mice, (2) temporal IPGTTs revealed that the recipient mice of the HET genotype were more glucose tolerant, compared to recipients of the WT splenocytes; (3) weekly blood glucose monitoring revealed that all WT recipient mice developed diabetes between 11-16 weeks of age. In contrast, onset of diabetes in the HET recipient mice was delayed 3 weeks and by 16 weeks of age, 50% of these mice remained diabetes-free, (4) HET donor T-cell differentiation to Th1 phenotype is mitigated, (5) HET donor T-cell production of select pro-inflammatory lipids (i.e., 6-keto PGF1α, PGE2, and DHETs) is decreased, relative to WT donors, and (5) similar lipid signatures are evident in the terminal plasma of recipient mice. These findings suggest that immune T-cell-iPLA2β is a critical contributor to T1D development and could be targeted for therapeutics.

Disclosure
T. White: None. C. Chalfant: None. S. Ramanadham: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
169-LB: Is It Time for Country-Specific Glucose Cut-Off Values for Diagnosing Gestational Diabetes Mellitus in the Indian Population?
Authors: BABU GIRIDHARA R. , LEWIS MELISSA G. , R DEEPA , LOBO EUNICE , KINRA SANJAY , MURTHY GVS V. 
Published: June 2020

Background: Gestational diabetes mellitus (GDM) affects nearly 5 million pregnancies in India and is associated with multiple adverse pregnancy outcomes. Exposure to intrauterine hyperglycemia predisposes infants to increased risk obesity and diabetes. Indian phenotype tends to deposit excess central fat, which is linked to insulin resistance. Our study aimed to determine the effect of varying plasma glucose concentrations in predicting adverse maternal and infant outcomes in participants of a birth cohort in India.
Methods: We examined a prospective cohort of pregnant women in the public hospitals of Bengaluru. We conducted a 2-hour 75g Oral glucose Tolerance Test (OGTT) in 1847, pregnant women between 24 to 36 weeks. We followed up women and children at delivery, and recorded skinfold thickness of babies at biceps, triceps, and subscapular region. We fitted 240 robust Poisson models to estimate the risk of the sum of skinfold thickness (SSFT) infants and caesarian section delivery with the FBS and PPBS. With one-unit increase beginning from FBS≥87 up to 92 mg/dL and PPBS ≥134 up to 153 mg/dL were tested with the sum of skinfold Thickness (SSST) and C section delivery.
Results: We found that 10.65% (95% CI 9.19%, 12.30%) of 1847 infants had SSFT above 90th percentile, and 46.91% (95% CI 44.45%, 49.38%) of the women underwent caesarian section. The results indicate that FBS≥87 mg/dL and PPBS of ≥134mg/dl was associated with risk of increased SSST in infants [adjusted RR 1.70 (95% CI 1.06, 2.74)] and caesarian section delivery [Adjusted RR 1.19 (1.07,1.32)] after adjusting for age, parity, socioeconomic status, height and adiposity in mothers.
Discussion: The pregnant women in India are at a higher risk of adverse birth outcomes with lower glucose cut-off values, compared to the international classification systems. These findings offer insights to revise the cut off points based on contextual settings in LMIC countries.

Disclosure
G.R. Babu: None. M.G. Lewis: None. D. R: None. E. Lobo: None. S. Kinra: None. G.V. Murthy: None.

Funding
UK Wellcome Trust/DBT India Alliance Fellowship (IA/CPHI/14/1/501499 to G.R.B.)
169-OR: Differential Effects of Amount, Intensity, and Mode of Exercise Training on the Diabetes Risk Index
Authors: ROSS LEANNA M. , SLENTZ CRIS A. , SHALAUROVA IRINA Y. , OTVOS JAMES D. , CONNELLY MARGERY A. , BALES CONNIE W. , HOUMARD JOSEPH A. , KRAUS WILLIAM E. 
Published: June 2020

Objective: Examine the effects of amount, intensity, and mode of exercise training on type 2 diabetes (T2D) risk.
Methods: A total of 531 men and women with dyslipidemia [STRRIDE I (n=222), STRRIDE AT/RT (n=142) or prediabetes [STRRIDE-PD (n=167)] were randomized to control group or one of 10 exercise interventions, ranging from doses of 8-22 kcal/kg/week; intensities of 50-75% V?O2peak; and duration of 6-9 months. Two groups included resistance training and one included dietary intervention (weight loss goal of 7%). Fasting plasma samples were obtained at baseline and 16-24 h after last exercise bout. The Diabetes Risk Index (DRI) and its components—Lipoprotein Insulin Resistance Index (LP-IR) and branched chain amino acids (BCAA) valine and leucine—were determined by NMR spectroscopy. DRI scores range from 1-100, the latter representing those at greatest T2D risk. Paired t-tests determined significance within groups (p&lt;0.05). Study-specific ANCOVA determined differences among groups.
Results: The inactive control group did not significantly change DRI score. After training, four of ten exercise groups significantly improved DRI scores, ranging from -2.8 ± 8.2 to -8.3 ± 10.4. In STRRIDE AT/RT, only the aerobic-plus-resistance group significantly improved DRI. In STRRIDE-PD, the moderate-intensity-plus-diet group had a greater DRI change than the other exercise-only moderate intensity groups. Reductions in DRI appeared to be driven largely by decreases in insulin resistance (LP-IR) but not dysmetabolism (BCAA), except for the moderate-intensity-plus-diet group, which exhibited a reduction in both.
Conclusions: Multiple exercise interventions led to improvements in DRI scores. Results provide compelling evidence that adding resistance to aerobic training elicits a synergistic effect on insulin resistance and T2D risk. In individuals with prediabetes, incorporating dietary intervention with aerobic training results in the most robust improvement in T2D risk.

Disclosure
L.M. Ross: None. C.A. Slentz: None. I.Y. Shalaurova: None. J.D. Otvos: Employee; Self; LabCorp. M.A. Connelly: Employee; Self; LabCorp. C.W. Bales: None. J.A. Houmard: None. W.E. Kraus: None.

Funding
National Institutes of Health (R01HL057354, R01DK081559, T32HL007101)
1701-P: The Role of UGT1a in Regulating Brown Adipose Tissue and Thermogenic Function
Authors: KODANI SEAN , LYNES MATTHEW , SHAMSI FARNAZ , WANG CHIH-HAO , SUGIMOTO SATORU , XUE RUIDAN , HUANG TIAN LIAN , WHITE ANDREW P. , CYPESS AARON M. , TSENG YU-HUA 
Published: June 2020

Increasing biological thermogenesis (the conversion of chemical energy to heat) has been proposed as an approach towards lowering blood glucose, improving insulin sensitivity and mitigating type 2 diabetes. Non-shivering thermogenesis occurs primarily in adipocytes that express uncoupling protein 1 (UCP1) including brown adipose tissue (BAT) and beige adipose tissue but does not substantially occur in white adipose tissue (WAT). To identify genes that regulate thermogenesis and BAT function, we recently compared genes expressed in paired human patient samples (n = 10) of the deep neck BAT located next to the carotid sheath and superficial subcutaneous WAT in the neck. We found UDP-glucuronide transferase 1A (UGT1A) is co-expressed in individuals with a high amount of the thermogenic protein uncoupling protein 1 (UCP1). This enzyme is known to glucuronidate metabolites, including bilirubin and xenobiotics, which increases their water solubility and excretion. Based on this function, we hypothesize UGT1A regulates BAT not through direct action of the enzyme but through modulating the availability of thermogenic molecules. Here, we characterized expression of different UGT1A isoforms in vivo and in vitro. Cold exposure is an effective method for activating BAT and increasing thermogenesis in mice. Interestingly, expression of multiple UGT1A isoforms, including UGT1A6a and UGT1A6b, are decreased in BAT of mice exposed to a cold environment (5°C) for 7 days. This finding is consistent with data in multiple publicly available datasets which have shown UGT1A6a/6b are decreased in cold exposure and other thermogenic stimuli. In vitro, most UGT1A isoforms were increased during the differentiation of murine brown adipocytes but only certain isoforms were differentially expressed during in vitro differentiation in human brown adipocytes. Based on these data, we propose that UGT1A may have a function related to thermogenesis and understanding its function could lead to novel approaches for activating BAT.

Disclosure
S. Kodani: None. M. Lynes: None. F. Shamsi: None. C. Wang: None. S. Sugimoto: None. R. Xue: None. T. Huang: None. A.P. White: None. A.M. Cypess: None. Y. Tseng: Consultant; Self; Boehringer Ingelheim International GmbH.

Funding
National Institutes of Health (R01DK07709, R01DK102898, T32DK007260)
1712-P: HIV-1 Vpr Couples Metabolic Inflexibility with White Adipose Tissue Thermogenesis
Authors: AGARWAL NEETI , SAHA PRADIP , HARTIG SEAN M. , BALASUBRAMANYAM ASHOK 
Published: June 2020

The HIV accessory protein Vpr contributes to cardinal metabolic defects noted in persons living with HIV (PLWH), including accelerated lipolysis, impaired fatty acid oxidation, slowed fatty acid export, and steatohepatitis (Agarwal et al, Sci Trans Med 2017). PLWH also manifest “beiging” and markers of thermogenesis within some white adipose tissue (WAT) depots, but paradoxically these changes correlate with decreased insulin sensitivity and hyperlipidemia. We sought to determine whether Vpr activity affects thermogenesis and the dynamics of beiging in two Vpr mouse models. UCP1 expression was strongly increased in subcutaneous fat of Vpr mice and showed equivalent copy number in WAT biopsies from PLWH. Histology confirmed browning of subcutaneous but not visceral WAT in the Vpr mouse models. Adipocytes derived from these depots showed increased oxygen consumption rate in subcutaneous but not visceral fat cells, also strongly indicative of beiging. Measurements of energy balance indicated Vpr mice display metabolic inflexibility and cannot shift efficiently from carbohydrates to fat during day-night cycles. Furthermore, Vpr mice mice showed a marked inability to defend body temperature when exposed to 4oC for 6 hours. Thus HIV-1 Vpr disrupts metabolic efficiency coupled with maladaptive subcutaneous WAT beiging. These data suggest an expanded role for Vpr in the pathogenesis of HIV-associated metabolic disorders.

Disclosure
N. Agarwal: None. P. Saha: None. S.M. Hartig: None. A. Balasubramanyam: None.

Funding
National Institutes of Health (R21/R33AI116208)