bluuebunny/crossref_metadata_2025 huggingface dataset:
404-P: Metformin Treatment Rescues Alterations of Insulin-Sensitive Glucose Transporters in the Lung of Insulin-Resistant Mice
Authors: CAMPOLO ALLISON , MARIA ZAHRA , HINSDALE MYRON , LIU LIN , LACOMBE VERONIQUE
Published: June 2019

Obesity and hyperglycemia have recently been identified as independent risk factors for the development of respiratory infections. Although the lung is a major organ to utilize glucose, the regulation of glucose transport in the healthy and diabetic lung has received little attention. We hypothesized that metformin would rescue diabetes-induced alterations of glucose transport in the lung. To test this hypothesis, we induced an insulin-resistant diabetic mouse model by feeding a high-fat diet for 16 weeks (n=10/group). A subset of mice was treated with metformin for 8 weeks. Protein content of class I glucose transporters (GLUTs -1, -2, -3, -4) and class III GLUTs (-8, -10, -12) was quantified by Western blotting in whole lung homogenates. Cell surface GLUTs were quantified using the biotinylated photolabeling technique. Glucose concentration in bronchoalveolar lavage (BAL) fluid was measured spectrophotometrically. After feeding a high-fat diet, mice became obese, mildly hyperglycemic, hyperinsulinemic, and insulin tolerant. Total protein content of GLUT4 and GLUT12 was significantly decreased in the lung of the insulin-resistant (IR) group (P <0.05). Following metformin treatment, protein content of GLUT4, but not GLUT12, was rescued in the lung of the treated IR mice (P <0.05). Cell-surface protein content of GLUT4 and GLUT8 was significantly decreased in the lung of IR mice, which was rescued in the treated group (P<0.05). IR mice demonstrated a trend towards a higher glucose concentration in the BAL fluid (P < 0.1). These novel findings suggest that 1) regulation of glucose transport is altered in the lung during obesity and hyperglycemia, potentially increasing the risk for pulmonary infection, and 2) metformin treatment rescues GLUT alterations in the lung of IR mice. Insights gained from this study could lead to the identification of significant metabolic therapeutic targets for diabetic patients affected by concurrent respiratory infections.

Disclosure

A. Campolo: None. Z. Maria: None. M. Hinsdale: None. L. Liu: None. V. Lacombe: None.

Funding

Harold Hamm Diabetes Center; National Institutes of Health
422-P: Long-Term Incidence of Cardiovascular Disease across the Natural History of Type 2 Diabetes
Authors: AN JAEJIN , NICHOLS GREGORY A. , QIAN LEI , WEI RONG , HARRISON TERESA , MUNIS MERCEDES A. , LI ZHUOXIN , WEISS TRACEY , IGLAY KRISTY , RAJPATHAK SWAPNIL , REYNOLDS KRISTI
Published: June 2019

The elevated risk of cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM) is well established, however, development of these comorbidities from T2DM diagnosis over an extended time period has not been adequately studied. We estimated the cumulative incidence of CVD in T2DM over the course of 15 years in a large U.S. integrated healthcare delivery system. The study population included adult T2DM patients diagnosed between 1/1/2003 and 12/31/2014 based on validated algorithms using the electronic health record (EHR). Patients were followed from 6 months after their T2DM diagnosis date through 6/30/2018. Patient demographics, CVD risk factors, medical history, and medication use were ascertained from the EHR. The cumulative incidence of myocardial infarction (MI), heart failure (HF) and all-cause mortality was estimated separately at 2, 5, 10, 13 and 15 years among the patients who did not have a prior history of each condition (at-risk population) using the Kaplan-Meier method. We identified 135,199 patients newly diagnosed with T2DM. Mean (SD) age was 58 (13) years, 48% were female, 36% were white, 35% Hispanic, 12% black, and 12% Asian. Median follow-up was 6 years. At baseline, 1.3% had MI and 3.5% had HF. By 15 years following T2DM diagnosis, 30.0% of the cohort died, 7.6% had MI and 11.5% HF. The 2-, 5-, 10-, 13-, and 15-year cumulative incidence among the population-at-risk are shown in the Table.

Disclosure

J. An: Research Support; Self; Merck & Co., Inc. G.A. Nichols: Research Support; Self; Amarin Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC., Merck Sharp & Dohme Corp. L. Qian: None. R. Wei: None. T. Harrison: None. M.A. Munis: None. Z. Li: None. T. Weiss: Employee; Self; Merck & Co., Inc. K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. S. Rajpathak: None. K. Reynolds: Research Support; Self; Amarin Corporation, Amgen Inc., Merck Sharp & Dohme Corp., Novartis AG.
424-P: HDL miR-181c as a Novel Biomarker for Diabetic Vascular Complications in Australian Aboriginal People
Authors: MORRISON KAITLIN R. , BURSILL CHRISTINA , SOLLY EMMA , SHEMESH TOMER , NICHOLLS STEPHEN , BROWN ALEX D. , TAN JOANNE T.M.
Published: June 2019

Diabetes is a major burden on Australia’s Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischemia-driven angiogenesis. MicroRNAs (miRNAs) are known to regulate angiogenesis. We have recently identified a novel anti-angiogenic role for miR-181c. High-density lipoproteins (HDL) are associated with reduced rates of diabetic complications and serve as carriers of miRNAs in the circulation. HDL miRNA profiles differ in disease states. We sought to determine if circulating miR-181c levels reflect the severity of diabetic complications in Australian Aboriginal people. HDL was isolated from plasma samples of Australian Aboriginal participants with or without diabetes and associated complications living in regional South Australia; and a cohort of non-Indigenous participants without diabetes. We found that HDL miR-181c levels were strikingly elevated in the group of Aboriginal people with diabetic complications. However, plasma miR-181c levels were overall lower in Australian Aboriginal participants compared to the non-Indigenous group. Angiogenic capacity of isolated HDL was assessed in vitro using the Matrigel tubulogenesis assay. Under high glucose (25 mM) conditions, cells treated with HDL from the group of Aboriginal people with diabetic complications had a reduced capacity to form tubules and had lower mRNA levels of the hypoxia angiogenic transcription factor HIF-1α compared to all other groups. This attenuation of pro-angiogenic capacity may be attributed to the concurrent increase in cellular miR-181c levels.

In conclusion, HDL from Aboriginal people with diabetic complications had reduced angiogenic capacity, highlighting its impaired function in the diabetic state and is potentially linked to the increased levels of the anti-angiogenic miRNA miR-181c. HDL miR-181c may be a novel biomarker for the extent of diabetic complications in Australian Aboriginal people.

Disclosure

K.R. Morrison: None. C. Bursill: None. E. Solly: None. T. Shemesh: None. S. Nicholls: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Cerenis, CSL Behring, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Omthera, Pfizer Inc., Resverlogix Corp., Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; Amgen Inc., AstraZeneca, Athernova, Cerenis, Eli Lilly and Company, InfraReDx, Novartis Pharmaceuticals Corporation, Resverlogix Corp., Sanofi. A.D. Brown: None. J.T.M. Tan: None.
439-P: Assessing the Relationship between Asthma and Cardiovascular Disease Risk in Type 2 Diabetes Using Revised Risk Estimates
Authors: BURGE MARK R. , ALDRETE KARISSA L. , EHRHART MARK , MURRAY-KREZAN CRISTINA
Published: June 2019

Purpose: Type 2 diabetes (T2D) and asthma are independent risk factors for cardiovascular disease (CVD), but CVD risk is reduced in individuals with T2D + Asthma compared to those with T2D alone when using the 2013 ACC/AHA CVD Risk Score. Because these guidelines may overestimate CVD risk by up to 20%, revised risk equations have recently been proposed. We hypothesize that using these revised risk score equations will not alter the relationship between asthma, T2D, and CVD Risk Score.

Methods: Data were extracted from Electronic Health Record using ICD-9/10 codes. Patients with both T2D and Asthma (n=603) were identified and compared to a group of matched patients with T2D Alone (n=603). Estimates of the 10-year risk of a major CVD event were derived using generalized linear models.

Results: As shown in the Table, 10 year CVD risk was significantly increased in the T2D Alone group compared to the T2D + Asthma group using both the 2013 ACC/AHA CVD Risk Score estimates and the revised 2018 CVD Risk Score estimates. CVD risk is approximately 2% higher in both groups using the newer estimates.

Conclusions: In this matched, case controlled retrospective study, Asthma conferred a protective effect against CVD risk over the next 10 years for patients with co-morbid T2D. This result was initially demonstrated with the 2013 ACC/AHA Risk Score estimates and confirmed with the 2018 revised Risk Score estimates.

Disclosure

M.R. Burge: None. K.L. Aldrete: None. M. Ehrhart: None. C. Murray-Krezan: None.

Funding

National Institutes of Health
453-P: Metabolic Syndrome Severity Score, All-Cause Mortality, and Incident Vascular Events in Type 2 Diabetes: A 13-Year, Single-Centre, Follow-Up Study
Authors: GAROFOLO MONIA , GUALDANI ELISA , LUCCHESI DANIELA , GIUSTI LAURA , SANCHO-BORNEZ VERONICA , DANIELE GIUSEPPE , MICCOLI ROBERTO , FRANCESCONI PAOLO , PENNO GIUSEPPE , PRATO STEFANO DEL
Published: June 2019

Metabolic Syndrome (MetS) is associated with CV events in T2DM. We assessed over a 13-years follow-up the association between a “MetS severity score”, derived from WC, sBP, HDL and triglycerides (courtesy Dr. Mark DeBoer) and both all-cause death and incident CV events in 986 T2DM. Compared to lowest quartile, Q2-4 showed a steeply worsening CV risk profile. A total of 230 deaths occurred over 12.9±2.7 years (23.3%; 18.0 x 1000 PYs). Death rate was J-shaped: Q1 22.4%; Q2 18.2%; Q3 25.9% and Q4 26.8% (p=0.090). Electing arbitrarily Q2 as reference, and after adjustment for confounders and, finally, for parameters of MetS score, HRs (95% CI) vs. Q2 for death were: Q1 1.46 (0.97-2.19; p=0.070), Q3 1.61 (1.09-2.38; p=0.016) and Q4 1.82 (1.20-2.75, p=0.005). Over 11.3±4.4 years, 276 major CV events occurred in 972 T2DM (28.4%; 25.2 x 1000 PYs); adjusted HRs vs. Q1 were: Q2 1.34 (0.93-1.93; p=0.117), Q3 1.99 (1.40-2.82, p<0.0001) and Q4 2.37 (1.66-3.39, p<0.0001). Over 11.8±4.0 years, 184 coronary events occurred (18.9%; 16.03 x 1000 PYs); adjusted HRs vs. Q1 were: Q2 1.79 (1.12-2.84; p=0.015), Q3 2.27 (1.44-3.60, p<0.0001) and Q4 2.99 (1.88-4.74, p<0.0001). Over 12.7±3.1 years, 84 heart failure occurred (8.6%; 6.78 x 1000 PYs); HRs vs. Q1 were: Q2 2.23 (1.01-4.90; p=0.046), Q3 3.38 (1.56-7.31, p=0.002) and Q4 4.60 (2.16-9.82, p<0.0001). Finally, over 12.8±3.1 years, 71 ESRD occurred (7.3%; 5.72 x 1000 PYs); HRs vs. Q1 were: Q2 1.27 (0.57-2.82; p=0.558), Q3 2.12 (1.01-4.45, p=0.048) and Q4 2.16 (1.01-4.65, p=0.048). Further correction for MetS score components excluded MetS score as an independent covariate of outcomes other than death. With the limitations imposed by sample size and the strenght of long-term observation, we suggest that in T2DM MetS score predicts all-cause mortality indipendent of main risk factors and of each component of MetS. MetS score was associated with CV outcomes and ESRD, but these associations were attenuated after adjustment for its components.

Disclosure

M. Garofolo: None. E. Gualdani: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.
46-LB: Improvement of Ischemic Lesions of Lower Limbs in Diabetic Mice by Liraglutide
Authors: CHAO ZHENG
Published: June 2019

Diabetic foot is a common reason of foot ulcer and amputation. Studies found GLP-1 receptor agonist (GLP-1RA) enhances the angiogenesis of endothelial progenitor cells (EPCs) on ischemic lower limbs in diabetic mice. But the cause is unclear. The blood perfusion and capillary density are observed in diabetic mice after the treat of GLP-1RA by establishing a model of ischemic hind limb. Primary EPCs being isolated and cultured we observed the number of peripheral EPCs the NO stimulated by GLP-1RA. The results that GLP-1RA enhance blood perfusion and capillary density of ischemic hind limbs.

Conclusion, High glucose decrease the expression of GLP-1R in EPCs and angiogenesis and migration of EPCs while the remedy of GLP-1RA Reverse this phenomenon.(A)The LDPI index were significantly higher in the liralutide group than that in the Vehicle group (N=8-10 per group).**:p<0.01, ***:p<0.001. (B) Quantitative analysis of (A). (C) The angiogenesis ability of EPCs was evaluated using a Matrigel-like structure formation assay. (D)Quantitative analysis of (C). the high glucose significantly impaired the angiogenic ability of EPCs, while GLP-1RA. Reverse this phenomenon, and this improvement showed a dose effect.**:p<0.01. (N=3-4 per group)(E). The results that high glucose significantly impaired the migration ability of EPCs, while GLP-1RA Reverse this phenomenon. **: p<0.01.(N=4 per group) (F) Quantitative analysis of (E).

Disclosure

Z. Chao: None.
463-P: Linagliptin Ameliorated Heart Damage Associated with the Suppression of Necroptosis in Type 1 Diabetic Mice
Authors: HIRAI TARO , TAKAGAKI YUTA , KANASAKI KEIZO , KOYA DAISUKE
Published: June 2019

Background: In diabetic patients, the incident of heart failure is two to five times greater when compared to that of general population. The influence of DPP-4 inhibitor on the heart failure and cardiac damage in diabetes is not completely elucidated yet. Therefore, to understand the pathobiology of heart damage in diabetes and the influence of DPP-4 inhibitor is emerged as significant. Necroptosis, recently identified as programmed cell death, had shown to be involved in heart damage of ischemic heart disease model. Here we found that intervention with DPP-4 inhibitor linagliptin (LINA) ameliorated heart damage in diabetic mice associated with the suppression of necroptosis.

Method: We utilized streptozotocin-induced diabetic CD-1 mice (STZ:200mg/kg). At 20 weeks after the onset of diabetes, diabetic mice were treated with LINA (STZ+LINA) for 4 weeks.

Result: Blood pressure, blood glucose, body and heart weights were not different between STZ and STZ+LINA. Ultrasonic Echocardiography analysis revealed that LVDd and LVDs were significantly decreased in STZ and STZ+LINA compared with control. STZ-induced diabetic CD-1 mice exhibited perivascular fibrosis evaluated by picrosirius red staining and strong immunoreactivity for DPP-4 expression in cardiac interstitium; STZ+LINA exhibited suppression of DPP-4 and amelioration of heart fibrosis. Diabetic CD-1 mice exhibited deficiency in myocardial stripe structure and endothelial damage in electron microscopy; LINA normalized all. When necroptosis was evaluated by associated kinases, RIP3 and MLKL, diabetic CD-1 mice were exhibited a strong RIP3 and MLKL mRNA and protein expression levels in myocyte; LINA suppressed RIP3 and MLKL levels in myocyte.

Conclusion: These results indicated that LINA restored cardiac structure associated with suppression of necroptosis in type 1 diabetic mice.

Disclosure

T. Hirai: None. Y. Takagaki: None. K. Kanasaki: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Toyama Pharmaceutical. D. Koya: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd.

Funding

Japan Society for the Promotion of Science
472-P: Associations between Ankle Brachial Index, Diabetes, and Sleep Apnea: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Database
Authors: ALSHEHRI MOHAMMED M. , ALQAHTANI ABDULFATTAH S. , ALENAZI AQEEL M. , ALOTHMAN SHAIMA , ALDHAHI MONIRA , GRAY COREY M. , ALQAHTANI BADER , KLUDING PATRICIA
Published: June 2019

Introduction: Sleep apnea and diabetes mellitus (DM) negatively impact cardiovascular health. One important indicator of cardiovascular health is the Ankle-Brachial Index (ABI). Either low (LABI) or high (HABI) are signs of peripheral vascular impairment. Impaired vascular health and DM, together, might provoke sleep apnea; however, information regarding these relationships is limited. Therefore, this study aimed to investigate the association between ABI, DM status, and severity of sleep apnea in people of Hispanic/Latino descent.

Methods: A cross sectional analysis from a multi-center epidemiologic study, HCHS/SOL‎, was utilized, including 8,378 participants (mean age 45.92?±?13.96, female = 49%, mean BMI=30.06?±?5.55). The sample was divided into 6 groups based on ADA guidelines (no-DM or DM) and ABI categories (LABI, normal ABI, or HABI). A linear regression was used to determine the strength of association between groups to predict the severity of sleep apnea, measured by the Apnea-Hypopnea Index (AHI). A Kruskal-Wallis H test was used for AHI comparisons between groups. Significance level was set at 0.01.

Results: There were significant differences between groups for mean AHI (P<0.001; no-DM+normal ABI= 19.28±16.57, DM+normal ABI = 26.85?±?21.87, no-DM+LABI = 17.63?±?18.22, DM?+LABI = 26.31?±?21.62, no-DM?+HABI = 27.12?±?19.82, and DM?+HABI = 33.0?±?22.01). Linear regression ?showed that DM and HABI was significantly associated with severe sleep apnea (β= 5.7, p=0.007) after controlling for age, waist-hip ratio, and Statin medication.

Conclusion: ?These data suggest that ?people with DM and HABI were more likely to have severe apnea compared to the other groups. People with DM, HABI, and severe sleep apnea might be at higher risk of cardiovascular complications. Thus, further research is required to elucidate the appropriate intervention to combat the high level of Peripheral artery disease.

Disclosure

M.M. Alshehri: None. A.S. Alqahtani: None. A.M. Alenazi: None. S. Alothman: None. M. Aldhahi: None. C.M. Gray: None. B. Alqahtani: None. P. Kluding: None.
478-P: Accelerating Atherosclerosis by Autoimmune Process in Nonobese Diabetic Mice Made ApoE Deficient by CRISPR/Cas9 Gene Editing
Authors: PARK KYOUNGMIN , LI QIAN , WANG HAIYAN , ST-LOUIS RONALD , YOKOMIZO HISASHI , MADDALONI ERNESTO , SHINJO TAKANORI , FU JIALIN , WU I-HSIEN , KISSLER STEPHAN , KING GEORGE L.
Published: June 2019

Although metabolic risk factors that accelerate atherosclerosis are shared between people with type 1 (T1D) and 2 (T2D) diabetes, it remains unknown whether autoimmunity in T1D contribute to cardiovascular pathologies, which have been reported for other autoimmune diseases. In order to determine the role of autoimmunity with and without overt diabetes, we generated ApoE deficient NOD (ApoE-/--NOD) mice by CRISPR/Cas9 gene editing. The ApoE-/- NOD mice spontaneously developed autoimmune diabetes and atherosclerosis. We also generated congenic ApoE-/--NOD mice that do not carry a protective MHC class II allele (CongNOD), and these mice are prone to atherosclerosis but do not develop insulitis or diabetes to control for the effects of the NOD background independently of autoimmunity. ApoE deficiency in NOD mice was ascertained by PCR and DNA sequencing in both ApoE-/--NOD mice and ApoE-/--CongNOD mice The ApoE protein expression levels in the liver and plasma of ApoE-/--NOD mice was also confirmed by immunoblot analysis and ELISA. Female and male ApoE-/--NOD mice exhibited diabetes frequencies (blood glucoses >500 mg/dL) of 70% and 25%, respectively. Histological analysis of pancreatic islets sections by H&E staining showed peri-insulitis (25%) and insulitis (75%), similar rates as hyperglycemia in NOD mice. Nondiabetic ApoE-/--NOD mice developed more severe atherosclerosis than ApoE-/--CongNOD mice after fed Western diet (6% vs. 1.5% plaque, P<0.01). Preliminary studies showed that greater extent of atherosclerosis was observed in diabetic ApoE-NOD than nondiabetic ApoE-/-NOD mice by 3.2 folds. Total plasma cholesterol (884mg/dL vs. 945mg/dL) and triglyceride (185mg/dL vs. 211mg/dL) levels were high but not significant different between ApoE-/--NOD mice and ApoE-/--CongNOD mice on either a regular diet or WD. These studies indicate that T1D autoimmunity with or without hyperglycemia can exacerbate the development of atherosclerosis.

Disclosure

K. Park: None. Q. Li: None. H. Wang: None. R. St-Louis: None. H. Yokomizo: None. E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc., Pikdare. T. Shinjo: None. J. Fu: None. I. Wu: None. S. Kissler: None. G.L. King: Research Support; Self; Sanofi.

Funding

Sanofi-Aventis; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053105-17)
48-LB: Long-Term A1C Benefit from Using One Drop
Authors: HIRSCH ASHLEY , OSBORN CHANDRA Y. , HEYMAN MARK , HUDDLESTON BRIAN , DACHIS JEFF
Published: June 2019

One Drop (OD) provides self-care support via an evidence-based mobile app, a Bluetooth-connected glucometer and testing supplies, and in-app coaching from CDEs. The app with coaching is associated with a 0.9 to 1.3% lab hemoglobin (A1c) improvement over 3 months. The full solution is associated with a 1.9% eA1c improvement over 3 months. We enrolled people with diabetes to participate in an IRB-approved study examining OD’s long-term effect on A1c. Adults with lab-verified ≥ 7.0% A1c and no prior OD account participated in a single-group longitudinal study. Participants used OD for an average 7.7 months. Lab A1c was assessed at baseline, 3, and 8 months. Descriptive statistics characterized the sample. Repeated measures ANOVA tested A1c change over time. Bonferroni-corrected post hoc tests examined A1c change between timepoints. Participants (N = 10) were 53 ± 7 years old and half female. Sphericity was assumed (Mauchly’s W = .30, p = .05). A1c significantly changed over time, F(2, 12) = 5.62, p < 0.019, partial eta = .48 (see Figure 1). When adjusted for multiple comparisons, baseline to 3-mo A1c change (MDiff = .64%, p = .10) and 3-mo to 8-mo Alc change trended significant (MDiff = 1.74 %, p = .10). Using OD for up to 8 months is associated with improved A1c. This is the first OD study to observe participants beyond 3 months and collect multiple measures of lab A1c over time. An accumulation of non-experimental and experimental evidence suggests OD improves A1c among people with diabetes.

Disclosure

A. Hirsch: Employee; Self; Informed Data Systems Inc. Research Support; Self; Fitbit, Inc., MannKind Corporation. Stock/Shareholder; Self; Informed Data Systems Inc. C.Y. Osborn: Employee; Self; One Drop. M. Heyman: Consultant; Self; Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Tandem Diabetes Care. Employee; Self; One Drop. B. Huddleston: Employee; Self; One Drop. J. Dachis: Stock/Shareholder; Self; Informed Data Systems Inc.
49-LB: Reported Utility of Automated Blood Glucose Forecasts
Authors: GOLDNER DANIEL R. , HEYMAN MARK , HIRSCH ASHLEY , OSBORN CHANDRA Y. , LUBLING OZ , HUDDLESTON BRIAN , VLAHA RICHARD L. , PRENGER KAI , MURTHY RAGHU , STARKE JEFFREY , BRICENO JHONATHAN , LEDVINA DINAH , DACHIS JEFF
Published: June 2019

Background: A growing number of people use apps to track diabetes data and identify retrospective patterns that can inform management behavior. In September 2018, One Drop launched Automated Decision Support, which predicts blood glucose 8 hours in the future for non-insulin-dependent users with type 2 diabetes (T2D). Predictions help inform diabetes decision-making prospectively, but only if users find them useful.

Objective: To understand how predictive insights facilitate behavior change in people with T2D, One Drop collected feedback from users and trained a machine learning model to predict when forecasts would be perceived as useful. This model was used to select timing and content of future forecasts and accompanying support messages. We then measured changes in feedback to assess forecast utility.

Methodology: An initial sample of 23,876 forecasts were sent via in-app notifications to 4679 users with T2D. Forecasts consisted of BG trend, duration, and level (“rising, but not too high, over the next 3 hours”) and, when appropriate, a support message relevant to forecast and user history. Forecast delivery was random, triggered with 50% probability when information was logged, no more than once/day/user.

Forecasts could be rated “Useful” or “Not Useful.” A machine learning model, trained on the initial sample, predicted the probability of each type of feedback. A second sample of 28838 forecasts were sent to 5506 users, with probability of usefulness determined by the model.

Results: In the 1st sample, 42.8% of forecasts received feedback from 69.6% of users; 87.1% was “Useful.” In the 2nd sample, 63.7% of forecasts received feedback from 67.1% of users; 92.4% was “Useful.”

Discussion: A new machine learning model tailored forecast delivery, reducing the “Not Useful” rate by 41.1% (from 12.9% of feedback to 7.6%). Correlations between useful forecasts and behavior change will be explored in future work.

Disclosure

D.R. Goldner: Employee; Self; One Drop. Stock/Shareholder; Self; One Drop. M. Heyman: Consultant; Self; Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Tandem Diabetes Care. Employee; Self; One Drop. A. Hirsch: Employee; Self; Informed Data Systems Inc. Research Support; Self; Fitbit, Inc., MannKind Corporation. Stock/Shareholder; Self; Informed Data Systems Inc. C.Y. Osborn: Employee; Self; One Drop. O. Lubling: Employee; Self; One Drop. B. Huddleston: Employee; Self; One Drop. R.L. Vlaha: Employee; Self; One Drop. K. Prenger: Employee; Self; One Drop. R. Murthy: Employee; Self; One Drop. J. Starke: Employee; Self; One Drop. J. Briceno: Employee; Self; One Drop. D. Ledvina: Employee; Self; One Drop. J. Dachis: Stock/Shareholder; Self; Informed Data Systems Inc.
493-P: Synchrotron Radiation Micro-CT Reveals Glomerular Loss without Glomerular or Renal Hypertrophy in Streptozotocin-Induced Type 1 Diabetic Mice
Authors: TAKIYAMA YUMI , SERA TOSHIHIRO , NAKAMURA MASANORI , BESSHO RYOICHI , TAKIYAMA TAKAO , OTA TSUGUHITO , HANEDA MASAKAZU
Published: June 2019

The glomerular number and size are major factors in predicting outcomes in renal disease. We have recently established synchrotron radiation microcomputed tomography (SRµCT) imaging of the glomeruli in perfused kidneys, and reported the glomerular and renal hypertrophy, but not glomerular loss in obese type 2 diabetic db/db mice. To visualize pathophysiological basis of diabetic kidney of type 1 diabetes, we here explored SRµCT imaging of the glomeruli in streptozotocin-induced type 1 diabetic male mice (STZ mice) and of control male C57BL/6J mice (control mice). STZ mice at the age of 22 weeks significantly showed hyperglycemia and elevated urinary albumin excretion, but not hypertension or body weight changes compared to control mice. There was approximately 22% loss of the total glomerular number (Nglom) of STZ mice compared to that of control mice (p<0.001). STZ mice had fewer glomerular number in all renal cortical zone of the whole kidney than control mice (p=0.003). However, type 1 diabetes had no impact on the mean glomerular volume (Vglom), coefficient of variation (CV; SD/mean) of glomerular volume, and renal volume (Vkidney) (Vglom, p=0.149; CV, p=0.591; Vkidney, p=0.093 vs. control mice, respectively). Nglom was significantly correlated with body weight (r=0.458, p=0.032), blood glucose levels (r=-0.623, p=0.002) or HbA1c (r=-0.530, p=0.011). Vglom was correlated with Vkidney (r=0.622, p=0.002) by each other. Multivariate regression analysis with the stepwise forward method identified blood glucose (β=-0.665, p<0.001) and systolic blood pressure (β=-0.499, p=0.001) as significant independent determinants of Nglom. Our study, for the first time, demonstrated a significant reduction of the total glomerular number in STZ mice, without affecting the glomerular volume or renal volume. These results indicate the glomerular pathology markedly differs between type 1 and type 2 diabetes.

Disclosure

Y. Takiyama: None. T. Sera: None. M. Nakamura: None. R. Bessho: None. T. Takiyama: None. T. Ota: None. M. Haneda: None.
5-OR: Cardioprotective Effect of Luseogliflozin in Patients with Type 2 Diabetes and Established Cardiovascular Disease
Authors: INA YUJIRO , KISHI TAKUYA , SEKIGUCHI NAOTAKA , SAKANE NAOKI
Published: June 2019

Recent published CV outcome trials have revealed that sodium-glucose cotransporter-2 inhibitors (SGLT2i) significantly reduced the combined CV endpoint and incidences of heart failure-associated hospitalizations in patients with type 2 diabetes mellitus (T2DM) and CV disease (CVD). However, detailed mechanisms of the benefits by SGLT2i still remain unknown. Especially, nobody can show the consensus opinion in the mechanistic effects of SGLT2i on the left ventricular (LV) diastolic dysfunction associated with T2DM. We focused the spectral tissue Doppler-derived E/e' ratio, which has been validated in simple and reproducible noninvasive assessment of LV diastolic pressures independent of rhythm, and evaluated whether or not the treatment of SGLT2i, luseogliflozin, used for 6 months could affect cardiac function in 25 patients with T2DM and CVD. Luseogliflozin used for 6 months significantly reduced HbA1c levels (8.2 ± 1.2% to 7.4 ± 0.6%, p < 0.01) and systolic blood pressure (SBP)(125.6 ± 18.1 mmHg to 119.3 ± 16.8 mmHg, p = 0.04) compared to baseline levels. Moreover, luseogliflozin also significant reduced left atrial (LA) (42.2 ± 5.7 mm to 39.9 ± 6.8 mm, p = 0.01) and LV diameters (diastolic, 49.5 ± 6.9 mm to 47.6 ± 7.6 mm, p = 0.01; systolic, 35.8 ± 9.1 mm to 33.9 ± 9.8 mm, p < 0.01). Remarkably, early annular tissue Doppler (e’) velocity and peak early diastolic velocity/basal septal diastolic velocity (E/e’) ratio were significantly improved, and these benefits were augmented in the group of e’< 6.0cm/sec of baseline (e’ velocity, 4.8 ± 0.6 cm/sec to 5.8 ± 0.9 cm/sec, p < 0.01; E/e’ ratio, 13.0 ± 4.9 to 10.9 ± 3.4, p = 0.03, respectively). There was a significant negative correlation between the changes in E/e’ ratio and baseline of E/e.’ These results indicated that lusegliflozin improved hemodynamics associated with LV diastolic function in the patients with T2DM and CVD, and support the cardio-protective effects of SGLT2i of T2DM with CVD.

Disclosure

Y. Ina: None. T. Kishi: None. N. Sekiguchi: None. N. Sakane: Board Member; Spouse/Partner; Kao Corporation.
503-P: Inhibition of Glucose Transporter 9 Increases Serum Uric Acid Level but Attenuates Renal Albumin Excretion in Streptozotocin-Induced Diabetic Rats: A Role of Hepatic Uric Acid Metabolism
Authors: CHEN CHUPING , RAN JIANMIN , ZHANG RUYI , CHEN GUANGSHU , ZHU PING , QIU JINGXIAN , TAN RONGSHAO , LIU YAN
Published: June 2019

Background: In previous studies, we confirmed that endogenous uric acid (UA) formation increases in the streptozotocin (STZ)-induced diabetic rats with renal injury. Yet changes of renal UA reabsorption and hepatic UA metabolism remain unclear in this model.

Methods: STZ-induced diabetic rats and control rats were treated with benzbromarone (BZ), a glucose transporter 9 (GLUT9) inhibitor for 8 weeks. At baseline, 4 and 8 weeks after BZ treatment, blood samples were collected for fasting blood glucose (FBG), serum uric acid (SUA), serum creatinine (SCr), and blood urea nitrogen (BUN). Simultaneous urinary samples were tested and daily urinary amount of albumin (UAE), uric acid (UUA), creatinine (UCR), urea nitrogen (UUN) were calculated. Gene expressions of GLUT9, xanthine oxidase (XO), urate transporter 1 (URAT1) in the kidney and GLUT9, XO as well as uricase in the liver were detected by RT-PCR.

Results: 1) Compared with normal rats, FBG, BUN, UUN, UAE and UUA were significantly increased, while SUA was significantly decreased in diabetic rats, while SCr and UCR levels were compared. Treatment with BZ did not change FBG in both rats. BZ significantly decreased SCr, BUN and UAE levels but increased SUA in diabetic rats. 2) In the kidney, expression of GLUT9 and XO was increased, while URAT1 was not altered in diabetic rats if compared with control rats. BZ treatment exerted no any effects on gene expression of GLUT9 and XO. 3) In the liver, gene expression of XO and uricase was compared between diabetic and normal rats, while GLUT9 was significantly upregulated in diabetic rats. BZ treatment remarkably inhibited GLUT9 expression but left XO and uricase unchanged in diabetic rats.

Conclusions: 1) Inhibition of hepatic GLUT9 in STZ-induced diabetic rats increased SUA indicates that GLUT9 pathway for UA metabolism is critical in this model. 2) BZ treatment attenuates urinary albumin excretion in diabetes.

Disclosure

C. Chen: None. J. Ran: None. R. Zhang: None. G. Chen: None. P. Zhu: None. J. Qiu: None. R. Tan: None. Y. Liu: None.
504-P: TGF-ß1 and VCAM-1 as Early Diagnostic Biomarkers of Diabetic Kidney Disease Progression
Authors: DARIA CHUB , PERTSEVA NATALIIA
Published: June 2019

Aim: To evaluate the significance of using transforming growth factor beta 1 (TGF-β1) and vascular adhesion molecule -1 (VCAM-1) as early prognostic markers of diabetic kidney disease (DKD) progression in patients with DM type 1 and 2.

Materials and Methods: The study included 66 patients with T1DM, 58 with T2DM and 20 healthy volunteers. Diabetic patients were divided into three groups depending on the estimated glomerular filtration rate. All patients were equal for age and sex. The endothelial function was determined by TGF-β1 and VCAM-1 levels. Recognitive Operating Characteristic - was used to assess the discrimination ability (diagnostic test value) to be a predictor of DKD progression.

Results: Patients of all study groups had significantly higher (p˂0,05) levels of TGF-b1 and VCAM-1 versus control group. That’s present endothelial dysfunction in DM patients. The diagnostic value of TGF-b1 and VCAM-1 was compared with diagnostic value of AU. The highest test’s sensitivity and specificity has TGF-b1, its predictive ability concerning DKD progression can be assessed as “excellent” for both types of DM (Se = 100.0; Sr = 100.0; AUC = 1.000; p < 0.001). VCAM-1 has “excellent” operating characteristics for predicting DKD progression in T2DM (Se = 100,0; SP = 88,89; AUC = 0,923; p <0.001) and “very good” in T1DM (Se = 86,36; Sp = 90.48; AUC = 0.866; p <0.001). AU has “good” operating characteristics concerning DKD progression: Se = 57,50; Sd = 97.44; AUC = 0.785; p <0,001 for type1 and 2 DM. That’s shows us evaluation of AU in DM has a high specificity, but low sensitivity of the prognosis DKD progression for both types of DM.

Conclusion: We provide evidences that TGF-β1 and VCAM-1 can be used for prediction of DKD progression in patients with type 1 and type 2 DM. Diagnostic capabilities of VCAM-1 and TGF-β1 significantly exceed the diagnostic capabilities of AU, which determines them as early markers.

Disclosure

C. Daria: None. N. Pertseva: None.
508-P: Gemigliptin Ameliorates Renal Fibrosis by Attenuating NLRP3-Mediated Inflammation in a Murine Model
Authors: JUNG GWONSOO , CHOI YEON-KYUNG , SEO JUNG BEOM , PARK SUNG DON , KIM NAYOUNG , KIM MIN-JI , KIM JUNG-GUK , LEE IN-KYU , PARK KEUN-GYU
Published: June 2019

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although activation of NOD-like receptor protein 3 (NLRP3) inflammasome has been reported to play an important role in the progression of renal fibrosis, the relevance of DDP-4 inhibitor to NLRP3 inflammation on its ameliorating effect on renal fibrosis has not been fully studied. The aim of this study was to investigate the association of renoprotective effect of gemigliptin with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.

Methods: We evaluated the effects of gemigliptin on renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. We quantitated levels of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment through immunohistochemical and western blot analysis. In human kidney tubular epithelial HK-2 cells, we defined the effect of gemigliptin on TGF-β-stimulated production of profibrotic proteins.

Results: We observed that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, caspase-1, ASC, and IL-1β, which had all been clearly increased by UUO. Furthermore, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin.

treatment. Additionally, gemigliptin treatment attenuated phosphorylated NF-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.

Conclusion: The present study demonstrated that the renoprotective effect of gemigliptin is associated with amelioration of NLRP3 inflammasome.

Disclosure

G. Jung: None. Y. Choi: None. J. Seo: None. S. Park: None. N. Kim: None. M. Kim: None. J. Kim: None. I. Lee: Board Member; Self; NovMetapharm Co, Inc. K. Park: None.

Funding

National Research Foundation of Korea
509-P: Utility of Serum Cystatin C in Early Kidney Dysfunction in Prediabetics
Authors: BRANDA JULIA I.F. , ALMEIDA BIANCA , VIVOLO SANDRA R.G.
Published: June 2019

Background: Serum cystatin C (sCys C) has been proposed as a marker of kidney function with advantages compared to creatinine. It is unclear whether renal damage begin in prediabetes (PDM), when sCys C could be a promisor marker of early kidney dysfunction. We investigated whether sCys C differed between normoglycemic (NG) and PDM subjects and contributed to the detection of kidney dysfunction.

Methods: A cross-sectional analysis of 947 nondiabetic participants (mean age 45.7 years) from the Brazilian Longitudinal Study of Adult Health was performed. sCys C (determined by ELISA) and CKD-EPI eGFR were compared between NG and PDM (fasting plasma glucose: 100-125 mg/dL or 2-hour post-load: 140-199 mg/dL or A1c: 5.7-6.4%). PDM were stratified in 4 groups according to altered sCys C and albumin excretion rate (AER): normal sCys C and AER (G1), abnormal sCys C and normal AER (G2), normal sCys C and abnormal AER (G3) and abnormal sCys C and AER (G4) were compared using ANOVA.

Results: PDM subjects (n = 671) had anthropometric and biochemical data higher than NG (n=276), higher sCys C levels [0.67 (0.41-0.95) vs. 0.48 (0.31-0.81), p<0.001] and lower eGFR (96.3±17.4 vs. 100.6±17.1 mL/min/1.73m2, p<0.001). In eGFR categories (60-<90, 90-<125 and ≥125 mL/min/1.73m2), sCys C were always higher in PDM subjects than in NG. Comparing NG individuals, hyperfiltrants had lower sCys C than normofiltrants (p=0.03) but not than mildly reduced eGFR individuals (p=0.12). Considering the PDM groups, eGFR gradually dropped from G1 to G4 (96.8±17.4 vs. 96.2±16.9 vs. 94.0±17.2 vs. 77.2±25.4 mL/min/1.73m2, p-trend = 0.06) and, as expected, mean eGFR in G4 was lower than in G1 (p=0.017).

Conclusion: Our data confirmed that sCys C is increased in PDM. Reduced sCys C only in NG hyperfiltrant subjects could suggest an inability of hyperfiltrant PDM to excrete Cys C. No statistical evidence that sCys C could be an early marker of kidney dysfunction in prediabetes was found; prospective studies should address its utility to detect dysfunction before AER elevation.

Disclosure

J.I.F. Branda: None. B. Almeida: None. S.R.G. Vivolo: None.
51-LB: The Impact of Digital Health Coaching on the Diabetes Distress Scale (DDS)
Authors: ALLISON MATTHEW , SRIVASTAVA UMA , BURTON STEPHEN BILLY , RASULNIA MAZI , PATEL DHIREN
Published: June 2019

The ADA’s recent release of the Standards of Medical Care in Diabetes recommends including technology-based methods for the delivery of effective diabetes self-management education and support. Self-management of diabetes involves meal planning, taking medications, blood glucose monitoring, physical activity, coordinating care, and others. The program developed by Pack Health addresses all of the tasks above and more through a structured 12-week program, evidence-based tools, and a non-prescriptive Health Advisor. The program has over 60 proactive outbound touchpoints that originate from the Health Advisor (via text messages, emails, and/or phone calls). The Pack Health program collects and utilizes patient-reported outcomes (PROs) along with clinical measures, self-reported by patients. All data is used for coaching sessions and evaluation purposes.

This study examines the impact of Digital Health Coaching on a national diabetes population (n=198) and an African American sub-population (n=57) enrolled in the South (AL, GA, FL, MS) upon completion of the initial 12-weeks of engagement. The DDS is a 17-item scale that captures four critical dimensions of distress: emotional burden, regimen distress, interpersonal distress and physical distress. DDS score benchmarks are established at little to no diabetes distress (<2.0), moderate diabetes distress (2.0-2.9), high diabetes distress (≥3.0). Health coaching demonstrates the following impact:

National Diabetes Population:

Baseline: 3.0; Post: 2.2; Improvement: 0.8

African Americans in the South:

Baseline: 3.0; Post: 2.1; Improvement: 0.9

The data above emphasizes that digital coaching program can have a significant impact on Diabetes Distress for a general population and African American population in the South.

Disclosure

M. Allison: None. U. Srivastava: None. S.B. Burton: None. M. Rasulnia: None. D. Patel: None.
51-OR: Medios—A Smartphone-Based Artificial Intelligence Algorithm in Screening for Diabetic Retinopathy
Authors: SOSALE BHAVANA , SOSALE ARAVIND R. , MURTHY HEMANTH , NARAYANA SRIKANTH , SHARMA USHA , GOWDA SAHANA G.V. , NAVEENAM MURALIDHAR
Published: June 2019

Background: Pupil dilatation, access to ophthalmologists, size and cost of fundus cameras, and network connectivity issues are barriers to diabetic retinopathy (DR) screening in primary care. This makes artificial intelligence a potential alternative in DR screening. This study aims to evaluate the performance of an offline AI algorithm - Medios in DR Screening using non mydriatic retinal images taken from the smartphone based Remidio Fundus on Phone (NM-FOP) retinal camera.

Methods: Non mydriatic retinal images from 900 patients with diabetes were captured prospectively with the Remidio NM FOP camera at Diacon Hospital, Bangalore, India. The images were graded by 5 ophthalmologists as per the International Diabetic Retinopathy Classification System and the majority diagnosis was considered as the ground truth. Two images [posterior pole (macula centered), nasal field] were captured per eye for each patient, and were analyzed offline on-device using the Medios AI. The diagnosis of Medios AI was compared to that of the ophthalmologist.

Results: DR was present in 252 patients. Performance of the AI for referable DR (Moderate NPDR or worse, or presence of DME) was - Sensitivity 93% (95% CI 91.3%-94.7%), Specificity: 92.5% (95% CI 90.8%-94.2%). Performance of the AI for all DR (Mild NPDR or worse, or presence of DME) was - Sensitivity: 83.3% (95% CI 80.9%-85.7%), Specificity: 95.5% (95% CI 94.1%-96.8%). Sensitivity for sight threatening DR (STDR) [severe NPDR, proliferative DR (PDR) or presence of DME] was 95.2% (95% CI 88.2%-98.6%). The 3 PDRs missed by the AI were post laser with no active changes visible. This is a common exclusion criteria in other studies, and when excluded, the sensitivity for STDR was found to be 98.7%.

Conclusion: This is one of the largest studies evaluating the performance of AI using non mydriatic retinal images offline. The Medios AI algorithm’s sensitivity and specificity exceeds the FDA mandated superiority end point and can be used for DR screening.

Disclosure

B. Sosale: None. A.R. Sosale: None. H. Murthy: None. S. Narayana: None. U. Sharma: None. S.G.V. Gowda: None. M. Naveenam: None.
518-P: Involvement of Low-Density Lipoprotein Receptor-Related Protein 5 in Chronic Kidney Diseases via Modulation of TGF-β-Smad2/3 Signaling
Authors: HE XUEMIN , CHENG RUI , HUANG CHAO , CHEN YANMING , MA JIAN-XING
Published: June 2019

Aims: Low-density lipoprotein receptor-related protein 5 (LRP5) is known as a co-receptor of canonical Wnt signaling. This study aimed to investigate LRP5’s role in chronic kidney diseases including diabetic and obstructive nephropathies, and its new role in regulating TGF-β-Smad2/3 signaling in renal fibrogenesis.

Methods: The expression of LRP5 was examined in the kidneys of Akita mice, db/db mice and mice with obstructive nephropathy. The regulation of TGF-β signaling by LRP5 was determined in both obstructed kidneys and in human proximal tubule epithelial cells exposed to TGF-β1. Interaction of LRP5 with TGF-β receptors was evaluated by Co-IP assays, immunostainings and cell fractionation.

Results: We found that LRP5 levels were substantially up-regulated in the renal tubules of diabetic mice and mice with obstructive nephropathy. In the obstructed kidneys, Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and attenuated the increases of TGF-β1 and TGF-β receptors (TβRI and TβRII), without affecting canonical Wnt signaling. Utilizing SBE-Luc reporter mice and immunostaining assays, LRP5 depletion was demonstrated to attenuate the activation and nuclear translocation of Smad2/3, whereas LRP5 overexpression enhanced TGF-β-Smad2/3 signaling in tubule epithelial cells. Obstruction-induced LRP5 and TβRI were co-localized in the injured tubules, and furthermore, LRP5 was co-precipitated with TβRI and TβRII. The extracellular domain of LRP5 was essential for its association with TGF-β receptors and profibrotic activity. In addition, LRP5 stabilized TGF-β receptors, increased their membrane presentation in the absence of TGF-β1, and promoted the TGF-β1-induced formation of TβRI/TβRII heterodimers and internalization of these receptors.

Conclusion: These findings reveal a novel profibrotic activity of LRP5 by interacting with TGF-β receptors, independent of canonical Wnt signaling.

Disclosure

X. He: None. R. Cheng: None. C. Huang: None. Y. Chen: None. J. Ma: None.