bluuebunny/crossref_metadata_2025_split huggingface dataset:
315-OR: The Membrane Protease Prostasin Promotes Insulin Secretion by Regulating the Epidermal Growth Factor Receptor Pathway
Authors: ISHII TOSHIHISA , UCHIMURA KOHEI , FURUYA FUMIHIKO 
Published: May 2022

Prostasin (PRSS8) is a serine protease that cleaves and regulates the activity of specific substrates. Epidermal growth factor receptor (EGFR) , which regulates insulin secretion and pancreatic β-cell proliferation, is activated via proteolytic shedding by PRSS8. In this study, we first found that PRSS8 is expressed in β-cells of mouse pancreatic islets. To clarify the molecular mechanisms of PRSS8-associated insulin secretion, we generated pancreatic β-cell-specific PRSS8 knockout (βKO) and PRSS8-overexpressing (βTG) mice. Overall, we observed glucose intolerance and decreased glucose-stimulated insulin secretion in the βKO mice compared to controls, whereas an increased response to glucose was observed in isolated islets from βTG mice. In vitro studies using MIN6 cells, we demonstrated that erlotinib, a specific inhibitor of EGFR, inhibits both EGF- and glucose-stimulated insulin secretion, and that glucose increases EGF secretion from β-cells. Following silencing of PRSS8, MIN6 cells showed lower levels of insulin secretion upon glucose stimulation, impaired EGFR signaling and lower expression levels of SNARE proteins. On the other hand, MIN6 cells overexpressing PRSS8 showed higher levels of insulin secretion at both the basal and glucose-stimulated insulin secretion, and higher phospho-EGFR levels. Furthermore, short-term exposure to glucose increased the expression level of endogenous PRSS8 protein in MIN6 cells, by blocking intracellular degradation. Our findings suggested that PRSS8 might be a blood glucose-dependent physiological modulator of insulin secretion via EGF-EGFR signaling in pancreatic β-cells.

Disclosure
T. Ishii: None. K. Uchimura: None. F. Furuya: None.

Funding
KAKENHI (19K17958 and 21K16367)
318-OR: Intermittent Fasting Improves ß-cell Function in Nonobese KATP-Induced Neonatal Diabetes through Reduction of Cellular Stress and Enhanced Autophagy
Authors: CASTELBLANCO ESMERALDA , SHYR ZEENAT A. , YAN ZIHAN , DIWAN ABHINAV , REMEDI MARIA S. 
Published: May 2022

Diabetes progression is characterized by loss of functional β-cell mass. Non-obese KATP-GOF mouse models of human neonatal diabetes developed severe diabetes due to lack of insulin secretion; with a marked loss of β-cell mass/identity and dedifferentiation as diabetes progresses. Intermittent fasting (IF) reduces body weight, improves diabetes and autophagy in humans and obese mice, but the mechanisms underlying this in lean individuals remains elusive. Upon diabetes development, non-obese KATP-GOF mice were divided in two groups: i) fed chow diet ad libitum (AL) , ii) subjected to IF (24h fast/24hr feed cycles) . IF-KATP-GOF mice showed reduced blood glucose without changes in body weight or lean-fat mass compared to AL-KATP-GOF mice. The markedly reduced insulin and increased proinsulin levels in islets from AL-KATP-GOF mice were restored to normal levels in IF-KATP-GOF islets. IF-KATP-GOF islets showed reduced ATF6 and sXBP1 message levels and decreased sXBP1 and TXNIP protein levels compared to AL-KATP-GOF islets, suggesting reduced oxidative and ER stress. Strikingly, the markedly increased autophagy markers LC3II and P62 in AL-KATP-GOF islets were reduced to control levels in IF-KATP-GOF, suggesting improved autophagy. Electron microscopy confirmed increased insulin granules, reduced mitochondrial and ER damage, and decreased autophagosome accumulation in IF-KATP-GOF. While liver G6PC and PCK1 (gluconeogenesis) , FAS (lypogenesis/lipolysis) , and CPT1 and ATGL (β-oxidation/lipolysis) messages were increased, CRCT2 and FOXO1 (gluconeogenesis) , GCK (glycolysis) and PPARα (β-oxidation) were decreased. PPARγ and PPARα were decreased in brown adipose tissue.
In conclusion, our studies in KATP-GOF mice indicate the beneficial effects of IF not only on improving functional β-cell mass through decreasing oxidative and ER stress and enhancing autophagy, but also improving liver and adipose tissue function.

Disclosure
E.Castelblanco: None. Z.A.Shyr: None. Z.Yan: None. A.Diwan: Consultant; Biomedical systems (ERT) , Dewpoint Therapeutics. M.S.Remedi: None.

Funding
National Institutes of Health (GDK123163)
325-OR: Associations of Systolic Blood Pressure (SBP) with the Incidence of Heart Failure (HF) According to Glucose Tolerance Status (GTS)
Authors: FUJIHARA KAZUYA , YAMADA MAYUKO H. , YAMAMOTO MASAHIKO , OE MOMOKO , OSAWA TAEKO , IWANAGA MIDORI , YAMADA TAKAHO , KODAMA SATORU , SONE HIROHITO 
Published: May 2022

Although a linear relationship between SBP and risk of coronary artery disease or cerebrovascular disease was observed regardless of GTS, this association in HF is little known. We analyzed data from a nationwide claims database from 20to 20on 589,621 individuals. A Cox proportional hazards model identified risks of HF among 5 levels of SBP according to GTS [i.e. normal glucose tolerance (NGT) , prediabetes, diabetes (DM) ]. Incidence of HF per 1,000 person-years was 0.for NGT, 0.18 for prediabetes, and 0.80 for DM. Compared with SBP &lt;1mmHg, hazard ratios (HR) (95% CI) for HF in the 4 higher NGT levels (120-129, 130-139, 140-149, ≥150 mmHg) increased from 1.93 (1.30-2.85) in the second level to 8.66 (5.44-13.39) in the fifth level. For prediabetes or DM, HF risk was significantly increased in the ≥150 mmHg group compared with the ≤1mmHg group. Compared with NGT and SBP ≤1mmHg, prediabetes or DM patients with SBP ≤1mmHg had approximately 2-fold or 5-fold risks of HF, respectively (Table) . Association of SBP with HF differs according to GTS. BP control is essential in those with NGT. The impact of risk factors other than SBP, such as poor glycemic control and physical inactivity, on the development of HF may increase with worsening of glucose status, suggesting that comprehensive management of risk factors other than BP is essential in those with prediabetes and DM to prevent HF.

Disclosure
K.Fujihara: None. M.H.Yamada: None. M.Yamamoto: None. M.Oe: None. T.Osawa: None. M.Iwanaga: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
JSPS (21K11569)
33-LB: Using Telehealth to Deliver Diabetes Self-Management Education and Support (DSMES) In Rural Communities
Authors: SAHASRANAM PREM , GAVINI FRANK , SODHI SANDEEP , GARNERO THERESA , THOMPSON JACQUELINE , SALINAS CAROLYN M. , BAXTER STORMIE S. 
Published: May 2022

The Centers for Disease Control and Prevention (CDC) National Diabetes Statistics Report 2020 emphasized that diabetes is an overwhelming national problem and especially prevalent in rural areas. Of the 12.3 million Californians with diabetes or prediabetes, only 1.23 million have been diagnosed, and 45% of those haven’t received diabetes education. Rural Californians have lower per capita income compared to urban Californians, equating to higher poverty rates (U.S. Department of Agriculture, 2021) , and they often face social service inaccessibility. Studies show that populations with low income have higher rates of unhealthy behaviors and are more likely to develop diabetes (Hsu et. al, 2012) . Revamping standardized diabetes prevention and education via a telehealth model to reach those in rural California has shown significant results. My Diabetes Tutor (MDT) , as part of a DSMES telehealth program, has provided a convenient and effective way to access diabetes education (DE) in rural areas and beyond. MDT delivers education for diabetes, gestational diabetes, prediabetes, and obesity in several languages from Certified Diabetes Care and Education Specialists. People have direct access to DE from home or a kiosk at their provider/health plan offices. Topics range from diabetes basics, nutrition, medication comprehension, emotional well-being, and reducing the risk of possible complications to understanding the use of insulin pumps and continuous glucose monitoring. People using MDT have shown an average A1C reduction of 1.2%, LDL decrease of 9.4 points, and improvements in blood pressure, weight, and self-care behaviors. The technology to deliver MDT DSMES was developed in collaboration with CharmHealth. MDT satisfies a great need to make DE accessible in rural California, which sets the stage for MDT’s planned national expansion, and to replicate this model to increase access to DE for people hospitalized with diabetes via virtual inpatient DE services.

Disclosure
P. Sahasranam: None. F. Gavini: None. S. Sodhi: None. T. Garnero: None. J. Thompson: Employee; Vida Health. Other Relationship; DayTwo Inc. C. M. Salinas: None. S. S. Baxter: None.
333-OR: Oxyntomodulin Analog LY3305677 (LY) Improves Glycemic Control and Weight Loss in Healthy Volunteers and Subjects with Type 2 Diabetes (T2D)
Authors: BENSON CHARLES , THAM LAI-SAN , DU YU , GURBUZ SIREL , ROBINS DEBORAH A. , MATHER KIEREN J. , TANG CHENG CAI , THOMAS MELISSA K. 
Published: May 2022

LY is an acylated peptide analog of oxyntomodulin, a dual glucagon and GLP-1 receptor agonist. We conducted 2 randomized, double-blind, phase 1 multiple ascending subcutaneous dosing studies in healthy subjects (S1, NCT03325387) and in T2D patients (S2, NCT03928379) to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics. In S1, 4 cohorts of healthy subjects received placebo or LY once-weekly (QW) for 4 weeks. In S2, T2D subjects received placebo or LY QW in 2 cohorts with doses escalated over 12 or 16 weeks. A total of 54 subjects completed S1 and 24 patients completed S2. The most common treatment-emergent adverse events in both studies (decreased appetite, nausea, and diarrhea) were mostly mild in severity, and no deaths or serious adverse events were reported. Pharmacokinetic results were consistent between healthy subjects and T2D patients and supported weekly dosing. In healthy subjects, fasting glucose levels were decreased from baseline with increasing LY doses, and reductions in mean body weight from baseline were generally seen with increasing doses, with the largest change observed on Day 29. In T2D subjects during weeks 12-16, preliminary results of mean HbA1c changes from baseline ranged from -1.56% to -2.16% in LY-treated vs. -0.43% to -0.70% in placebo subjects, and mean body weight changes from baseline ranged from -2.30 kg to -11.24 kg in LY-treated vs. -0.35 kg to -2.03 kg in placebo subjects. Fasting glucose, triglycerides, cholesterol, and glucagon levels were decreased from baseline with LY vs. placebo at weeks 12-16. We conclude that LY was well tolerated in both studies, with a safety profile similar to selective GLP-1 receptor agonists. LY has a promising pharmacodynamic profile with potential for therapeutic benefit in T2D, obesity, or other metabolic diseases.

Disclosure
C.Benson: None. L.Tham: Employee; Eli Lilly and Company. Y.Du: None. S.Gurbuz: Employee; Eli Lilly and Company. D.A.Robins: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Tang: Employee; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
34-LB: Feasibility of Onboarding and Supporting Diabetes Technologies in Youth with Type 1 Diabetes during the COVID-19 Pandemic and Beyond
Authors: PELLIZZARI MARGARET , FISHBEIN JOANNA , FRANK GRAEME , NWOSU BENJAMIN U. 
Published: May 2022

Background: Prior to COVID-19 lockdown, all new insulin pump training was done in house with the patient and families in attendance. However, the pandemic lockdown made it difficult for in-person education. Therefore, we embarked on virtual trainings as well as in-person training for new insulin pump starts.
Aim: To evaluate the feasibility and effectiveness of remote and in-person trainings by comparing management metrics in the years of 2020 and 2021.
Methods: We compared the age, race, sex, glycemic control at 6 months post insulin pump initiation, incidence of severe hypoglycemic episodes, and diabetic ketoacidosis (DKA) among the two training models.
Results: There were 118 insulin pump starts during the study period, of which 73 (62%) were in-person: (49 (67%) male, mean ± SD age was 10.6 ± 4.0 years, and 40 (55%) White, 11 (15%) Black and 22 (30%) other; and 39 (33%) were remote: (19 (49%) male, mean ± SD age: 11.6 ± 4.0 years, and 26 (67%) White, 4 (10%) Black, and 9 (23%) other race. There were no cases of severe hypoglycemia requiring a third-party assistance, hospitalizations, or DKA in the first 6 months after insulin pump initiation in either group. The proportion of subjects with optimal glycemic control (A1c of ≤7%) at 6 months following pump initiation was similar between the two training groups after adjusting for baseline A1c and BMI percentile group (p=0.35) .
Conclusion: This study found no evidence that remote pump training was less safe than in-person training. Therefore, remote training could be an alternative method to promote health equity by increasing access to diabetes technology for youth with type 1 diabetes in whom in-person training may be a challenge. A larger study is warranted to further evaluate the safety and effectiveness of this alternative method.

Disclosure
M. Pellizzari: None. J. Fishbein: None. G. Frank: None. B. U. Nwosu: None.
387-P: Novel Mitochondrial Complex I Modulator Reduces Diabetes-Associated Expression of Inflammation and Fibrosis Markers in Human Proximal Tubular Epithelial Cells
Authors: ABOOLIAN ARA , URNER SOFIA , RODEN MICHAEL , JANDELEIT-DAHM KARIN 
Published: May 2022

Diabetic kidney disease (DKD) is a chronic microvascular complication of diabetes and accounts for 30-40% of all diabetic patients. Patients with DKD experience a progressive and irreversible decline of renal function until dialysis and kidney transplantation become the last line of intervention. Renal loss of function is driven by the diabetic milieu causing an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense mechanisms. The excessive amounts of ROS, driven either by mitochondria or by NADPH oxidases (NOXs) , cause inflammation and eventually lead to fibrosis and kidney failure. Methods: To address this problem, we cultivated healthy primary human renal cells (renal proximal tubular epithelial cells) under diabetic conditions. The cells were treated either with 5mM normal glucose (NG) , or 25mM high glucose with 10ng/ml TNF-α or TGF-β (HG) for 24h. In addition, a novel mitochondrial complex I modulator (BIM, 250nM) that has been designed to interfere with the ROS production at mitochondrial complex I has been tested in combination with the treatments. We analyzed the gene expression of different oxidative stress, inflammation as well as fibrosis markers. Results: On the transcriptional level, a treatment with BIM resulted in a significant downregulation of the HG treatment-induced expression of the oxidative stress markers SOD2 (by 40%) , NOX4 (by 61%) and NOX5 (by 34%) , the inflammation markers IL1B (by 29%) and TNFA (by 22%) , as well as the fibrosis markers TGFB1 (by 23%) , COL4A1 (by 50%) and CTGF (by 43%) , as determined by a two-way ANOVA and Tukey’s multiple comparison. Conclusion: The reduction of these markers after treatment with the complex I modulator suggests renoprotective properties in vitro. Further in vivo experiments in diabetic db/db mice will reveal whether the novel mitochondrial complex I modulator can attenuate renal injury in DKD.

Disclosure
A.Aboolian: None. S.Urner: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. K.Jandeleit-dahm: None.
399-P: Associations among Biomarkers of Inflammation, Tubular Injury, and Lipid Metabolism with Gestational Diabetes Mellitus (GDM) Status, Microalbuminuria, and Retinopathy in the MARIGOLD Study
Authors: LIU HONGYAN , SRIDHAR VIKAS S. , LOVBLOM LEIF ERIK , FEIG DENICE , HERER ELAINE , KISS ALEX , LIPSCOMBE LORRAINE , YIP PAUL M. , CHERNEY DAVID , SHAH BAIJU R. 
Published: May 2022

Levels of hyperglycemia below those for diagnosis of diabetes are associated with microvascular injury, though the duration required to induce these complications remains poorly understood. This is especially relevant in patients with GDM due to its transient nature, which can nevertheless predispose to microvascular disease. Our aim was to assess whether mechanistic pathways associated with microvascular complications are upregulated in pregnant women with GDM or microvascular disease.
In this analysis, urinary albumin excretion and biomarkers of inflammation, lipoprotein metabolism, and tubular injury were quantified in 355 women at 32-40 weeks of gestation, with and without GDM. Adjusted associations between all biomarkers and each outcome variable - GDM status, microalbuminuria, and retinopathy - were performed using logistic regression.
Significant associations between GDM status and ApoA1, Il-6, IL-8, sTNFR I/II, NGAL, VEGF and vWF were observed (Figure 1A) . Increased CRP and sTNFR-II were associated with higher levels of albuminuria (Figure 1B) . CRP (Figure 1C) and previous GDM were associated with retinopathy.
In conclusion, GDM and its relatively short-term exposure to hyperglycemia are associated with pathways involved in diabetes and microvascular complications.

Disclosure
H.Liu: None. B.R.Shah: None. V.S.Sridhar: None. L.Lovblom: None. D.Feig: Advisory Panel; Novo Nordisk, Research Support; Apotex. E.Herer: None. A.Kiss: None. L.Lipscombe: n/a. P.M.Yip: None. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk.
4-OR: IL6R Signaling in Adipogenesis Mediates GLP-1 Analog Effects on Adipose Tissue Beiging
Authors: GUTIERREZ ABSALON D. , GAO ZHANGUO , YU YONGMEI , KOLONIN MIKHAIL 
Published: May 2022

Mechanisms underlying antidiabetes effects of GLP-1 analogs such as liraglutide, collectively termed incretins, remain incompletely understood. While incretins boost insulin secretion, they also modulate the immune system and have anti-obesity effects. We discovered that prediabetic patients treated with incretins have increased thermogenic gene expression in supraclavicular adipose tissue (AT) . Interestingly, incretin-treated patients were found to have elevated levels of IL6 plasma, consistent with the observation that incretin treatment induces IL6 secretion by human monocytes. We hypothesized that incretins induce adipocyte browning via IL6 and used the mouse model to test if IL6 receptor (IL6Ra) signaling underlies the effects of the incretin-IL6 axis. We show that liraglutide transiently increases IL6 in circulation and ILRa signaling in AT while metronomic liraglutide treatment results in AT browning and improved glucose clearance in mice. IL6-blocking antibody treatment inhibited the thermogenic and antidiabetes effects of liraglutide. Based on the observation that IL6 induces thermogenic gene expression in cultured adipocytes, we hypothesized that the incretin-IL6 axis directly induces adipocyte browning. To test this, we generated mice with IL6Ra knockout in Pdgfrb-positive adipocyte progenitors (APC-KO) and in adipocytes (AD-KO) . We show that liraglutide-induced weight loss does not depend on IL6 signaling in the adipocyte lineage. However, both IL6Ra APC-KO and AD-KO mice failed to undergo thermogenic adipocyte browning and glucose utilization increase in response to liraglutide treatment. We conclude that the antidiabetes effects of metronomically administered incretins are mediated by transient upregulation of IL6, which activates canonical ILRa signaling and thermogenesis in adipocytes.

Disclosure
A.D.Gutierrez: None. Z.Gao: None. Y.Yu: None. M.Kolonin: n/a.

Funding
National Institutes of Health (NIDDK 5R21DK122234)
401-P: Development of Predictive Models for Health Care Outcomes of Patients with Chronic Kidney Disease and Type 2 Diabetes
Authors: SHEER RICHARD , NAIR RADHIKA , PASQUALE MARGARET K. , EVERS THOMAS , COCKRELL MEGHAN M. , GAY ALAIN , SINGH RAKESH , SCHMEDT NIKLAS 
Published: May 2022

Progression of chronic kidney disease (CKD) is associated with increased risk of cardiovascular or renal events that contribute to increasing healthcare costs. The purpose of this study was to develop predictive models for rapid progression of CKD, days out of the home, and high costs for patients with both CKD and type 2 diabetes (T2D) . This retrospective observational cohort study used administrative claims data for patients with CKD (stage 3-4) and T2D aged 65-89 years enrolled in a Humana Medicare Advantage Prescription Drug plan 1/1/2012-12/31/2017. Patients were enrolled ≥1 year pre-index and followed up to one year post-index. Outcomes included rapid progression of CKD (&gt;1 decrease in estimated glomerular filtration rate [eGFR] &gt;5 mL/min/1.73m2 per year) , days out of the home (days spent out of their residence [e.g., hospital]; ≥2% days out of the home) and high costs (75-90th and &gt;90th percentiles) post-index. Pre-index demographic and clinical characteristics, selected based on the LASSO technique, were included in logistic regression models to generate parameter estimates and model performance statistics. We identified 169,876 patients with CKD stage 3-4 and T2D. The C-statistics for the models ranged from 0.694 to 0.745. Lower initial eGFR led to incrementally higher risk for more days out of the home and high costs. Patients with urinary albumin to creatinine ratio (UACR) ≥300 mg/g had three times increased risk for rapid progression of CKD, 57% higher risk of more days out of the home, and, among those in the 75-90th cost percentile, had 38% higher costs than patients with UACR&lt;30 mg/g. The presence of congestive heart failure, anemia, or higher pre-index utilization (≥5 physician visits) increased the risk for all outcomes. The predictive models developed in this study can be potentially used as decision support tools for clinicians and payers, and the risk scores from these models can be applied to future outcomes studies focused on patients with T2D and CKD.

Disclosure
R. Nair: None. M.K. Pasquale: Consultant; Bayer AG. T. Evers: Employee; Bayer AG. M.M. Cockrell: Employee; Humana. Stock/Shareholder; Humana. A. Gay: Employee; Bayer AG. R. Singh: None. N. Schmedt: Employee; Bayer AG.

Funding
This study was funded by Bayer.