bluuebunny/crossref_metadata_2025_split huggingface dataset:
1625-P: Association of Patient- and Disease-Related Factors with Glycemic Target Achievement in Type 1 Diabetes (T1D) in the SAGE Study
Authors: SEUFERT JOCHEN , IKEGAMI HIROSHI , BRETTE SANDRINE , PILORGET VALERIE , LAUAND FELIPE , WILMOT EMMA G. , RENARD ERIC , GAGLIARDINO JUAN J. 
Published: June 2020

Most people with T1D do not achieve HbA1c targets, but this may vary with patient- and disease-related factors.
SAGE was a multinational, cross-sectional study using data from medical records and interviews of eligible people with T1D for ≥1 year, aged ≥26 years (N=3858). The relationship between each group of selected factors (sociodemographics, diabetes complications and comorbidities, T1D treatment, structure and process of medical care) and HbA1c target achievement (both general [HbA1c &lt;7 %] and individualized) were evaluated.
Overall, 24.3% of people achieved HbA1c &lt;7 %; 20.9% achieved individualized targets. For both targets, better achievement was associated with: lower body mass index, diastolic blood pressure, and total daily insulin dose; ≥1 symptomatic hypoglycemic event (&lt;54 mg/dL) within the last 3 months; higher levels of education; and having health insurance (Table). Poorer target achievement was associated with ≥1 severe hyperglycemic event leading to diabetic ketoacidosis within the last 6 months, microvascular complications, and dyslipidemia. Older people were more likely to achieve individualized targets while younger people were more likely to achieve HbA1c &lt;7 %.
HbA1c target achievement remains a challenge but SAGE identified factors that appear to be associated with HbA1c target achievement, offering opportunities for intervention.

Disclosure
J. Seufert: Research Support; Self; Sanofi. Speaker’s Bureau; Self; Sanofi. H. Ikegami: None. S. Brette: Other Relationship; Self; Sanofi. V. Pilorget: Employee; Self; Sanofi. F. Lauand: Employee; Self; Sanofi. E.G. Wilmot: Advisory Panel; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Sanofi. E. Renard: Board Member; Self; Abbott, Insulet Corporation, Novo Nordisk A/S, Roche Diabetes Care. Consultant; Self; Air Liquide, Eli Lilly and Company, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. J.J. Gagliardino: None.
1637-P: Role of mTORC1 Regulation in the T1D Organ Donor Pancreas
Authors: BRUGGEMAN BRITTANY S. , BEACHY DAWN , JACOBSEN LAURA M. , NICK HARRY S. , ATKINSON MARK A. , SCHATZ DESMOND , WASSERFALL CLIVE 
Published: June 2020

Current evidence suggests that alteration in cellular metabolism leads to pancreatic β-cell dysfunction and loss in type 1 diabetes (T1D). The mammalian target of rapamycin, mTOR is a key regulator of cell survival and growth in response to intracellular energy levels, nutrients, and growth factor signaling. Dysregulated mTOR complex 1 (mTORC1) has been implicated in β-cell loss and dysfunction in T2D but has not been well studied in T1D. We hypothesized that genes associated with three pathways involved in the regulation of mTORC1 would display altered expression in T1D organ donor pancreata compared to nondiabetic controls. We isolated total RNA from 30 T1D and 30 unaffected control human organ donor pancreata obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD) program and performed real-time qPCR on 26 genes related to these pathways, all of which demonstrated significant (p&lt;0.05) induction. In relation to cellular energy balance, we observed induction of the AMPK-related genes. Concerning nutrient availability and the GCN2/ATF4 pathway, genes associated with all Sestrins and the GATOR 1 and GATOR 2 complexes were induced. In relation to growth factor signaling, components of the PI3K/AKT pathway were induced (Table 1). Both AMPK and PI3K/AKT pathways converge on TSC2, which had the largest degree of induction observed (22.4x). To conclude, our results clearly indicate dysregulation of mTORC1 in the T1D donor pancreas.

Disclosure
B.S. Bruggeman: None. D. Beachy: None. L.M. Jacobsen: None. H.S. Nick: None. M.A. Atkinson: None. D. Schatz: None. C. Wasserfall: None.
1646-P: Role Of Microbiota In Diabetes-Associated Colorectal Cancer
Authors: NOURELDEIN MOHAMED H. , EID ASSAAD A. 
Published: June 2020

Diabetes changes the microbiota of the host, a condition known as dysbiosis. Dysbiosis have emerged to be an important contributing factor for the pathogenesis of diabetes and diabetes-associated colorectal cancer. In this study we tangled some of the molecular mechanisms that links diabetes to CRC that are in tune relation with dysbiosis. To test our hypothesis, MKRmice that can spontaneously develop type 2 diabetes were used in our work. For CRC induction, another subset of mice was treated with azoxymethane (AOM) and dextran sulfate sodium. (DSS), to identify the link between both diabetes and CRC. In parallel experiments, a subset of control mice was depleted of their microbiota after weaning, then mice were inoculated with fecal microbial transplant (FMT) from diabetic mice and mice with CRC. After 5 weeks of transplantation, all mice groups were treated with AOM and DSS. Further, a subset of the diabetic mice and diabetic mice with CRC were treated with probiotics or butyrate. At the end of the treatment, 16S rRNA sequencing was performed to identify different microbial communities in the fecal samples. Besides, at sacrifice, blood was collected, and colons were harvested for molecular, and biochemical analysis. Our preliminary results show that diabetes is associated with a defined microbial signature characterized by reduction of butyrate-forming bacteria which is associated with gastrointestinal complications.These changes are reversed upon treatment with probiotics or butyrate. Inoculation of control mice with diabetic microbiota and cancer microbiota resulted in the development of more aggressive CRC. Our data also show that IL-1βand NOX4 are over-expressed in diabetic mice as a result of activation of HDAC3 in colon tissue. Collectively our data suggest that diabetes is associated with dysbiosis characterized by lower abundance of butyrate-forming bacteria leading to less butyrate production and activation of HDAC3 resulting in over-expression of IL-1βand NOX4 leading to CRC.

Disclosure
M.H. Noureldein: None. A.A. Eid: None.
1648-P: Identification and Functional Analysis of E59Q Mutation in NEUROD1 Gene in a Chinese MODY Family
Authors: LIU LIMEI , CHEN YATING , ZHANG JUAN , JIANG YANYAN , LU MING , GE XIAOXU , JIA WEIPING 
Published: June 2020

Objectives: In contrast to the common MODY2, MODY3 and MODY5, MODY6 is a relatively rare subtype of MODY. To investigate whether NEUROD1 is responsible for Chinese MODY, we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.
Methods: PCR direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for MODY2, MODY3 and MODY5 genes. The functional significances of newly identified mutations were analyzed by studies on clinical phenotypes, pathophysiology and three-dimensional (3D) structure.
Results: 1) E59Q (c.175 G&gt;C, p.Glu59Gln), a heterozygous mutation in NEUROD1 gene, was identified in one of the MODY families. 2) Glu59 residue in NeuroD1 is highly conserved across mammalian species. 3) Four diabetic patients (proband and her son, brother and sister) carring the mutation were thinner with BMI of 21.0 (20.3-21.2). In comparison with unaffected relatives (n = 6), E59Q carriers showed obviously decreased insulin secretion at fasting and postprandial status (both p&lt;0.05). The proband’s father with E59Q mutation was normal glucose tolerance, suggesting non-penetrants. 4) The E59Q mutation was not detected in other probands or in the 201 nondiabetic control subjects. 5) The negatively charged Glu59 forms hydrogen bonds and strong salt bridges with the surrounding positively charged Arg54 and Lys88, and the main chains of Glu59 forms hydrogen bonds with Gly56 and Asp61, respectively. In the E59Q mutation, the salt bridges of Gln59 side chain disrupts, forming the new hydrogen bonds between Gln59 and Arg54.
Conclusions: NEUROD1-E59Q mutation clearly affected the interaction between E59 residue and its surrounding amino acids and thus changed the molecular conformation of N-terminal in NeuroD1. The abnormal conformation of NeuroD1 may decrease the E59Q mutant binding to the insulin promoter and activity of insulin transcription, therefore causing MODY6 subtype with defected insulin secretion.

Disclosure
L. Liu: None. Y. Chen: None. J. Zhang: None. Y. Jiang: None. M. Lu: None. X. Ge: None. W. Jia: None.

Funding
National Natural Science Foundation of China (81970686, 81770791, 81471012, 81270876); Shanghai Jiao Tong University (YG2019ZDA08); Shanghai Leading Talent (SLJ15055)
1656-P: FGF-21 Receptor Variants Demonstrate Severe Insulin Resistance in a Mouse Model of Insulin Mediated Pseudoacromegaly
Authors: STONE STEPHEN I. , LUPU TRAIAN , URANO FUMIHIKO , ORNITZ DAVID M. 
Published: June 2020

Insulin mediated pseduoacromegaly (IMPA) is a rare insulin resistance syndrome characterized by tall stature, acanthosis nigricans, obesity, and acromegaloid features. Subjects with IMPA have normal growth hormone and IGF-1. However, their insulin levels are markedly elevated. To date, no molecular or genetic etiology has been demonstrated as a definitive cause of IMPA. We previously described an adolescent female diagnosed with IMPA. Exome sequencing identified 2 rare, predicted deleterious, variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB) which form the receptor for fibroblast growth factor 21 (FGF-21). Due to FGF-21’s role in insulin signaling, we hypothesized that these mutations may be contributing to our proband’s condition. Our study aimed to knock-in these FGFR1/KLB variants into a mouse model using CRISPR/Cas9 gene editing technology. After embryo microinjection, we were able to generate 4 pups mosaic for the missense mutations in FGFR1 or KLB. The resulting founder mice were backcrossed to wild type mice, and then bred to recapitulate the same digenic geneotype found in our adolescent proband with IMPA. When exposed to a high fat diet, double mutant (FGFR1/KLB) mice demonstrate hyperglycemia (158.0 compared to 125.3 mg/dL, p=&lt;0.0001). At 9 weeks-old, the double mutant mice weighed 40.9 g compared to 25.4 g (p=0.0177). These mice underwent a 2 g/kg intraperitoneal glucose tolerance test. While fasting, both the double mutant and wild type mice had normal glucose (87 and 76 mg/dL). However fasting insulin was elevated in the double mutant mice (1246.1 to 231.5 pg/mL). 30 minutes post glucose, the double mutant mice demonstrated hyperglycemia (414 to 274 mg/dL) and marked hyperinsulinemia (2,358.0 to 884.3 pg/mL). Although further characterization of these mice is required, thus far, these studies suggest that our proband’s digenic variants in FGFR1/KLB are likely to be pathogenic and are a potential cause of IMPA.

Disclosure
S.I. Stone: Research Support; Self; National Institutes of Health. Speaker’s Bureau; Self; Rhythm Pharmaceuticals. T. Lupu: None. F. Urano: Stock/Shareholder; Self; CytRx Corporation. Other Relationship; Self; AETAS Pharma, Amylyx Pharmaceuticals, Mitochon, National Center for Advancing Translational Sciences, Novus Biologicals?. D.M. Ornitz: None.

Funding
National Institutes of Health (R21HD098872); Washington University (P30DK020579); National Center for Advancing Translational Sciences (UL1TR002345)
1658-P: A Novel Mutation in Hepatocyte Nuclear Factor-1 Beta (HNF1B) in Maturity-Onset Diabetes of the Young 5 (MODY5)
Authors: FUJITA YUKI , HYO TAKANORI , MATSUBARA MIHO , HAMAMOTO YOSHIYUKI , TANAKA DAISUKE , SEINO YUTAKA 
Published: June 2020

Maturity-onset diabetes of the young (MODY) is a group of dominantly inherited non-autoimmune diabetes characterized by early onset. Delayed diagnosis or misdiagnosis as type 1 or 2 diabetes is common, but early and correct diagnosis of MODY is important because it significantly alters the management of both the patient and his or her relatives. MODY5 is caused by mutations in the HNF1B, associated with renal and pancreatic abnormalities. Recently, we had identified a novel pathogenic mutation in IVS3-1G&gt;C of HNF1B, in a Japanese MODY family. A 30-year-old male presented to our office with a diagnosis of NIDDM at age 15; autoimmune antibodies were negative, glycemia was initially managed with basal-bolus insulin. Abdominal ultrasound showed bilateral hyperechogenic kidneys but unlike with the reported typical abnormalities in MODY5, only a few renal cysts were observed, and pancreas was intact. An initial diagnosis of early-onset type 2 diabetes was made. However, the case subsequently showed high probability of MODY, when he reported a strong family history of early-onset diabetes in his sister, his father and paternal grandmother. Genetic testing performed in him, his sister and his father revealed shared unreported gene mutation g.37731831C&gt;G (GRCH38 Chr17) in the HNF1B gene suggesting a diagnosis of MODY5. The mutation locates in the splicing site which may result in the production of abnormal proteins or failure of protein synthesis. Our MODY5 case was unique in the point that despite the mild renal morphological abnormalities, the proband had renal dysfunction and microalbuminuria from the early stage of disease, evoking the importance of considering the possibility of monogenic diabetes even in scarce structural abnormalities but having atypical diabetes with strong family history. It also suggests the necessity of further investigation of the exact mechanism of the development of diabetes and the cause of abnormalities in the kidney by this certain mutation.

Disclosure
Y. Fujita: None. T. Hyo: Speaker’s Bureau; Self; ARKRAY, Kissei Pharmaceutical Co., Ltd., LifeScan, Inc., Medtronic, Novo Nordisk Inc. M. Matsubara: None. Y. Hamamoto: Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc. D. Tanaka: None. Y. Seino: Research Support; Self; ARKRAY, Bayer Yakuhin, Ltd., Boehringer Ingelheim International GmbH, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Speaker’s Bureau; Self; Becton, Dickinson and Company, Eli Lilly Japan K.K., Kao Corporation, Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
1671-P: Pathogenesis of Obesity-Driven Metabolic Sequelae Is Associated with Th17 Metabolic Switch and Inflammatory Hepatic Th17 Cells
Authors: MORENO-FERNANDEZ MARIA E. , OATES JARREN , DAMEN MICHELLE S. , DOLL JESSICA R. , STANKIEWICZ TRACI E. , DIVANOVIC SENAD 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is a major global health issue. Lack of effective therapies to NAFLD is attributed to limited knowledge of disease etiopathogenesis. Emerging evidence reveal key contribution of the Th17 axis in NAFLD. However, the characteristics and mechanisms underlying the pathogenic potential of Th17 cells in NAFLD remain unknown. Here, we uncover a unique population of inflammatory hepatic CXCR3+Th17 cells (ihTh17) that contribute to NAFLD progression. Longitudinal hepatic accrual of ihTh17 cells correlated with NAFLD severity in mice and was dependent on obesity and CXCR3 axis activation. ihTh17 cells, compared to conventional CXCR3-Th17 cells, exhibited increased open chromatin marks in enhancer regions of inflammatory and metabolic genes, increased glycolytic skewing and metabolic capacity, and were able to simultaneously produce an array of pro inflammatory cytokines that directly promoted hepatocellular damage. Adoptive transfer of ihTh17 cells accelerated and exacerbated NAFLD pathogenesis in vivo. Modulation of the metabolic state of ihTh17 cells was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell hepatic accrual and inflammatory capacity, CXCR3 axis activation, and hepatic expression of glycolysis-associated genes were conserved in humans with NAFLD and positively correlated with disease severity. In sum, we show that the obesity-associated environment regulates Th17 cell metabolism and competence towards a unique inflammatory hepatic Th17 fate in turn contributing to NAFLD progression. Notably, modulation of these pathways holds potential for development of novel therapeutic strategies to NAFLD.

Disclosure
M.E. Moreno-Fernandez: None. J. Oates: None. M.S. Damen: None. J.R. Doll: None. T.E. Stankiewicz: None. S. Divanovic: Consultant; Self; Janssen Pharmaceuticals, Inc., Pfizer Inc.

Funding
American Diabetes Association (1-19-PMF-019 to M.E.M-F.); National Institutes of Health (R01DK099222, R01DK099222-02S1P30, DK078392)
1677-P: Higher Frequency of HLA DRB1*08:03 and DRB1*04:01 Observed in A-beta+ Ketosis-Prone Type 2 Diabetes in Japanese Subjects
Authors: SHIMADA AKIRA , SATOMURA ATSUSHI , SUZUKI SEIYA , HAISA AKIFUMI , OIKAWA YOICHI 
Published: June 2020

Ketosis-prone type 2 diabetes, especially islet-associated autoantibody negative and beta-cell function reserved (A-beta+; KPD) group, is recognized as atypical diabetes. Because we detected insulin peptide reactive T cells in these KPD subjects, we realized that KPD possesses characteristics of type 1 diabetes (ADA meeting, 2017). Therefore, in this study, we examined HLA types. After institutional review board permission was obtained, written informed consent and blood samples were obtained from the enrolled Japanese subjects (KPD: 22 males and 0 female, mean onset age 36.4 years of age; acute onset type 1 diabetes (AT1D): 21 males and 22 females, mean onset age 36.3 years of age; slowly progressive type 1 diabetes (SP): 10 males and 10 females, mean onset age 49.0 years of age). Then the HLA allele frequency was compared to normal controls (http://hla.or.jp/med/frequency_search/ja/allele/search/R/). The frequencies of HLA DRB1*04:05 and DRB1*09:01, which are known susceptible alleles in Japanese type 1 diabetes, were not higher in KPD (13.6%, 27.3%, respectively) subjects as compared to controls (13.5%, 14.3%, respectively), whereas were significantly higher in AT1D (41.9%, 53.5%, respectively; both p&lt;0.001) and SP subjects (45.0%, 40.0%, respectively; both p&lt;0.002). However, interestingly, the frequency of HLA DRB1*08:03 was significantly higher in KPD (34.8%, p&lt;0.001) subjects as compared to controls (8.3%), whereas it was not the case both in AT1D (4.7%) and SP (10.0%) subjects. Moreover, the frequency of HLA DRB1*04:01 which is known susceptible alleles in Caucasian type 1 diabetes was significantly higher in KPD (18.2%, p&lt;0.001) subjects as compared to controls (0.9%), whereas it was not the case both in AT1D (2.3%) and SP (5.0%) subjects.
In conclusion, although KPD subjects possess similar insulin peptide T cell responses to type 1 diabetes, different genetic background seems to exist probably leading to different clinical phenotype.

Disclosure
A. Shimada: Advisory Panel; Self; Astellas Pharma Inc. Speaker’s Bureau; Self; Eli Lilly Japan K.K., Novo Nordisk Inc., Sanofi-Aventis. A. Satomura: None. S. Suzuki: None. A. Haisa: None. Y. Oikawa: None.

Funding
Saitama Medical University
1682-P: Cotransplantation of Islets with Adipose-Derived Stem Cells Synergistically Reduced Blood Glucose in STZ-Induced Diabetic Rats
Authors: CHEN XIAO-DONG , LI SHENGXIAN , WANG HANZHOU 
Published: June 2020

Mesenchymal stem cells (MSCs) not only serve as a cell reservoir, replacing damaged cells, but also as a “drug store”, providing trophic factors that exert multiple potent cellular effects, such as anti-apoptotic, anti-fibrotic, anti-inflammatory, and immunomodulatory. There is increasing evidence that MSC trophic factors are able to improve the ability of β-cells to secrete insulin in vitro and promote islet graft survival in vivo. Here, we report that co-transplantation of freshly isolated islets with adipose-derived mesenchymal stem cells (Ad-MSCs) results in a rapid, significant reduction in hyperglycemia in streptozotocin (STZ)-induced diabetic rats. Lewis rats (n=30) were injected intraperitoneally with STZ (80 mg/kg); by day 3 post-injection, 24 animals (∼80%) achieved elevated blood glucose levels that stabilized at ∼300 mg/dL. On day 14, STZ-treated rats received the following transplants via hepatic portal vein infusion: PBS (negative controls), Lewis (isografts) or Fischer (allografts) islets alone or combined with Lewis rat Ad-MSCs. Initially, co-transplantation of islets (isografts or allografts) with Ad-MSCs dramatically reduced blood glucose levels compared to transplantation of islets alone (∼60% vs. ∼30%). However, only isografts combined with Ad-MSCs promoted the retention of transplanted islet function, resulting in the maintenance of blood glucose levels at ∼47% of the pre-transplantation level (=100%) through 70 days post-transplantation. Morphologically, these co-transplants in liver were larger in size, had more capillaries, and produced more insulin than islets alone. Although islets (iso- or allo-grafts) co-transplanted with Ad-MSCs appeared to provide an accelerated normalization of blood glucose levels, no evidence was found that allograft rejection was reduced. We conclude that co-transplantation improved islet viability more, with a prolonged anti-hyperglycemic effect, than islets alone.

Disclosure
X. Chen: None. S. Li: None. H. Wang: None.

Funding
San Antonio Medical Foundation
1691-P: Alcohol-Related Liver Disease as Independent Risk Factor for Posttransplant Diabetes Mellitus in Liver Recipients
Authors: CAMPOS MARIANA B. , BOIN ILKA D. , NETO ARNALDO M. 
Published: June 2020

Background and Aims: There are few data related to identification of risk factors for post transplant diabetes mellitus (PTDM) in liver transplantation (Tx). The aim of this study was to investigate the risk factors for PTDM.
Patients and methods: A retrospective study of adult patients submitted to liver Tx. Data for sex, age, BMI, pre and PTDM, Tx cause, presence of hepatocellular carcinoma (HCC), use of immunosuppressants, hepatitis B, hepatitis C (HepC) and liver biopsy were analyzed. Mann-Whitney and Chi Square tests as well as a multivariate logistic regression were performed.
Results: Among 207 consecutive patients, 60.4% had no diabetes (group 1), 18.8% had pre Tx DM (group 2) and 20.8% were classified as PTDM (group 3). The major cause of transplantation was HepC (48.8%). Triglycerides (164 vs. 106mg/dL, p= 0.002) and creatinine (1.24 vs. 1.1mg/dL, p = 0.029) were higher in group 2 than in group 1, probably due to long-standing DM and metabolic syndrome in group 2. Comparisons using the Chi-Square test showed higher frequencies in group 3 than group 1 and 2, respectively, for HepC (65.1% vs. 35.1% and 37.9%, p=0.004), tacrolimus use (95.3% vs. 81.6% and 71.1%, p&lt;0.001) and prednisone use (48.8% vs. 24% and 36.8%, p=0.009). HCC before Tx was more common in group 2 than in groups 1 and 3 (64.1% vs. 40.8% and 41.9%, respectively; p=0.034). Regarding biopsy data, interface activity was more severe in groups 1 and 3 compared to group 2 (62.2% and 64%% vs. 11%; p=0.040, respectively). The independent risk factors for PTDM according to the multivariate logistic model were HepC (OR 4.4; CI 95% 1.73-11.22; p=0.002), alcoholism (OR = 3.7, 95% CI, 1.2-11.5, p = 0.025), the use of tacrolimus (OR = 6.3, 95% CI 1.2-32.5, p = 0.029) and prednisone (OR = 7.2, 95% CI 2.4-21.8, p&lt;0.001).
Conclusion: Alcohol-related liver disease is an independent risk factor for PTDM in liver recipients. Patients with HepC and those exposed to tacrolimus and prednisone are other groups of high risk for PTDM.

Disclosure
M.B. Campos: None. I.D. Boin: None. A.M. Neto: None.