bluuebunny/crossref_metadata_2025 huggingface dataset:
240-OR: Impact of Insulin Treatment on Primary Outcomes in Cardiovascular Outcome Trials
Authors: KHATIB JOANNA , SHAO YIXUE , SHI LIZHENG , FONSECA VIVIAN
Published: June 2019

Objective: Several Cardiovascular Outcome Trials (CVOTs) have demonstrated benefits compared to placebo. However, the patients included were heterogeneous, including several with long duration diabetes, insulin treatment may be a surrogate for duration and severity of disease. We conducted a meta-analysis to evaluate the impact of concurrent insulin treatment on the odds of meeting the primary outcome in recent CVOTs.

Methods: PubMed and google scholar were searched for CVOTs with new drugs for diabetes. We found 10 publications, of which 7 provided outcomes according to insulin use. We compared the risk ratio of the primary endpoint in the group taking insulin with those not taking insulin by extracting the number of events in both groups along with total number of patients. We also removed the 2 trials that used dipeptidyl peptidase 4 inhibitors, since none of the drugs had shown benefit in the trials. The I-square was used to assess between-study heterogeneity and all analyses were performed using STATA program version 15.1. Fixed effect models were used in these analyses due to low heterogeneity. This study was conducted in compliance with PRISMA guidelines.

Results: When all 7 trials were included in the meta-analysis (EXSCEL, SUSTAIN6, SAVORTIMI, EMPAREG, LEADER, EXAMINE, and DECLARE), the risk ratio of the primary outcome was significantly increased indicating that patients using insulin with drug are more likely to have the primary cardiovascular outcome than the group of patients using drug without insulin. The RR was 1.43 (95% confidence interval: 1.32, 1.55).

Conclusion: In recent CVOTs which have demonstrated a benefit of the study drug on the primary outcome compared to usual care, the concomitant use of Insulin along with the study drugs led to a higher risk of cardiovascular events than in patients who were on the drugs without insulin. The reason for this increased risk is unclear but may be related to the likely longer duration of diabetes and poorer antecedent control which led to the use of insulin.

Disclosure

J. Khatib: None. Y. Shao: None. L. Shi: None. V. Fonseca: Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Abbott, Asahi Kasei Corporation, Novo Nordisk Inc., Sanofi US, Takeda Pharmaceutical Company Limited. Research Support; Self; Bayer US. Stock/Shareholder; Self; Amgen Inc., BRAVO4HEALTH, Mellitus Health.
2479-PUB: Mesenchymal Stromal Cells Improves Motor Function and Increases Collagen Macromolecular Organization in Muscles of Diabetic Rats
Authors: LUNA GENOVEVA L. , SABADINE MARIA AUGUSTA , ESTRADA-BONILLA YISEL CAROLINA , FREITAS ANÍBAL FERNANDA , LEAL ÂNGELA M.
Published: June 2019

Diabetes mellitus affects the skeletal muscle connective tissue and leads to significant physical performance impairment. The use of mesenchymal stromal cells (MSCs) is an attractive strategy to modify the microenvironment and promote tissue repair and regeneration. Male Wistar rats (225 ± 25 g) were randomly assigned to 3 groups: Control (C), Diabetic (DM) and Diabetic treated with MSCs (DM-MSCs). Diabetes was induced by Streptozotocin (50 µg/kg). Bone marrow cells were isolated from the tibia and femur. After 10 weeks of DM induction, DM-MSC rats received 4 i.p. injections of MSCs (1 x 106). Ten weeks after MSC transplantation motor performance was evaluated by Rota Rod test and the anterior tibial (TA) muscles were collected for morphometric and quantification of collagen birefringence by polarizing microscopy analysis. Statistical significance was set at 0.05. Fasting glycemia was significantly higher and body mass was significantly lower in the Diabetic (DM) and Diabetic treated with MSCs (DM + MSCs) groups compared with control group. Motor performance of the DM group (30.1 ± 9.6 s) was significantly reduced when compared to the C group (727.2 ± 92 s) and increased significantly in DM + MSCs group (786.8 ± 109.5 s). The TA muscle mass was significantly reduced in DM and DM + MSCs groups compared with C group. The muscle fiber cross sectional area followed the same pattern. The connective tissue increased in DM group compared with C group and decreased in DM + MSCs. The percentage collagen birefringence quantified in the connective tissue of the TA muscle decreased significantly in DM group when compared to C group and increased in DM + MSCs group. Motor performance was positively correlated with collagen birefringence (r = 0.83; P < 0.0001) and negatively correlated with percentage of connective tissue (r = -0.94; P < 0.0001). The results indicate that improves both motor function and the collagen macromolecular organization in type 1 DM.

Disclosure

G.L. Luna: None. M.A. Sabadine: None. Y. Estrada-Bonilla: None. F. Freitas Aníbal: None. Â.M. Leal: None.

Funding

Conselho Nacional de Desenvolvimen to Científico e Tecnológico Processo (447518/2014-3)
250-LB: Affinity Purification and Identification of Unique, Shared, Anti-IA-2 B-Cell Clonotypes: A Proteomic Approach to Understanding Pathophysiological Mechanisms Underpinning Humoral Autoimmunity in Type 1 Diabetes
Authors: MENDIS THILINI , WANG JING JING , PIETROPAOLO MASSIMO , JACKSON MICHAEL W.
Published: June 2019

Immune destruction of beta (β) cells is a feature of type 1 diabetes (T1D), yet the pathophysiological role of autoantibodies (Abs) is poorly understood. Recently, proteomic interrogation of Abs indicates that restricted heavy (H) and light (L) chain gene usage underpins targeting of classic autoantigens in systemic autoimmunity. In the current study, we have taken a similar approach to characterise B cell clonotypes resulting in targeting of the major T1D autoantigen, IA-2. Firstly, we developed a novel ELISA assay for the major IA-2 epitopes using an MBP-fusion protein (FP) incorporating intracellular domain of IA-2. We next established ELISA-based affinity purification (AP) method using the IA-2-MBP FP to isolate enriched IA-2 specific Abs from 2 patients with verified (by RSR commercial ELISA) anti-IA-2 autoimmunity. The AP IA-2 Abs were then analysed for Ig H and L chain clonality, variable region gene usage and AA sequence using high-res electrophoretic fractionation and de-novo/database-driven analysis of AA peptides (TripleTOF 5600+ MS). We report the presence of 2 unique Ig Kappa-restricted clonotypes giving rise to IA-2 autoimmunity; namely a IGHV3.23 H chain paired with either a IGKV1.9 or IGKV3.20 L chain. Remarkably, both clones were present in AP Ig from 2 unrelated T1D patients, with shared AA replacement mutations. The Ig signatures were not present in healthy, age/sex matched controls, T1D patients negative for anti-IA-2, or Lupus. These extraordinary findings suggest the pathogenic mechanisms leading to IA-2 autoimmunity may be virtually identical across individuals, leading to the intriguing possibility of intervention in the processes underpinning the disease. Furthermore, the ability to AP and identify genuine human clonal IA-2 Abs will unlock functional studies aimed at establishing the role of these Abs in the pathophysiology of β cell loss.

Disclosure

T. Mendis: None. J. Wang: None. M. Pietropaolo: None. M.W. Jackson: None.
256-LB: Adipose Tissue T-Cells Assume a Dysfunctional Phenotype in Obese Mice and Humans
Authors: PORSCHE CARA E. , DELPROPOSTO JENNIFER , GELETKA LYNN M. , O’ROURKE ROBERT W. , LUMENG CAREY
Published: June 2019

Adipose tissue induced chronic low-grade inflammation is a critical link between obesity and insulin resistance. Despite studies demonstrating the importance of adipose tissue T cells (ATT) in insulin resistance, fundamental gaps in knowledge regarding CD4+ ATT function impedes progress towards understanding their role in diabetes. Little is known about the mechanisms of ATT activation and chemokine profiles. We hypothesized that high fat diet induced obesity would potentiate ATT inflammatory properties. To maximize the viability and number of ATTs in-vitro, T cell activation assays were performed by adding α-CD3/CD28 beads to the entire stromal vascular fraction (SVF). Three days after T cell receptor (TCR) stimulation, supernatants were collected and cells were analyzed using flow cytometry. Surprisingly, ATTs from obese epididymal white adipose tissue had senescent characteristics. Stimulation failed to induce CD25 upregulation, ATT proliferation, or heightened IFNγ and IL-2 secretion, which is seen in lean samples. Human samples collected from diabetic bariatric surgery patients also have an exhausted phenotype unlike nondiabetic controls. Both cell intrinsic and extrinsic factors are implicated in ATT dysfunction. Diabetic humans and mice both have significantly increased expression of the co-inhibitory receptor, PD1, on the cell surface. Despite experiments showing that T cell intrinsic factors, such as major-histocompatibility complex II signals are necessary for ATT dysfunction in obese mice, blocking PD1 fails to rescue this phenotype. Most likely this is due to additional extrinsic factors, since co-culturing lean ATTs in obese SVF results in reduced pro-inflammatory cytokine secretion post-TCR stimulation. Further studies are required to elucidate whether ATT dysfunction is a protective mechanism that reduces inflammation, and whether relieving intrinsic and extrinsic blocks on ATTs results in a more robust inflammatory response and worsened glucose tolerance.

Disclosure

C.E. Porsche: None. J. DelProposto: None. L.M. Geletka: None. R.W. O’Rourke: None. C. Lumeng: None.

Funding

National Institutes of Health (F31DK118811, T32HL125242 to C.E.P.), R01DK090262-06A1 (to C.L.)
269-LB: PVT1 Induces the Insulin Resistance of Obesity-Related Metabolic Diseases via Modulation of Transcription Factor Foxo1 through Binding with PTBP1
Authors: LIN XIHUA , GUI WEIWEI , LI HONG
Published: June 2019

Insulin resistance (IR) is the pathophysiological basis of obesity-related metabolic diseases. PVT1 (Plasmacytoma Variant Translocation-1) has been confirmed to be involved in the occurrence and progression of diabetic nephropathy, but its role and mechanism in IR remain unclear. Our study found that:1)The expression of PVT1 was increased in high-fat diet-induced obese IR mice; 2) Specific overexpression of PVT1 by tissue fixed point injection of adenovirus in epididymal adipose tissue promoted IR in obese DIO mice, increased heterotopic lipid deposition, and damaged liver function; 3) Systemic knockdown of PVT1 by tail vein injection of PVT1 shRNA lentivirus effectively improved the IR status of db/db obesity model mice, reduced lipid deposition, reduced liver weight and alleviated liver function injury; 4) PVT1 activated the transcriptional activity of the transcription factor FoxO1 (Forkhead box protein O1), and regulated its downstream target genes such as PEPCK, G6Pase, Gck and Glut4; 5) Knockdown of PVT1 inhibited IRS-PI3K-Akt insulin signaling pathway by activating the phosphorylation of Akt, thus regulated FoxO1 trans-localization; 6) Biotin-RNA Pull-down assay followed by mass spectrometry detection and combined with the CLIP-seq data of RBP-RNA binding in starBaseV3 database showed that PVT1 combines with PTBP1 (Polypyrimidine tract-binding protein-1), proving that PTBP1 was necessary in the process of PVT1 regulating FoxO1 to improve IR, and exploring its specific molecular regulatory mechanism. To sum up, we hope to elucidate the specific molecular mechanism of the regulation of transcription factor FoxO1 by PVT1 combined with PTBP1, so as to provide a new target for the prevention and treatment of IR.

Disclosure

X. Lin: None. W. Gui: None. H. Li: None.

Funding

National Natural Science Foundation of China
280-OR: Machine Learning to Predict Hypoglycemic Events from Continuous Glucose Monitoring Data
Authors: AGRAWAL PRATIK , CAO LINGTAO , CHANG YUAN-CHI , JACKSON GRETCHEN P. , KEFAYATI SARAH , PAVULURI VENKATA , SATHE SAKET , TURAGA DEEPAK S. , NGUEYEP RODRIGUE , VITKIN EDWARD , VU LONG , ZHONG YUXIANG
Published: June 2019

Introduction: Hypoglycemia is a potentially life-threatening complication of diabetes that can result in seizures, coma, and death, if left untreated. We have built a machine learning system that can predict occurrences of low glucose events from continuous glucose monitoring (CGM) data within 2 to 4 hours before an event.

Methods: IBM Research scientists developed a machine learning system based on a random forest model to predict from data, provided by Medtronic Guardian™ Connect CGM, whether or not a patient’s glucose level will fall below 70 mg/dl, which was defined as a hypoglycemic event. The model was built based on de-identified data collected from voluntary uploads that measured sensor glucose (SG) levels of users every 5 minutes. The system employed 120 million SG data points collected across many years from approximately 10,000 patients. All the patients in the data set were type 1 diabetics who had used a CGM device for at least 11 days and for a median of 272 days. The training features of the ensemble classifier were extracted from the users’ temporal glucose measurements and past event patterns. This was engineered to account for short- and long-term effects of glucose and seasonal elements observed in multiple patients. The random forest method was selected for its robustness, its accuracy, and its ease of maintenance. The data were divided into 80% training and 20% holdout test sets. The model performance was assessed by area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the lead time, which is the time elapsed between the first alert and the time of occurrence of the predicted event.

Results: The model performed with AUC of 0.9, and it is capable of alerting patients more than an hour lead time in 80% of events.

Conclusions: Managing and avoiding hypoglycemia is significant challenge for patients. Systems using modern machine learning techniques have the potential to improve the care of individuals with diabetes and reduce life-threatening complications for these patients.

Disclosure

P. Agrawal: Employee; Self; Medtronic MiniMed, Inc. Stock/Shareholder; Self; Medtronic. L. Cao: None. Y. Chang: None. G.P. Jackson: Employee; Self; IBM. S. Kefayati: None. V. Pavuluri: None. S. Sathe: None. D.S. Turaga: Other Relationship; Self; Medtronic. R. Ngueyep: None. E. Vitkin: Employee; Self; IBM. L. Vu: None. Y. Zhong: None.
291-LB: Long Noncoding RNA H19 Improves Insulin Resistance in Skeletal Muscle by Regulating Heterogeneous Nuclear Ribonucleoprotein A1
Authors: LIN XIHUA , GUI WEIWEI , LI HONG
Published: June 2019

Skeletal muscles play a pivotal role in glucose and lipid metabolism, and it has become a consensus that impaired lipid metabolism leads to ectopic lipid accumulation in skeletal muscles, which ultimately causes systematic insulin resistant. Previous reports have shown that down-regulation of long non-coding RNA(lncRNA) H19 in skeletal muscle impairs glucose metabolism. To better understand the impact of H19 on insulin resistance, here we focused on the relationships between H19 and fatty acid metabolism in skeletal muscle. In our research, decreased H19 expression was found in skeletal muscle of db/db mice compared with db/m mice. In vivo overexpression of H19 via injection of recombinant H19-adenovirus by tail-vein in db/db mice significantly improved glucose tolerance, lowered serum insulin, TG and skeletal muscle TG levels, which were consistent with improved skeletal muscle H&E and oil red staining contrast to vehicle-treated db/db mice, indicating that overexpression of H19 in db/db mice ameliorated ectopic lipid accumulation in skeletal muscle. As expected, similar effects were observed in vitro. Overexpression of H19 in muscle cells treated with palmitate acid reduced lipid contents,promoted mitochondrial synthesis and ATP productions,and increased the expression of fatty acid oxidation related genes and mitochondrial respiratory chain complexes.Finally, it was drawn from RNA pull-down and RIP that heterogeneous nuclear ribonucleoprotein A1(hnRNPA1)is the target gene of H19, whose function in mitochondria has not been reported yet. Furthermore, we identified PGC1a and CPT1b were among the target genes of hnRNPA1 by searching widely used bioinformatics databases and preliminary RIP validation. Based on these results, we put forth our hypothesis that lncRNA H19 could improve insulin resistance by promoting mitochondrial biosynthesis and fatty acid oxidation in skeletal muscle, through regulating hnRNPA1.

Disclosure

X. Lin: None. W. Gui: None. H. Li: None.

Funding

National Natural Science Foundation of China (81873653)
306-OR: Gene-Environment Interactions for Type 2 Diabetes in UK Biobank
Authors: NAG ABHISHEK , MAHAJAN ANUBHA , MCCARTHY MARK
Published: June 2019

Diet and lifestyle-related obesogenic environmental factors influence type 2 diabetes (T2D) risk, but there is little evidence that gene-environment (GxE) interactions underlie T2D susceptibility. We investigated whether obesogenic environmental factors (which, of course, are themselves partly genetic) interact with T2D-associated genetic variants to accentuate T2D risk using 375,736 unrelated European subjects from UK Biobank (16,430 T2D cases, 359,306 controls). We captured individual genetic risk of T2D with a weighted genetic risk score (T2D-GRS) based on 403 established T2D-associated variants from European-ancestry GWAS. We also constructed six distinct partitioned GRSs by classifying T2D-associated variants based on their likely pathophysiological mechanism (related to e.g., adiposity (T2D-GRSadiposity), beta-cell function, insulin action, mixed features). A logistic regression model was fitted to test for interactions between each GRS and environmental factor (duration and frequency of moderate/vigorous physical activity, sedentary lifestyle, MET, alcohol intake, dietary fat content, Townsend deprivation index (TDI), daytime nap and depression) on T2D, adjusted for age, sex, genotyping array and ethnic background (10 principal components). There was no evidence of statistically-significant interaction between any of the environmental factors and either the combined or partitioned T2D-GRS (p>0.0006, Bonferroni for 77 independent tests). There was suggestive interaction between frequency of alcohol intake and T2D-GRSadiposity on T2D risk (betainteraction=0.08 [95% CI=0.02-0.14]; pinteraction=0.008). These findings stand in contrast with strong interactions between the same environmental factors and T2D-GRSadiposity when using BMI as the outcome (e.g., for TDI, pinteraction=10-17). Our study finds little evidence of substantial interaction between individual T2D genetic risk profiles and obesogenic environmental factors with respect to T2D as the outcome.

Disclosure

A. Nag: None. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck & Co., Inc. Consultant; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited.
31-LB: Identification of Repurposable Drug Candidate for Diabetic Peripheral Neuropathy Using High-Throughput Drug-Perturbation Data
Authors: GUO KAI , FELDMAN EVA L. , HUR JUNGUK
Published: June 2019

Diabetic peripheral neuropathy (DPN) is a common complication of prediabetes and type 2 diabetes (T2D) for which there are limited treatment options. We recently demonstrated that dietary reversal (DR) corrects the DPN phenotype using mouse models of prediabetes and T2D. However, it is still important to develop therapeutic agents for treating DPN in addition to life style changes such as DR. In this study, we employed an in silico omics-based systems approach to identify small-molecule drugs with a high potential of reversing or halting DPN. The NIH Library of Integrated Network-based Cellular Signatures (LINCS) drug-perturbation transcriptomic data were obtained, which measured gene expression changes after treatment of 83 human cells with over 20,000 small-molecule compounds using the L1000 assay platform. Gene expression signature of DPN, consisting of highly up- or down-regulated genes, was defined based on the dysregulated genes, identified from sciatic nerves RNA-Seq data of C57BL/6J mice fed with high-fat diet (60% kcal fat for 19 weeks). This DPN signature was compared against the LINCS perturbation data using the CLUE Query app from the Broad Institute and our in-house analysis pipeline. The top small-molecule drugs, demonstrating opposite expression profiles of the DPN signature, included various protein synthesis inhibitors, calcium channel blockers, and adrenergic receptor antagonists such as cephaeline, levetiracetam, and esmolol, respectively. Although the anti-DPN effects of these drugs need to be systematically examined, our systems approach provides a list of drugs with a potential for being used to treat DPN.

Disclosure

K. Guo: None. E.L. Feldman: None. J. Hur: None.

Funding

National Institutes of Health (R24DK082841); University of Michigan
315-LB: Intervention Program on Lifestyle Changes and Weight Reduction for Workers in Remote Areas, Based on Therapeutic Education and Telemedicine Coordination
Authors: MOCIULSKY JULIANA , RUIZ PABLO , ZARATE PABLO C. , CURA LEILA , GANDUGLIA CAZABAN MERCEDES M.
Published: June 2019

Introduction: Overweight and obesity are frequently found risk factors in oil industry workers in Argentinian Patagonia with limited access to health care system.

Objective: Implement an intervention program based on lifestyle changes for weight reduction among oil industry workers of Patagonia; coordinated by telemedicine from the City of Buenos Aires and carried out by local nurses.

Materials and Methods: Nurses in 10 different oil fields, were trained in motivational interviewing, nutrition and physical activity fundamentals. Employees were invited to a 3 months structured program, including workshops on healthy nutrition habits, and weekly consultations to infirmaries for weight control and brief motivational interviews. Participants received a health notebook for self-record of: food intake, physical activity, weight progress and therapeutic objectives. Coordinators monitored the program through video and teleconferences, plus 3 on-site visits.

Results: Of 220 participants, 178 (94% males) were included for data analysis, excluding those with BMI<25 kg/m2. Initial data showed 41% overweight, 59% obesity (36.5% grade I, 17.4% grade II and 5.1% grade III) and 93,3% of dyslipidemia among participants. Adherence, measured by assistance to consultations, was 48,9 % high, 37,6% satisfactory and 13,5% low. Median weight loss was 2.5 kg (IQR 1.2 - 4.8) and 2.7% of initial weight (IQR 1.4 - 4.8). High adherence group had an average weight reduction of 4,8kg (95% CI 4.1 - 5.6). Overall, 24% of population lost more than 5% of initial weight, and 7 participants weight loss was greater than 10%.

Conclusions: A structured intervention program in remote areas, coordinated by telemedicine can be a successful tool for weight loss and reduction of cardiometabolic risk factors.

Disclosure

J. Mociulsky: None. P. Ruiz: None. P.C. Zarate: None. L. Cura: None. M.M. Ganduglia Cazaban: Consultant; Self; AstraZeneca. Speaker’s Bureau; Self; Merck & Co., Inc.
316-LB: Medically Reproducing Bariatric Surgery (MRB): A Proof-of-Concept Study
Authors: DAR MOAHAD , SMYTHE KEVIN F. , LEGGETT-FRAZIER NANCY K. , YANCY WILLIAM S.
Published: June 2019

Introduction: Roux-en-Y gastric bypass (RYGB) leads to durable type 2 diabetes (DM2) remission. Increased glucagon-like peptide-1 (GLP-1) levels and caloric restriction are known sequela of RYGB and independently improve DM2 control.

Hypothesis: Since Liraglutide increases GLP-1 levels and the OPTIFAST program induces caloric restriction, we hypothesize that Liraglutide + OPTIFAST will medically reproduce RYGB and lead to DM2 remission, weight loss, decreased medication intensity and improved health related quality of life (HRQL).

Methods: The Medically Reproducing Bariatric surgery (MRB) study is a pilot study that tested whether poorly controlled DM2 subjects on Liraglutide ± other diabetic medicines experienced DM2 remission after completing the 24 week OPTIFAST program. Primary outcome: glycemic control. Secondary outcome: weight, medication intensity and HRQL measured by Problem Areas In Diabetes (PAID) score.

Results:

Conclusion: Responders (yellow) vis-a-vis Non-responders (plain) experienced significant improvements in glycemic control, weight, medication intensity and HRQL. Responders vis-a-vis Non-responders had much better compliance during the OPTIFAST weight loss phase (week 1-12) when 800 calories per day were being consumed. Non-responders still experienced modest improvement in weight loss and HRQL. No serious adverse events occurred. The MRB approach merits further study.

Disclosure

M. Dar: None. K.F. Smythe: None. N.K. Leggett-Frazier: None. W.S. Yancy: None.

Funding

Nestl?
376-P: Type 2 Diabetes Individuals Are at High Risk of Continuous Glucose Monitoring Detected Hypoglycemia Regardless of Degree of Metabolic Control
Authors: SZYMANSKA-GARBACZ ELEKTRA , BORKOWSKA ANNA , CZUPRYNIAK LESZEK
Published: June 2019

Type 2 diabetes patients, especially those with poor metabolic control or treated with oral hypoglycemic agents (OHA) only are often regarded as being at lower risk of hypoglycemia than type 1 diabetes subjects. We used continuous glucose monitoring system (CGMS) in 69 type 2 diabetes individuals (mean [±SD] age 63±9 years, duration of diabetes 12±7 years, BMI 31.8±5.2 kg/m2, HbA1c 8.4±0.7%, 74% treated with insulin ± OHA, 26% - treated with OHA only, including sulfonylureas) to assess the hypoglycemia prevalence. Each patient underwent blinded CGMS (iPro2, Medtronic) for 5.8±0.8 days, duration of the time spent at blood glucose (BG) <70 mg/dl was determined and expressed as a percentage of total CGMS use time (T hypo). Clinically statistical hypoglycemia (CSH) episodes defined as BG <54 mg/dl lasting >15 minutes were also recorded. Overall, hypoglycemia was detected in 28 (40.6%) patients, including five treated with OHA only. T hypo ranged from 1 to 15% (6.1±4.7%), and was twice as long in insulin treated individuals than in those on OHA only (8.8±5.1 vs. 4.2±3.6; p<0.05). 57% of all patients experiencing hypoglycemia (including two treated with OHA only) had at least one episode of nocturnal CSH, with BG as low as 40 mg/dl, and none was symptomatic. To assess the relationship between hypoglycemia risk and degree of metabolic control the study subjects were divided into two subgroups: with good (n=29; HbA1c 7.2±0.6, range 6-8%) and poor (n=40; HbA1c 9.6±0.8, range 9-12%) metabolic control. Hypoglycemia was recorded in 37.9 and 42.5%, nocturnal hypoglycemia - in 54.5 and 58.8% of subjects from each group, and T hypo was 6.7±4.9 and 5.7±4.6%, respectively (p>0.05).

In conclusion, 40% of type 2 diabetes individuals experience hypoglycemia when assessed with CGMS for 5-6 days, with majority having asymptomatic nighttime events. Importantly, the high prevalence of CGMS detected hypoglycemia was not related to the degree of metabolic control of diabetes.

Disclosure

E. Szymanska-Garbacz: None. A. Borkowska: None. L. Czupryniak: None.
416-P: The Ceramide-Based Coronary Event Risk Test (CERT) Predicts Cardiovascular Mortality in Cardiovascular Disease Patients with Type 2 Diabetes Mellitus as Well as in Those without Diabetes
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , SAELY CHRISTOPH H. , LAAKSONEN REJO , LAAPERI MITJA , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , BAUMGARTNER IRIS , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2019

The recently introduced Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses circulating ceramide concentrations to allocate patients into one of four risk categories. We here aimed at investigating the power of CERT to predict cardiovascular mortality in 1087 patients with established cardiovascular disease (CVD) including 360 patients with type 2 diabetes (T2DM). At baseline, the prevalence of T2DM increased through CERT categories (29.1, 31.1, 37.4, and 53.4%, respectively, ptrend<0.001). Prospectively, we recorded 130 cardiovascular deaths during a mean follow-up time of 8.1±3.2 years. Overall, cardiovascular mortality increased with increasing CERT categories (Figure) and was higher in T2DM patients than in those who did not have diabetes (17.7 vs. 9.4%; p<0.001). In Cox regression models, CERT categories predicted cardiovascular mortality in patients with T2DM (unadjusted HR 1.60 [1.28-2.01]; p<0.001; HR adjusted for age, gender, BMI, smoking, LDL cholesterol, HDL cholesterol, hypertension, and statin use 1.65 [1.27-2.15]; p<0.001) and in those without diabetes (unadjusted HR 1.43 [1.10-1.85]; p=0.008 and adjusted HR 1.41 [1.07-1.85]; p=0.015). We conclude that CERT predicts cardiovascular mortality in CVD patients with T2DM as well as in those without diabetes.

Disclosure

A. Leiherer: None. A. Muendlein: None. C.H. Saely: None. R. Laaksonen: None. M. Laaperi: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. I. Baumgartner: None. P. Fraunberger: None. H. Drexel: None.
502-P: Urinary Levels of Deoxyribonuclease-1 and Lysosomal Alpha-Glucosidase Were Associated with the Progression of Diabetic Nephropathy
Authors: KABURAGI YASUSHI , ITO EMI , UNOKI-KUBOTA HIROYUKI
Published: June 2019

Recent reports showed early progressive renal function decline precedes the onset of microalbuminuria, indicating the need for new factors predicting diabetic nephropathy (DN) that work alone or as a complement to urinary albumin and eGFR. To identify urinary proteins associated with DN, we carried out a 2D-DIGE-based proteomic analysis using the urine obtained from healthy control subjects (H; n=8), type 2 diabetic patients without nephropathy (T2DM; n=16), and stage II DN patients (DN2; n=16). From the total 3034 protein spots detected, a total of 34 proteins were identified as the candidate protein differentially excreted in DN2 or T2DM. Thirty proteins out of 34 candidates were then validated by multiple reaction monitoring assay using an independent sample set (H: n=14, T2DM: n=13, DN2: n=14, stages III to IV DN: n=17), where 26 proteins were validated to be differentially excreted in DN. Among them, the levels of deoxyribonuclease-1 and lysosomal alpha-glucosidase were significantly correlated with both ACR and eGFR, and were also significantly lower in patients with an eGFR < 60 compared with patients with an eGFR ≥ 60. We further analyzed gene expressions of DNase I and lysosomal alpha glucosidase in kidneys of DN patients using Nephroseq database (https://www.nephroseq.org), and found that DNase I gene was significantly downregulated in DN tubulointerstitum and glomeruli, and that lysosomal alpha glucosidase gene tend to decreased in DN tubulointerstitum. Finally, the urinary DNase I levels were found to be higher in patients who progressed to a more severe DN stage or had early renal decline than in patients who did not. These findings suggest a possible role for the identified proteins in the progression of DN, although further validation studies are required.

Disclosure

Y. Kaburagi: None. E. Ito: None. H. Unoki-Kubota: None.

Funding

Japan Society for the Promotion of Science
517-P: Communication from Tubular Epithelial Cells to Podocytes through Bim/NFAT2 Pathway
Authors: XU CHUNMEI , ZHOU XIAOJUN , SHEN XUE , JIANG SHAN , XIE TIANYUE , ZOU ZHIWEI , ZHANG QIAN , ZHANG RUI , XING YIQIAN , LIAO LIN , DONG JIANJUN
Published: June 2019

Background: Our previous research revealed that the apoptosis of proximal tubular epithelial cells (PTECs) occupied a vital position in the early change of diabetic nephropathy (DN) and Bcl-interacting mediator (Bim) was the key factor to be involved in it. Whereas, Bim could also control T cell activation and play a specific regulatory role in other aspects besides inducing cell apoptosis. Changes of podocytes are classic hallmarks of the lesions of DN. Here, the study aims to investigate the specific influence of PTECs which have been damaged on the podocyte injury.

Methods: Bim expression in PTECs was modulated, and subsequently podocyte cytoskeleton was determined at different points of time (24, 48, 72 hours) by building transwell co-culture system under high glucose (40mmol/l HG).

Results: HG exposure for 48 hours induced the significant changes in podocyte cytoskeleton accompanied with high expression of Bim in PTECs. When co-cultured with PTECs, exacerbated filamentous actin (F-actin) rearrangement and markedly reduced synaptopodin level in podocytes were found compared with single cultured podocytes under HG. Gene knockdown of Bim in PTECs ameliorated above abnormalities in podocytes. Further screening for NFAT subtypes, the key downstream factors of Bim, found that NFAT2 level in PTECs was obviously decreased when suppressing Bim expression. Upregulating NFAT2 disrupted beneficial effects on podocyte F-actin arrangement which was achieved by inhibiting Bim in PTECs.

Conclusion: Our preliminary data have indicated that the apoptosis of PTECs mediates the early lesion of DN. It seemed corroborative that there exists crosstalk between PTECs and podocytes; Bim, the pivotal factor related to apoptosis of PTECs participates in the crosstalk by promoting NFAT2 activation, then contributes to injury of podocyte cytoskeleton, emphasizing the role of Bim/NFAT2 pathway in the control of early DN progression from tubular lesions to glomerular abnormalities.

Disclosure

C. Xu: None. X. Zhou: None. X. Shen: None. S. Jiang: None. T. Xie: None. Z. Zou: None. Q. Zhang: None. R. Zhang: None. Y. Xing: None. L. Liao: None. J. Dong: None.

Funding

National Natural Science Foundation of China (81570742, 81670757, 81770822, 81800732); Shandong Provincial Natural Science Foundation of China (ZR2017LH025); Shandong Provincial Medicine and Health Science and Technology Development Program (2017WS461)
582-P: Disambiguating the Nucleus Ambiguous with Single-Cell Transcriptomics
Authors: COVERDELL TATIANA , IVISON RACHAEL , TAO JENKANG , CAMPBELL JOHN
Published: June 2019

The nucleus ambiguous (nAmb), a hindbrain region which degenerates in diabetes models, is the major parasympathetic input to the heart but also innervates the larynx and esophagus to control swallowing. These disparate functional roles are likely mediated by distinct nAmb neuron subtypes. Yet, the molecular identities of these subtypes are mostly unknown, limiting access to them for functional studies. Therefore, we classified mouse nAmb neurons using single-nuclei RNA-Seq (sNuc-Seq). First, we labeled nAmb neuron nuclei by injecting an adeno-associated viral (AAV) vector which Cre-dependently expresses a nuclear-localized mCherry protein into the nAmb of adult male Chat-IRES-Cre mice, in which all nAmb neurons (and few nearby ones) express Cre recombinase. We later dissected the nAmb, isolated its cell nuclei, and sorted the H2b-mCherry+ ones singly into microplate wells with fluorescence assisted cell sorting (FACS). We then used SmartSeq2 to generate cDNA sequencing libraries from the single-nuclei poly-adenylated RNA samples and deeply sequenced them to near-saturating depths for gene detection. Clustering the samples based on expression of their highly variable genes revealed six molecularly-distinct neuron subtypes, four of which localized to nAmb based on in situ detection of their marker transcripts. Comparing their gene expression revealed candidate transcriptional markers for each neuron subtype (Crhr2; Uts2; Vipr2; and Tbx3). In light of previous studies, three nAmb populations (Crhr2 neurons, Uts2 neurons, and Vipr2 neurons) are likely motor neurons innervating the larynx and esophagus, as they expressed high levels of CGRP (Calca) but little to no PACAP (Adcyap1). The opposite was true for the fourth subtype, Tbx3 neurons, raising the possibility that they are the cardiovagal nAmb neurons. Additional studies are underway to identify (1) tissues innervated by each marker-defined nAmb neuron type and (2) their role in controlling heart rate, laryngeal or esophageal muscle tone.

Disclosure

T. Coverdell: None. R. Ivison: None. J. Tao: None. J. Campbell: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-18-INI-14 to J.C.)
60-LB: Evaluating the Efficacy of a Novel Insulin Dosing Regimen to Prevent Lows at High-Intensity Diabetes Sports Camp
Authors: TERRY AMANDA M. , BOLLEPALLI SUREKA , SMITH LAURA , RODRIGUEZ HENRY
Published: June 2019

Objectives: To determine the efficacy of reductions in long acting and basal insulin to prevent lows in T1D sports campers. The Sam Fuld’s T1D Sports Camp is a camp for children with T1D taking place each February. It involves high-intensity exercise for up to six hours in a day. We began adjusting our insulin dosing recommendation in 2017 to prevent incidence of hypoglycemia and ensure more campers are able to fully participate.

Methods: We compared incidence of hypo and hyperglycemic events at camp from 2016-2019. Using bg data recorded for all T1D campers. Starting in 2017, we recommended MDI campers decrease long acting insulin by 30% the night before camp and pump users decrease basal rates by 30% beginning at breakfast prior to camp. In 2019, meal boluses for lunch were also cut by 50%.

Results: From 2016 to 2018 there was a 40% decrease in campers with low bgs, and an expected increase in hyperglycemic values. In 2019, we saw an increase in lows compared with 2018 with lower overall prevalence than seen in prior years and fewer hyperglycemic events than in 2018.

Of those campers who followed the recommendations, in 2017, no incidents of hypo or hypoglycemia occurred, in 2018 there were just three incidents of hyperglycemia and in 2019, one bg value < 50 mg/dL and 8 bg values > 250 mg/dL (mostly in the morning).

Conclusion: More research is needed to determine the best dosing guidelines for intense exercise in children with T1D.

Disclosure

A.M. Terry: None. S. Bollepalli: None. L. Smith: None. H. Rodriguez: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Pharm Corp, MannKind Corporation, Medtronic MiniMed, Inc. Research Support; Spouse/Partner; Medtronic MiniMed, Inc. Research Support; Self; Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.
604-P: Automated Diabetic Retinopathy Screening in the Primary Care Setting Improves Compliance with Follow-Up Ophthalmic Care
Authors: LIU JAMES C. , RAMCHAL SHAWN , GIBSON ELLA , KUO JESSICA , SOLANKI KAUSHAL , BHASKARANAND MALAVIKA , FONDAHN EMILY , RAJAGOPAL RITHWICK
Published: June 2019

Purpose: Diabetic retinopathy (DR) is a leading cause of blindness, yet a majority of adults with diabetes are noncompliant with annual ophthalmic screening recommendations. We hypothesized that point-of-care automated DR could increase the rate of compliance with recommended retinal surveillance in patients with diabetes when administered during primary care visits.

Methods: We performed a prospective cohort study of adults ages 18 or older with diabetes seen at a primary care clinic from 3/1/18 to 8/31/18. A retrospective chart review of adults with diabetes from the same clinic was also conducted and served as a historical control. Participants were screened using non-mydriatic fundus photography and automated DR screening software (Eyenuk Inc.). Those with positive or inconclusive screening results were referred to ophthalmology for comprehensive evaluation. Rates of compliance with referral recommendations were compared between the study participants and historical control.

Results: One hundred and sixty-five adults with diabetes were included in the prospective study cohort. Twelve (7.3%) screened positive for referable DR, 23 (13.9%) screened positive for vision threatening DR, and 47 (28.4%) had an inconclusive screening result. Those that screened negative (83 participants) were all confirmed not to have DR by independent review from a retina specialist. The rate of compliance with follow-up eye care in referred participants was 54.9% compared to a historical rate of 18.7% (p<0.0001, chi-squared).

Conclusions: The use of automated DR screening at our institution's primary care clinic reduced referrals for those with no retinopathy and increased the rate of compliance with follow-up eye care in those with positive or inconclusive screening results. These findings suggest that implementation of automated screening could effectively increase compliance with ophthalmic care among those with referable DR.

Disclosure

J.C. Liu: None. S. Ramchal: None. E. Gibson: None. K. Solanki: Employee; Self; Eyenuk Inc. Stock/Shareholder; Self; Eyenuk Inc. M. Bhaskaranand: Employee; Self; Eyenuk Inc. E. Fondahn: Consultant; Self; Greeley Company. R. Rajagopal: None.
64-LB: Aerobic Exercise Decreases Hepatic Glucose Production via Asprosin Pathway in Diabetic Rats
Authors: KO JEONGRIM , KIM TAE NYUN , SEO DAE YUN , HAN JIN
Published: June 2019

The asprosin, a novel protein hormone released from white adipose tissue, plays an important role in the regulation of glucose metabolism for diabetes prevention. Aerobic exercise has been shown to improve type 1 diabetes (T1DM); however, exercise-induced asprosin production and its role in physiological regulation of metabolic pathways are still unclear. The aims of this study investigation were 1) to determine whether aerobic exercise could decrease asprosin levels in the liver of streptozotocin (STZ)-induced diabetic rats 2) to assess whether exercise-induced asprosin levels could contribute to asprosin-dependent downstream pathways for diabetes prevention. Five-weeks-old male Sprague-Dawley rats (n = 18) were randomly divided into control (CON), STZ-induced diabetes (STZ), and STZ with aerobic exercise (STZ-Ex) groups (n = 6 each). T1DM was induced by a single dose of STZ (65 mg/kg i.p.). The exercise group ran on treadmill for 60 min at a speed 20 m/min (4 times per week for 8 weeks). Following the 8-week experiment, the levels of asprosin, protein kinase A (PKA), 5’ adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt), peroxisome proliferator-activated receptor gamma coactivator-1α, β (PGC-1α, β), fibronectin type III domain-containing protein 5 (FNDC5), and uncoupling protein 3 (UCP3) were analyzed in liver. Protein expression of asprosin and PKA were significantly lower but AMPK, Akt, PGC-1β, and SOD2 were significantly higher in STZ-Ex group compared with STZ group. These findings suggest that aerobic exercise might serve as a potential physiological treatment for type 1 diabetes by decreasing asprosin and PKA levels in the liver.

Disclosure

J. Ko: None. T. Kim: None. D. Seo: None. J. Han: None.

Funding

Korean Ministry of Education (2010-0020224, 2018R1D1A1B07040370); Korean Ministry of Science, ICT and Future Planning (2018R1A2A3074998)
73-OR: Development of SteadiFlow Technology, an Advanced Insulin Delivery Cannula Featuring Extended Duration of Use, More Reliable Insulin Delivery, and Reduced Inflammatory Tissue Response
Authors: JOSEPH JEFFREY I. , TORJMAN MARC C. , LOEUM CHANNY , EISLER GABRIELLA J. , STRASMA PAUL J. , KHALF ABDURIZZAGH
Published: June 2019

There is great clinical need for an insulin infusion set that produces reliable and consistent insulin absorption (PK) from dose to dose and functions reliably for 7 or more days. Capillary Biomedical, Inc. is developing SteadiFlow technology which features a soft yet kink-proof cannula with 1 distal orifice and 3 additional orifices distributed over the final 6 mm of the distal end of the cannula. We compared the performance of the SteadiSet to commercial insulin infusion sets with a Teflon cannula in large ambulatory swine.

Investigational infusion sets featuring SteadiFlow technology and commercial Teflon infusion set were inserted into the subcutaneous tissue of swine’s abdomen every other day for 14 days. Insulin lispro (U-5) was infused through the catheters using the same basal/bolus pattern. On day # 14, a 70 ul bolus of insulin/x-ray contrast agent was infused through each CSII catheter. The tissue surrounding each CSII was excised 5 minutes later, frozen, and imaged using a high-resolution micro-CT scanner. The tissue was then processed and stained to produce high-resolution histology images.

Histology images revealed a significantly thinner and smaller area of inflammatory tissue around the SteadiSet cannulas compared with the commercial Teflon cannulas. Micro-CT images revealed a significantly larger surface area of insulin/x-ray contrast agent delivered into the adjacent tissue when infused through the SteadiSet infusion sets compared with the commercial infusion sets with a Teflon cannula. A glucose clamp PK/PD study performed in swine using SteadiSet infusion sets implanted for 6 days showed reliable performance and relatively consistent insulin absorption into the circulation. Human clinical trials are planned for early 2019 to evaluate SteadiFlow technology for reliability, glucose control performance, and PK/PD metrics in patients with type 1 diabetes.

Disclosure

J.I. Joseph: Advisory Panel; Self; CapillaryBiomedical, Inc., Thermalin Diabetes, Inc. Research Support; Self; Capillary Biomedical, inc., Thermalin Diabetes, Inc. Stock/Shareholder; Self; Capillary Biomedical, Inc. M.C. Torjman: Other Relationship; Self; Capillary Biomedical, Inc. C. Loeum: Stock/Shareholder; Self; Capillary Biomedical, Inc. G.J. Eisler: None. P.J. Strasma: Employee; Self; Capillary Biomedical, Inc. A. Khalf: None.

Funding

JDRF; Capillary Biomedical, Inc.