bluuebunny/crossref_metadata_2025_split huggingface dataset:
25-LB: SGLT2 Inhibitor Attenuates Inflammatory Response in Diabetic Kidney Disease by Inhibiting GSDMD-Related Pyroptosis
Authors: REN SHIJING , XUE YAOMING 
Published: June 2020

Background: Pyroptosis is a form of programmed cell death mediated by inflammatory responses.This research aimed to study the potential mechanism of pyroptosis pathway played in promoting diabetic kidney disease (DKD) progression, and to investigate Canagliflozin(CANA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, protect kidneys by inhibiting the activation of pyroptosis pathway. This research can provide new ideas for the prevention and treatment of DKD.
Methods: Human tubular (HK-2) cells were cultured in DMEM medium and were divided into normal control group (NC group), high glucose group (HG group), high glucose with CANA group, bovine serum albumin group(BSA group), BSA with CANA group. After 24 hours of culture, qPCR, Western blotting and ELISA were used to detect the activation, expression and secretion of classic NLRP3/Caspase(Casp)-1/Gasdermin D (GSDMD) pyroptosis pathway, including NLRP3, Casp-1, interleukin (IL)-1β, IL-18 and GSDMD,etc. Detect the expression of NKAIN4, a Na+-K+-ATP enzyme-acting protein. LDH release test and Light microscopy was used to analyze cell death and rupture of the cell membrane.
Results: Compared with NC group, in HG group and BSA group, the amount of dead HK-2 cells is higher, the expression levels of NLRP3, Casp-1, IL-1 β, IL-18, GSDMD and NKAIN4 were significantly up-regulated, the concentration of IL-1 β, IL-18 and LDH in the cultured medium were elevated. When using Canagliflozin, these data mentioned above were suppressed compared with HG group and BSA group .
Conclusions: 1. Pyroptotic cell death of HK-2 cells induced by HG and BSA may promotes DKD progression, renal function deterioration, and inflammation. 2. SGLT2 inhibitor Canagliflozin can attenuate inflammatory response by inhibiting GSDMD-related pyroptosis in DKD. This may because CANA attenuate the activation of Na+-K+-ATP enzyme, transport of K+ and activation of NLRP3. Its specific mechanism and animal experiments are being further studied.

Disclosure
S. Ren: None. Y. Xue: None.
25-OR: Acid–Base Changes during Diabetic Ketoacidosis (DKA) in T1DM with and without SGLT2 Inhibitor (SGLT2i)
Authors: MURSIC INES , SVEHLIKOVA EVA , REGITTNIG WERNER , AUGUSTIN THOMAS , MAGNES CHRISTOPH , EBERL ANITA , HEISE TIM , KLEIN OLIVER , WOLF MICHAEL , URSCHITZ MARTINA , BRUNNER MARTINA , SOURIJ HARALD , PIEBER THOMAS 
Published: June 2020

Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM.
Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a maximum of 12h, followed by recovery phase (12h).
Results: SGLT2i led to significantly lower plasma glucose (PG) values during insulin depletion (PGmax with/without SGLT2i: 174±40 (mean±SD) vs. 302±48 mg/dL; 95% CI for ratio: 0.51-0.60), but to higher beta-hydroxybutyrate (BHB) values (Figure) and a steeper BHB increase (delta BHB: 8.1±2.0 vs. 6.0±1.7 µmol/L/min; 95% CI for ratio: 1.22-1.49). pH, bicarbonate and base excess during insulin depletion were comparable. Baseline glucagon (7.8±2.5 vs. 5.0±1.6 pmol/L; 95% CI for ratio: 1.26-1.95) and FFA levels (0.65±0.27 vs. 0.43±0.31 mmol/L; 95% CI for ratio: 1.08-2.28) were higher with SGLT2i, but data indicate that after increase during insulin depletion comparable concentrations were reached for both.
Conclusions: SGLT2i keeps PG in near normal ranges during DKA development and recovery, potentially impeding DKA diagnosis. While SGLT2i leads to higher ketone levels, increased baseline glucagon and FFA, an effect on pH and acidosis was not demonstrated.

Disclosure
I. Mursic: None. E. Svehlikova: None. W. Regittnig: None. T. Augustin: None. C. Magnes: None. A. Eberl: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. O. Klein: None. M. Wolf: None. M. Urschitz: None. M. Brunner: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K.
260-OR: Transdifferentiation of a-Cells and Redifferentiation of InsulinLo ß-Cells Dominate ß-Cell Regeneration in Late-Stage Diabetic NOD Mice Cured with Induction of Mixed Chimerism and Administration of Gastrin and Epidermal Growth Factor
Authors: TANG SHANSHAN , ZHANG MINGFENG , SANTAMARIA PERE , RIGGS ARTHUR D. , JIN LIANG , ZENG DE-FU 
Published: June 2020

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells. Cure of established T1D requires both reversal of autoimmunity and regeneration of β cells. Autoimmune NOD mice closely resemble human T1D. We have reported that administration of gastrin and epidermal growth factor (GE) allows β cell regeneration and cure of late-stage T1D in NOD mice after reversal of autoimmunity by induction of MHC-mismatched mixed chimerism. β cell regeneration in non-autoimmune diabetic mice can come from differentiation of Sox9+ pancreatic ductal progenitors, parenchymal progenitors, and transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune NOD mice remains unclear.
Using NOD mice with inducible Sox9-EGFP, we found that Sox9+ pancreatic ductal progenitors only accounted for a small fraction of total β cell regeneration. Using Nestin-EGFP mice, we did not see any β cells originating from Nestin+ parenchymal progenitor cells.
Using NOD mice with inducible glucagon-RFP, we found that ∼50% of regenerated β cells were from α cell transdifferentiation in mice after induction of mixed chimerism and GE, although mixed chimerism alone induced few α to β cell transdifferentiation in mice. In addition, using NOD mice with inducible insulin-EGFP, we found that the majority of residual β cells in late-stage diabetic NOD mice were insulinlo, and they became insulinhi after induction of mixed chimerism and GE treatment.
Taken together, transdifferentiation of α to β cells and re-differentiation of insulinlo cells are the major sources of β cell regeneration in late-stage diabetic NOD mice after induction of mixed chimerism and administration of GE. How hyperglycemia and GE differentially regulate α cell transdifferentiation and β cell re-differentiation is under investigation. This work is supported by the Wanek Family fund.

Disclosure
S. Tang: None. M. Zhang: None. P. Santamaria: Board Member; Self; Parvus Therapeutics. A.D. Riggs: None. L. Jin: None. D. Zeng: None.

Funding
Todd and Karen Wanek Family Foundation Ltd.
281-OR: Type 2 Diabetes Diagnosed between 16-30 Years in South Asian and White Individuals Is Phenotypically Similar
Authors: MISRA SHIVANI , GODSLAND IAN F. , BHARDWAJ NIKITA , OLIVER NICK , OWEN KATHARINE R. , JOHNSTON DESMOND G. ,   ESQ.
Published: June 2020

Aim: The incidence of type 2 diabetes is increasing rapidly in young adults. Older south Asian people (SA) develop type 2 diabetes at leaner BMI compared to white and are less likely to be obese. We hypothesised that obesity may be a bigger driver of young-onset type 2 diabetes in SA people and studied the BMI difference in white and SA people with young adult-onset type 2 diabetes.
Methods: Data from two UK cross-sectional cohorts were examined to identify adults diagnosed with any type of diabetes &lt;30 years. We defined type 2 diabetes as a fasting C-peptide level &gt;600pmol/L and negativity to GAD-antibodies (YDX study) and GAD, IA-2 and ZnT8 antibodies (MY DIABETES study). We studied phenotypic differences between SA and white ethnicity.
Results: Sixty white and 71 SA people with type 2 diabetes diagnosed &lt;30 years were identified, of which 92% (n= 55) white and 83% (n=59) SA were diagnosed 16-30 years. Median age-at-diagnosis (25 vs. 24 years, p=0.6) and duration (8.8 vs. 9.5 years, p=0.8) were similar between white and SA ethnicity. BMI, though lower in SAs than white (29 vs. 32 kg/m2, p=0.0007), was consistent with ethnic-specific obesity. HbA1c (68 vs. 60 mmol/mol, p=0.1), HDL (1.0 vs. 1.1mmol/L) and triglycerides (2.2 mmol/L vs. 1.7) were similar in white vs. SA. Fasting C-peptide was no different between ethnicities 847 pmol/L white vs. 1018 SA, p=0.1. Percentage insulin-treated was similar between both groups: white 54%, SA 66% p=0.2.
Conclusion: Type 2 diabetes diagnosed between 16-30 years is associated significantly with the presence of obesity in both ethnicities. The similarity observed in glycaemia, lipid profiles and fasting C-peptide along with similar durations, suggest the degree of insulin resistance to be equal across ethnic groups. This young-onset south Asian phenotype may contrast older-onset cases where SA people are observed to be significantly leaner and more insulin resistant than white counterparts.

Disclosure
S. Misra: None. I.F. Godsland: None. N. Bhardwaj: None. N. Oliver: Advisory Panel; Self; Medtronic, Roche Diabetes Care, UNEEG. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. K.R. Owen: None. D.G. Johnston: None.

Funding
Diabetes Research & Wellness Foundation; European Foundation for the Study of Diabetes
295-OR: Estrogen Receptor a Controls Energy Homeostasis in White and Brown Adipose Tissue by Regulating Polg1 Expression and Mitochondrial Remodeling
Authors: ZHOU ZHENQI , HEVENER ANDREA L. 
Published: June 2020

Obesity is heightened during aging. Although the role of the estrogen receptor (ER)α to prevent obesity is supported by our previous work, ERα actions in adipocytes remain inadequately understood. Gene expression analysis from UKTwins Study, METSIM Study, and the study of the UCLA Hybrid Mouse Diversity Panel show that ESR1/Esr1 is inversely associated with adiposity and markers of metabolic health in both humans and mice. To determine the mechanistic role(s) of ERα in fat, we generated 2 adipose tissue-specific knockout mouse lines by selectively deleting Esr1 from white and brown adipose tissue (FERKO and ERαKOBAT, respectively). In white adipose tissue, Esr1 controls oxidative metabolism by reducing the E3 ubiquitin ligase Parkin-mediated mitochondrial degradation. Indeed, we report that adipose tissue-selective Parkin knockout mice have reduced body fat and elevated adipocyte mtDNA content. In brown adipose tissue, Esr1 is a requisite for mitochondrial remodeling and cold-induced thermogenesis. Although the role of mitochondrial metabolism differs between white and brown fat, the unique mitochondrial phenotypes observed in white and brown Esr1-deficient adipocytes, appear to be the consequence of reduced expression of the mtDNA polymerase, Polg1. We provide direct evidence that ERα binds the Polg1 promoter to control its expression, and that selective phenotypes of ERα deficiency are recapitulated by Polg1 deletion. Collectively our findings show that ERα has strong heritability in adipose tissue and support strategies targeting cell-specific actions of ERα to combat diseases associated with metabolic dysfunction.

Disclosure
Z. Zhou: None. A.L. Hevener: None.

Funding
National Institutes of Health (U54DK120342)
296-OR: Identification and Characterization of New Players in Insulin-Controlled GLUT4 Trafficking
Authors: SHEN JINGSHI 
Published: June 2020

The anabolic hormone insulin promotes glucose uptake by triggering the translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the cell surface through exocytosis. Upon the termination of insulin signaling, GLUT4 gradually returns to intracellular storage compartments through endocytosis. Defects in GLUT4 translocation are a hallmark of insulin resistance (IR) and type 2 diabetes (T2D). Our team has performed genome-scale genetic screens to systematically dissect GLUT4 exocytosis and endocytosis. The screens recovered known GLUT4 trafficking regulators but most of the hits were not previously linked to the GLUT4 pathway. A regulator of GLUT4 endocytosis identified in the screens is AAGAB, a soluble factor of 34 kDa. AAGAB controls the stepwise assembly of AP2 adaptor, a central cargo adaptor in clathrin-mediated endocytosis. Unexpectedly, we found that AAGAB also binds to Munc18c and directly inhibits SNARE-Munc18-mediated GLUT4 vesicle fusion. Thus, AAGAB plays a dual role in GLUT4 trafficking. I will also discuss OSBPL8 and OSBPL10, two negative regulators of GLUT4 translocation identified in our screens. OSBPL8 and OSBPL10 are putative lipid transfer proteins operating between intracellular organelles. We propose that OSBPL8 and OSBPL10 regulate lipid dynamics required for insulin signaling, thereby influencing the activities of GLUT4 exocytic regulators. These genetic studies will likely facilitate the identification of new therapeutic targets for IR and T2D.

Disclosure
J. Shen: None.

Funding
American Diabetes Association (1-19-IBS-305); National Institutes of Health (DK095367, GM126960)
323-OR: Synergism between Protein Quality Control Pathways to Maintain Alpha-Cell Mass and Function
Authors: REINERT RACHEL B. , CUI XIANWEI , SHRESTHA NEHA , QI LING 
Published: June 2020

Endocrine cells rely on efficient prohormone synthesis, folding, and elimination of misfolded peptides for proper function. Endoplasmic reticulum-associated degradation (ERAD) and autophagy are two primary mechanisms of cellular protein quality control, and each are required for normal beta cell function. However, their role in alpha cells has largely been unexplored. ERAD is mediated by two highly conserved ER membrane proteins: Hrd1, a ubiquitin ligase that retrotranslocates and ubiquitinates misfolded ER proteins for proteasomal degradation, and Sel1L, an adaptor protein required for Hrd1 stability and function. Autophagy is a conserved mechanism for recycling ER and cytosolic products via lysosomal degradation and requires a precise signaling sequence for activation, involving key autophagosome protein Atg7. To investigate the role of ERAD and autophagy in alpha cells, we targeted deletion of Sel1L and/or Atg7 with the Cre-lox system, using mice expressing Cre recombinase under the proglucagon promoter. Sel1LΔGcg, Atg7ΔGcg, and Sel1L;Atg7ΔGcg mice all showed normal growth and oral glucose tolerance. Sel1LΔGcg mice had dilated ER and reduced glucagon content in alpha cells following ERAD inactivation, but glucagon secretory capacity in vivo was largely maintained. In contrast, disruption of autophagy in Atg7ΔGcg mice led to alpha cell hypertrophy and vacuolization, and reduced glucagon secretion in vivo following insulin-induced hypoglycemia and 2-deoxyglucose-mediated glucoprivation. These secretory defects were exacerbated in Sel1L;Atg7ΔGcg mice, which also had reduced glucagon secretion after a 24 hour fast and a 77% reduction in pancreatic glucagon content. By immunohistochemistry, very few alpha cells were present in islets of adult Sel1L;Atg7ΔGcg mice. Our data demonstrate that alpha cells are more susceptible to defective autophagy rather than defective Sel1L-Hrd1 ERAD, but that these pathways act synergistically to maintain functional alpha cell mass.

Disclosure
R.B. Reinert: None. X. Cui: None. N. Shrestha: None. L. Qi: None.

Funding
National Institutes of Health (T32DK007245)
332-OR: Medicare Part B Fee-for-Service Claims for Diabetes-Related Eye Diseases
Authors: LUNDEEN ELIZABETH A. , REIN DAVID B. , WITTENBORN JOHN , SAADDINE JINAN B. 
Published: June 2020

Background: Diabetic retinopathy is the leading cause of incident blindness among working age U.S. adults. Only slightly more than half of Medicare beneficiaries with diabetes receive an annual eye exam, and this rate is lower among Hispanic and black beneficiaries compared to white beneficiaries.
Objective: We examine racial/ethnic differences in diabetes-related eye disease and treatment claims, among Medicare beneficiaries with diabetes.
Methods: We analyzed 2017 Medicare claims for 8,341,000 beneficiaries (both ≥65 years and &lt;65 years with disabilities) with diagnosed diabetes who were continuously enrolled during 2017 in Part B fee-for-service (FFS) insurance. Diagnoses for diabetes and diabetes-related eye diseases were defined using ICD-10-CM diagnosis codes and treatments were classified using procedure codes in the claims. We present crude national percentages.
Results: In 2017, 28% of FFS beneficiaries had diabetes. Of these, 9.6% had a claim for any diabetes-related eye disease; this annual rate was higher among Hispanic (13.1%), non-Hispanic black (11.2%), and Asian/Pacific Islander (11.4%) beneficiaries than among white beneficiaries (8.7%). Early/mild diabetic retinopathy was the most prevalent form (6.3%) and diabetic macular edema was the least prevalent (0.6%). Of beneficiaries with diabetes-related eye disease, 15.2% had at least one type of treatment; treatment types received were anti-vascular endothelial growth factor injections (11.8%), laser photocoagulation (4.7%), vitrectomy (1.3%), and retinal detachment repair (0.7%). Annual prevalence of any treatment was higher among Hispanic (19.0%) and non-Hispanic black (15.5%) beneficiaries compared to white beneficiaries (14.7%); it was lowest among Asian/Pacific Islander beneficiaries (12.9%).
Conclusions: Annually, around one-in-ten Medicare Part B FFS beneficiaries with diabetes has a claim for diabetes-related eye disease, and this rate is higher among Hispanic and black beneficiaries.

Disclosure
E.A. Lundeen: None. D.B. Rein: None. J. Wittenborn: None. J.B. Saaddine: None.
337-OR: Continuous Glucose Monitoring Shared Medical Appointments Improve A1C and Diabetes Self-Efficacy
Authors: ISAACS DIANA , SIMONYAN ANA , BLANCHETTE JULIA E. , LEKIC SANELA , NOE DAWN , GALLOWAY NICHOLAS R. 
Published: June 2020

Background: Personal continuous glucose monitoring (CGM) is patient owned and often inaccessible due to cost and insurance requirements. Professional CGM is clinic owned, worn for 3-14 days and is an affordable, underutilized option. The present study combined diabetes education and professional CGM into a shared medical appointment (SMA). The SMA allows providers to deliver diabetes education in the setting of medical management and peer support. It was hypothesized that the SMA method of delivering professional CGM would positively impact clinical outcomes (improvements in self-efficacy, A1c and medication doses).
Methods: Adults with type 1 and type 2 diabetes who attended the two-part CGM SMA at a large academic medical center were included in this retrospective, single-center study. The CGM SMA included 4-6 patients, diabetes educator and pharmacist. Participants wore professional CGM for 7 days. The primary outcome was change in diabetes self-efficacy through a validated 8-item Likert scale. Secondary objectives were changes in A1c, and changes in diabetes medications (dosage adjustments, time of administration). Paired t-tests were used to analyze change in A1c and diabetes self-efficacy scores.
Results: Diabetes self-efficacy scores increased by a mean of 1.63 ± 2.09 points (p&lt;.001) out of 10 points. The A1c decreased by a mean of 0.80 ± 1.52% (p&lt;.001) with a mean follow-up A1C of 7.80 ± 1.60%. Those with baseline A1c ≤8.0% (n=70) experienced a decrease in A1c of 0.24% compared to 1.20% in those with A1c &gt; 8.0% (n=101). Participants utilizing the real time device (n=133) experienced a decrease in A1c by 0.75% compared to 1.0% in those with the blinded device (n=38). Most medication changes made in the CGM SMA were dosage adjustments and changes in administration time.
Discussion: The CGM SMA is a novel practice model incorporating diabetes education, peer support, professional CGM, and inter-professional care that demonstrated improvements in diabetes self-efficacy and A1c.

Disclosure
D. Isaacs: Consultant; Self; Companion Medical, LifeScan, Inc. Speaker’s Bureau; Self; Dexcom, Inc., Novo Nordisk Inc., Xeris Pharmaceuticals, Inc. A. Simonyan: None. J.E. Blanchette: Other Relationship; Self; Tandem Diabetes Care. S. Lekic: None. D. Noe: Consultant; Self; Pyure Organic Stevia. N.R. Galloway: None.
339-OR: Increased Diabetes Self-Efficacy and Transition Readiness in Teens with Uncontrolled Type 1 Diabetes Receiving a Group Education Curriculum
Authors: GARVEY KATHARINE , DEAN TAYLOR , CHRISTENSEN SINEAD , RICE KRISTEN , RICH VIRGINIA B. , TERRIO SHANNON , BERBERT LAURA , LIU ENJU , LAFFEL LORI M. 
Published: June 2020

Suboptimal teen self-care is associated with poor transition outcomes in T1D. Innovative curricula may optimize self-care engagement and transition preparation. We evaluated a pilot RCT to improve self-care and transition readiness in teens with uncontrolled T1D. Teens (N=40) were randomized to Self-Management, Adherence and Readiness for Transition in T1D (SMART T1D) curriculum or control group. The SMART T1D group participated in 3 evening peer group sessions facilitated by RN/CDEs over ∼9 months. Controls received 3 educational newsletters. All maintained routine 1:1 T1D care. Outcomes included diabetes self-care (SCI-R), transition readiness (RISQ), burden (PAID), self-efficacy (DMSE), and quality of life (Peds-QL Diabetes) and HbA1c, all assessed as change from baseline in intent-to-treat analyses with paired 1-sided t-tests. Teens were 50% male, 85% white, age 15.7±1.2 years, T1D duration 6.4±3.9 years, A1c 9.5±1.2%; 63% pump users. 38/40 completed the study. The SMART T1D group demonstrated significantly improved diabetes self-efficacy and transition readiness and a trend of improved HbA1c while control group did not (Table 1). Other domains showed no change, with a trend for increased burden in controls. SMART T1D feedback was highly positive. Peer group education may be promising for enhancing teen self-care and transition preparation.

Disclosure
K. Garvey: None. T. Dean: None. S. Christensen: None. K. Rice: None. V.B. Rich: None. S. Terrio: None. L. Berbert: None. E. Liu: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK202655)