bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-LB: Effect of Somatostatin Receptor 2 Antagonism (SSTR2a) on Oral Glucose Tolerance (OGT) in a Rat Model of Type 2 Diabetes (T2D)
Authors: D'SOUZA NINOSCHKA C. , ALEALI NADIA , SHAKERI DORSA , HOFFMAN EMILY G. , ATHERLEY SARA C. , CHAMPSI SABRINA , EL-ZAHED MAYA , LIGGINS RICHARD , CHAN OWEN , RIDDELL MICHAEL C. 
Published: June 2023

Background: Hypoglycemia remains a concern for insulin-treated individuals living with diabetes. SSTR2a increases the endogenous glucagon counterregulatory response during hypoglycemia in rodent models of diabetes, but its impact on OGT is unclear. We examined the impact of SSTR2a on OGT in a rodent model of T2D maintained on basal insulin therapy.
Methods: High fat fed (HFF), low dose streptozotocin (35 mg/kg) T2D rats received SSTR2a treatment (ZT-01 3 mg/kg) or vehicle (N=8-9/group) immediately before a fasted OGT test (OGTT, 2 g/kg). Glycemia, glucagon and c-peptide levels were measured pre- and post-dose and monitored for 120 minutes.
Results: The OGTT resulted in comparable rises in blood glucose levels in both groups, consistent with an animal model of T2D. Glucagon levels rose within 15 minutes of SSTR2a and glucose administration (120 ± 70 vs 4.8 ± 3, p=0.006) and remained higher than controls for the duration of the OGTT. C-peptide levels also increased from baseline by 116 ± 77% in SSTR2a-treated animals compared to 28.9 ± 70% in controls.
Conclusion: SSTR2a treatment increases glucagon and c-peptide levels following oral glucose ingestion in this rat model of T2D. These preliminary findings suggest that the use of the SSTR2a should not adversely impact glucose control around meals if used as a preventive therapy against insulin-induced hypoglycemia.

Disclosure
N. C. D'souza: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. N. Aleali: None. D. Shakeri: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. El-zahed: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None.

Funding
GlycoNet (CD-85)
201-LB: Benefit of Dual Therapy with GLP-1 RA and SGLT2i on Renal Outcomes in Type 2 Diabetes
Authors: ZAREINI BOCHRA , GERDS THOMAS A. , SØRENSEN KATHRINE K. , CLEMMENSEN KIM K.B. , KVIST KAJSA , DAVID JENS-PETER , TORP-PEDERSEN CHRISTIAN 
Published: June 2023

Background: There is increased use of dual glucagon like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapy, but real-world evidence on the renal benefit is lacking.
Aim: To compare the dual use of GLP-1 RA and SGLT2i to other dual second-line type 2 diabetes therapies with respect to renal outcomes.
Methods: From 2010-2021 patients from the Danish nationwide registries were followed from start of dual second-line type 2 diabetes treatment. Outcomes were chronic renal disease, end-stage renal disease and &gt;50% eGFR decrease from baseline. The estimated risk following 1 of 4 dual therapy combinations was determined using a longitudinal causal inference framework assuming all patients followed one dual therapy for 5 years.
Results: In total 87,201 persons were included (GLP-1 RA and SGLT2i: 14,831, GLP-1 RA and DPP4/SU/TZD: 20,417, SGLT2i and DPP4/SU/TZD: 22,803, dual DPP4/SU/TZD: 29,150). The 5-year risk ratio (95%CI) of dual GLP-1 RA and SGLT2i therapy compared to reference (dual DPP4/SU/TZD) for chronic renal disease: 1.03 (0.97;1.08), end-stage renal disease: 0.12 (0.09;0.15) and &gt;50% decrease in eGFR: 0.52 (0.45;0.59).
Conclusion: Dual therapy with GLP-1 RA and SGLT2i compared to other dual therapies results in greater risk reduction of end-stage renal disease and eGFR decline, while dual SGLT2i and DPP4/SU/TZD showed greater risk reduction of chronic renal disease.

Disclosure
B. Zareini: None. T. A. Gerds: None. K. K. Sørensen: None. K. K. Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. K. Kvist: Employee; Novo Nordisk A/S. J. David: Employee; Novo Nordisk A/S, Sanofi. C. Torp-pedersen: Research Support; Novo Nordisk, Bayer Inc.
203-OR: Features of Human Th-Like Regulatory T Cells in the Pathogenesis of Type 1 Diabetes
Authors: QIN YAO , LI YUXIAO , DAI LIUYAN , WEI QIANYING , HUANG MEI , ZHANG MEI 
Published: June 2023

Background: The imbalance between Tregs, Bregs and proinflammatory Th cells plays a vital role in the pathogenesis and development of T1D. Accumulating evidence has revealed that Treg has phenotypic plastic changes into other subsets under pathological conditions. However, whether Tregs convert into other immune cell types in T1D and the potential influencing factors remain unknown. This study aimed to examine the changes of Th-like Tregs in T1D patients and determine whether Th cells and IL-10+ Bregs play roles in Treg polarization.
Methods: A total of 49 T1D patients and 20 healthy controls (HC) were recruited in this study. Flow cytometry was used to measure Treg plasticity (including CD4+Foxp3+IFN-γ+ Th1-like, CD4+Foxp3+IL-4+ Th2-like and CD4+Foxp3+IL-17+ Th17-like Tregs), the proportion of CD27+CD39hi Bregs, and Th cell subsets (including Th1, Th2 and Th17 cells) in the peripheral blood. Cytokines were detected by ELISA.
Results: The frequencies of Th1-like Tregs and Th17-like Tregs in T1D were lower than those in HC, while the proportion of Th17 cells was significantly increased in T1D. The frequency of Bregs was markedly higher in T1D relative to HC, but IL-10 expression of Bregs was reduced. Interestingly, compared with lean and overweight patients, Th1-like Tregs were higher in patients with normal weight, but Treg plasticity was not affected by disease status (age at diagnosis, islet autoantibodies and β-cell function) or T1D risk loci (rs3118470 or rs2104286) in IL2RA. Additionally, positive correlations between Th1-like Tregs and Th17-like Tregs and between Bregs and Th2-like Tregs were observed in T1D. Meanwhile, the frequency of Th1-like Tregs was negatively related to IL-6 and the frequency of Th2-like Tregs was negatively associated with TNF-α.
Conclusion: Our results firstly explored the features of human Th-like Tregs in the pathogenesis in T1D, which might contribute to improve our understanding of the pathogenic mechanisms of T1D.

Disclosure
Y.Qin: None. Y.Li: None. L.Dai: None. Q.Wei: None. M.Huang: None. M.Zhang: None.

Funding
National Natural Science Foundation of China (81974103, 82000747)
214-LB: Plasma Proteomic Markers of Iron and Risk of Diabetes in a Biracial Cohort
Authors: CONWAY REBECCA B. , YOUNG KENDRA , PRATTE KATHERINE A. , KINNEY GREGORY L. , AUSTIN ERIN , LI YISHA , BOWLER RUSSEL , MCCLAIN DONALD A. , CRAPPO JAMES 
Published: June 2023

Higher levels of iron have been linked to increased diabetes risk among European and European American (EA) populations; whether this is true for other populations where anemia is more common is unknown. Ferritin is an iron storage protein linked to diabetes risk; transferrin transports catalytic iron, reducing its oxidative damage. We tested whether proteomic measurements of ferritin and transferrin were associated with diabetes risk in a biracial cohort of current and former smokers. EA and African American (AA) participants from the COPDGene Cohort who were free of diabetes (n=4,671) at study baseline were followed for the incidence of diabetes. The Somascan was used on plasma measured at followup to determine relative amounts of proteins among participants. Logistic regression was used to calculate OR (95% CIs) of the cross-sectional relationship of natural log transformed ferritin and transferrin with diabetes risk. During an average of 5.6 years of follow-up, the incidence of diabetes was 7.9%. Ferritin was associated with increased diabetes risk (OR=1.29, 1.04-1.61), while higher transferrin linked with decreased risk (OR=0.19, 0.06-0.56) controlling for age, sex, BMI, hepcidin and smoking. When stratified by race, increased risk was associated with higher ferritin only among AA (OR=1.46, 1.07-2.01) and not for EA (OR=1.11, 0.81-1.52). Stratification by sex revealed that the relationship of ferritin was similar among AA men and women and EA women, with non-significant ORs ranging from 1.49-1.55; but null association among EA men (OR = 1.00, 0.65-1.52). Similarly, ORs for transferrin non-significantly ranged from 0.24-0.29 for AA men and women and EA women, but for EA men there was a significant 93% decreased risk for each natural long increase in transferrin (OR=0.07, 0.001-0.60). Our data suggest that higher body iron stores, as measured by ferritin, increases diabetes risk among both AA and EA. Ferritin may be a better marker for AA men and women and EA women while transferrin is a better marker for EU men.

Disclosure
R. B. Conway: None. K. Young: None. K. A. Pratte: None. G. L. Kinney: None. E. Austin: None. Y. Li: None. R. Bowler: None. D. A. Mcclain: None. J. Crappo: None.

Funding
National Heart, Lung, and Blood Institute (U01HL089897, U01HL089856); AstraZeneca; Bayer Pharmaceuticals; Boehringer Ingelheim; Genentech; GlaxoSmithKline; Novartis; Pfizer Inc.; Sunovion
217-LB: Heterogeneity of Single Cells Obtained from Peripheral Blood Mononuclear Cells Collected from Youth with Recent-Onset Type 1 Diabetes
Authors: WU WENTING , PARKS-SCHENCK CORINNE , GUO TINGBO , ZHANG CHI , MIRMIRA RAGHAVENDRA G. , EVANS-MOLINA CARMELLA 
Published: June 2023

Whole blood bulk RNA sequencing has been used to guide T1D clinical trial design and assess response to disease modifying interventions, whereas it is with limited information about cell specific gene expression changes. Here, we aimed to apply computational strategies to deconvolute cell type composition using cell specific gene expression references. Single-cell RNA sequencing (scRNA-seq) was conducted to profile 108,795 peripheral blood mononuclear cells obtained from 5 youth within 48 hrs of Stage 3 T1D onset (avg age 11.4; 3M;2F) and 5 age- and sex-matched controls and identified 31 distinct cell clusters. In T1D, the proportion of CD4+ T central memory (TCM) cells was increased (P = 0.018), while plasmacytoid dendritic cells (pDC), platelets, and hematopoietic stem and progenitor cells (HSPC) proportions were reduced (P = 0.021, 0.012 and 0.017 respectively) compared to controls. The most robust transcriptomic changes were observed in CD14+ and CD16+ monocyte populations and CD1C+ conventional type-2 dendritic (cDC2) cells. Using this scRNA-seq reference dataset, we ran computational algorithms CIBERSORTx and our in-house reference-free method ICTD to deconvolute cell proportions using public clinical trial data testing the anti-CD20 monoclonal antibody rituximab (n=37) vs. placebo (n=17). Strong correlation was observed between the methods for cell proportion estimates (P &lt; 2.2*10-16). It showed that B cell subsets were reduced by rituximab. At baseline, non-responders had a higher proportion of CD8+ T cells (P = 0.04), and responders had higher proportions of neutrophils (P =0.04). These data suggest that deconvolution approaches can be utilized for secondary analysis of existing clinical trial bulk RNA-seq data, to link cell specific immune signatures associated with drug responder status.

Disclosure
W. Wu: None. C. Parks-schenck: None. T. Guo: None. C. Zhang: None. R. G. Mirmira: None. C. Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc.

Funding
dkNET; Indiana University Center for Diabetes and Metabolic Diseases; National Institutes of Health (U01DK127786)
219-OR: Glucagon Counterregulation in a Hypoglycemic Clamp in Type 1 Diabetes Is Increased by ZT-01, a Novel Somatostatin Receptor 2 Antagonist—A Phase 1b Study
Authors: ABITBOL ALEXANDER , PEERS SUSAN , SIMONSON ERIC , MIDMER MICHAEL , RIDDELL MICHAEL , LIGGINS RICHARD 
Published: June 2023

This study evaluated the effect of ZT-01 on glucagon counterregulation during hypoglycemia in adults with type 1 diabetes, in a Phase 1b randomized, three-arm, double-blind crossover trial in 23 hypoglycemia aware adults with T1D. Participants underwent three hypoglycemic clamp procedures with 3 or 20 mg ZT-01 or placebo dosed 1 h prior to stepwise glucose clamp conditions using variable rate IV insulin infusion: euglycemia (5.0 ± 0.5 mmol/L), level 1 (3.5 ± 0.3 mmol/L, L1), and level 2 hypoglycemia (2.6 ± 0.2 mmol/L, L2).
With ZT-01, peak glucagon increased by up to 15.1 ± 10.5 and 27.1 ± 17.3 pg/mL, in L1 and L2 hypoglycemia, respectively, compared with no increase in L1 and an 8.4 ± 8.4 pg/mL increase in L2 hypoglycemia with placebo (p&lt;0.0001, figure). A counterregulatory response of increased glucose level coinciding with an increased glucagon level was observed more frequently with ZT-01 than placebo. No clinically significant effects on other counterregulatory hormones or hypoglycemia symptom scores were observed with ZT-01. A transient rise in glucagon and blood glucose was observed with ZT-01 post-dose prior to hypoglycemia. No SAEs were reported and no TEAEs were observed with ZT-01.
This study demonstrates proof-of-concept that ZT-01 significantly enhances the defective counterregulatory response in people with T1D during L1 and L2 hypoglycemia.

Disclosure
A.Abitbol: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Dexcom, Inc., Novo Nordisk Canada Inc., Janssen Pharmaceuticals, Inc., Research Support; Abbott Diabetes, Lilly Diabetes, Zucara Therapeutics, Novo Nordisk Canada Inc., Moderna, Inc., Senseonics, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Amgen Canada, Dexcom, Inc., Novo Nordisk Canada Inc., HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi. S.Peers: Employee; Zucara Therapeutics. E.Simonson: None. M.Midmer: Board Member; Zucara Therapeutics, Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. R.Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics.
22-LB: MiRNA Profiling of Exosomes Derived from Perivascular Adipocyte Tissue in Type 2 Diabetic Mice
Authors: CHEN SHUZHEN , POLAKI VENKATA , BIHL JI , WANG JINJU 
Published: June 2023

Background: Exosomes (EXs), a major type of extracellular vesicles, are emerging as a novel type of intercellular communicators. MicroRNAs (miRs) are one of the major executors of EXs. The previous study shows that lean and obesity adipocyte tissue EXs could elicit different effects in response to insulin sensitivity, the underlying mechanism is related to their carried miRs. Given EX cargoes and function vary on their cellular status, we speculate the miR profiling of EXs derived from the perivascular adipose tissue (PVAT) is altered in diabetic conditions.
Methods: EXs were isolated from the PVAT tissue of type 2 diabetic db/db and control db/c mice. EX size and concentration were analyzed by nanoparticle tracking analysis. The miR profiling of PVAT-EXs was analyzed by mmu-miR miRome profiling kit. The miRs of interest were further validated by qRT-PCR.
Results: 1) The PVAT-EXs level was higher in diabetic db/db mice than that in non-diabetic db/c mice; 2) In db/db mice, exosomal miRs profile was changed. The exosomal miRs, miR-223, miR-181a, miR-146a, miR-34a, and miR-210, were either down-regulated or up-regulated &gt; 3-fold when comparing that in db/c mice. Among these candidate miRs, miR-181a, miR-223, miR-210, and miR-146a might be involved in modulating adipose tissue inflammation and/or vascular function. MiR-34a could participate in white adipose tissue browning, macrophage polarization, and glucose tolerance. Conclusion: Our data have demonstrated that the miR profiling of PVAT-derived EXs is changed in type 2 diabetic conditions, which suggests the functions of these EXs might be altered in diabetic conditions.

Disclosure
S. Chen: None. V. Polaki: None. J. Bihl: None. J. Wang: None.
22-OR: High Glucose Metabolism Fuels Cathepsin L Maturation to Promote SARS-CoV-2 Infection in Patients with Diabetes
Authors: ZHAO MIAOMIAO , HE QIONG , YANG JIN-KUI 
Published: June 2023

Patients with diabetes are more likely to develop severe COVID-19 and deaths. However, the underlying mechanism remains poorly understood. Previously, we identified a widely expressed lysosome protease Cathepsin L (CTSL) promotes SARS-CoV-2 infection and may be a promising drug target (PMID: 33774649, 35668062). Here, we show that patients with diabetes have elevated CTSL concentration and activity in patients with or without COVID-19. The CTSL levels are positively correlated with HbA1c in humans. Hyperglycemic clamp study suggests that high glucose increases CTSL activity in healthy individuals. In vitro, we find that high glucose, but not high insulin, level promotes SARS-CoV-2 infection in wildtype (WT) cells. However, these promoting effects are largely reduced in CTSL-knockout (KO) cells. By using lung tissues from healthy, diabetic patients, WT and db/db mice, we find diabetes promotes CTSL maturation. Further, we identify that high glucose level, but not high insulin level, promotes CTSL activity. The matured CTSL levels are significantly increased in diabetic tissues. High glucose promotes CTSL translocation from the endoplasmic reticulum (ER) to lysosome through the ER-Golgi-lysosome axis (Fig.1). Our study reports the biological and potential clinical significance of glucose metabolism in CTSL maturation to promotes SARS-CoV-2 infection in patients with diabetes.

Disclosure
M.Zhao: None. Q.He: None. J.Yang: None.

Funding
National Natural Science Foundation of China (81930019)
221-OR: Retrospective Review of Genetic Mutations and Treatments in Patients with Monogenic Diabetes of the Youth (MODY)
Authors: DENG LILY , SHAH AMY S. , KRISHNAMURTHY MANSA 
Published: June 2023

Monogenic diabetes results from specific genetic mutations that result in diabetes mellitus. Clinical phenotypes differ based on the genetic defect, and treatment options are driven by the underlying genetic cause. Thus, accurate genetic diagnosis and evaluation of response to treatment is essential. Retrospective chart review was utilized to identify patients with MODY at a single institution who had confirmed genetic mutations. Demographics, co-morbidities, initial islet cell autoantibodies, diagnosis and treatment, and current treatments were evaluated. Patients diagnosed with MODY (n=92) comprised of 3% of the total patient population diagnosed with diabetes (78% T1DM, 19% T2DM) between 2000 to present day. For patients with MODY, the average age of diabetes diagnosis was 10.3 years and their mean HgbA1c was 8.0% at diagnosis. Three and a half percent of patients with MODY had ketoacidosis at diagnosis and 6.7% had positive islet cell autoantibodies. Among patients with MODY, the most common gene mutations were HNF1A, GCK, and HNF1B. Novel genetic mutations in PDX1, RFX6, BLK and KFL11 were also identified. Current treatment modalities of patients with MODY were compared (insulin, Metformin, Sulfonylureas, Metformin-Glyburide, insulin-Metformin, GLP-1 receptor agonists). For each medication, reduction in HgbA1c was seen at follow-up (0.05-1.15% reduction). All medications except for insulin and Metformin-Glyburide demonstrated a reduction in BMI at follow-up. The greatest reduction in BMI was observed in patients on GLP-1 receptor agonists and insulin-Metformin (3.3% and 8.89% respectively). Our study highlights the importance of genetic testing in patients who present with diabetes without ketoacidosis and that testing positive for islet antibodies does not preclude patients from a MODY diagnosis. Moreover, future investigation of GLP-1 receptor agonist as a treatment for MODY patients is warranted.

Disclosure
L.Deng: None. A.S.Shah: None. M.Krishnamurthy: None.
224-OR: The Efficacy and Safety of HSK 16149 in Chinese with Diabetic Peripheral Neuropathic Pain—A Randomized, Double-Blinded, Placebo and Pregabalin-Controlled Phase II/III Study
Authors: GUO XIAOHUI , ZHANG TINGTING , YUAN GEHENG , YUKUN LI , HUA MA JIAN , HONG-MEI LI 
Published: June 2023

Background: Chronic diabetic peripheral neuropathic pain (DPNP) is common and difficult to treat. The recommended medications are either inadequate effective or limited by the side effects. This study aims to evaluate the efficacy and safety of HSK16149, a potent, selective ligand of the a2δ subunit of voltage-gated calcium channels (VGCC), as analgesia treatment for DPNP.
Materials and Methods: This was a randomized, double-blind, placebo and active-controlled phase II/III study of patients aged ≥18 years with diabetic peripheral neuropathy in China. Firstly, the patients with moderate to severe pain were randomized to receive placebo, HSK 16149 40,80 mg/d without titration, and HSK16149 120, 160mg/d, pregabalin 300mg/d with 1 week titration on average. Then more patients were recruited and randomized to placebo and two HSK16149 dose groups, continued the treatment for up to 13 weeks. The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 13. The secondary endpoint was the responder rates as ≥30% and ≥50% improvement in ADPS.
Results: Compared with placebo, the pain was reduced since week 1 in HSK16149 groups. At week 13, the mean ADPS change from baseline was -1.23, -2.24 and -2.16 for placebo (n=177), HSK 16149 40mg/d (n=178) and 80mg/d (n=179), showing statistical significance for both HSK groups versus placebo (P&lt;0.0001). The 30% and 50% responder rate were both significantly greater for two HSK groups versus placebo (≥30%: 57.3%, 51.4% versus 31.6%; ≥50%: 32.0%, 36.3% versus 18.1%) at week 13. Most treatment-emergent adverse events (TEAE) in HSK16149 groups were mild to moderate, and the most frequent TEAEs were dizziness and somnolence, which were always transient and needed no additional treatment.
Conclusions: HSK 16149 rapidly improved analgesia without titration and was efficacious in relieving pain in Chinese DPNP patients, and well tolerated.

Disclosure
X.Guo: None. T.Zhang: None. G.Yuan: None. L.Yukun: None. J.Ma: None. L.Hong-mei: None.