bluuebunny/crossref_metadata_2025_split huggingface dataset:
263-OR: Higher Glycemic Threshold for Glucagon Suppression in Impaired Fasting Glucose and Impaired Glucose Tolerance
Authors: KOHLENBERG JACOB D. , LAURENTI MARCELLO C. , EGAN AOIFE M. , COBELLI CLAUDIO , MAN CHIARA DALLA , VELLA ADRIAN 
Published: June 2021

Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. Graded Glucose Infusion (GGI) is a technique used to assess Insulin Secretion Rate (ISR) in response to rising glucose concentrations. We used GGI to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 32 nondiabetic, weight-stable individuals (54 ± 2 yrs, 29 ± 1 Kg/M2) categorized on the basis of fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/L (until 08:30) enabling the subsequent measurement of the glycemic threshold for ISR and GSR. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. β-cell responsivity (Φ) was estimated from the relationship of ISR to glucose. The glycemic threshold for glucagon suppression was higher in subjects with impaired fasting glucose (IFG) than normal fasting glucose (NFG), 10.9 ± 0.8 vs. 8.3 ± 0.5 mmol/L, p&lt;0.01, IFG vs. NFG respectively. This was also the case in subjects with impaired glucose tolerance (IGT) compared to normal glucose tolerance (NGT), 10.3 ± 0.7 vs. 8.5 ± 0.7 mmol/L, p=0.05. Φ did not differ in subjects with IGT vs. NGT (p=0.33) or in subjects with IFG vs. NFG (p=0.48). The glycemic threshold for stimulation of ISR was higher in subjects with IFG than NFG, 5.7 +/- 0.3 vs. 5.0 +/- 0.1 mmol/L, p&lt;0.01, IFG vs. NFG respectively, but no different in subjects with IGT vs. NGT, 5.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/L, p=0.06, IGT vs. NGT respectively. These data show that in nondiabetic humans, IFG but not IGT is associated with a higher glycemic threshold for insulin secretion, and both IFG and IGT are associated with a higher glycemic threshold for glucagon suppression.

Disclosure
J. D. Kohlenberg: None. M. C. Laurenti: None. A. M. Egan: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk.

Funding
Endocrine Fellows Foundation (DK078646DK116231)
27-LB: Impact of the March–May 2020 Confinement on the Clinical-Biological Profiles of Diabetic Patients Hospitalized in Diabetology
Authors: MAHJOUB FATEN , AMOR NADIA BEN , BERRICHE OLFA , JAMOUSSI HENDA 
Published: June 2021

Objective: In Tunisia, a total confinement was imposed from March 20 until May 4, 2020. The aim of our work was to assess the impact of this 2-month confinement on the clinical and biological profile of diabetic patients hospitalized in diabetology.
Patients and Methods: This is a cross-sectional, observational, descriptive study that involved 110 diabetic patients hospitalized in department A of the National Institute of Nutrition and Food Technology of Tunis (Tunisia) from June 1 until June 30, 2020.
Results : The mean age of the patients was 49.72±11.99years with ranges ranging from 16 to 77 years old; 63.6% of patients were female and 73.6% of patients were type 2. The average duration of diabetes was 11.53±8.62years, with extremes ranging from 0to24 years. The mean level of glycated hemoglobin was 12.03±3.97% and the Body-Mass-Index was 29.44kg/m² with extremes ranging from 16.26to40.19kg/m². Weight gain was reported in 73% of patients with an average of 4.77±1.98kg within 2 months of confinement, with extremes ranging from 2to11kg. Two patients (1.8%) were hospitalized for inaugural diabetic ketosis. The others were admitted for an imbalance(81.8%) or an acute decompensation of their diabetes(16.4%). The factors of imbalance or decompensation were: a poor compliance with hygienic-dietetic measures(90.9%); a medication poor compliance(41.8%), more than half of which(54.3%) was due to the inability of the patient to go to the local health center to obtain his medication; lipodystrophies(42.7% of patients on insulin); a stomatological infection(8.2%); an urinary tract infection(4.5%) and an acute coronary syndrome(0.9%).
Conclusions : The diabetic patient is at high risk of a severe form of Covid-19. However, the confinement imposed by the pandemic seems to be one of the factors of diabetes imbalance (in particular by weight gain and poor adherence to therapy). It is therefore essential to strengthen the education and treatment of diabetic patients.

Disclosure
F. Mahjoub: None. N. Ben Amor: None. O. Berriche: None. H. Jamoussi: None.
27-OR: Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated with Medication Response in the Study to Understand the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)
Authors: LI JOSEPHINE H. , KAUR VARINDERPAL , BRENNER LAURA , MERCADER JOSEP M. , FLOREZ JOSE C. 
Published: June 2021

SUGAR-MGH is a pharmacogenetic resource for characterizing genetic influences on pharmacological perturbations relevant to type 2 diabetes (T2D). 1,000 participants who were naïve to T2D treatment received 5 mg glipizide, followed by 4 doses of 500 mg metformin and a 75-g oral glucose tolerance test (OGTT) a week later. Glucose and insulin were measured at pre-specified endpoints after glipizide and during the OGTT. Incretin levels were measured in a subset. We calculated physiologic endpoints reflecting insulin secretion, insulin sensitivity, and incretin secretion. The mean age was 47 years, 54% were women, &gt;35% were non-white, and the mean BMI was 30.2 kg/m2. 890 participants underwent genome-wide genotyping using the Illumina Multi-Ethnic Genotyping Array, and high-quality imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and endpoints. We identified 21 genome-wide significant variants, of which 3 met experiment-wide significance (P&lt;8.3×10-9 for 2 drugs × 3 physiological hypotheses tested). The most significant association was between an African ancestry-specific variant (minor allele frequency=0.026) at rs149403252 and lower fasting glucose following metformin, adjusted for baseline glucose (P=1.9×10-9). We tested the influence of 429 known T2D-associated variants and found that the protective C allele of rs703972 near ZMIZ1 was associated with increased secretion of active GLP-1 in response to metformin (P=1.6×10-5), suggesting that an enhanced incretin response may be a mechanism by which this variant decreases T2D risk. We illustrate that a genome-wide approach in a multi-ethnic human perturbation study can uncover new variation associated with drug response and provide insight into mechanisms of action of known T2D genetic variation.

Disclosure
J. H. Li: None. V. Kaur: None. L. Brenner: Research Support; Self; Apple. J. M. Mercader: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk.

Funding
National Institutes of Health (R01DK088214, R03DK077675, P30DK036836, M01RR01066, 1UL1RR025758-04, 8UL1TR000170-05, T32DK007028)
277-OR: Use of Noncarbohydrate Fuels Is Associated with Materno-Fetal Complications in Type 1 Diabetes Pregnancy: Metabolomics Analysis of the CONCEPTT Trial
Authors: MEEK CLAIRE L. , STEWART ZOE , FURSE SAMUEL , YAMAMOTO JENNIFER M. , FEIG DENICE , KOULMAN ALBERT , MURPHY HELEN R. 
Published: June 2021

Aims: We assessed metabolomic signatures in maternal and cord blood associated with suboptimal outcomes in the continuous glucose monitoring in women with type 1 diabetes in pregnancy trial (CONCEPTT).
Methods: Serum samples from 162 mothers (12, 24 and 34 weeks’ gestation) and 93 cord blood samples were analysed for 1049 metabolites and 1041 lipids using ultra-performance liquid chromatography-tandem mass spectroscopy. We used adjusted and unadjusted logistic regression of metabolomic variables using adjudicated outcomes: extremely-large-for-gestational-age (ELGA; &gt;97.5th centile), pre-eclampsia and neonatal hypoglycaemia with modified Bonferroni false discovery rate p≤0.001.
Results: All materno-fetal complications studied were associated with reliance on non-carbohydrate sources of fuel. Lipids through beta oxidation were the main fuel source in ELGA (24 and 34 weeks), neonatal hypoglycaemia (12 weeks only) and pre-eclampsia (12 and 24 weeks). Marked protein catabolism was evident in neonatal hypoglycaemia (34 weeks) and pre-eclampsia (24 and 34 weeks). Cord blood in ELGA infants showed evidence of simultaneous beta oxidation and de novo lipogenesis, a biologically futile cycle of creating and destroying lipids, which consumes excess energy and substrate. Cord blood from infants with neonatal hypoglycaemia showed evidence of pronounced protein catabolism providing glucogenic amino acids for gluconeogenesis.
Conclusions: Reliance on lipid or protein sources for fuel was associated with ELGA, neonatal hypoglycaemia and pre-eclampsia. Carbohydrate metabolism was insufficient to meet cellular energy demands, possibly due to insufficient insulin, insufficient dietary carbohydrate or both. Improving outcomes in type 1 diabetes pregnancy may require greater focus on normalising carbohydrate metabolism through optimal carbohydrate intake and matched insulin dosing.

Disclosure
C. L. Meek: None. Z. Stewart: None. S. Furse: None. J. M. Yamamoto: None. D. Feig: Advisory Panel; Self; Novo Nordisk. A. Koulman: None. H. R. Murphy: None.

Funding
JDRF (17/2011/533, 80/2010/585); Diabetes UK (DUK-HKF 17/0005712, DUK-PG 17/0005633.BBSRC BB/M027252/1)
28-OR: Identification of Ancestry-Specific Alleles in a Genome-Wide Association Study (GWAS) for Metformin (MET) Response in the Diabetes Prevention Program (DPP)
Authors: LI JOSEPHINE H. , PERRY JAMES A. , JABLONSKI KATHLEEN A. , CHEN LING , SRINIVASAN SHYLAJA , TODD JENNIFER N. , HARDEN MAEGAN , MERCADER JOSEP M. , FRANKS PAUL W. , HANSON ROBERT L. , KAHN STEVEN E. , KNOWLER WILLIAM C. , POLLIN TONI I. , FLOREZ JOSE C. , GROUP DPP RESEARCH 
Published: June 2021

Genome-wide significant (GWS) loci for glycemic response to MET in type 2 diabetes (T2D) reported elsewhere have not replicated in the DPP. Thus, to assess whether pharmacogenetic interactions may differ in impaired glucose tolerance (IGT), we conducted a GWAS in the DPP for MET response, defined by diabetes incidence and change in quantitative traits (fasting glucose, 2-hour glucose on oral glucose tolerance test, hemoglobin A1c [HbA1c], fasting insulin, insulin sensitivity index, and weight). Samples were genotyped on the Illumina HumanCore Exome array and imputed on the 1000 Genomes Phase3 panel. Cox proportional hazards models tested associations with diabetes incidence in MET (n=876) and placebo (PBO, n=887) arms. Multiple linear regression using an additive model evaluated for association with 1-year change in quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-environment (G×E) interaction between MET and PBO. Results were filtered to minor allele frequency (MAF) &gt;1% and imputation score &gt;0.7. We identified 3 GWS variants after correcting for correlated traits (P&lt;9×10-9). In MET, a variant near ENOSF1 was associated with an increase in % HbA1c (rs144322333, β=0.39 [95% CI 0.28, 0.50], P=2.8×10-12) and was mainly found in African ancestry participants (MAFAFR=0.07, MAFEUR=0.002). A variant near OMSR was associated with greater weight loss (kg) in MET (rs145591055, β=-7.55 [95% CI -9.88, -5.22], P=3.2×10-10) and found in 10% of Native Americans. Neither variant had an impact in PBO; the interaction with treatment arm was significant for rs144322333 (G×E P=1.4×10-6) and rs145591055 (G×E P=1.5×10-5). No GWS associations emerged for diabetes incidence.
In summary, a GWAS for MET response in participants with IGT revealed novel associations that require validation in ancestry-specific populations and may have implications for tailored therapy.

Disclosure
J. H. Li: None. R. L. Hanson: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. D. Research group: None. J. A. Perry: None. K. A. Jablonski: None. L. Chen: None. S. Srinivasan: None. J. N. Todd: None. M. Harden: None. J. M. Mercader: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)
29-OR: Regulatory Loop of IR Signaling for Adipocyte Mitochondrial Homeostasis
Authors: SAKAGUCHI MASAJI , OKAGAWA SHOTA , OKUBO YUMA , FUKUDA KAZUKI , IGATA MOTOYUKI , KAWASHIMA JUNJI , KONDO TATSUYA , ARAKI EIICHI 
Published: June 2021

Insulin and IGF1 signaling initiate Tyr phosphorylation of IR/IGF1R and adaptor IRSs, leading to Ser/Thr phosphorylation of PI3K/AKT and MAPK/ERK pathways essential for the maintenance of brown and white adipose tissues (BAT and WAT). Lack of insulin-signaling in adipose tissues caused metabolic disease in mice with hyperglycemia, hyperlipidemia, and fatty liver, but the mice recovered adipose tissues by regenerating adipocytes. We addressed the mechanism of how adipose tissues regenerate using adipocyte-specific and inducible IR/IGF1R knockout mice (Ai-DKO). We identified a reduction of protein phosphatase protector, α4, which can regulate Ser/Thr phosphorylation of down-stream insulin signaling. shRNA-mediated α4 knockdown (KD) in BAT affected not only insulin-stimulated down-stream Ser/Thr phosphorylation of AKT (S473) but also affected up-stream Tyr phosphorylation of IRβ (Y1162/1163) and IRS1 (Y612). Proteomics analysis of α4-binding molecule identified Y-box protein 1 (YBX1), which functions as a transcription factor for Tyr phosphatase PTP1B. We observed increased PTP1B expression in α4-KO preadipocytes. As the impact of α4 in vivo, inducible adipocyte-specific α4 KO (Ai-α4 KO) mice with tamoxifen-inducible Cre-ERT2 transgene showed cold intolerance, diabetes, ectopic lipid accumulation in the liver, and pancreatic islet hyperplasia, with an increase of C18: 0-ceramide in WAT and BAT. RNA-seq showed a marked reduction of genes associated with mitochondrial fatty acid oxidation and the increases in inflammatory cytokine pathways in Ai-α4 KO WAT and BAT, implicating the cause of fat tissue loss was the increased adipocyte apoptosis. The α4 to PTP1B loop is critical for fat tissue maintenance by regulating IR tyrosine phosphorylation.

Disclosure
M. Sakaguchi: None. S. Okagawa: None. Y. Okubo: None. K. Fukuda: None. M. Igata: None. J. Kawashima: None. T. Kondo: None. E. Araki: Other Relationship; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Kowa Company, Ltd.

Funding
Japan Society for the Promotion of Science; Merck Sharp & Dohme Corp; Takeda Foundation
291-OR: GPR31 Appears to Mediate the Downstream Actions of 12-Lipoxygenase in the Setting of Diabetic Inflammation
Authors: TERSEY SARAH A. , WALSH MELISSA , HERNANDEZ-PEREZ MARIMAR , DOWGIELEWICZ JONATHAN , KULKARNI ABHISHEK , ANDERSON RYAN , MIRMIRA RAGHAVENDRA G. 
Published: June 2021

Inflammation in macrophages and pancreatic islets is a hallmark of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) is expressed in macrophages and β cells, produces the eicosanoid 12(S)-HETE and promotes inflammation. GPR31 has recently been identified as the 12(S)-HETE receptor. To clarify the role of GPR31 in diabetic inflammation, we generated Gpr31b-/- mice on the C57BL/6J background. Gpr31-/- mice are viable, with normal body weight, glucose tolerance, and β-cell mass, similar to 12-LOX knockout mice. Upon low dose streptozotocin treatment to induce β-cell inflammation, Gpr31b-/- mice remained normoglycemic unlike wildtype littermates, and exhibited no reductions in β-cell mass. Isolated islets treated with the insulin receptor antagonist S961 to mimic insulin resistance showed the expected decrease in Ins1, Pdx1, and Gpx1 mRNA levels. By contrast, in Gpr31b-/- islets, these genes remained unaltered. Additionally, Gpr31b-/- islets showed a trend towards a decrease in ER stress markers Ddit3 and spliced-Xbp1 expression. To examine GPR31 in macrophage inflammation, we first interrogated its role in the generation of proinflammatory macrophages upon polarization in vitro to the M1 state; under these conditions, we found no differences between Gpr31b-/- and wildtype macrophages, suggesting that GPR31 does not play a role in macrophage polarization. To test a role for GPR31 in proinflammatory macrophage function, we leveraged a zebrafish tailfin injury model, in which macrophages migrate to the site of tailfin injury. Compared to control fish, fish harboring knockdown of GPR31 showed reduced numbers of macrophages at the site of injury. Taken together, our data support the notion that the effects of 12-LOX are mediated through GPR31, and that GPR31 appears to promote proinflammatory responses in both macrophages and pancreatic islets.

Disclosure
S. A. Tersey: None. M. Walsh: None. M. Hernandez-perez: None. J. Dowgielewicz: None. A. Kulkarni: None. R. Anderson: None. R. G. Mirmira: Advisory Panel; Self; Hibercell Inc., Sigilon Therapeutics, Inc., Veralox Therapeutics, Employee; Spouse/Partner; Beta Bionics, Inc.

Funding
National Center for Advancing Translational Sciences (R03TR003381)
304-OR: Association of Eating Patterns and Diabetic Kidney Disease in Type 2 Diabetes
Authors: RODRIGUES CÍNTIA C.R. , RIBOLDI BÁRBARA P. , RODRIGUES TICIANA C. , SARMENTO ROBERTA A. , ANTONIO JULIANA P. , BORBA RAQUEL A. , VIEIRA ADRIELE P. , PASINI ISADORA S. , DE ALMEIDA JUSSARA C. 
Published: June 2021

Evaluation of association of eating patterns with diabetes kidney disease (DKD) in patients with type 2 diabetes (T2DM) was performed. Cross-sectionally, T2DM patients underwent clinical, laboratory, and nutritional assessments. Dietary information was evaluated by a quantitative food frequency questionnaire validated for diabetes and converted into daily intakes. The eating patterns were identified by cluster analysis. DKD was defined as estimated glomerular filtration rate &lt;60 mL/min/1.73m2 and persistently elevated urinary albumin excretion (≥14 mg/dL). A chi-square test, one-way analysis of variance (ANOVA/Bonferroni’s post hoc test) and Kruskal-Wallis test (Bonferroni post hoc correction) were used to test differences across the eating patterns. Poisson regression analysis was used to investigate the associations between eating patterns and DKD. IBM SPSS Statistics 25.0 (p&lt;0.05). A total of 329 T2DM patients were evaluated: 10 years (5-19) diabetes duration; HbA1c=8.7±2.0%; 62±10 years old; BMI=30.9±4.2kg/m². Four eating patterns were identified: (1) high intake of dairy products, fruits, and vegetables; (2) ultra-processed foods; (3) high intake of refined carbohydrates, processed meats, and solids fats; and (4) high intake of red meat and sugary beverages. Age, sex, sedentary lifestyle, maximum doses of anti-glycemic agent in addition to fasting plasma glucose levels were different among the patterns. Poisson regression models confirmed the association of Pattern 2 (PR=1.48; 95% CI=1.10-1.99; P=0.010) and Pattern 4 (PR=1.93; 95% CI=1.29-2.89; P=0.001) with presence of DKD after adjusting for confounders.
In conclusion, eating patterns with higher consumption of ultra-processed foods or red meat and sugary beverages were associated with the presence of DKD when compared to patterns rich in dairy products, fruits, and vegetables in this sample of T2DM outpatients.

Disclosure
C. C. R. Rodrigues: None. B. P. Riboldi: None. T. C. Rodrigues: None. R. A. Sarmento: None. J. P. Antonio: None. R. A. Borba: None. A. P. Vieira: None. I. S. Pasini: None. J. C. De almeida: None.
325-OR: Genetic and Socioeconomic Factors Are Independently Associated with Type 2 Diabetes
Authors: CROMER SARA JANE , LAKHANI CHIRAG M. , MERCADER JOSEP M. , MAJARIAN TIM , FLOREZ JOSE C. , MANNING ALISA , MERINO JORDI , UDLER MIRIAM 
Published: June 2021

Genetics and socioeconomic status (SES) are key drivers of increased type 2 diabetes (T2D) risk, but the extent to which they impact disease in an additive or non-additive manner is unknown. We examined T2D prevalence using cross-sectional electronic health record (EHR) data from 27,771 participants of European ancestry in the Mass General Brigham Biobank. A polygenic score for T2D was derived using a previously published globally expanded score (gePS). Multiple area-based socioeconomic risk estimates were evaluated (including deprivation indices and a machine learning model incorporating hundreds of census variables) with similar impact on T2D risk; here, an individual’s estimated SES risk was defined as the percent of residents in their census tract with less than high school education. T2D status was derived using a machine-learning algorithm validated by expert chart review to have 90% positive predictive value. The age and sex-adjusted odds of T2D was 1.72 (95% CI 1.63-1.81, p&lt;0.001) per SD increase of T2D gePS and 1.36 (95% CI 1.31-1.42, p&lt;0.001) per SD increase in socioeconomic risk. In a combined model of gePS and socioeconomic risk, these associations persisted, with no evidence of interaction. Persons in the highest quintile of both genetic and socioeconomic risk had an almost 3-fold risk of T2D compared to those of middle quintile risk for both (OR 2.67, 95% CI 2.08-3.44, p&lt;0.001). Notably, the T2D risk of individuals in the highest quintile of genetic risk but lowest quintile of socioeconomic risk was indistinguishable from that of those in the middle quintile for both risk factors (OR 1.13, 95% CI 0.85-1.51). These data provide evidence for the independent associations of genetic risk and SES with T2D and suggest that living in a community with high SES is associated with reduced T2D risk, even among those at increased genetic risk. Our findings raise the hypothesis that interventions targeted at specific elements of SES, such as education, may reduce risk of T2D in those with high genetic risk.

Disclosure
S. Cromer: Employee; Spouse/Partner; Johnson & Johnson Medical Devices Companies. C. M. Lakhani: Consultant; Self; xy. ai. J. M. Mercader: None. T. Majarian: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. A. Manning: Employee; Spouse/Partner; Emulate, Inc, Stock/Shareholder; Spouse/Partner; Invitae. J. Merino: None. M. Udler: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007028)