bluuebunny/crossref_metadata_2025_split huggingface dataset:
35-OR: Multicenter MRI Assessment of the Pancreas in Type 1 Diabetes (MAP-T1D) Predicts Progression of Type 1 Diabetes
Authors: VIROSTKO JOHN , WRIGHT JORDAN J. , WILLIAMS JONATHAN M. , HILMES MELISSA A. , TRIOLO TAYLOR M. , BRONCUCIA HALI C. , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , PHILIPSON LOUIS H. , KAY THOMAS , THOMAS HELEN E. , GREELEY SIRI ATMA W. , STECK ANDREA , POWERS ALVIN C. , MOORE DANIEL J. 
Published: May 2022

Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for T1D. To determine whether pancreas MRI predicts T1D progression, we measured pancreas size and shape longitudinally in Type 1 Diabetes TrialNet Pathway to Prevention study participants. To increase enrollment and expand this study across multiple TrialNet sites, we established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols and ensure the consistency of imaging results across sites. Using this standardized protocol (PMID: 34428220) , we performed longitudinal pancreas MRI in 41 multiple autoantibody-positive individuals (mean age y.o., range 8 - 45 y.o., 49% female) at three TrialNet Clinical Centers. Average time between study entry and diabetes diagnosis for individuals who progressed to Stage 3 was 54 months while non-progressors were followed for a median time of 63 months. Five study participants who developed Stage 3 T1D during follow up had a smaller pancreas (29.5 ± 9.0 ml vs. 54.8 ± 22.5 ml, p = 0.02) and smaller pancreas volume normalized by body weight (0.61 ± 0.18 ml/kg vs. 0.85 ± 0.23 ml, p = 0.03) at study entry compared with those who did not progress to Stage 3. We found that pancreas volume was stable over time, with no significant increase or decrease up to four years after the initial MRI (total of 123 MRIs) . There was no significant change in pancreas size in the five individuals who progressed to Stage 3 T1D. The shape of the pancreas at study onset was also different in the five individuals who progressed to Stage 3 T1D compared with non-progressors, with larger surface area to volume ratio (p = 0.02) , and shorter principal axes (p = 0.05, shortest axis; p = 0.02, second shortest axis) . These data suggest that small pancreas size and altered shape predicts progression from Stage 2 to Stage 3 T1D.

Disclosure
J.Virostko: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. T.Kay: None. H.E.Thomas: Research Support; Captix Biomedical, CSL Limited, Pandion Therapeutics, Procyon Technologies. S.W.Greeley: None. A.Steck: None. A.C.Powers: None. D.J.Moore: None. J.J.Wright: None. J.M.Williams: None. M.A.Hilmes: None. T.M.Triolo: None. H.C.Broncucia: None. L.Du: None. H.Kang: None. W.E.Russell: None.

Funding
NIDDK (R03DK129979, U24DK097771, UC4 DK106993, DK020593) ; JDRF International (3-SRA-2015-102-M-B, 3-SRA-2019-759-M-B) ; Thomas J. Beatson, Jr. Foundation (2021-003)
354-OR: Estimating the Relative Influence (RI) of Genetic Risk of Glycemic Traits on Osteoporosis and Fractures in 409,633 Participants in the UK Biobank Using Machine Learning
Authors: DESHMUKH HARSHAL , PAPAGEORGIOU MARIA , MARK-WAGSTAFF CHARLOTTE , AKBAR SHAHZAD , BHAIJI AMIRA , SHAH NAJEEB , SATHYAPALAN THOZHUKAT 
Published: May 2022

Introduction: We used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for glycemic traits with osteoporosis and fracture in the UK Biobank population.
Methods: The study was performed with 409,633 participants in the UKBIobank. We identified 4626 SNPs associated with glycemic traits from the NGHRI catalogue for GWAS studies. Weighted genetic risk scores (wGRS) were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on osteoporosis and self-reported all-cause fractures in the UK Biobank population. We split the data into training (2/3) and testing set (1/3) and calculated the discriminatory power of the models using the area under the curve (AUC) with the testing model.
Results: The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m2. The study population had 41954 (10.2%) all-cause fractures and 4995 (1.2%) participants with osteoporosis. In the GBM model, top wGRS associated with all-cause fractures were wGRS for Type 1 diabetes (RI=4.49) and fasting glucose (4.17) . In contrast, the top wGRS associated with osteoporosis were wGRS for acute insulin response to glucose (RI=6.74) and Type 1 diabetes (RI=5.62) . Both models showed low to moderate discriminatory power with the area under the AUC of 0.57 (CI: 0.56-0.57) for fractures and 0.75 (CI: 0.74-0.76) for osteoporosis.
Conclusion: We showed a differential effect of wGRS for various glycemic traits on the risk of fractures and osteoporosis in the UK Biobank population. However, the machine-learning model with wGRS for glycemic traits demonstrated limited capacity to predict fractures and osteoporosis in the general population.

Disclosure
H.Deshmukh: None. M.Papageorgiou: None. C.Mark-wagstaff: None. S.Akbar: None. A.Bhaiji: None. N.Shah: None. T.Sathyapalan: n/a.

Funding
Dr Harshal Deshmukh is funded by NIHR clinical lectureship
361-OR: Proinsulin Processing Efficiency Differs in Youth and Adults with IGT or Untreated T2D
Authors: HANNON TAMARA S. , SAM SUSAN , TJADEN ASHLEY H. , EDELSTEIN SHARON , NADEAU KRISTEN J. , ARSLANIAN SILVA A. , CREE-GREEN MELANIE , EHRMANN DAVID A. , MATHER KIEREN J. , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: May 2022

Disproportionately increased proinsulin (PI) relative to C-peptide (CP) is a marker of inefficient β cell PI processing. To determine whether PI processing differs between youth (Y) and adults (A) with impaired glucose tolerance (IGT) and drug naïve T2D, we measured PI and CP in 58 Y (81% IGT, 69% female, 26% white, 22% black, 40% Hispanic, BMI=37±6 kg/m2) and 322 A (71% IGT, 52% female, 47% white, 28% black, 19% Hispanic, BMI=35±5 kg/m2) in the Restoring Insulin Secretion (RISE) Study. We assessed fasting PI, CP, PI/CP, and acute PI (API) and CP (ACP) responses to glucose (Rg) (APIRg, ACPRg, APIRg/ACPRg) and arginine at maximal (Rmax) glycemic potentiation (APIRmax, ACPRmax, APIRmax/ACPRmax) during a hyperglycemic clamp. Fasting PI, CP, and PI/CP were higher in Y vs. A, suggesting PI processing in the fasted state is lower in Y (Table) . APIRg and APCPg were higher in Y, and APIRg/ACPRg was similar. APIRmax, but not ACPRmax, was lower in Y. Thus, APIRmax/ACPmax was lower in Y, suggesting PI processing at maximal β cell stimulation is greater in Y. These results suggest that increased fasting β-cell secretory demand in Y may decrease the time available for PI processing and cause the release of more immature granules during fasting. Y may utilize a larger pool of granules in which PI processing is more complete when secretory demand is maximal.

Disclosure
T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. S.Sam: None. A.H.Tjaden: None. S.Edelstein: None. K.J.Nadeau: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. M.Cree-green: None. D.A.Ehrmann: None. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding
American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California
370-OR: Proinflammatory Stress Activates Neutral Sphingomyelinase 2 Based Generation of Ceramide-Enriched ß-Cell Exosomes
Authors: XU JERRY , SIMS EMILY K. 
Published: May 2022

Data suggest that β cell exosomes, extracellular vesicles released by exocytosis of multivesicular endosomes (MVEs) , may act as paracrine effectors in islet health. However, mechanisms linking β cell stress to changes in exosomes and whether activation of these pathways can impact diabetes remain less explored. In other cells, the enzyme neutral spingomyelinase 2 (nSMase2) induces ceramide dependent MVE vesicle formation and release of ceramide-enriched exosomes. We hypothesized that β cell inflammatory stress engages ceramide-dependent exosomal formation pathways, and that ceramide-enriched exosomes could then impact surrounding β cells. To test this we treated INS-1 β cells with 24 hrs of 5 ng/mL of IL1β. nSMase 2 and ceramide expression were quantified with immunoblot and/or flow cytometry and exosomes were isolated using a tetraspanin bead-based pulldown. IL1β increased β cell nSMase2 expression and ceramide expression in concert. Direct nSMase2 activation with 24 hrs of 5-ng/mL Caffeic acid phenethyl ester (CAPE) also increased β cell ceramide staining. IL1β and CAPE treatments also yielded increased ceramide expression on β cell exosomes. Human islets exhibited similar increases in cellular nSMase2 and ceramide staining after 24-hr cytokine mix treatment (5ng/mL IL1β, 10ng/mL TNFα, and 100ng/mL IFNγ) . To test the potential for transfer of β cell exosomes to surrounding cells, we generated INS-1 cells with GFP tagged CD9 (exosome transmembrane protein) , which release GFP labeled exosomes. Flow cytometry staining in wild-type INS-1 cells after 24-hr transwell coculture with CD9-GFP cells showed that cocultured wild-type cells exhibited increased green fluorescence, suggesting transfer of CD9-GFP exosomes. Our findings suggest that nSMase2 activity may regulate β cell exosome subpopulations under conditions of inflammatory stress. Future work will interrogate impacts on exosome cargo and physiologic impacts of transfer on recipient cells.

Disclosure
J.Xu: None. E.K.Sims: Other Relationship; Medscape, Patent.

Funding
5 R01DK121929
380-P: Burden of Low Interstitial Fluid Glucose Levels among Type 2 Diabetes Patients with Chronic Kidney Disease and Its Associated Variables
Authors: TIAN KRISTY , ANG LI C. , GOH SU-YEN , BEE YONG MONG , CHOO JASON , TEH MING M. 
Published: May 2022

Background: Type 2 diabetes (T2D) patients with chronic kidney disease (CKD) are at high risk of hypoglycemia due to decreased renal gluconeogenesis and clearance of diabetes medications. This study aims to quantify the burden of hypoglycemia in this population, and identify potential risk factors.
Methods: Outpatient T2D subjects with CKD (eGFR &lt;60ml/min per 1.73m2) were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low interstitial fluid glucose (IFG) burden. IFG values of less than 72mg/dL and 50mg/dL that persisted for at least 15 minutes were defined as ‘low sensor glucose (LSG) ’ and ‘very low sensor glucose (VLSG) ’ respectively. Occurrence of VLSG events were correlated with patient-reported symptoms. Univariate analysis with Poisson regression was performed to look for predictive factors for LSG and VLSG events.
Results: A total of 77 subjects with CKD were included in the study, 46 (59.7%) male and 31 (40.3%) female. The subjects were 67.9 ± 8.9 years old with duration of diabetes of 22.0 ± 12.1 years and HbA1c of 8.1 ± 1.9%. The subjects wore the sensor for 14.3 ± 1.6 days. Sixty-five subjects (84.4%) experienced a total of 612 LSG events (mean number of events per subject 8.0 ± 8.6) with total duration of 1834 ± 2812 minutes while 44 subjects (57.1%) experienced a total of 244 VLSG events (mean number of events per subject 5.6 ± 5.9) with total duration of 1080 ± 1838 minutes. Majority of subjects who experienced VLSG events (90.9%) did not report associated symptoms. Lower HbA1c and lower mean glucose were associated with LSG (rate ratio of 0.79 (0.70 - 0.89) and 0.71 (0.66 - 0.76) respectively with p values &lt;0.05) . Similar results were found for VLSG events. Interestingly, the degree of renal impairment did not predict for LSG or VLSG events.
Conclusion: Clinicians must consider what appropriate glycemic targets should be for T2D patients with CKD as this modifiable risk factor is highly predictive of hypoglycemic events.

Disclosure
K.Tian: None. L.C.Ang: None. S.Goh: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Sanofi. Y.Bee: None. J.Choo: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novartis AG, Consultant; AstraZeneca, Nitto Denko Asia Technical Centre, Novartis AG, Research Support; AstraZeneca, Nitto Denko Asia Technical Centre, Speaker's Bureau; Abbott, Bayer AG. M.M.Teh: None.
383-P: Clinical Practice Gap Analysis of Severe Hypoglycemia Assessment and Treatment in Patients with Diabetes
Authors: LARKIN AMY , LE ANNE , SCHRAND JULIE 
Published: May 2022

Introduction: Understanding clinical practice gaps in the assessment and treatment of severe hypoglycemia in patients with diabetes can inform development of tools to improve physician practices. Methods: A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their knowledge, attitudes, and confidence with regard to severe hypoglycemia. The survey was available online to physicians across the globe without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from May 4, 2021, to July 12, 2021. Results: In total, 64 diabetologists/endocrinologists (D/Es) and 187 primary care physicians (PCPs) completed the full assessment within the data collection period.
When asked how many of their patients with diabetes have a prescription for glucagon, 88% of D/Es estimated &lt;50% (and 69% estimated &lt;20%) , 93% of PCPs estimated &lt;50% (and 87% estimated &lt;20%) . Conclusion: This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to assessment and treatment of severe hypoglycemia in patients with diabetes. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.

Disclosure
A.Larkin: None. A.Le: None. J.Schrand: None.

Funding
Developed through independent educational grant from Xeris Pharmaceuticals
385-P: Effects of Ertugliflozin on Podocyte in High-Fat Diet–Induced Diabetic Kidney Disease Model, In Vivo and In Vitro
Authors: KIM HAE KYUNG , KIM YOUNGJOON , KIM RYEONG-HYEON , LEE SIWOO , YANG YURIM , PARK HYUNKI , JEON NARA , LEE MINYOUNG , LEE YONG-HO , CHA BONG-SOO , LEE HYANGKYU , LIM BEOM JIN , CHOI HOON YOUNG , KANG EUN SEOK 
Published: May 2022

Early stage of diabetic kidney disease (DKD) involves loss of podocytes, consequently causing albuminuria. SGLT2 inhibitors demonstrated renoprotective effects in DKD, but the mechanism for protection in early DKD is unclear. Here, we investigated the effects of ertugliflozin in high-fat diet (HFD) -induced DKD model, in vivo and in vitro. 5-week-old male C57BL/6J mice were supplemented with HFD for 24 weeks to develop HFD-induced DKD. Ertugliflozin was administrated orally by pre-mixing with HFD for 16 weeks. We evaluated body weight, random blood glucose levels, albuminuria and glucose and insulin tolerance test were performed at 12 weeks after ertugliflozin administration. The renal cortex was collected for histologic examination and SGLT2 expression on podocytes were measured. Albuminuria was significantly decreased in ertugliflozin group compared with HFD group at 12 weeks of ertugliflozin administration (p=0.011) . Body weight, random and fasting blood glucose was not significantly different between HFD group. Glucose and insulin tolerance test showed significant improvement in ertugliflozin group compared with HFD group at 12 weeks (p=0.0004) . In immunohistochemistry studies, glomerular volume and mesangial expansion were attenuated in the ertugliflozin group by 27.6% and 27.8% respectively, compared to HFD group (p=0.002 and p=0.005, respectively) . Glomerular basement membrane thickness was decreased by 45.4% in ertugliflozin group compared to HFD group (p=0.0004) . Significant increase of SGLT2 mRNA expression by 1.6-4.8 fold after 24 hour-albumin expose was observed and SGLT2 protein was increased 1.1-1.3 fold compared to control. Ertugliflozin attenuated diabetic kidney disease in HFD-induced DKD by mitigating glomerular integrity, preserving podocyte morphology, with decreased albuminuria. Upregulation of SGLT2 in podocyte in albuminuric DKD could be suggested as possible target for renoprotective action of SGLT2 inhibitor.

Disclosure
H.Kim: None. B.Cha: None. H.Lee: None. B.Lim: None. H.Choi: None. E.Kang: None. Y.Kim: None. R.Kim: None. S.Lee: None. Y.Yang: None. H.Park: None. N.Jeon: None. M.Lee: None. Y.Lee: None.

Funding
Severance Hospital Research fund for Clinical excellence (SHRC) (C-2021-0007)
388-P: Renal ROCK2 Activity in Folic Acid-Induced Nephropathy
Authors: SEKIGUCHI KENSUKE , MATOBA KEIICHIRO , UKICHI RIKAKO , NAGAI YOSUKE , TAKEDA YUSUKE , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI 
Published: May 2022

The small GTPase Rho and its effector Rho-kinase (ROCK) are involved in the pathogenesis of diabetic nephropathy. In chronic kidney diseases including diabetic nephropathy, tubulointerstitial fibrosis is closely related to renal outcome. We have previously reported that ROCK inhibition suppressed the progression of diabetic nephropathy in murine models. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 is known to be involved in the endocytosis of albumin in tubular epithelial cells via megalin/cubilin-dependent mechanism. On the other hand, the role of renal tubular ROCK2 has not been elucidated.In the present study, we aimed to establish the role of renal tubular ROCK2 in the pathogenesis of chronic kidney disease using a tubulointerstitial injury model known as folic acid-induced nephropathy (FAN) . Masson’s trichrome staining showed an elevated collagen deposition in the kidneys of FAN group compared with vehicle-treated group. We detected a relative upregulation of ROCK2 at protein levels in FAN group, compared with vehicle-treated group. Immunoprecipitation assay demonstrated that the kinase activity of ROCK2 relatively increased in FAN group. Based on these findings, we conclude that ROCK2 has an important contribution to tubulointerstitial fibrosis. ROCK2 may become a therapeutic target for the treatment of chronic kidney disease.

Disclosure
K.Sekiguchi: None. K.Matoba: None. R.Ukichi: None. Y.Nagai: None. Y.Takeda: None. Y.Kanazawa: None. K.Utsunomiya: None. R.Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation.
392-P: Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus
Authors: GAICH GREGORY , BILIC SANELA , DAGON YOSSI , GUSTAFSON THOMAS , LAWLER JOHN , JOHNSON LESLIE , RUDOLPH-OWEN LORI 
Published: May 2022

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN) . Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM) . Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction.
GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist that protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN.
In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK) , and immunogenicity of GFB-024 in 38 healthy overweight and obese (BMI 25 - 40 kg/m2) participants, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects. PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested.
In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing.

Disclosure
G.Gaich: Consultant; 89 bio, Inc., Employee; Goldfinch Bio, Inc. S.Bilic: Consultant; Goldfinch Bio, Inc. Y.Dagon: Employee; Goldfinch Bio, Inc. T.Gustafson: Employee; Goldfinch Bio, Inc., Janssen Pharmaceuticals, Inc. J.Lawler: Employee; Goldfinch Bio, Inc. L.Johnson: Employee; Goldfinch Bio, Inc. L.Rudolph-owen: Employee; Goldfinch Bio, Inc.