bluuebunny/crossref_metadata_2025 huggingface dataset:
2166-P: Sel1L-Hrd1 ERAD Is a Key Regulator of Beta-Cell Function and Identity
Authors: SHRESTHA NEHA , LI XIN , JI YEWEI , REINERT RACHEL B. , ARVAN PETER , QI LING
Published: June 2019

βcell survival and dedifferentiation are two hotly-debated mechanisms underlying βcell loss in type 2 diabetes; however, the underlying molecular mechanism remains largely unclear. Here we compare two principal protein quality control mechanisms, ER-associated protein degradation (ERAD) and autophagy and find that ERAD plays an important role in βcell dedifferentiation. Mice with βcell-specific Sel1L-Hrd1 deletion exhibit early-onset hyperglycemia and glucose intolerance as early as ~5 weeks of age. Surprisingly, in contrast to other tissue specific models of Sel1L-Hrd1 ERAD deficiency in which prohormones accumulate within the ER, Sel1L-Hrd1 ERAD deficiency impairs βcell function by attenuating insulin expression without an overt defect in proinsulin maturation and also triggers marked βcell dedifferentiation. There is, however, no overt activation of unfolded protein response (UPR) or proinsulin aggregation. In striking contrast to ERAD deficiency, loss of macroautophagy, a major mechanism for bulk protein degradation and organelle turnover, in βcells causes massive cell loss and hyperglycemia, but not βcell dedifferentiation. Thus, our data reveal a novel role of Sel1L-Hrd1 ERAD in the maintenance of βcell identify and demonstrate that impairment of ERAD contributes to the progression of type 2 diabetes in a manner distinct from that of autophagy.

Disclosure

N. Shrestha: None. X. Li: None. Y. Ji: None. R.B. Reinert: None. P. Arvan: None. L. Qi: None.

Funding

National Institutes of Health
2176-P: miRNA-374 Improves Glucotoxicity-Induced Beta-Cell Dysfunction and Glucose Metabolism Dysfunction through the Regulation of PGC-1 Alpha
Authors: KIM JIWON , YOU YOUNG HYE , LEE EUN YOUNG , YOON KUN-HO
Published: June 2019

Glucotoxicity plays a major role in the progressive deterioration of β-cell function and development of type 2 diabetes mellitus. MicroRNAs (miRNAs) represent small noncoding RNAs that play a role in many diseases, including diabetes. This study was to search the common gene mechanism between liver and pancreas in diabetic condition such as glucotoxicity and to search the miRNAs related to glucotoxicity-induced β-cell dysfunction and glucose metabolism dysfunction in liver. To study the role of miRNAs in glucotoxicity-induced β-cell dysfunction and glucose metabolism dysfunction, we analyzed the miRNA expression patterns of primary rat islets and hepatocytes for three days after exposure to glucotoxicity and confirmed up-regulated and down-regulated miRNAs. Overexpression of miR-374 suppressed PGC-1α expression in glucotoxicity. miR-374 was found to target the 3'-untranslated region (3'UTR) of PGC-1α through miR-374 binding sites and to downregulated PGC-1α protein abundance at the post-transcriptional level by luciferase activity assay combined with mutational analysis. Here we demonstrate that miR-374 mediated suppression of PGC-1α gene expression is an important initiation step of glucotoxicity induced β-cell dysfunction and glucose metabolism dysfunction in liver and appropriate new target for early treatment.

Disclosure

J. Kim: None. Y. You: None. E. Lee: None. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited.
2177-P: Role of De Novo Sphingolipid Metabolites in Oleate-Induced Pancreatic ß-Cell Proliferation in Rats
Authors: CASTELL ANNE-LAURE , VIVOLI ALEXIS , MOULLÉ VALENTINE S. , GHISLAIN JULIEN , POITOUT VINCENT
Published: June 2019

Fatty acids (FA) are major regulators of pancreatic β-cell function. In a rat model of nutrient excess we previously showed that FA potentiate glucose-induced β-cell proliferation. Sphingolipids, derived from the intracellular metabolism of FA, act as cellular mediators in the regulation of pancreatic β-cell function. However, the contribution of sphingolipid species to FA-induced β-cell proliferation is unknown.

Objective: To determine the role of de novo sphingolipid synthesis in FA-induced β-cell proliferation.

Methods: Isolated rat islets were exposed to oleate or palmitate (0.5 mM) in the presence of 16.7 mM glucose for 48h. Sphingosine kinase (SphK) 1 and 2 expression was measured by real-time PCR. Serine palmitoyl transferase (SPT), SphK, and the S1P3 receptor were inhibited with Myriocin, SKI II and TY52156, respectively. β-cell proliferation was assessed in cryosections by immunohistochemical detection of insulin and the proliferation marker Ki67 or by flow cytometry by labeling for C-peptide and EdU incorporation. Wistar rats were infused for 72 hours with glucose and a lipid emulsion (CLI) to induce β-cell proliferation.

Results: The monounsaturated FA oleate, but not the saturated FA palmitate, increased β-cell proliferation. Blocking de novo sphingolipid synthesis by SPT inhibition decreased oleate-induced β-cell proliferation as did inhibition of SphK and S1P3 receptor activation. Sphk1/2 mRNA levels in islets were not significantly changed following nutrient infusion in rats or FA exposure ex vivo.

Conclusion: β-cell proliferation in response to oleate requires de novo sphingolipid synthesis and S1P3 signaling. Analyses are underway to assess the contribution of SphK products sphingosine-1-phosphate and dihydrosphinganine-1-phosphate in S1P3-mediated β-cell proliferation.

Disclosure

A. Castell: None. A. Vivoli: None. V.S. Moullé: None. J. Ghislain: None. V. Poitout: None.

Funding

National Institutes of Health; Canadian Institutes of Health Research
218-LB: Hypoglycemia Burden in T2D Patients: Rationale, Methodology, and Comparative Results of a Multisetting Nationwide Study Series
Authors: ALÃO SÍLVIA , CONCEICAO SANTOS LELITA , ARAUJO FRANCISCO , DORES JORGE M. , PELICANO-ROMANO JOÃO , CONCEICAO JOAO M. , MJ PAULA
Published: June 2019

Introduction: Hypoglycemia places a significant burden, accounting for adverse clinical and financial outcomes.

Objective: Integrated approach to determine burden of hypoglycemia in T2D patients in Portugal, accessed in an Outpatient Setting (pharmacies), Emergency Rooms (ERs) and Hospital Wards, contributing for a full country perspective of complementary settings.

Methods: A series of 3 HypoglycemIa in POrtugal Studies (HIPOS) were developed: HIPOS-PHARMA, HIPOS-ER and HIPOS-WARD. They were observational, cross-sectional, multicentric studies designed to evaluate adult T2D patients treated with AHA attending pharmacies and reporting hypoglycemic events (PHARMA), admitted in ERs or hospitalized (WARD) for hypoglycemia. These studies were implemented over a period of non-consecutive 35 months (Jan13-Aug18) and with a national coverage.

Results: Mild to moderate hypoglycemia in the 3 months prior recruitment were reported by 17.8% of the 1890 individuals enrolled by 233 pharmacies during HIPOS-PHARMA and were more likely in patients taking insulin and/or secretagogues. Only 46% of patients reported the episode to a HCP. Severe hypoglycemia accounted for 0.074% (n=238) of the 425,706 ER admissions in the 7 HIPOS-ER hospitals and occurred mainly on insulin- (55.0%) and secretagogue-based therapy (31.5%). When these patients needed hospitalization (44%), the mean total cost per hypoglycemic event was € 3,163 (€ 230 - € 26,818). As for HIPOS-WARD, 152 individuals were enrolled in 18 centers, 40.4% had previous hypoglycemia (last 12 months), and were also on insulin (42.1%) or secretagogues (34.9%).

Conclusion: This study series allowed for the first time a nationwide multi-setting perspective of hypoglycemia in T2D patients, signaling that this event still represents a relevant burden in Portugal, despite significant improvements in hypoglycemia prevention strategies and the growing number AHA with low hypoglycemia risk.

Disclosure

S. Alão: Employee; Self; Merck Sharp & Dohme Corp. L.C. Santos: Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. F. Araujo: None. J.M. Dores: Advisory Panel; Self; Merck Sharp & Dohme Corp. J. Pelicano-Romano: Employee; Self; Merck & Co., Inc. J.M. Conceicao: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. P. Mj: Employee; Self; Merck Sharp & Dohme Corp.
2189-P: Human IAPP Destabilizes IRF1 Protein to Reduce PD-L1 Expression in INS1 Cells
Authors: MORITA SHUHEI , ISHIBASHI TATSUYA , ARIYASU HIROYUKI , IWAKURA HIROSHI , NISHI MASAHIRO , FURUTA HIROTO , AKAMIZU TAKASHI
Published: June 2019

Background: Programmed death-ligand 1 (PD-L1) plays a critical role to protect β-cells against immune attack. Interferon regulatory factor 1 (IRF1) is a key transcriptional factor to regulate PD-L1 expression, which is induced by various cytokines through JAK/STAT pathway. Human islet amyloid polypeptide (hIAPP) activates resident macrophages to accelerate proinflammatory phenotype of islets. However, it is still unknown if hIAPP regulates the local inflammatory response in β-cells under immune attack. hIAPP knock-in mice induce diabetic phenotype only following high-fat feeding. In addition, most type 2 diabetic patients who have S20G-IAPP mutation show severe diabetic phenotype; however, other people who have it show only modest or no impairment of glucose tolerance. These evidences suggest that cytotoxic effect of hIAPP is not strong enough by itself, but may require another factor, like local immune dysregulation, to induce diabetic phenotype. These backgrounds encouraged us to investigate if and how hIAPP regulates IRF1/PD-L1 pathway in β-cells.

Methods: We evaluated the effect of hIAPP on IRF1/PD-L1 pathway by using recombinant rat(r) and human IAPP in INS1 cells. Doxycycline-inducible rIAPP- and hIAPP-overexpressing INS1 cells were used to confirm the results. Interferon (INF)-γ was used to activate JAK/STAT pathway.

Results: Recombinant hIAPP rather than rIAPP reduced endogenous and INF-γ-induced PD-L1 expression. Similarly, hIAPP-overexpression reduced PD-L1 expression. Recombinant both rat and human IAPP showed limited effect on phosphorylation of STAT1 and STAT3 induced by INF-γ. Protein levels of IRF1 induced by INF-γ were reduced by recombinant hIAPP; however, its mRNA levels were not reduced. Cycloheximide chase study revealed the destabilization of IRF1 protein under hIAPP treatment.

Conclusion: Our results suggest that hIAPP could destabilize IRF1 protein to reduce PD-L1 expression in INS1 cells.

Disclosure

S. Morita: None. T. Ishibashi: None. H. Ariyasu: None. H. Iwakura: None. M. Nishi: None. H. Furuta: None. T. Akamizu: None.
219-LB: Different Associations between Serum Urate and Diabetic Complications in Middle-Aged and Elderly Patients
Authors: WAN HENG , WANG YUYING , CHEN YI , WANG CHIYU , ZHANG WEN , XIA FANGZHEN , WANG NINGJIAN , LU YINGLI
Published: June 2019

Aim: The objective of the study was to investigate whether higher serum urate (SUA) level has consistent association with cardiovascular disease (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR) in Chinese adults with type 2 diabetes mellitus (T2DM).

Methods: 4,767 diabetic participants were enrolled from seven communities in Huangpu and Pudong District, Shanghai, China in 2018. Participants underwent several checkups, which included the measurement of anthropometric parameters, blood pressure, glucose, lipid profiles, SUA and urine albumin/creatinine ratio (ACR).

Results: Compared with the first SUA group, the third group increased the prevalence of CVD by 27% (OR 1.27; 95% CI 1.04, 1.55) (P for trend <0.05) and increased the prevalence of DKD by 88% (OR 1.88; 95% CI 1.48, 2.40) for KDOQI definition. Compared with first group, OR (95% CI) of DR ranging from non-retinopathy (NDR) to proliferative diabetic retinopathy (PDR) in ordinal logistic regression associated with SUA level was 0.81 (0.59, 1.10) for the third group, (P for trend=0.086) and OR (95% CI) of the number of diabetic complications ranging from 0 to 2 in ordinal logistic regression associated with SUA level was 1.75 (1.44, 2.12) for the third group (P for trend< 0.01). These associations were all full adjusted.

Conclusions: Higher SUA level was associated with increased odds of CVD, DKD and variety of the diabetic complications, not DR, in middle-aged and elderly diabetic Chinese adults, which means lowering SUA level may be critical for prevention and intervention of diabetic complications.

Disclosure

H. Wan: None. Y. Wang: None. Y. Chen: None. C. Wang: None. W. Zhang: None. F. Xia: None. N. Wang: None. Y. Lu: None.
2195-P: Identification of the Regulatory Mechanism of mTORC1 Signaling Activity in Pancreatic Beta Cells in GCN2 Knockout Mice
Authors: KUDO MICHIYO , ASAHARA SHUN-ICHIRO , KANNO AYUMI , KIDO YOSHIAKI
Published: June 2019

Background and Objective: A single-nucleotide polymorphism (SNP) analysis of Japanese type 2 diabetes (T2DM) patients has revealed a significant correlation between a SNP of GCN2 and T2DM. We have demonstrated that islets isolated from GCN2 knockout (GCN2-/-) mice fed a high-fat diet (HFD) exhibited decreased expression of ATF4, a downstream molecule of GCN2, and pancreatic β-cell failure via hyperactivation of mTORC1 signaling. However, the mechanism of activated mTORC1 signaling has remained unclear. Therefore, our objective is to identify the regulatory mechanism of mTORC1 signaling activity in pancreatic β-cells of GCN2-/- mice fed an HFD.

Methods: We analyzed using islets isolated from GCN2-/- mice and wild type mice fed an HFD, and pancreatic β-cell lines.

Results: In pancreatic islets isolated from GCN2-/- mice fed an HFD, the phosphorylation of TSC2 was enhanced. Therefore, we speculated that there would be a pathway which regulated mTORC1 signaling via TSC2. It has been reported that TSC2 phosphorylation is regulated by its association with 14-3-3. We started to identify the molecule X downstream of GCN2, which involved in the regulation of mTORC1 signaling activity by competitively inhibiting the binding of TSC2 and 14-3-3. We carried out a proteome analysis to explore the molecules whose binding with 14-3-3 varied depending on the presence or the absence of GCN2. As a result, five molecules were listed, and Asparaginase was identified as the candidate of the molecule X. We revealed that Asparaginase was abundantly expressed in pancreatic islets following heart in mice tissues. In glucose loaded MIN6 cells and amino acid deficient MIN6 cells, the expression of Asparaginase was increased. Furthermore, the increased expression of Asparaginase by amino acid deficiency was decreased by ATF4 knocking down.

Conclusion: It was suggested that Asparaginase was involved in the regulation of mTORC1 signaling activity downstream of GCN2-ATF4 pathway.

Disclosure

M. Kudo: None. S. Asahara: Research Support; Spouse/Partner; AstraZeneca. A. Kanno: None. Y. Kido: Research Support; Self; AstraZeneca.
22-LB: Baseline and Short-Term Change in Plasma Uric Acid on Fenofibrate Predict Cardiovascular Risk: A Post Hoc Analysis of FIELD
Authors: YIMING CAO JACOB , WALDMAN BORIS , OCONNELL RACHEL L. , SULLIVAN DAVID , GEBSKI VAL , JANUSZEWSKI ANDRZEJ S. , MARSCHNER IAN , SCOTT RUSSELL , TASKINEN MARJA-RIITTA , SIMES R. JOHN , MCGILL NEIL , JENKINS ALICIA J. , KEECH ANTHONY C.
Published: June 2019

Background: Fenofibrate increases renal clearance of uric acid (UA). Relationships between baseline and short-term changes in plasma UA with fenofibrate and subsequent cardiovascular risk in patients with type 2 diabetes (T2D) are unknown.

Method: Post hoc analyses of the FIELD trial explored the relationships between CVD events and 1) baseline UA level; and 2) short-term change in UA level over 6-week single-blind active fenofibrate run-in.

Results: The FIELD trial showed 11% fewer cardiovascular events in patients with T2D assigned to fenofibrate compared to placebo over 5 years (HR = 0.89, 95% CI: 0.80-0.99, p = 0.035). Baseline UA (n=9622) ranged between 0.11 to 0.79 mmol/L (mean = 0.33, SD = 0.078). Each 0.1 mmol/L higher baseline UA increased CVD events by 21% (HR = 1.21 95% CI: 1.13-1.29, p < 0.001; Fig. 1A), and remained after adjusting for other classic risk factors (HR = 1.12, 95% CI: 1.04-1.21, p = 0.002). Fall in UA level with fenofibrate run-in also predicted lower CVD risk, adjusted for baseline UA and irrespective of trial treatment allocation (HR = 0.86, 95% CI: 0.76-0.97, p = 0.015; Fig. 1B).

Discussion: Baseline and short-term fenofibrate-induced lowering of UA predict cardiovascular risk in patients with T2D, irrespective of long-term trial treatment allocation. The reduction in total CVD events with fenofibrate was not shown to be mediated through lowering of UA levels.

Disclosure

J.Y. Cao: None. B. Waldman: None. R.L. OConnell: None. D. Sullivan: None. V. Gebski: None. A.S. Januszewski: None. I. Marschner: None. R. Scott: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. R. Simes: None. N. McGill: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.C. Keech: None.
2202-PUB: Time in Hypoglycemia Recorded by Continuous Glucose Monitoring in Subjects with Type 1 Diabetes in a Single Center in Costa Rica
Authors: CALVO JAVIER
Published: June 2019

Glycemic variability and frequent hypoglycemic episodes are some of the most difficult issues in the management of type 1 diabetes (T1D). We performed a retrospective analysis that included 27 subjects from 13 to 54 years of age diagnosed with T1D, using a multiple daily insulin injection treatment and under continuous glucose monitoring with a Medtronic iPro2 device for six days. We divided the sample in two groups: A) those with 10% or less of the time in hypoglycemia and B) those with more than 10% of time in hypoglycemia. Their median age was 27.8 years, 48.1% were males, with a median duration of disease of 13 years and a median of A1C of 7.8%. The time in range (blood glucose from 70 to 180 mg/dL) was 44% in both groups. The group of patients with more than 10% of the time in hypoglycemia had a lower A1C (7.5 vs. 7.9%, p=0.034) along with a higher number of hypoglycemic episodes in the night time (0 vs. 3, p<0.001), as well as increased episodes during the entire day (2 vs. 12.0 p<0.001). Patients who spent more time in range also showed lower levels of A1C, although all of them had more than 10% of time in hypoglycemia.

In conclusion, adequate A1C levels do not assure adequate control of disease given the increased time in hypoglycemia observed in this set of patients.

Figure 1. Correlation Between Mean A1c and Time in Range in Patients with T1D A1C, Glycated Hemoglobin; SD, Standard Deviation.

Disclosure

J. Calvo: None.
2207-PUB: Does Hypoglycemia Increase the Risk of Cardiac Arrhythmia?
Authors: MUSSO CARLA , SFORZA NOELIA S. , MOROSAN ALLO YANINA JIMENA , CLEMENTE ROMINA G. , PAVESI ADRIAN , FOLINO CLAUDIA C.
Published: June 2019

Hypoglycemia may exert proarrhythmogenic effects on the heart and insulin induced hypoglycemia has been considered responsible for nocturnal death in diabetic patients. Even so hypoglycemia associated fatal cardiac arrhythmia is difficult to document.

Objective: examined the effect of hypoglycemia on episodes of arrhythmias and cardiac repolarization disorders in diabetic mellitus (DM) patients.

Design and Methods: prospective study in which we included 30 subjects with DM who underwent of simultaneous ambulatory 24 hours electrocardiographic holter and continuous interstitial glucose monitoring (FREE STYLE system). Inclusion criteria: men and women > or = 50 years old with a type 2 insulin-treated DM and 2 or more major cardiovascular risk factors (hypertension, dyslipidemia, active smoking, overweight or obesity) or subjects older than 18 years old with a history of type 1 DM of more than 10 years who sign an informed consent. Exclusion criteria: pacemakers, treatment with drugs that prolong QT, chronic atrial fibrillation or branch blocks, previous stroke, heart failure stage III-IV, Wolf Parkinson White Syndrome.

Results: A total of 30 patients with DM participated in this study; 14 patients with type 1 DM (46.67%) and 16 patients with type 2 DM (53.33%). Within the group of type 1 DM, 61.54% presented hypoglycemic events vs. 56.25% of the patients in type 2 DM group, (p= 0.774) which correlates with the increased risk of hypoglycemic events in type 1 DM group. A total of 60% of the patients presented hypoglycemic events (n= 18) independently of glucose levels, and 40% of the patients (n=12) did not present it. Most of the hypoglycemic events (72.22% p=0.035) did not correlate with an arrhythmia event or cardiac repolarization disorder.

Conclusions: In our group of patients, high cardiovascular risks and long-term duration of type 1 or type 2 DM were strong enough factors to develop arrhythmia, independently of glucose levels. Maybe it would be necessary to study patients with a 48-hour holter in order to find out this association.

Disclosure

C. Musso: None. N.S. Sforza: None. Y.J. Morosan Allo: None. R.G. Clemente: None. A. Pavesi: None. C.C. Folino: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc.
2209-PUB: Type 2 Diabetes and Different Manifestations of Preexisting Cardiovascular Disease as Predictors of Specific Cardiovascular Events
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN-PURIN DANIELA , LARCHER BARBARA , MADER ARTHUR , STERNBAUER SIMON , SCHINDEWOLF MARC , BAUMGARTNER IRIS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2019

Coronary artery disease (CAD) and peripheral artery disease (PAD) confer an increased risk of cardiovascular events that is particularly high when type 2 diabetes (T2DM) is present in addition to cardiovascular disease (CVD). Here, we aimed at investigating the impact of T2DM and of the manifestation of pre-existing cardiovascular disease (PAD vs. CAD) as predictors of specific cardiovascular events. We prospectively recorded cardiovascular events over 10 years in 1777 patients with established CVD, including 1312 patients with CAD, of whom 29.3% had T2DM and 465 patients with PAD, of whom 43.9% had T2DM. T2DM after multivariate adjustment significantly predicted cardiovascular mortality (n=102; HR 1.77 [1.33-2.36]; p<0.001), myocardial infarction (n=74; HR 1.50 [1.10-2.04]; p=0.010), ischemic stroke (n=54; HR 1.69 [1.16-2.46]; p=0.007), and revascularization of non-coronary arteries (n=134; HR 1.66 [1.29-2.13]; p<0.001) independently from the manifestation of CVD. The presence of PAD versus that of CAD after adjustment for conventional cardiovascular risk factors including T2DM predicted myocardial infarction (HR 2.33 [1.61-3.37]; p<0.001) and revascularization of non-coronary arteries (HR 7.48 [5.51-10.16]; p<0.001). Neither T2DM nor the presence of PAD vs. that of CAD was significantly associated with percutaneous coronary interventions (n=246) or coronary artery bypass graftings (n=94) in our cohort. We conclude that both T2DM and the manifestation of pre-existing CVD predict cardiovascular events in patients with established CVD.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin-Purin: None. B. Larcher: None. A. Mader: None. S. Sternbauer: None. M. Schindewolf: None. I. Baumgartner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
2215-PUB: Serum Levels of the Advanced Glycation End Product (AGE) Pentosidine Do Not Correlate with the Extent of Coronary Artery Disease Assessed by SYNTAX Score
Authors: BASMAN CRAIG , AVTANSKI DIMITER , ZISKOVICH KARINA , JONAS REBECCA , FISHMAN SARAH , SONMEZ HALIS , RASHID UMAR , KODRA ARBER , STOFFELS GUILLAUME , LESSER MARTIN , SINGH VARINDER , PORETSKY LEONID
Published: June 2019

Advanced glycation end-products (AGEs) are endogenously produced or exogenously derived glycated proteins and lipoproteins. The accumulation of AGEs may have a variety of adverse effects since they cause oxidative stress and thus may act as contributing factors to the development of disease states such as, for example, complications of diabetes mellitus. The aim of this study was to investigate whether the levels of three AGEs (pentosidine, N(6)-carboxymethyllysine [CML], and methylglyoxal [MGO]) and the soluble form of the AGE receptor (sRAGE) may be used as markers for the presence and extent of coronary artery disease (CAD). We recruited 363 consecutive patients with suspected CAD who presented for cardiac catheterization at Lenox Hill Hospital in New York City (54% of patients were male, 48% of the patients had diabetes). At the time of this abstract submission 169 patients had circulating pentosidine levels measured (74 of these patients had diabetes). We examined relations between pentosidine levels, HbA1c, LDL, and the extend of CAD (measured by SYNTAX score). Serum pentosidine levels did not significantly correlate with any of other parameters. There was, however, a positive correlation between HbA1c levels and the SYNTAX score (Spearman correlation coefficients of 0.26, ρ = 0.0001 for the entire group; 0.18, ρ = 0.01 for patients without diabetes; and 0.29, ρ= 0.0001 for patients with diabetes).

In conclusion, our preliminary results demonstrate that in patients with suspected CAD undergoing cardiac catheterization, SYNTAX score does not correlate with pentosidine levels but correlates positively with HbA1c. The data on all three AGEs and sRAGE in the entire cohort of 363 patients will be presented at the meeting.

Disclosure

C. Basman: None. D. Avtanski: None. K. Ziskovich: None. R. Jonas: None. S. Fishman: None. H. Sonmez: None. U. Rashid: None. A. Kodra: None. G. Stoffels: None. M. Lesser: None. V. Singh: None. L. Poretsky: None.

Funding

The Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research
2216-PUB: More Precise Assessment of Flow-Mediated Dilation (FMD) by Measuring at Maximum Dilatory Peak Time (MDP) in Subjects With and Without Type 2 Diabetes (T2D)
Authors: HERBRAND THERESA , COESTER HANS VEIT , DEVRIES J. HANS , HEISS CHRISTIAN , HEISE TIM , KELM MALTE , SANSONE ROBERTO
Published: June 2019

FMD is widely used to quantify endothelial function. FMD is calculated from the artery’s baseline diameter and peak diameter during reactive hyperemia. To this day, many published FMD results are based on values assessed at predefined time points, e.g., 60 s after start of hyperemia, rather than at the time of MDP. This may limit the accuracy and reproducibility of FMD. We hypothesized that FMD values at MDP would be higher and more reproducible than at predefined times, resulting in a lower number of subjects needed to show significance for a given difference in FMD. FMD was measured in subjects with and without T2D by ultrasound (12 MHz transducer; GE Logiq P7, GE Healthcare, Germany). In a subset of subjects, FMD was measured again after 30 days. All measurements were performed by certified physicians and evaluated by three certified FMD analysts using Brachial Analyzer 5 (MIA LLC, U.S.). FMD values at 60 s and 90 s after start of hyperemia were compared to FMD at MDP using ANOVA. In this study, 100 healthy middle-aged subjects and 52 subjects with T2D (mean ± SD age 56 ± 5.4 years, T2D HbA1c 7.2 ± 0.7%) underwent FMD. FMD was measured again in 25 healthy subjects after 30 days. Overall, FMD was lower at predefined time points compared to MDP (least square mean difference (95% CI)) 60 s vs. MDP 1.12% ( 1.56; -0.68); p<0.0001 and 90 s vs. MDP 1.82% ( 2.27; 1.37); p<0.0001). The intra-subject variability was lowest for MDP compared to 60 s and 90 s (15% vs. 36% vs. 51%). Assuming 80% power and alpha at 0.05, the MDP requires 15 people to detect a 1% difference in FMD versus 26 and 31 subjects if determined at 60 s and 90 s. This study demonstrated significantly higher FMD values and superior reproducibility of the individually determined maximum dilatory peak compared to peaks at predefined time points. This roughly halves the number of study participants needed to detect a 1% difference in FMD.

Disclosure

T. Herbrand: None. H. Coester: None. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S. Employee; Self; Profil Institute for Metabolic Research. Research Support; Self; Medtronic. Speaker's Bureau; Self; Novo Nordisk A/S. C. Heiss: None. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. M. Kelm: None. R. Sansone: None.
2227-PUB: Relationship between Depression and Cardiovascular Outcomes in T2DM Patients: A Propensity Score-Matched Analysis of ACCORD Trial
Authors: CHEN YUNZHI , ZHUANG DIAODONG , LIANG HUA , CHEN XIJIE , XU XIAO
Published: June 2019

Background: Despite the fact that depression increases risk for cardiovascular disease (CVD), there has met a controversy that evidences linking well depression management to CVD outcomes improvement have yet to be established. In this study, we aim to explore relationship between depression and CVD outcomes among T2DM patients in intensive and standard glycemic therapy cohort.

Method: The ACCORD database was divided into intensive glycemic therapy cohort and standard cohort. And we applied logistic regression model to assess the association between depression and CVD outcomes (primary outcome and secondary outcomes), using the propensity score method to adjust for age, gender, BMI, waist, CVD history, race, live alone, education, SBP, DBP, TRIG, CPK, alcohol, VLDL, heart failure and smoke in each cohort.

Result: 2272 patients were included in the standard glycemic therapy cohort and 2192 in the intensive cohort finally. Propensity score adjusted logistic models showed that there was no significant difference in CVD outcomes between depressed and non-depressed patients in the standard glycemic therapy cohort. While in the intensive glycemic therapy cohort, the risk of congestive heart failure was significantly higher in patients with depression than in the non-depressed group (p=0.019, OR: 1.608, 95% CI: 1.082-2.39). Besides, depressed patients seemed to more likely to develop non-fatal myocardial infarction (P=0.058, OR: 1.417, 95% CI: 0.989-2.032).

Conclusion: On equal terms, T2DM patients with depression have a greater risk of congestive heart failure in patients receiving intensive glycemic therapy, while a larger prospective randomized controlled trial focusing on this endpoint is needed to verify our result.

Disclosure

Y. Chen: None. D. Zhuang: None. H. Liang: None. X. Chen: None. X. Xu: None.
2233-PUB: Clinical Features and Biomarkers of Nonalbuminuric and Albuminuric Patterns of Chronic Kidney Disease in Subjects with Type 2 Diabetes
Authors: KORBUT ANTON I. , KLIMONTOV VADIM
Published: June 2019

The Aim: to define the phenotypes of non-albuminuric and albuminuric chronic kidney disease (NA-CKD and A-CKD) in subjects with type 2 diabetes (T2D).

Methods: One hundred and eighty four T2D patients were included in the study. Patients with urinary albumin to creatinine ratio (UACR) <3 mg/mmol and estimated glomerular filtration rate (eGFR) <60 ml/min×1.73 m2 were classified as NA-CKD group (n=111). Individuals with persistent UACR >3 mg/mmol and eGFR <60 ml/min×1.73 m2 were considered as A-CKD patients (n=73). Urinary nephrin and podocin, as podocyte injury markers, and whey acidic protein four-disulfide core domain protein 2 (WFDC-2), which is considered as a marker of tubulointerstitial involvement, were assessed by ELISA and compared to control (20 nondiabetic subjects).

Results: The NA-CKD pattern was associated with female sex (p=0.04), reduced HbA1c levels (p=0.04) and diuretic use (p=0.001). Patients with A-CKD, as compared to NA-CKD one, demonstrated lower body weight (p=0.02), waist-to-hip ratio (p=0.009), HDL-cholesterol (p=0.01), and lymphocyte count (p=0.002). Age, diabetes duration, the prevalence of diabetic retinopathy, coronary artery disease, myocardial infarction, chronic heart failure and stroke did not differ between the groups. The nephrin and podocin concentrations, adjusted to urinary creatinine, were increased significantly in subjects with A-CKD only (p=0.002 and 0.04 respectively). The excretion of WFDC-2 was elevated in both NA-CKD and A-CKD groups (p=0.01 and p=0.0003 respectively).

Conclusion: In T2D subjects, female gender, acceptable glycemic control and treatment with diuretics are associated with NA-CKD, whereas abdominal obesity, poor glycemic control, and elevated urinary excretion of podocyte markers are the features of A-CKD. Urinary WFDC-2 excretion is increased in both CKD phenotypes.

Disclosure

A.I. Korbut: None. V. Klimontov: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi.
2237-PUB: Validation of the Simple Diagnostic Criteria in Japan
Authors: HIMENO TATSUHITO , SHIBATA YUKA , SHIMODA HIROMI , KONDO MASAKI , TSUNEKAWA SHIN , KATO YOSHIRO , NAKAMURA JIRO , KAMIYA HIDEKI
Published: June 2019

Introduction: The simple diagnostic criteria (SDC) proposed by Diabetic Neuropathy Study Group in Japan has been widely accepted in our country. However, the diagnostic ability has not yet been fully validated. In the present study, we examined the usefulness of SDC in diagnosis of diabetic polyneuropathy (DPN).

Methods: We evaluated admitted 114 diabetic subjects who were diagnosed as DPN employing three independent decision rules consisting SDC: physical signs and symptoms (PHY), nerve conduction study (NCS), or coefficient of variation of RR interval (CVR-R) on electrocardiogram (CVRR).

#1. PHY rule: satisfied any two or more of following three items: the presence of symptoms considered to be due to DPN, the decrease or disappearance of bilateral Achilles tendon reflexes, and decreased vibration in the bilateral medial malleoli.

#2. NCS rule: one or more nerve conduction abnormalities in two or more nerves out of 12 peripheral nerves.

#3. CVRR rule: less than 2% of CVR-R.

The diagnostic accuracy was evaluated using the NCS rule as the reference standard.

Result:

1. Ninety-six subjects (84.2%) diagnosed as DPN. The proportions of DPN were 37.7% for PHY, 74.6% for NCS, and 43.9% for CVRR.

2. The diagnostic accuracy of PHY and/or CVRR.

Discussion: Diagnosis by NCS showed the highest prevalence. The sensitivity of PHY was improved by a combination with CVRR. DPN can be identified effectively utilizing SDC.

Disclosure

T. Himeno: None. Y. Shibata: None. H. Shimoda: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: Speaker's Bureau; Self; Merck & Co., Inc. J. Nakamura: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceu. Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. H. Kamiya: Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Novo Nordisk Oharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K.
2247-PUB: Comparative Analysis of the Thickness of Inner Retinal Layers among African Immigrants Based on Their Status of Glucose Tolerance
Authors: HWANG CHRISTOPHER K. , AGRON ELVIRA , SUMNER ANNE E. , BRIKER SARA M. , ADUWO JESSICA Y. , DUBOSE CHRISTOPHER , CHEW EMILY
Published: June 2019

Inner retinal neurodegeneration was found, independent of the severity of retinopathy in persons with diabetes (DM). However, it is unknown whether the inner retinal neurodegeneration is evident in people with prediabetes (preDM) or asymptomatic people with newly diagnosed DM. In this cross-sectional study, we prospectively enrolled African immigrants who self-identified as being healthy with no prior history of diabetes. Each participant was tested for diabetes with an OGTT and underwent a comprehensive eye exam with spectral-domain optical coherence tomography and stereoscopic fundus photographs. The thickness of parafoveal (PA) retinal nerve fiber layer (RNFL), perifoveal (PE) RNFL, PA ganglion cell + inner plexiform layers (G+I), and PE G+I were measured using an automated segmentation software. A total of 211 African immigrants enrolled in the study. After excluding participants with a history or signs of glaucoma and other conditions that could affect retinal structural integrity, there were 21 DM participants (76% male, age 46 (28-61y) (mean (range))), 72 preDM participants (61.1% male, age 42.4 (23-65)), and 91 normal glucose tolerant (NGT) participants (58% male, age 36 (20-62y)). From the 91 NGT control subgroup, 52 age-sex-matched participants were selected for comparative analyses (64% male, age 43 (32-62y)). Among participants in the 3 subgroups (DM, preDM, NGT), there was no significant difference in the mean thickness of PA RNFL (24.7 (2.4) (mean (SD)), 24.9 (2.1), 24.6 (2.8), respectively, P=0.863), PE RNFL (35.9 (3.8), 36.7 (4.1), 35.4 (3.2), P=0.794), PA G+I (88.8 (5.6), 90.6 (10.3), 89.7 (7.2), P=0.415), or PE G+I (65.0 (5.0), 67.2 (5.6), 67.4 (4.2), P=0.194). With this limited sample size, we were unable to find in fircan an association of neurodegeneration in persons with PDM and NDM. Future studies with larger sample size may provide further supporting evidence for such an association.

Disclosure

C.K. Hwang: None. E. Agron: None. A.E. Sumner: None. S.M. Briker: None. J.Y. Aduwo: None. C. DuBose: None. E. Chew: None.
2254-PUB: Durability and Effectiveness of Split-Thickness Skin Grafting of the Plantar Foot
Authors: WALTERS ELLIOT , PANDYA MIRA , RAJPAL NEHA , ABBOUD MICHEL M. , ATTINGER CHRISTOPHER , KIM PAUL J.
Published: June 2019

Background: Split-thickness skin grafting (STSG) is an effective coverage method for chronic foot ulcers. Many of these ulcers develop on the plantar aspect of the foot. Split-thickness skin grafting may be a high-risk operation in such a high wear area. However, outcomes data is lacking for patients receiving STSG to the plantar aspect of the foot, especially in terms of recurrence. The purpose of this study is to retrospectively compare outcomes of STSG to plantar and non-plantar chronic ulcers.

Methods: Medical records for all patients receiving STSG from 2014-2016 at our institution were reviewed under IRB approval. Major outcome measures included time to healing and time to ulcer recurrence.

Results: There were 158 patients with 182 STSGs identified. Fifty-two STSGs were located on the plantar surface of the foot and 130 STSGs on a non-plantar surface. Percent take at 30 days was not significant between the two groups (56% plantar vs. 60% non-plantar, p=0.199). However, plantar surface STSGs were significantly less likely to be healed at 60, 90, and 365 days (p<0.05). STSGs on the plantar surface were 3.7 times more likely to experience a grafting complication (OR 3.7, 95% CI 1.82-7.50). After 12 months of follow-up there was no significant difference in ulcer recurrence (17% plantar vs. 10% non-plantar, p=0.172).

Conclusions: Split-thickness skin grafting to the plantar surface of the foot is more likely to experience complications and take longer to heal than on non-plantar surfaces but the durability of the graft approximates that of non-plantar surface grafts. This suggests that STSG to the plantar surface of the foot may require more upfront investment from the patient and the surgeon but remains a viable wound coverage option.

Disclosure

E. Walters: None. M. Pandya: None. N. Rajpal: None. M.M. Abboud: None. C. Attinger: Consultant; Self; Acelity, Integra LifeSciences. P.J. Kim: Consultant; Self; Acelity, Integra LifeSciences.
2261-PUB: Update on U.S. Federal Government Programs for Diabetes
Authors: POWELL CLYDETTE
Published: June 2019

The U.S. Congress passed Public Law 115-80 in November 2017 requiring the Department of Health and Human Services (HHS) to establish a National Clinical Care Commission. The purpose of this Commission is to evaluate and make recommendations to the U.S. Secretary of Health and to the U.S. Congress regarding improvements to the coordination and leveraging of programs within HHS and other federal agencies (e.g., Veterans Administration) that relate to diabetes and its complications. The Commission was launched in October 2018 and now is reviewing the large scope of federal efforts that support clinicians in providing integrated, high-quality care to individuals with diabetes and its complications. These efforts include identifying current activities and gaps in coordination of federal education and awareness around prevention; treatment; use of new and existing technologies; methods for outreach and dissemination of education and awareness materials; and whether there are opportunities for consolidation of inappropriately overlapping or duplicative federal programs related to diabetes and its complications. This session will provide an overview of the current work of the National Clinical Care Commission with examples from some federal agencies, such as the Centers for Medicare and Medicaid Services, the Agency for Health Care Research and Quality, and the Veterans Administration.

Disclosure

C. Powell: None.
2267-PUB: Skeletal Muscle mRNA Transcriptional Signature of Response to Exercise of Patients in Different Stages of Glucose Tolerance
Authors: SZCZERBINSKI LUKASZ , NIEMIRA MAGDALENA , SZCZERBINSKI KAROL , PUCHTA URSZULA , CITKO ANNA , SIEWIEC ELWIRA , ZAPOLSKA JOANNA , TAYLOR MARK , LARSEN STEEN , GORSKA MARIA , KRETOWSKI ADAM
Published: June 2019

Physical activity is an effective method to prevent and treat type 2 diabetes (T2D); however, the mechanisms of its beneficial effects have not been precisely elucidated. Skeletal muscle is a major contributor to overall glucose homeostasis in the body and is responsible for the efficacy of exercise intervention in the prevention and treatment of T2D. Currently, there is a lack of studies investigating the transcriptional signature of exercise training on skeletal muscles of patients with different stages of glucose tolerance.

Thus, the aim of this study was to identify the mRNA signature of skeletal muscle adaptation to three-month exercise intervention in patients with different dysregulations of glucose metabolism.

For this project we included 35 sedentary males, aged 24-65 years old, with BMI 26-33 kg/m2, divided into three groups: 15 normoglycemics, 12 prediabetics and 8 subjects with type 2 diabetes, treated with metformin only. RNA samples were obtained from biopsied Vastus lateralis muscles, before and after a 3-month supervised exercise intervention that occurred thrice weekly and consisted of mixed aerobic (60-70% of individual’s VO2max) and strength (60-70% of the repetition maximum for each exercise) activities. Selected groups of patients did not differ in age, BMI, number of performed trainings or diet during the intervention. mRNA sequencing was performed on an Illumina HiSeq 4000.

We found highly significant differential mRNA expression in normoglycemics vs. T2D and prediabetic subjects, mostly related to mitochondrial processes, including the oxidative phosphorylation and thermogenesis pathways. Furthermore, we found that exercise intervention mostly affected these pathways, suggesting that a major defect of skeletal muscle in type 2 diabetes development is related to mitochondrial function and can be diminished by exercise.

Disclosure

L. Szczerbinski: None. M. Niemira: None. K. Szczerbinski: None. U. Puchta: None. A. Citko: None. E. Siewiec: None. J. Zapolska: None. M. Taylor: None. S. Larsen: None. M. Gorska: None. A. Kretowski: None.

Funding

Polish Diabetes Association; Polish Ministry of Science and Higher Education
2277-PUB: Lower Serum Albumin, Sodium, Calcium, and Phosphorus in Elderly Diabetic Patients with Community-Acquired Pneumonia
Authors: ZHENG FANGQIU
Published: June 2019

Objectives: To compare the laboratory features between elderly (aged ≥60) diabetic patients with community-acquired pneumonia(CAP) and elderly diabetic patients without CAP.

Methods: This is a retrospective data analysis of in-hospital subjects. A total of 121 elderly patients diagnosed with type 2 diabetes: 41 with CAP and 80 without CAP. The course of disease was similar between the two groups. Mean (SD) age of patients with CAP was 70.84 (5.37) years, mean (SD) age of patients without CAP was 68.32(5.19) years. Laboratory data of the two groups were compared using univariate analysis.

Results: Fasting serum albumin, sodium, calcium, phosphorus and 24-hour urine calcium, 24-hour urine phosphorus in elderly diabetic patients with CAP were significantly lower than those in elderly diabetic patients without CAP. Elderly diabetic patients with CAP had lower albumin: 33.73 (4.85) vs. 38.84 (4.93) g/L, p<0.05, sodium: 134.98 (7.05) vs. 138.77 (6.77) mmol/L, p<0.05, calcium:2.23 (0.13) vs. 2.35 (0.15) mmol/L, p<0.05, phosphorus: 0.92 (0.22) vs. 1.14 (0.22) mmol/L, p<0.05, 24-hour urine calcium: 111.30 (75.02) vs. 185.23 (127.49) mg/24 hours, p<0.05, and 24-hour urine phosphorus:340.48 (227.62) vs. 462.19 (286.73) mg/24 hours, p<0.05. No significant differences were found in levels of fasting blood glucose, insulin, HbA1c, blood urea nitrogen, creatinine, alkaline phosphatase.

Conclusion: In-hospital type 2 diabetes patients aged 60 and older complicated by CAP had a lower serum albumin, sodium, calcium and phosphorus compared with elderly diabetic patients without CAP. These differences should elicit medical attention and may be the risk factors for the elderly diabetic patients complicating CAP.

Disclosure

F. Zheng: None.