bluuebunny/crossref_metadata_2025_split huggingface dataset:
1282-P: Genetic Susceptibility of Dipeptidyl Peptidase-4 Inhibitor–Associated Bullous Pemphigoid in Chinese Patients with Type 2 Diabetes
Authors: SHI MAI , YANG AIMIN , CHOW ELAINE , LAU ERIC S. , TAM CLAUDIA H. , MA RONALD C. , CHEUNG MAN TUNG CHRISTINA , CHAN JULIANA C. , CHAN WAI SZE AGNES 
Published: May 2022

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) .
Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP.
Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users.
Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele.

Disclosure
M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None.

Funding
The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .
1284-P: Genetic and Lifestyle Associations with Cardiometabolic Traits and Diabetes Risk Factors in Ethnically Diverse Africans
Authors: HUI DANIEL , HARRIS DANIEL , MCQUILLAN MICHAEL , HANSEN MATTHEW , RANCIARO ALESSIA , BEGGS WILLIAM , MPOLOKA SUNUNGUKO W. , WOLDEMESKEL DAWIT , NJAMNSHI ALFRED K.K. , NYAMBO THOMAS B. , CHANOCK STEPHEN , TISHKOFF SARAH A. 
Published: May 2022

African ancestry populations are underrepresented in human genetic studies, which leaves a knowledge gap about genetic and environmental risk factors for metabolic disease which can bias healthcare treatment. To alleviate these shortcomings, we conducted a series of genome-wide association studies of cardiometabolic traits in a diverse sampling of ∼2,500 (max sample size) ethnically and geographically diverse Africans from populations practicing agriculturalist, hunter-gatherer, and pastoralist subsistence strategies. This study includes the Fulani pastoralists who have a relatively high incidence of adult-onset diabetes, despite having a low average body mass index (BMI) . All individuals in the present study are sampled from rural populations that have relatively homogeneous lifestyles and diet within a community. This unique aspect to the study cohort allows for within- and between- group comparisons to identify trait variation attributable to genetics vs. lifestyle variation. Subjects were genotyped on a new African-focused SNP array from the Human Heredity and Health in Africa (H3 Africa) consortium. Genome-wide data was imputed based on a panel of African whole-genome sequences and data from the 1000 genomes project, resulting in a total of million variants for trait association analysis. Genetic associations were tested for BMI, blood pressure, and blood biomarkers of cardiometabolic health. We checked for replication of genotype/phenotype associations by comparison to large non-African cohorts studied for the same traits. We find that most associations identified in non-African populations do not replicate in the Africans. However, we identified a number of novel loci associated with cardiometabolic traits in the African populations. This study has important implications for identifying genetic risk factors that may play a role in metabolic disease in individuals of African ancestry. Funded by ADA Pathway award 1-19-VSN-02.

Disclosure
D.Hui: None. T.B.Nyambo: None. S.Chanock: None. S.A.Tishkoff: None. D.Harris: None. M.Mcquillan: None. M.Hansen: None. A.Ranciaro: None. W.Beggs: None. S.W.Mpoloka: None. D.Woldemeskel: None. A.K.K.Njamnshi: None.

Funding
American Diabetes Association (1-19-VSN-02) ; National Institutes of Health (R35 GM134957-01, R01AR076241, 5T32DK007314-39, 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154-01)
1291-P: Bioinformatics Analysis of Gene Networks Associated with Glucose Variability and Inflammatory Pathways in Diabetes
Authors: SAIK OLGA V. , KLIMONTOV VADIM 
Published: May 2022

Aim: To identify key genes linking glucose variability (GV) and inflammatory pathways in diabetes.
Methods: Text mining-based reconstruction and analysis of the gene networks associated with GV and low-grade inflammation in diabetes were performed by the ANDSystem (www-bionet.sscc.ru/and/cell/) . Key elements of the networks were identified by the highest value of cross-talk centrality (CTC) and cross-talk specificity (CTS) . A comparative analysis of two networks was applied to identify genes that are up- or down-regulated by glucose fluctuations and involve in the inflammatory pathways.
Results: We revealed sixty one genes related to GV and inflammation (Table) . Based on CTC values, TP53, TNF, NFKB1, IL1B, IL6, CASP3, MMP2, MMP9, TGFB1, and VEGFA were identified as the principal hubs in the gene network of inflammation that are regulated by GV. The UCP2, GPX1, SOD2, ANGPT2, GLP1R, HGF, SPP1, MAPK9, TIMP1, and MMP1 genes demonstrated the highest CTS values.
Conclusions: The obtained results improve the understanding of the molecular mechanisms of the proinflammatory effect of GV in diabetes. The role of the identified molecules as key drivers of GV-induced inflammation needs further experimental verification.

Disclosure
O.V.Saik: None. V.Klimontov: None.

Funding
Russian Science Foundation (20-15-00057)
1297-P: Berberine Derivatives as Novel Antidiabetes Agents Targeting Intestinal AMPK and Antimicrobial Peptide-Controlled Gut Microbiome
Authors: ZHANG ERYUN 
Published: May 2022

Mammalian 5′-AMP-activated protein kinase (AMPK) is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target for glucose control in type 2 diabetes (T2D) . Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, AMPK functions in the intestine, the first-line organ for nutrient processing, remains largely elusive. We have uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptide (AMP) -controlled gut microbiota and their metabolites. Therefore, the intestinal AMPK-AMP-microbiota-BAT axis is a potential target for the treatment of T2D. Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, has been used to treat T2D in animal models as well as human trials, while offsetting renal, cardiovascular, hepatic, and respiratory risks. However, its poor bioavailability severely limits its application and development. As such, there is a dire need to explore structural modifications of berberine to obtain better pharmacological properties and elucidate its underlying mechanisms of action. Berberine can activate AMPK indirectly by inhibition of mitochondrial respiration in the adipocyte, myotubes and liver; however, its effects on intestinal AMPK are still unknown. We have successfully synthesized natural and non-natural novel berberine derivatives. We will determine their antidiabetes effects and elucidate the underlying mechanisms of action in targeting the intestinal AMPK-AMP pathways for T2D treatment. Moreover, our study will provide a better structure-activity relationship to guide the future design of berberine derivatives with higher potency and improved bioavailability.

Disclosure
E.Zhang: None.
130-OR: The Association between High Out-of-Pocket Costs and Incidence of Treatment Intensification with an SGLT2 Inhibitor (SGLT2i) or GLP-1 Agonist (GLP-1a) in Patients with Type 2 Diabetes and Established Cardiovascular Disease: A Retrospective Cohort Study
Authors: LUO JING , FELDMAN ROBERT , ROTHENBERGER SCOTT D. , HERNANDEZ INMACULADA , KORYTKOWSKI MARY T. , GELLAD WALID F. 
Published: May 2022

The use of SGLT2i and GLP-1RA in patients with T2D remains low despite their known CV benefits. This may be due in part to high drug costs. We sought to assess the association between out-of-pocket (OOP) costs and the likelihood of initiating these two classes in patients with T2D and established CVD. We conducted a cohort study using claims data (Optum) , which included commercial and Medicare Advantage beneficiaries. Adults with T2D on metformin monotherapy between 12/5/17 and 12/31/were eligible. We excluded those:1) not continuously enrolled for ≥1 yr prior to their first metformin dispensing,2) with no evidence of established CVD, or3) whose OOP costs (defined as the sum of copays and deductibles for a 30-day supply) for SGLT2i or GLP-1RA could not be determined. We used Cox proportional hazards models adjusting for demographics, clinical characteristics, insurance plan, provider and laboratory characteristics to estimate hazard ratios (HR) of initiation across quartiles (Q) of OOP costs, with Q1 representing the lowest and Q4 the highest OOP costs. The cohort included 72,743 patients (mean[SD] age 72[9.4], 56% male) followed for a median of 914 days. Most (88%) were covered by a Medicare Advantage plan. The unadjusted incidence of initiating a SGLT2i (or GLP-1RA) was 2.8% (2.1%) in Q4 vs. 3.8% (2.8%) in Q1 of OOP costs. The median time to initiation of a SGLT2i/GLP-1RA was longer in Q4 (418/325 days) vs. Q1 (395/3 days) of OOP costs. In fully adjusted models, the HR for Q4 vs. Q1 of OOP costs was 0.79 (95%CI 0.70 to 0.90) for initiating a SGLT2i and 0.88 (95%CI: 0.77 to 1.01) for a GLP-1RA. In this national cohort of patients w/ T2D and established CVD, beneficiaries enrolled in plans in the highest quartile of OOP costs were significantly less likely to initiate a SGLT2i or GLP-1RA compared to those enrolled in plans in the lower quartile.

Disclosure
J.Luo: None. R.Feldman: None. S.D.Rothenberger: None. I.Hernandez: Consultant; Bristol-Myers Squibb Company, Pfizer Inc. M.T.Korytkowski: None. W.F.Gellad: None.

Funding
NIDDK (K23DK120956) NCATS (KL2TR001856)
1308-P: Role of Medial Amygdala Neurons in Regulating the Metabolic Responses to Homeostatic Challenge
Authors: DEVARAKONDA KAVYA , O’CONNOR RICAHRD , ALVARSSON ALEXANDRA , LI ROSEMARY Y. , GONZALEZ MARIA JIMENEZ , KENNY PAUL , STANLEY SARAH 
Published: May 2022

Neural signals play a critical role in metabolic regulation by controlling behavior and coordinating glucose production and uptake in peripheral organs. Physiological and psychological stimuli that disrupt homeostasis - stressors - result in metabolic and behavioral adaptations but our understanding of the precise circuits underlying these adaptations remains incomplete. Here we used in vivo calcium imaging, viral tracing and neural manipulation to determine the contribution of medial amygdala (MeA) circuits to the metabolic responses to stress. Social and psychological stressors result in hyperglycemia. These stressors also rapidly increased fluorescence of genetic calcium indicators (GCamp) in MeA neurons. Chemogenetic activation of MeA neurons significantly increased blood glucose without altering pancreatic hormone release and suppressed feeding. Viral tracing revealed distinct MeA subpopulations projecting to the bed nucleus of the stria terminalis (BNST) and to the ventromedial hypothalamus (VMH) . Chemogenetic stimulation of MeA projections to the VMH but not BNST increased blood glucose during glucose tolerance testing via sympathetic activation of hepatic gluconeogenesis, without effects on pancreatic or adrenal hormones. Conversely, silencing of MeA neurons projecting to the VMH blunted stress-induced hyperglycemia. Together these findings suggest a crucial role for MeA circuits in the metabolic response to stressors with dissociation of sympathetic, hormonal, and behavioral adaptations to homeostatic challenge.

Disclosure
K.Devarakonda: None. R.O’connor: None. A.Alvarsson: None. R.Y.Li: None. M.Jimenez gonzalez: None. P.Kenny: None. S.Stanley: None.

Funding
American Diabetes Association (1-17-ACE-31) ; National Institutes of Health (R01NS097184, OT2OD024912, F31DK129016 and R01DK124461) National Science Foundation (1930163) Department of Defense (W81XWH-20-1-0156, W81XWH-20-1-0345) Naomi Berries Diabetes Center Russell Berrie Foundation AwardRevson Foundation
131-LB: Prevalence of Vitamin B12–Monitoring among Patients Receiving Metformin in a Public Hospital
Authors: GHIYA RONAK D. , FAYFMAN MAYA 
Published: May 2022

Background: Metformin reduces intestinal absorption of Vitamin B12 in up to 30% of patients and lowers serum Vitamin B12 concentrations in 5-10%. In 2017, the American Diabetes Association (ADA) updated its guidelines to recommend patients taking metformin undergo regular monitoring of Vitamin B12 levels. To better understand acceptance and application of these guidelines, we undertook an assessment of such monitoring within a single hospital center serving the low-income population in Atlanta, GA to assist in guiding optimal monitoring and patient management.
Methods: Data was collected from a single hospital center using electronic medical records (EMR) and the SlicerDicer tool to identify all outpatients for whom metformin was prescribed either as a single agent or in combination therapy during January 1 - December 31, 2021 and then measure Vitamin B12 prescribing among primary care patients and patients followed by endocrinology and further analyze which patients had neuropathy.
Results: During the period studied, of the total 2,336,914 patients documented in the EMR, 30,803 (0.01%) were outpatients prescribed metformin either as a single agent or in combination therapy. Of these, 816 patients (2.6%) had Vitamin B12 levels ordered and measured. The prevalence of Vitamin B12 levels ordered and measured was 7.5% (674 of 8,975) among patients seen in primary care clinics and 2.3% among those followed in endocrinology (25 of 1,081) (chi-square p&lt;0.0001) . 621 (6.9%) of the metformin-treated primary care patients had neuropathy, and of those 63 had Vitamin B12 levels. 134 (12.4%) of the endocrinology patients had neuropathy, and of those 5 had Vitamin B12 levels. (chi-square p&lt;0.0001)
Conclusion: Among two outpatient cohorts who were prescribed metformin, there was suboptimal adherence to the ADA’s recommendation for regular monitoring of Vitamin B12 levels. Approaches for increasing and optimizing ordering and monitoring Vitamin B12 levels will be developed. Increased awareness of the relationship between metformin and Vitamin B12 deficiency and standardized approaches to monitoring are needed.

Disclosure
R. D. Ghiya: None. M. Fayfman: None.
1312-P: Impaired Beta-Cell Function in Older Patients Corresponds to Changes in Salience Network Connectivity
Authors: DEAJON-JACKSON JELANI , LACADIE CHERYL , WATT CHARLES , SCHEINOST DUSTIN , HWANG JANICE J. 
Published: May 2022

The salience network (anterior cingulate cortex (ACC) —insula) plays an important role in regulating attention and memory in the context of decision making and has also been shown to be highly responsive to changes in peripheral glucose levels. Increased age is also associated with changes in glucose homeostasis and the salience network. To investigate these relationships, 40 healthy, cognitively normal, non-diabetic subjects (20 Young (age mean 28±1 years, BMI 28.1 ±1.1 kg/m2, HbA1c 5.3±0.1%) and 20 Old (age mean of 73±2 years, BMI 26.9±0.9 kg/m2, HbA1c 5.5±0.1%)) underwent an OGTT, resting state functional connectivity (FC) MRI brain scanning, and cognitive assessments (Cambridge Neuropsychological Test Automated Battery) . Despite similar BMI, HbA1C, and fasting glucose levels, older individuals had lower disposition index (young: 9±2, old: 3.3±0.4, p=0.005) indicating impaired β-cell function. There were no differences in measures of insulin sensitivity (HOMA-IR (p=0.38) or Matsuda index (p=0.70) . A seed-based analysis using a predefined cubic voxel in the ACC showed differences in FC between the ACC and the left insula (Main Effect by group, P&lt;0.001) with lower connectivity values in Old compared to Young subjects. This connectivity value also correlated with errors on the Paired Associate Learning task, which tests attention and memory (r=-0.5, P=0.001) . Moreover, the connectivity values correlated with the disposition index in older subjects (r=0.49, P=0.03) but not younger subjects (P=0.9) . Thus, in our cohort of healthy, cognitively normal older subjects, impairments in beta-cell function are associated with altered functional connectivity within the salience network. These findings highlight the need for future investigations to determine whether mild age-related changes in glycemic control contribute to neurocognitive changes in older patients.

Disclosure
J.Deajon-jackson: None. C.Lacadie: None. C.Watt: None. D.Scheinost: None. J.J.Hwang: None.

Funding
Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342)
1315-P: Optogenetic Activation of Vagal Motor Neurons in Mice Modulates Heart Rate but Not Blood Glucose Levels
Authors: CAMPBELL JOHN , CONLEY NICHOLAS J. , KAUFFMAN LILY S. 
Published: May 2022

Parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) control glucose metabolism through the vagus nerve and so are potential targets for diabetes treatment. Yet, little is known about the molecular identity and organization of glucose-regulating DMV neurons. To identify these neurons for further investigation, we optogenetically activated them in mice while measuring blood glucose. We targeted a light-sensitive ion channel, CaTCh, selectively to DMV neurons based on their co-expression of Chat and Phox2b, which resulted in CaTCh expression in most or all DMV neurons but no surrounding neurons. To photostimulate CaTCh+ DMV neurons, we then implanted optical fibers over the DMV in 9 adult Chat::Phox2b::CaTCh mice (4 females, 5 males; mean age ± S.D., 24 ± 13 weeks) . After acclimation we fasted the mice overnight and then delivered pulses of blue laser light (20Hz, 10ms pulse, 3 sec off, 1 sec on) for 15 min to activate DMV neurons. We used a glucometer on tail blood samples drawn every 5 minutes for 1 hour, beginning 20 minutes before and ending 25 minutes after photostimulation. Before, during, and after photostimulation, blood glucose averaged 2± 35 mg/dL, 220 ± 36 mg/dL, and 215 ± 45 mg/dL and did not change significantly with photostimulation (p&gt;0.05, ANOVA) . To rule out stress as a confound, we repeated these studies after anesthetizing 4-hour fasted mice with isoflurane but still did not detect a significant effect of photostimulation on blood glucose. Interestingly, however, heart rate decreased significantly with photostimulation (pre, 5± 23 bpm; during, 429 ± 32 bpm; post, 517 ± 24 bpm; p&lt;0.001, ANOVA) , indicating that the photostimulation parameters were sufficient to activate vagal neurons. Further work is underway to address whether the lack of effect of DMV poststimulation on blood glucose is due to antagonistic signaling (e.g., coincident release of insulin and glucagon) or represents a limitation of the method.

Disclosure
J.Campbell: None. N.J.Conley: None. L.S.Kauffman: None.

Funding
American Diabetes Association (1-18-INI-14) ;
132-LB: Effectiveness of Interventions to Improve Cardiovascular Risk Factors in U.S. Asian Persons with Type 2 Diabetes—A Systematic Review and Meta-analysis
Authors: XIAO JASON , YU JIELU , DECKARD AMBER , WAN WEN , STAAB ERIN M. , RODRIGUEZ ALEX W. , SHETTY RAJ , LAITEERAPONG NEDA 
Published: May 2022

Objective: Asian persons have an increased risk of type 2 diabetes (T2D) compared to non-Hispanic white persons, with approximately two in five individuals being diagnosed. The prevalence of T2D among this population has grown in recent years as Asian persons are the fastest growing racial/ethnic group in the US. We conducted a meta-analysis of US randomized controlled trials (RCTs) to evaluate the effectiveness of T2D interventions at improving systolic blood pressure (SBP) , diastolic blood pressure (DBP) , and HbA1c among this population.
Methods: An electronic search of literature in PubMed, Scopus, CINAHL, PsycINFO, and Medline was conducted from 1985 to 2019 for studies evaluating T2D interventions among predominantly minority populations. This analysis was limited to RCTs with an average &gt;6% of total participants identifying as Asian, utilizing the 2020 US Census as standard. Interventions focusing on the efficacy of a drug, device, diet, surgery, or procedure were excluded. A random effects meta-analysis was performed to calculate the pooled effect size of the various outcomes.
Results: Of the articles reviewed, 9 met inclusion criteria. All 9 included HbA1c and 5 included SBP/DBP. Participants were 62.8% Asian and 40.3% female with a mean age of 53.4 years. Interventions included diabetes education programs, utilization of community health workers, bilingual counseling, and cognitive therapy. There was a 0.36% decrease in HbA1c in the experimental group when compared to the control group (95% CI -0.48 to -0.25, p=0.80, I2=0%) . Compared to control, these interventions had minimal effects on SBP (-0.08, 95% CI -0.22 to 0.07, p=0.73, I2=0%) and DBP (0.01, 95% CI -0.22 to 0.25, p=0.23, I2=29%) .
Conclusion: This meta-analysis found that RCTs for T2D in Asian persons modestly lowered HbA1c, with minimal impact on SBP/DBP. Future analysis should include observational studies to evaluate a larger sample and investigate their impact on other markers of health, as well as characterize these effects by level of intervention to inform health policy.

Disclosure
J. Xiao: None. J. Yu: None. A. Deckard: None. W. Wan: n/a. E. M. Staab: None. A. W. Rodriguez: None. R. Shetty: None. N. Laiteerapong: None.