bluuebunny/crossref_metadata_2025_split huggingface dataset:
393-P: Combination Treatment with Lisinopril and Empagliflozin Improves Urine and Histological Markers of Diabetic Kidney Disease in Female Renin-AAV UNx db/db Mice
Authors: ØSTERGAARD METTE V. , CHRISTENSEN MICHAEL , SECHER THOMAS , SKYTTE JACOB L. , ROOSTALU URMAS , SALINAS CASPER G. , SEMBACH FREDERIKKE E. , FINK LISBETH N. , VRANG NIELS 
Published: June 2021

Introduction: Emerging treatments of diabetic kidney disease (DKD) include SGLT2 inhibitors and GLP-1 receptor agonists that are nephroprotective beyond their blood glucose lowering effects. To confirm the translatability of a mouse model for drug discovery in DKD, we tested the efficacy of an ACE inhibitor and a SGLT2 inhibitor in the reninAAV UNx db/db mouse model.
Methods: Female db/db mice were injected with a renin-encoding adeno-associated virus construct (reninAAV) to induce hypertension and uninephrectomized (UNx). At 12 weeks of age, dosing with vehicle, lisinopril, empagliflozin, or the combination (combo) was initiated. Plasma and urine markers were measured after 12 weeks of dosing and terminal kidney samples were collected for 3D light sheet microscopy and 2D histology.
Results: In reninAAV UNx db/db mice, treatment with empagliflozin and combo reduced fed BG and HbA1c compared to vehicle. Treatment with lisinopril and combo reduced urine ACR and KIM1-to-creatinine compared to vehicle, while treatment with empagliflozin alone worsened urine ACR. Glomerular hypertrophy as assessed by 3D imaging was reduced in combo treated reninAAV UNx db/db mice compared to vehicle, while treatment with empagliflozin alone worsened glomerular hypertrophy. The total number of glomeruli per kidney was unaffected by treatments. Compared to vehicle treatment, lisinopril and combo treatment reduced the fraction of score 3+4 glomeruli, and glomerulosclerosis index (GSI) was reduced by with lisinopril and combo treatment. Treatment with empagliflozin alone worsened GSI. Morphometric analyses showed that lisinopril and combo treatment reduced kidney CD11b and KIM1 load.
Conclusion: Responses to the combination treatment with lisinopril and empagliflozin showed improvement of urine and histological markers of DKD. Together, these data confirm the translatability of the reninAAV UNx db/db mouse model of DKD.

Disclosure
M. V. Østergaard: None. M. Christensen: None. T. Secher: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Self; Gubra, Stock/Shareholder; Spouse/Partner; Novo Nordisk. J. L. Skytte: None. U. Roostalu: Employee; Self; Gubra. C. G. Salinas: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. F. E. Sembach: None. L. N. Fink: Employee; Self; Gubra, Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra, Employee; Self; Gubra, Stock/Shareholder; Self; Gubra.
402-P: Liraglutide Might Have Synergistic Renal Protection Effect with SGLT2 Inhibitors in Rapidly Progressive Diabetic Kidney Disease
Authors: KASHIMA KOJI , SHIMIZU HIROYUKI , YAMADA MASANOBU 
Published: June 2021

Objective: SGLT2 inhibitor (SGLT2i) and GLP-1 receptor agonist (GLP-1RA) should be considered for patients with type 2 diabetes (T2D) with CKD. But very few data are available whether synergistic effects of both drugs exist. We assessed annual eGFR decline rate by adding SGLT2i in patients with T2D on GLP-1RA therapy.
Methods: A total of 75 patients with T2D with CKD stage 3-4, treated by SGLT2i (empagliflozin 65%) were analyzed. The duration of diabetes at the time of recruitment were as follows: stage 3a (n=29); 11.9±5.4 yrs, stage 3b (n=28); 19.9±12.1 yrs, and stage 4 (n=18); 13.8±8.5 yrs. Macroalbuminuria existed in 49% (37/75). Average age was 70.3±12.2 yrs old. GLP-1RA (Liraglutide: n=36) was initially or additionally used in 41%, 64% and 44% respectively for glucose management, considering for ASCVD. Individual eGFR decline rate (slope) was calculated from the data for 46±20 months before using SGLT2i and 31±9 months after adding it. The effects on slopes by SGLT-2i, GLP-1RA combination therapies (GLP-1RA initiated at different timing) were compared with those without GLP-1RA therapy.
Results: 1) i) Baseline on GLP-1RA initiation therapy -5.2±5.3 improved to -2.2±1.4 (P&lt;0.05) after SGLT2i added. (n=11) ii) Slopes -5.0±3.5 improved to -1.2±4.5 (P&lt;0.03) with simultaneous intensification by SGLT2i + GLP-1RA. (n=13) iii) Slopes -14.6±18.0 improved to -5.4±5.5 (P&lt;0.05) by intensification by GLP-RA, then improved to -2.6±3.3 (P&lt;0.05) with SGLT2i added. (n=14) In this rapidly declining group, macroalbuminuria highly existed in 71% (10/14), and nephrosis existed in 36% (5/14), but nephrosis all came into remission through this therapy. 2) SGLT2i monotherapy (n=37): Slopes -4.1±3.0 improved to -1.2±3.1 ml/min/1.73m2/year (P&lt;0.001) after SGLT2i added. On this background, macroalbuminuria less existed (46%), and nephrosis existed none.
Conclusion: Liraglutide might have synergistic renal protection effects with SGLT2i in rapidly progressive DKD.

Disclosure
K. Kashima: None. H. Shimizu: None. M. Yamada: None.
411-P: Fibroblast Growth Factor 23 and Diabetic Kidney Disease Phenotypes in Type 2 Diabetes
Authors: GAROFOLO MONIA , PELOSINI CATERINA , LUCCHESI DANIELA , FALCETTA PIERPAOLO , SESSA MARIA RITA , PRATO STEFANO DEL , PENNO GIUSEPPE 
Published: June 2021

Fibroblast growth factor 23 (FGF23) targets tubular epithelial cells to promote phosphaturia and it has been associated with adverse outcomes in chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes (T2D). We evaluated intact FGF23 (iFGF23) levels (plasma EDTA; chemiluminescence immunoassay) in 182 T2D subjects with no-DKD (n = 46), with albuminuria alone (ACR ≥30 mg/g; DKD stages 1-2, n = 48), with eGFR &lt;60 ml/min/1.73m2 alone (Alb-DKD; n = 42) and with both albuminuria and eGFR &lt;60 (Alb+DKD; n = 46). There was no difference in ACR between DKD stages 1-2 and Alb+DKD (97 [IQR 49-329] and 268 [62-736] mg/g); eGFR (CKD-EPI formula based on creatinine [eGFRcreat = 49 [45-54] and 45 [35-52] ml/min/1.73m2] or based on creatinine and cystatin-C) did not differ between Alb-DKD and Alb+DKD. Age, DD, HbA1c, triglycerides, uric acid and fibrinogen increased across DKD groups, while HDL cholesterol decreased, with no other significant difference in clinical and laboratory parameters. BP-lowering agents, RAS blockers and lipid-lowering drugs were slightly more frequent in albuminuric groups. Alb+DKD had the highest levels of inflammatory biomarkers: uric acid, hs-CRP and fibrinogen. In the whole cohort, iFGF23 was significantly and directly correlated with these 3 biomarkers. iFGF23 increased steeply (p&lt;0.0001) across DKD groups (no DKD: 48.2 [IQR 37.3-61.5] pg/ml; DKD stages 1-2: 53.0 [42.5-61.4]; Alb-DKD: 60.4 [45.1-73.4] and Alb+DKD 76.6 [60.1-96.3]), with iFGF23 of Alb+DKD higher as compared to no-DKD (p&lt;0.0001), DKD stages 1-2 (p&lt;0.0001), and also Alb-DKD (p=0.008). In the whole cohort, iFGF23 was mildly associated with ACR (r = 0.260; p=0.001) and more strongly inversely related with eGFRcreat (r = -0.483, p&lt;0.0001). Our results suggest that, for the same degree of eGFR reduction, higher iFGF23 levels in Alb+DKD as compared to Alb-DKD might be expression of more advanced renal damage and/or of an overwhelming inflammation.

Disclosure
M. Garofolo: Consultant; Self; Eli Lilly and Company. C. Pelosini: None. D. Lucchesi: None. P. Falcetta: None. M. Sessa: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.
42-LB: Medication Adherence in Young Adults with Youth-Onset Type 2 Diabetes: The iCount Study
Authors: TRIEF PAULA M. , USCHNER DIANE , TUNG MELINDA , DREWS KIMBERLY , KALICHMAN SETH , ANDERSON BARBARA , BULGER JANE D. , WEINSTOCK RUTH S. 
Published: June 2021

Background: Medication adherence is poor in young adults (YAs) with youth-onset type 2 diabetes (T2D). Little is known about intrapersonal factors that may relate to adherence.
Aims: To assess associations of intrapersonal factors to medication adherence in Treatment Options for Adolescents and Youth (TODAY2) YAs.
Methods: Validated measures (attitudes, beliefs, self-efficacy, distress, depression, anxiety) and insulin use surveys, were completed at a TODAY2 visit. Adherence to oral hypoglycemia agents (OHAs) was assessed with 3 monthly unannounced phone pill counts. Those taking ≥ 80% of pills/insulin classified “high-adherent;” &lt; 80% of pills/insulin, “low-adherent.” If taking none, reasons were queried and adjudicated (no need vs. low-adherent). Logistic regressions assessed factors associated with OHA/insulin adherence controlling for gender, race/ethnicity, education, duration, healthcare coverage, and HbA1c.
Results: Of 381 YAs in iCount (mean age 26 yrs, 68% female, 20% non-Hispanic white, 38% non-Hispanic Black, 36% Hispanic, 64.9% &lt;$25k income, mean HbA1c 9.4%), 224 were taking OHAs. As 12 lacked adherence scores, 212 were in OHA analyses; 70.0% were low-adherent to OHAs. Negative beliefs about medicines were associated with low OHA adherence in univariate, but not multivariate analyses. No measured intrapersonal factor was associated with OHA adherence. Of 192 in insulin analyses, 37.0% were low-adherent to insulin. Low insulin adherence was associated with less belief in seriousness of T2D (p=0.036), more concern that medications are overused (p=0.005) and diabetes distress (p=0.020). Insulin adherence did not relate to other diabetes attitudes or beliefs, depressive symptoms or anxiety. Limitations: small N with high depressive/anxiety symptoms; self-reported insulin use.
Conclusion: Poor medication adherence is common in YAs with youth-onset T2D. More needs to be learned about factors associated with adherence to develop tailored, effective interventions.

Disclosure
P. M. Trief: None. D. Uschner: None. M. Tung: None. K. Drews: None. S. Kalichman: None. B. Anderson: None. J. D. Bulger: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1RO1DK110456-01A1; U01DK61230)
423-P: Altered Microvascular Perfusion of the Pain-Processing Areas of the Brain during the Experience of Spontaneous Neuropathic Pain
Authors: GREIG MARNI , SLOAN GORDON P. , SHILLO PALLAI RAPPAI , SELVARAJAH DINESH , WILKINSON IAIN D. , TESFAYE SOLOMON 
Published: June 2021

Objective: We have previously reported increased thalamic vascularity in painful diabetic peripheral neuropathy (PDPN) but the microvascular perfusion characteristics of the other pain processing areas of the brain (Pain Matrix - PM) with or without pain at the time of scanning have not been assessed. The aim thus was to measure the cerebral perfusion of the PM areas using MR-Dynamic Susceptibility Contrast (MR-DSC).
Methods: 55 T1DM subjects (20 PDPN, 23 painless-DPN, 13 no-DPN) and 19 healthy volunteers (HV) underwent clinical, neurophysiological and MR-DSC of the passage of IV-gadolinium-chelate through the cerebral vascular bed (3-Tesla, Philips, Netherlands) at rest. The PDPN group was further divided into those that had neuropathic pain during scan - P+ and no pain - P-) and the intensity of pain at the time of scanning was recorded. The Mean Transit Time -MTT and the time-to-peak -TTP concentrations of gadolinium in PM areas (Thalamus, Insular Cortex - IC, Anterior Cingulate Cortex - ACC) were measured. Results: Subjects experiencing spontaneous neuropathic pain (P+, n=10, VAS score≥4) during scanning had shorter mean TTP at the Right-Thalamus: P+ vs. painless-DPN p=0.017, P+ vs. HV p=0.033; Right-IC: P+ vs. painless-DPN p=0.048; and POWM: P+ vs. P- p=0.009, P+ vs. painless-DPN p=0.034, P+ vs. HV p=0.011. The MTT at the Right-Thalamus: P+ vs. HV p=0.043 and at the Left-IC: HV vs. No-DPN p=036, were also significant.
Conclusion: This is the first study to show there is altered cerebral perfusion in the pain processing areas of of the brain, with shorter TTP during spontaneous pain at the time of scanning. This seems to be related to a bolus dispersal factor as MTT, and CBF do not match the TTP and the control area is also affected. However, whether this altered perfusion is primary or secondary to the experience of pain is yet to be determined. This novel finding may serve as objective marker of spontaneous neuropathic pain, and a target for the development of novel treatments.

Disclosure
M. Greig: None. G. P. Sloan: None. P. Shillo: None. D. Selvarajah: None. I. D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc.

Funding
European Foundation for the Study of Diabetes
427-P: Prevalence and Treatment of Diabetic Macular Edema and Vision-Threatening Diabetic Retinopathy among Commercially Insured Adults Aged &lt;65 Years
Authors: LUNDEEN ELIZABETH A. , KIM MINCHUL , REIN DAVID B. , WITTENBORN JOHN , CAI CINDY , SAADDINE JINAN B. 
Published: June 2021

While diabetes prevalence in U.S. adults has increased in the last three decades, less is known about trends in ocular complications of diabetes, particularly in adults aged &lt;65 years. We examined trends in prevalence and treatment of diabetic macular edema (DME) or vision-threatening diabetic retinopathy (DR) among commercially insured adults with diabetes. We analyzed claims from 2012 to 2018 using the IBM® MarketScan® Database, a national convenience sample of employer-sponsored health insurance. Analyses for each cross-sectional year included adults (18-64 years) with type 1 or 2 diabetes continuously enrolled for the calendar year (range: n=980,705 to n=1,715,815). Outcomes included the annual prevalence of those with ≥1 claim for: 1) DME or vision-threatening DR (severe non-proliferative DR or proliferative DR), 2) DME of any type, alone or with any stage of DR, and 3) treatment (anti-vascular endothelial growth factor [VEGF] injection, laser surgery/photocoagulation, vitrectomy, or retinal detachment repair). From 2012 to 2018, annual diabetes prevalence ranged from 7.3% to 7.8%. Annual prevalence of adults with diabetes who had ≥1 claim for DME or vision-threatening DR increased from 1.9% to 3.1% (Annual percent change [APC]: 0.23); any type of DME increased from 0.9% to 2.4% (APC: 0.29). Among those with DME or vision-threatening DR, annual prevalence of having ≥1 claim for treatment increased for anti-VEGF injection (21.9% to 31.2%; APC: 1.81) and decreased for laser surgery/photocoagulation (33.6% to 18.9%; APC: -2.65), vitrectomy (6.5% to 3.8%; APC: -0.48), and retinal detachment repair (3.9% to 2.9%; APC: -0.15). P-values for all trends were &lt;0.01. From 2012 to 2018, among commercially insured adults aged &lt;65 years, the annual prevalence of those with claims for DME or vision-threatening DR and DME of any type increased, coinciding with an increase in the use of anti-VEGF injection, a contemporary first-line treatment.

Disclosure
E. A. Lundeen: None. M. Kim: None. D. B. Rein: None. J. Wittenborn: None. C. Cai: None. J. B. Saaddine: None.
441-P: The Association between Time-in-Range %, Measured by Continuous Glucose Monitoring (CGM) and Physical and Functional Indices amongst Older People with Type 2 Diabetes: A Cross-Sectional Study
Authors: BASSON-SHLEYMOVICH YAMIT , CUKIERMAN-YAFFE TALI , YAHALOM-PERI TAL , AZMON MICHAL , PELTZ-SINVANI NAAMA 
Published: June 2021

People with diabetes have an increased risk for mobility disability and a more rapid decline in muscle mass (sarcopenia) compared to those without diabetes. Studies have demonstrated an association between A1C and Sarcopenia. Less is known regarding the relationship with Time In Range (TIR).
Aims: To assess among older people with diabetes type 2, the cross sectional association between: TIR and aerobic capacity, gait speed, strength, balance and frailty indices.
Methods: A cross sectional study, conducted amongst people with diabetes over the age of 60. Participants were provided with a blinded CGM system- (I Pro2 carelink, Medtronic) for 1 week and underwent elaborate physical-functional assessment in the beginning and at the end of that week. The association between the % of time in range (TIR) and several physical indices was determined using linear regression.
Results: This analysis pertains to 81 men and women. After adjustment for age and gender, a 1% higher TIR (70-180) was associated with a 0.246 higher score on the 6-minute walk score, a measure of aerobic capacity and endurance (P-value=0.019) and 0.212 lower score on the Timed Up and Go(TUG), a measure of fall risk and balance (P-value=0.045).
Conclusion: Higher % TIR is associated with better scores on indices of aerobic capacity and a measure predicting falls. Future studies are needed in order to elucidated if glucose levels are merely a marker of disease severity, or if there is possibly a causal relationship.

Disclosure
Y. Basson-shleymovich: None. T. Cukierman-yaffe: Advisory Panel; Self; AstraZeneca, Research Support; Self; Medtronic, MSD Corporation, Speaker’s Bureau; Self; Eli Lilly and Company, Medtronic, MSD Corporation, Novo Nordisk, Sanofi. T. Yahalom-peri: None. M. Azmon: None. N. Peltz-sinvani: None.

Funding
European Foundation for the Study of Diabetes; Medtronic
443-P: Outcomes of Bedside Diabetic Foot Amputation by a Diabetologist
Authors: FERON FLORINE , RIVELINE JEAN-PIERRE , GAUTIER JEAN-FRANÇOIS , KEVORKIAN JEAN-PHILIPPE 
Published: June 2021

Complying with simple operating rules, a diabetologist might perform Bedside Toe Amputation (BTA) for necrosis complicating diabetic foot ulcer (DFU) in case of inappropriate delay scheduled or disagreement with the amputation level proposed by the surgeon. We conducted a monocentric, retrospective, observational study in our diabetes department. Patients with DFU and isolated toe necrosis indicating a transphalangeal amputation (TPA), a metatarsophalangeal disarticulation (MPD) or a single transmetatarsal amputation (TMA) decided during a multidisciplinary DFU team were included. The primary endpoint was the need for reoperation or reamputation (partial/complete TMA, transtibial (TTA) or transfemoral (TFA)) performed by a surgeon. From May 2016 to September 2020, 147 out of 709 patients admitted for DFU required a surgical treatment (21%). After DFU team agreement and patient’s informed consent obtained, 101/147 patients needed TPA, MPD or TMA (69%) and 43/101 were performed at bedside by the diabetologist (43%). The characteristics of the population were: men=75%, age=65±14 years, type 2 diabetes=95%, duration of diabetes=19±11 years, preoperative arteriography=84%, preoperative revascularization=30%, mean number of permeable arteries at the time of the procedure=2±0.9, permeable dorsal arch=58%, permeable plantar arch=45%. Type of BTA: TPA=28%, MPD=65%, TMA=7%. Median follow-up=12 months. Secondary conventional surgery was needed for 13 patients (30%) (TMA/TTA/debridement respectively in 54, 30 and 16% cases). Poor vascular arterial bed was the significant determinant of failure (≤ 1 leg artery, p=0.006). Annual mortality rates in the groups with or without the need for a surgeon were respectively 15 and 10% (p=0.6). Performed by a diabetologist, BTA might be an option to treat limited toe necrosis complicating DFU in case of ≥ 2 leg arteries permeable at the time of the procedure. A head-to-head comparison with conventional surgery is now required.

Disclosure
F. Feron: None. J. Riveline: None. J. Gautier: None. J. Kevorkian: None.
448-P: Serum Inflammatory Markers Are Not Correlated with Detection of Osteomyelitis by 99mTC-WBC SPECT/CT Imaging in Subjects with Diabetes and Foot Infection
Authors: SHERWOOD AMBER , RUBITSCHUNG KATIE L. , KILLEEN AMANDA L. , CRISOLOGO PETER , GRIGOROPOULOS KATERINA , PAJOUH AMANDA , KEP JENNIFER , WUKICH DANE , FONTAINE JAVIER LA , LAVERY LAWRENCE A. , OZ ORHAN K. 
Published: June 2021

Osteomyelitis is a common complication in diabetic foot ulcers. Accurate and early detection of diabetic foot osteomyelitis (DFO) is key to optimizing clinical outcomes and avoiding amputation. Using bone biopsy histopathology as the gold diagnostic standard, we evaluate the sensitivity and specificity of radiolabeled white blood cell imaging combined with CT (99mTc-WBC SPECT/CT) for the evaluation of DFO. We also assess the ability of the inflammatory markers CRP and ESR to predict osteomyelitis diagnosis by 99mTc-WBC SPECT/CT imaging. Subjects with diabetes and foot ulcerations presenting to a large tertiary care facility were examined by podiatry. Of the 48 subjects who consented to participation, 44 completed imaging, labwork, and underwent biopsy. Serum CRP and ESR were collected within three days of consent. In all cases, WBC imaging studies were performed prior to biopsy. The WBC SPECT/CT scans were read by an experienced Nuclear Medicine radiologist. Pathology was performed in the hospital laboratory and interpreted by a pathologist experienced in MSK infections. SPECT/CT and pathology reads were coded as either positive or negative for osteomyelitis. Sensitivity and specificity of 99mTc-WBC SPECT/CT for DFO diagnosis was 90.9% and 73.7%, respectively. WBC imaging had a PPV of 80.0%, and 87.5% NPV (n=41). CRP and ESR serum levels were grouped according to positive or negative DFO diagnosis as determined by WBC scan. Neither CRP (p=0.9895) nor ESR levels (p=0.8382) were correlated with DFO diagnosis based on WBC imaging results. Using bone biopsy results as the reference standard, radiolabeled 99mTc-WBC SPECT/CT demonstrates sensitivity for DFO. However, CRP and ESR were not found to be predictive in the diagnostic interpretation of 99mTc-WBC SPECT/CT imaging for the diagnosis of DFO.

Disclosure
A. Sherwood: None. L. A. Lavery: None. O. K. Oz: n/a. K. L. Rubitschung: None. A. L. Killeen: None. P. Crisologo: None. K. Grigoropoulos: None. A. Pajouh: None. J. Kep: None. D. Wukich: Consultant; Self; Orthofix Medical Inc., Wright Medical Group, Other Relationship; Self; Arthrex, Inc. J. La fontaine: None.

Funding
American Diabetes Association (1-17-ICTS-056 to O.K.O.)