bluuebunny/crossref_metadata_2025 huggingface dataset:
519-P: Acute Kidney Injury Sensitivity in Diabetic Murine Model
Authors: SONG SANG HEON , KIM SANG SOO , KIM IN JOO
Published: June 2019

Background: We recently reported that diabetes can upregulate two discrete isoforms of the MMP-2 (full length and N-terminal truncated, FL-MMP-2, NTT-MMP-2) in renal tubules and especially, inducible NTT-MMP-2 could be related to renal tubular damage. Also, pyrrolidinedithiocarbamate (PDTC), NF-Kb inhibitor, can suppress NTT-MMP-2 selectively. This study was conducted to analyze the effects of acute kidney injury on diabetic animal model and test the effect of PDTC in acute kidney injury with diabetes.

Methods: We performed unilateral ischemia-reperfusion injury (uIRI) in streptozotocin-induced diabetic animals as a model of acute kidney injury and followed for 48 hours and six weeks. Mice were randomized into four groups as follows; control (A), non-DM+uIRI (B), DM+uIRI (C), DM+uIRI+PDTC (D).

Results: In a 48-hour experiment, tubular necrosis was more severe in diabetic IR kidney compared with nondiabetic IR kidney. Outer medulla in group C was becoming devastated and led to the extensive coagulative necrosis. Those findings were diminished by PDTC. Peritubular capillary density was increased by PDTC and cortical macrophage density was decreased by PDTC compared to group B and C. The nitrotyrosin was lesser expressed by PDTC compared to group B and C. In a six-week experiment, IRI caused the kidney to be stiffen and shrink both in group B and C and PDTC can ameliorate these gross changes compared to group C. Peritubular capillary density was increased by PDTC compared to group C. Cortical macrophage density was higher than group B and D and PDTC ameliorate the recruitment of macrophage in renal cortex. The expression of cleaved caspase-3/caspase 3 in group C was higher than group B and D.

Conclusion: Ischemia-reperfusion injury caused more intense renal damage in diabetic murine model and could lead to chronic renal change related to inflammation and apoptotic pathway. These changes may be mitigated by PDTC treatment associated with anti-oxidative mechanism and inhibition of NTT-MMP-2.

Disclosure

S. Song: None. S. Kim: None. I. Kim: None.

Funding

National Research Foundation of Korea (2016R1A2B4008243)
525-P: Integrated Mirnome and Proteomic Analyses in Plasma and Progression to ESRD in Diabetes
Authors: SATAKE EIICHIRO , SKUPIEN JAN , MD DOM ZAIPUL I. , KOBAYASHI HIROKI , IHARA KATSUHITO , PEZZOLESI MARCUS G. , NIEWCZAS MONIKA , KROLEWSKI ANDRZEJ
Published: June 2019

Background: MicroRNAs (miRNAs) are involved in gene regulation and play important roles in the etiology of various diseases including diabetic kidney disease. The objective of this study was to determine miRNAs profile and their target proteins associated with risk of progression to end-stage renal disease (ESRD) in diabetes.

Methods: Using HTG edge sequence platform, 2,083 miRNAs were measured in baseline plasma specimens of patients with renal impairment (CKD stage 3 and 4). We also measured 1,029 protein levels using SomaScan proteomics platform to assess the target proteins of candidate miRNAs. We studied 375 patients with diabetes: 239 patients with type 1 diabetes as our exploratory panel and 136 patients with type 2 diabetes as our replication panel.

Results: We identified 19 circulating miRNAs that were strongly associated with progression to ESRD in both T1D and T2D. Among them, 4 representative miRNAs were selected. In pathway analysis, Axon guidance (AG) was the most significant pathway enriched by genes targeted by the representative miRNAs. Our proteomics platform included 41 AG proteins and 6 of them were identified to be associated with ESRD in T1D and T2D. Mediation analysis revealed that 10-83% of the miRNAs effect on ESRD is mediated through axon guidance proteins, namely 2 Ephrin ligands and 4 Ephrin receptors.

Conclusions: Our results suggest that certain miRNAs play a significant etiological role in progression of diabetic kidney disease to ESRD mediated by axon guidance proteins. These miRNAs and AG proteins have the potential to be used as novel therapeutic targets and prognostic biomarkers.

Disclosure

E. Satake: None. J. Skupien: None. Z.I. Md Dom: None. H. Kobayashi: None. K. Ihara: None. M.G. Pezzolesi: None. M. Niewczas: None. A. Krolewski: None.

Funding

National Institutes of Health; Novo Nordisk Foundation; Sunstar Foundation
53-LB: Availability of Diabetes Self-Management Education and Support Programs in United States Counties
Authors: JAYAPAUL-PHILIP BINA , DAI SHIFAN , WOGHIREN EFOMO , RUTLEDGE GIA E.
Published: June 2019

Authors developed an interactive map visualizing county level availability of Diabetes Self-Management Education and Support (DSMES) site or program locations. Location data were overlaid with diabetes prevalence data and socio-economic status data. Over 4200 locations were geocoded including 3471 sites (American Diabetes Association recognized) and 802 program locations (American Association of Diabetes Educators accredited). Counties were characterized as having or not having DSMES class locations. Counties were additionally characterized based on tertiles of diabetes prevalence and socio-economic disadvantage (using the Area Deprivation Index (ADI) score). This analysis showed that 48 percent of U.S. counties (1515/3142 counties and county equivalents) had a DSMES program with at least one site or program location. Approximately 39% of counties in the highest diabetes prevalence tertile (greatest diabetes burden) had DSMES programs compared to 53% in the middle tertile of diabetes prevalence and 54% in the lowest tertile of diabetes prevalence. Approximately 26% of counties in the tertile with highest ADI scores (representing greatest socio-economic disadvantage) had DSMES programs compared to 48% in the middle tertile and 69% percent in the tertile with the lowest ADI scores (least socio-economic disadvantage). This interactive map is a tool that can be used at a national level and by state and local health departments and others to prioritize establishment and expansion of programs in underserved counties with higher rates of diabetes prevalence and greater socio-economic disadvantage.

Disclosure

B. Jayapaul-Philip: None. S. Dai: None. E. Woghiren: None. G.E. Rutledge: None.
541-P: The Il-8-CXCR1/2 Axis and Its Targeting in Diabetic Kidney Disease
Authors: ROCCHIO FRANCESCA , NASR MOUFIDA BEN , D'ADDIO FRANCESCA , LORETELLI CRISTIAN , USUELLI VERA , ASSI EMMA , NIEWCZAS MONIKA , ESSAWY BASSET EL , PEZZOLESI MARCUS G. , CORRADI DOMENICO , ZUCCOTTI GIANVINCENZO , FIORINA PAOLO
Published: June 2019

Introduction: Recent studies suggested a major involvement of the inflammation process in the onset and maintenance of diabetic kidney disease (DKD). We aimed to evaluate the role of the IL-8-CXCR1/2 pathway in DKD.

Material and Methods: Human studies: We measured the urinary IL-8 levels from a cohort of 1182 patients affected by type 2 diabetes (T2D) using Luminex and quantified IL-8 protein/mRNA expression in kidney samples by immunohistochemistry, immunofluorescence and RT-PCR. Murine in vivo studies: The expression of KC (a murine homologue of IL-8) was quantified during the progression of DKD while the effect of CXCR1/2 blockade was analyzed in diabetic Lepdb/db mice. In vitro studies: We mechanistically determined the impact of the IL-8-CXCR1/2 pathway in vitro in an immortalized cell line of human podocytes.

Results: (i) Human studies: IL-8 urinary levels are increased in T2D patients with DKD. In addition, we found that those with microalbuminuria showed high urinary IL-8 levels which are associated with a higher Glomerular Filtration Rate (GFR) decline, a significant increase of the Albumin/Creatine Ratio (ACR) and development of worst renal outcomes. Patients affected by T2D and DKD have higher IL-8 glomerular expression compared to controls. CXCR1/2 are mainly localized at glomerular level and expressed by podocytes while IL-8 is localized in CD31+ endothelial cells. (ii) Murine studies: KC blockade reduces albuminuria and renal damage in Lepdb/db mice. (iii) In vitro studies: Podocytes express high levels of CXCR1/2. Treatments with the recombinant IL-8 induce DNA damage in podocytes while CXCR1/2 blockade prevent it.

Conclusion: IL-8-CXCR1/2 pathway may have a role in DKD onset by inducing a podocyte-mediated damage and its blockade may represent an add-on therapy to current therapeutic strategies.

Disclosure

F. Rocchio: None. M. Ben Nasr: None. F. D'Addio: None. C. Loretelli: None. V. Usuelli: None. E. Assi: None. M. Niewczas: None. B. El Essawy: None. M.G. Pezzolesi: None. D. Corradi: None. G. Zuccotti: None. P. Fiorina: None.
545-P: The Difference in the Effects on Microalbuminuria Depending on the Order of GLP-1RA and SGLT2i Therapy in Type 2 Diabetes
Authors: OHARA MASAYA , MOTOYAMA KOKA , TAMAI ANNA , SAKURA TAKESHI , YAKUSHIJI YOSUKE , HOSOI MASAYUKI
Published: June 2019

Background: It has been reported that the combination therapy of Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i) decrease micro-albuminuria in type 2 diabetes (T2DM) with nephropathy. There is the possibility that protective effects on estimate glomerular filtration rate (eGFR) and micro-albuminuria are different between (1) GLP-1RA add-on therapy to SGLT2i and (2) SGLT2i to GLP-1RA.

Objective: In this study, we aimed to clarify whether there are differences in the changes of eGFR and micro-albuminuria depending on the order of combination therapy between (1) and (2) in T2DM.

Method: We studied 69 patients with T2DM who took GLP-1RA together with SGLT2i in Our Hospital, retrospectively. We investigated urine albumin to creatinine ratio (ACR), eGFR, body mass index (BMI), systolic blood pressure (SBP), HbA1c, UA, Na, Cl, hematocrit (Ht) and platelet (Plt) before and after six months of the therapy. Six months changes (delta:Δ) of clinical parameters were compared between each combination therapy.

Result: In all subjects, HbA1c, BMI and logACR were significantly decreased with the therapies, respectively. As the comparison of Δ in each clinical factors between (1) and (2) groups, ΔHbA1c of (1) significantly showed lower levels than (2). Whereas ΔNa and ΔCl of (1) significantly showed higher levels. Multiple regression analysis including ΔPlt, ΔHt, ΔUA, ΔBMI, ΔHbA1c, and the type of combination therapy as an independent factor for eGFR, ΔUA, ΔHt and ΔHbA1c were the significant contributing factors. Multiple regression analysis including ΔBMI, ΔHDL-C, ΔHbA1c, age, sex and the type of combination therapy as an independent factor for ΔlogACR, ΔHDL-C was the significant contributing factor. The type of combination therapy was not shown as a significant associated factor for ΔlogACR.

Conclusions: Both GLP-1RA add-on therapy to SGLT2i and SGLT2i to GLP-1RA equally reduce albuminuria in T2DM with nephropathy.

Disclosure

M. Ohara: None. K. Motoyama: None. A. Tamai: None. T. Sakura: None. Y. Yakushiji: None. M. Hosoi: Speaker's Bureau; Self; Eli Lilly and Company.
546-P: Deep Learning Predictions of Diabetic Retinopathy Associated with Progression of Renal Disease in Type 1 Diabetes
Authors: MELLOR JOSEPH C. , STORKEY AMOS J. , COLHOUN HELEN , MCKEIGUE PAUL M. ,   ON BEHALF OF THE SDRNT1BIO INVESTIGATORS
Published: June 2019

Background and Aims: We considered if deep learning (DL) models trained to predict diabetic retinopathy (DR) are also useful for prediction of renal disease in people with type 1 diabetes.

Materials and Methods: We used 35000 retinal images and associated ground truth DR grades from the online Kaggle dataset. These were used to train a Resnet convolutional neural network (CNN) to predict the ground truth DR grades. The CNN was then applied to retinal images for each patient in the SDRNT1BIO available from the national screening program generating 10 DL outputs corresponding to DR gradings for both eyes. Longitudinal eGFR readings and risk factor data were available for the SDRNT1BIO through linkage to clinical records. Univariate associations of DL outputs with final eGFR at follow-up was tested via linear regression models. A penalised Bayesian approach using 10-fold cross-validation was used to select the most predictive DL features and assess prediction performance.

Results: We found 7 DL outputs had a significant univariate association with follow-up eGFR adjusting for age, sex, duration of diabetes, baseline eGFR, and length of follow-up at p<10-4. 4 DL outputs remained significant on adjusting for the screening program manual DR grading of the image (p ranging from 1.62x10-8 to 9.9x10-5). For predicting achieved eGFR we found that DL outputs improved test log-likelihood by 22.2 natural log units (equivalent to a p-value of < 10-9) increasing the R2, from 0.64 to 0.65.

Conclusion: This small study demonstrates that retinal images contain information for predicting eGFR decline and that deep learning can extract this information. Future work on a larger dataset using DL to predict renal disease progression directly is therefore warranted.

Disclosure

J.C. Mellor: None. A.J. Storkey: None. H. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. P.M. McKeigue: Advisory Panel; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Stock/Shareholder; Spouse/Partner; Bayer AG, Roche Pharma.
55-LB: Mobile Phone Text Message Intervention on Self-Care Activities and Food Choices among Patients with Type 2 Diabetes
Authors: NEPPER MARTHA J.
Published: June 2019

This study examined the effects of educational text messages on diabetes self-care, cardiovascular disease (CVD) risk awareness and food choices (home food availability) among patients with type 2 diabetes. Quasi-experimental design was used with 40 patients (58.0±10.6 years) in the intervention and 39 (55.7±12.2 years) in the control group. In addition to the usual care provided for all participants, the intervention group received three educational text messages weekly for 12 weeks (total of 36 text messages). Pre- and post-intervention measures were collected for both groups. Analysis of covariance was used to assess the intervention effects. Ninety-four percent (94%) of the participants receiving text messages indicated the usefulness of this program and would highly recommend this program to others with type 2 diabetes. The intervention group either maintained the same level at baseline or demonstrated a trend of improvement in self-care activities (healthy eating, exercise, blood glucose testing, medication adherence and foot care) after intervention. Non-statistical significant improvements in weekly MET (Metabolic Equivalent Test) minutes for total minutes of exercise (absolute change=768 minutes; p=0.62) and moderate/vigorous physical activities (absolute change=1688 minutes, p=0.62) were observed for the intervention group. There was no significant differences in nutrients intake (carbohydrate, sugar, added sugar, total fat, and saturated fat) between the intervention and control group at baseline and at 12-week follow-up and no significant changes were observed for dietary nutrients after intervention. However, significant increases in scores of CVD awareness (P=0.04) and availability of fresh fruits (P=0.01) and fresh vegetables (P=0.02) in the home were observed for intervention relative to control group. The pilot results suggest the feasibility and usefulness of the text message program for diabetes education.

Disclosure

M.J. Nepper: None.

Funding

University of Nebraska-Lincoln
552-P: Baroreflex Function and Postprandial Hypotension in Older Adults With and Without Type 2 Diabetes
Authors: MADDEN KENNETH M. , FELDMAN BORIS , MENEILLY GRAYDON S.
Published: June 2019

Background: Type 2 diabetes (T2DM) is a common etiology of postprandial hypotension (PPH), possibly as a result of autonomic neuropathy resulting in baroreflex dysfunction. We examined baroreflex function in older adults with PPH (with and without T2DM) during a standardized meal test.

Methods: 57 adults with PPH (age >= 65; 30 without T2DM, 27 with T2DM) were recruited sequentially from a geriatric medicine clinic (mean age 77.9±0.9 years, 54% female) and had meal tests performed. A Finometer (Finapres Medical Systems) was used to monitor blood pressure. The baroreflex effectiveness index (BEI, percent) was calculated using the sequence method.

Results: Baseline BEI showed no association with the average PPH response (p=0.521), the maximal PPH response (p=0.282), or the number of hypotensive episodes (p=0.859). As shown in Figure 1, baseline BEI was lower in subjects with T2DM than in those without T2DM (p<0.001), but this impairment in baroreflex function was not observed postprandially. There was no significant difference in the average PPH response between those with and without T2DM (p=0.358).

Conclusions: Although older subjects with PPH secondary to T2DM have lower baseline baroreflex function than older subjects with PPH without T2DM, this baroreflex impairment was not associated with the size of the PPH response. This suggests that PPH in the T2DM is not due to impairments in the arterial baroreflex.

Disclosure

K.M. Madden: None. B. Feldman: None. G.S. Meneilly: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc.

Funding

Allan M. McGavin Foundation; Canadian Diabetes Association
553-P: Differential Effects of High-Intensity Interval Training on Somatosensory and Autonomic Nerve Function in Patients with Type 2 Diabetes
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , APOSTOLOPOULOU MARIA , PESTA DOMINIK , RODEN MICHAEL , ZIEGLER DAN
Published: June 2019

It remains unclear, whether exercise training as part of lifestyle intervention has favorable effects on the development or progression of diabetic neuropathy in patients with type 2 diabetes (T2D). Therefore, we assessed peripheral and autonomic nerve fiber function and morphology in patients with T2D as well as in individuals with normal glucose tolerance (CON) before and after a high intensity interval training (HIIT) intervention program over 12 weeks. The T2D group included 20 male individuals ([median (1st; 3rd quartile)] age: 56 (53; 63) years; diabetes duration: 5 (2; 9) years; BMI: 31.2 (28.6; 32.8) kg/m²; HbA1c: 6.9 (6.4; 8.0)%). The CON group was matched for age, sex, and BMI (n=23; age: 57 (53; 60) years; BMI: 30.3 (28.4; 32.2) kg/m²; HbA1c: 5.4 (5.2; 5.7)). Somatosensory and autonomic nerve tests included nerve conduction velocity, quantitative sensory testing, skin biopsy, corneal confocal microscopy, cardiovascular autonomic function tests (CAFT), and spontaneous baroreflex sensitivity (BRS). After 12 weeks of HIIT, no improvement in somatosensory nerve tests was detected in T2D or CON. In both groups, resting heart rate decreased ([mean±SEM] baseline vs. follow-up: T2D: 68.8±2.3 vs. 63.4±1.8 bpm; CON: 65.1±1.8 vs. 60.2±1.9 bpm; both P<0.05). The change in systolic blood pressure after standing up (-13.9±2.6 vs. -9.4±2.2 mmHg) and three BRS sequence analysis indices (e.g., BRS-slope: 7.9±1.9 vs. 12.6±5.1 ms/mmHg) improved in T2D (P<0.05), while the standard deviation of normal RR intervals (SDNN; 36.1±2.6 vs. 55.3±8.8 ms; P<0.05) and coefficient of variation (CV; 3.8±0.3 vs. 5.2±0.7%; P<0.05) improved in CON.

In conclusion, while cardiovascular autonomic function improved moderately after 12 weeks of HIIT in male T2D patients, a longer training period may be required to achieve favorable effects on somatosensory nerve function or morphology.

Disclosure

G.J. Bönhof: None. A. Strom: None. M. Apostolopoulou: None. D. Pesta: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D. Ziegler: Advisory Panel; Self; Allergan, TrigoCare. Consultant; Self; Mitsubishi Tanabe Pharma Corporation, Mylan, Novartis Pharmaceuticals Corporation, Wörwag. Speaker's Bureau; Self; Berlin-Chemie AG.

Funding

German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research
554-P: Glycemic Variation Predicts Microvascular Risk in both ACCORD and VADT
Authors: ZHOU JIN , REAVEN PETER
Published: June 2019

The relationship of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) is controversial. Using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veteran Affairs Diabetes Trial (VADT), we investigated this relationship. In ACCORD, fasting glucose was measured every 4 months during the first year then annually for up to 84 months in 10251 individuals. In the VADT, fasting glucose were measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV). In Cox proportional hazard models, log CV in both ACCORD and the VADT were associated with development of future microvascular outcomes (composite of nephropathy and retinopathy) even after adjusting for other risk factors, including average glycemic control (Figure 1). Additional adjustment for severe hypoglycemic episodes did not account for the effect of glucose variability. This analysis indicates that variability of fasting glucose may play a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.

Disclosure

J. Zhou: None. P. Reaven: Advisory Panel; Self; Boston Heart Diagnostics. Research Support; Self; AstraZeneca, Novo Nordisk Inc.

Funding

National Institutes of Health
558-P: Rate of Progression of Utah Early Neuropathy Symptom Score in Diabetic Neuropathy
Authors: SINGLETON J. ROBINSON , HAUER PETER E. , REVERE CATHY , FOSTER-PALMER STORMY C. , APERGHIS ADRIENNE B. , SMITH A. GORDON
Published: June 2019

The Utah Early Neuropathy Scale (UENS) is a brief, validated exam scale focused on injury to small diameter nociceptive fibers. Twenty-four of 42 possible points are related to measurement of length dependent loss of pin sensation in legs and feet. While the UENS has been accepted as a standard clinical measure for diagnosis of small fiber neuropathy, its utility as a primary outcome measure in clinical trials has not been evaluated. Here we report natural history progression of the UENS. In an NIDDK DP3 single center study, 190 patients with diabetes were screened for neuropathy using Toronto criteria, then 83 found to have neuropathy were followed longitudinally at 9-month intervals for up to 27 months using a variety of clinical and ancillary measures, including the UENS. Among those with neuropathy, baseline UENS score significantly correlated with scores of symptom questionnaires including the Norfolk Quality of Life-Diabetes Neuropathy (NQoL-DN) and the NTSS-6; with nerve conduction study measures including sural sensory amplitude, peroneal amplitude and proximal conduction velocity; with intraepidermal nerve fiber density (IENFD) from distal thigh and distal leg 3m punch skin biopsies; but not with confocal corneal microscopy measures of nerve fiber length and density. Overall, 75 participants were followed for 9 months, and 56 for at least 18 months for a total of 149 9-month segments. UENS worsened (increased) 1.08 (+/- StDev 3.51) points per 9-month segment overall. For those followed at least 18 months, there was a 2.2 (+/-4.1) point increase over this period. Change in UENS significantly correlated with change in NQoL-DN and IENFD, among other measures. The UENS is an objective, responsive, validated clinical instrument for which a linear natural progression slope can be measured, and would be an appropriate primary endpoint in small fiber neuropathy clinical trials.

Disclosure

J. Singleton: None. P.E. Hauer: None. C. Revere: None. S.C. Foster-Palmer: None. A.B. Aperghis: None. A. Smith: Consultant; Self; Alexion Pharmaceuticals, Inc., Disarm, Regenesis.

Funding

National Institutes of Health (DP3DK104394)
559-P: The Triglyceride Glucose Index (TyG Index), Surrogate Marker of Insulin Resistance and Dementia: Population-Based Study
Authors: HONG SANG MO , HAN KYUNGDO , PARK CHEOL-YOUNG
Published: June 2019

Background: Recent several studies in both humans and animal models suggest that insulin resistance has negative effects on cognition, there were few evidences from large papulation study. In the current study, we evaluated the potential relationships between the triglyceride glucose index (TyG index), surrogate marker of insulin resistance, and dementia using a large-scale population dataset from the National Health Information Database (NHID).

Methods: We did a retrospective, observational, cohort study of 13,149,723 persons aged older than 40 years from 2009 to 2015 using NHID. We used the TyG index as a measures of insulin resistance and divided the subjects into quartiles groups based on TyG index. The incidence of demetia was assessed using the hazard ratios (HRs) estimated with cox proportional hazard modeling.

Results: During a median follow-up period of 5.26 years, dementia was diagnosed in 252,114 (1.92%) participants. Among them, Alzheimer disease (AD) were diagnosed 73% and vascular dementia (VD) were diagnosed 27%. Multivariate-adjusted hazard ratios (HRs) for patients in highest quartile of TyG index were higher for dementia (HRs =1.147; 95% confidence intervals [CI] 1.132-1.161), for AD (HRs =1.120; 95% CI 1.103-1.136), and for VD (HRs =1.220; 95% CI 1.177-1.264) compared with subjects in the lowest quartile of TyG index. These effects were independent of age, sex, smoking, physical activity, body mass index, systolic blood pressure, and total cholesterol.

Conclusions: In our large population study, TyG index, surrogate marker of insulin resistance was associated with an increased risk of dementia, even including AD, and it was independent of traditional cardiovascular risk factors.

Disclosure

S. Hong: None. K. Han: None. C. Park: None.
572-P: Lower Insulin Secretion Is Associated with Parahippocampal Gyrus Atrophy in Elderly Patients with Type 2 Diabetes Mellitus
Authors: ADACHI YUKO , OTA KAZUKI , ISHII RYOKO , CHO KEIHO , HIRAMATSU YUKI , MASUDA SEIZABURO , KOSEKI SAYO , HAYASHI TOMOHITO , KOMATSU NANA , UEDA ERI , MIZUGUCHI YASUFUMI , MINAMI ISAO , YAMADA TETSUYA , WATANABE TAKAYUKI
Published: June 2019

Objectives: Alzheimer's disease (AD) is increasingly recognized as an important comorbidity of diabetes mellitus and is often accompanied by parahippocampal gyrus atrophy (PGA). But the associations between diabetes-related parameters and PGA are not well known. Voxel-based morphometry (VBM) recently became a popular tool for the early diagnosis of AD. One of the clinically useful tools using magnetic resonance imaging (MRI) is the Voxel-based Specific Regional Analysis system for AD (VSRAD) that evaluates the degree of volume loss of parahippocampal gyrus by comparing grey matter with the original normal database template. We examined the risk factors for PGA by using VSRAD in patients with type 2 diabetes mellitus (T2DM).

Methods: A total of 137 patients aged ≥ 50 years with T2DM (mean age 67.8 ± 9.8 years) underwent brain MRI scans and comprehensive health examinations. Volume of interest (VOI) was measured using VSRAD for each patient. We examined associations between the severity of VOI atrophy and diabetes-related parameters such as HbA1c, fasting plasma glucose (FPG), C-peptide (CPR) index (plasma CPR/FPG x 100) and Hasegawa Dementia Scale-Revised (HDS-R) score, consisting of 9 simple questions with a maximum score of 30. PGA was defined as the VOI atrophy more than 1.0.

Results: Mean HbA1c was 9.3 ± 2.2%. HDS-R (median (range)) score was 28 (12 - 30). CPR index (median (range)) was 1.29 (0.03 - 8.88). The severity of VOI atrophy was more than 1.0 in 36 patients. The VOI atrophy was negatively correlated with HDS-R score (R = - 0.261, p < 0.02). By a using multivariate logistic regression analysis, age (OR 1.08, 95% CI 1.03 - 1.14) and CPR index (OR 0.477, 95% CI 0.233 - 0.977) were significantly associated with PGA.

Conclusions: The HDS-R score was significantly correlated with the VOI atrophy. Older age and lower insulin secretion were significantly associated with PGA in patients with T2DM.

Disclosure

Y. Adachi: None. K. Ota: None. R. Ishii: None. K. Cho: None. Y. Hiramatsu: None. S. Masuda: None. S. Koseki: None. T. Hayashi: None. N. Komatsu: None. E. Ueda: None. Y. Mizuguchi: None. I. Minami: None. T. Yamada: None. T. Watanabe: None.
583-P: Increase in Mitochondrial Ceramide Contributes to Diabetes-Induced Retinal Endothelial Cell Damage
Authors: PEGOUSKE DAVID , LEVITSKY YAN , HAMMER SANDRA , LYDIC TODD A. , MUCHNIK ARTEM , PROSHLYAKOV DENIS A. , BUSIK JULIA V.
Published: June 2019

Mitochondrial damage precedes histopathological abnormalities in diabetic retinopathy (DR). Retinal endothelial cells (REC) have the highest level of Acid Sphingomyelinase (ASM) expression in the retina and the increase in ASM activity and ceramide production were shown to promote diabetes-induced pro-inflammatory and pro-apoptotic changes in the retina and REC. The role of diabetes-induced increase in ASM and ceramide production in mitochondrial damage in the retina and REC is not known.

Retinal mitochondria from control, STZ-induced diabetic and ASM-/- rodent models, as well as Bovine REC (BREC) treated with diabetogenic conditions were isolated by differential centrifugation. Sphingolipids were analyzed by eSI-MS. Respiration was measured using a novel custom designed microrespirometer. Mitochondrial sphingomyelin (mSM) decreased (62 ± 1% compared to control 72.5 ± 7%, P<;0.05, n=3) and mitochondrial ceramide (mCer) increased (38 ± 4% compared to control 26.5 ± 6.5%, P<0.05, n=3 in 7 weeks diabetic rat retina. ASM-/- mouse model showed increased mSM (85.0 ± 6.7%) compared to wild type (77.0 ± 2.8%) and decreased mCer (11.5 ± 3.6%) compared to wild type (17.6 ± 3.6%, P<0.05, n=3), confirming that ASM is an essential contributor to mitochondrial ceramide regulation. Pre-treatment of BREC with an ASM inhibitor Desipramine revealed a 1.75-fold increase in maximal respiratory capacity compared to control cells. Diabetes results in decreased mitochondrial sphingomyelin and increased mitochondrial ceramide consistent with ASM-dependent ceramide production. Inhibition of ASM in BREC results in increased maximal, but not basal, respiratory rates. These results support the hypothesis that ASM activation and mitochondrial ceramide accumulation leads to inhibition of oxidative phosphorylation and REC damage in diabetic environment.

Disclosure

D. Pegouske: None. Y. Levitsky: None. S. Hammer: None. T.A. Lydic: None. A. Muchnik: None. D.A. Proshlyakov: None. J.V. Busik: None.

Funding

National Institutes of Health (R01EY028049, R01EY016077)
589-P: Could Diabetic Retinopathy Predict Cerebrovascular Disease? Evidence from Our Observation and Pooling Studies
Authors: ZHOU JIAN-BO , ZHANG RUI-HENG , ZHU XIAO-RONG , YANG JIN-KUI
Published: June 2019

Background: Diabetic retinopathy (DR) is linked to cerebrovascular disease. However, the extent to which DR may confer the risk of incidence stroke is unclear.

Research Design and Methods: This study included two sets. Firstly, a prospective cohort set was performed to explore the relationship of proliferative diabetic retinopathy (PDR) to silent cerebral infarction (SCI). Then an accumulated evidence from cohort studies were evaluated to calculate adjusted hazard ratios of stroke events.

Results: During an average of 5.3 years follow-up, 39 (26 in PDR group and 13 in NDR group) SCI events occurred. After adjusted by covariates, the risk of SCI was significantly higher in the PDR group compared with NDR group (HR=2.69, 95% CI 1.24-5.84). Accumulated evidence from seven cohort studies with 20243 diabetic patients showed that DR was significantly associated with a higher risk of stroke (HR=1.73, 95% CI 1.30-2.16), even after adjusted by covariates (HR=1.54, 95% CI 1.14-1.93). Mild DR, macular edema and cotton wool spots in retina also conferred risk of stroke. There was an explainable low heterogeneity and no evidence of publication bias.

Conclusions: Different signs of DR predict incidence of asymptomatic and symptomatic stroke. Regular retinal examination has important clinical implications for the prevention of stroke in diabetic patients.

Disclosure

J. Zhou: None. R. Zhang: None. X. Zhu: None. J. Yang: None.

Funding

National Natural Science Foundation of China (81870556, 81670738)
59-OR: Liraglutide Preserved Insulin Secretion in Adults with Newly Diagnosed Type 1 Diabetes: The NewLira Trial
Authors: DEJGAARD THOMAS F. , FRANDSEN CHRISTIAN S. , KIELGAST URD , ANDERSEN HENRIK U. , THORSTEINSSON BIRGER , KRARUP THURE , HOLST JENS J. , MADSBAD STEN
Published: June 2019

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in adults with type 1 diabetes and residual beta-cell function. This randomized, double-blind, placebo-controlled, 52-week trial evaluated the efficacy of liraglutide 1.8 mg QD added to insulin treatment in adults diagnosed with type 1 diabetes within 6 weeks prior to screening. At randomization, at end-of-treatment (week 52) and at follow-up (week 58), a 240-min. liquid mixed meal test (237 kcal Nestlé BOOST) was conducted to evaluate the C-peptide response. In total, 65 adults (age 18-40 years) with newly diagnosed type 1 diabetes, stimulated C-peptide ≥200 pmol/L and BMI >20 kg/m2 were randomized (1:1) to liraglutide or placebo added to insulin treatment. Baseline characteristics were similar between groups (mean±SD) age 27±5 years, fasting C-peptide 359±226 pM and diabetes duration 4.4±1.2 weeks. At end-of-treatment, liraglutide sustained stimulated C-peptide secretion and reduced insulin dose compared with placebo (Table). At 6 weeks post-treatment, stimulated C-peptide levels and total insulin dose did not differ between the groups. No difference was found between groups in HbA1c or BMI (Table). No events of severe hypoglycemia or ketoacidosis were reported. In conclusion, liraglutide preserved postprandial insulin secretion one year after diagnosis of type 1 diabetes. The effects had disappeared 6 weeks post-treatment.

Disclosure

T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. C.S. Frandsen: None. U. Kielgast: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Sanofi. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. T. Krarup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None.

Funding

Novo Nordisk
592-P: Diabetic Retinopathy Grade as Predictor of Outcomes in Patients with Type 2 Diabetes and Lower Extremity Amputations—Multicentric Longitudinal Seven-Year Study
Authors: SHAH KIRAN , NATARAJAN SUNDARAM , PARSEWAR VISHWANATH , SHIVANE VYANKATESH K.
Published: June 2019

Lower Extremity Amputations (LEA) and Diabetic Retinopathy (DR) are debilitating complications in patients with T2DM. We prospectively explored the association of grades of DR with the outcomes and the risk factors in patients (n=2500) with LEA (January 2011 to December 2017) Goodness of fit was examined using Pearson Chi Square test. Severe neuropathy (n=1341, 53.6%), osteomyelitis (n=1274, 50.9%), and gangrene (n=1242, 49.6%), were the predominant comorbidities. DR was observed in 56% (n=1400) of patients (NPDR n=962, 38%; PDR n=438, 16%). DR and LEA were strongly related with the highest association observed for amputations of both lower limbs (n=640), followed by above knee (n=365), below knee (n=249) and toes (n=146) (p<0.00001). 73.8% of patients with DR (n=1034) had HbA1c >11%. The seven year follow-up was characterized by a high incidence of new diabetic ulcers and amputations (62.8% n=1571, p<0.00001). The incidence of new ulcers was highest in the NPDR group (n=483, 50.2%) whereas the incidence of new amputations was highest in the PDR group (n=238, 54.3%). The all-cause mortality was 41.9% (n=1048, p<0.00001). Patients with NPDR reported highest mortality (n=508, 48.4%). Myocardial Infarction (n=316, 30.01%) was leading cause of mortality in patients with NPDR (n=237, 42.3%) whereas Congestive Heart Failure (n=604, 57.6%), was predominant cause of mortality in patients with PDR (n=350, 70.5%) (p<0.00001). The incidence of mortality 29.4% (n=308) was highest in the 7th year of follow-up. We observed that grades of DR had independent higher predictive values for new ulcers, new amputations and all-cause mortality. Patients with NPDR had worst outcomes. This long-term prospective study highlights the importance of grades of DR to predict outcomes beyond ocular morbidity and implement an integrated multidisciplinary approach for this composite complication, as a consequence of diabetes.

Disclosure

K. Shah: None. S. Natarajan: None. V. Parsewar: None. V.K. Shivane: None.
596-P: Previous Dramatic Reduction of HbA1c and Retinopathy in Type 2 Diabetes
Authors: LARROUMET ALICE , KOROBELNIK JEAN-FRANCOIS , FOUSSARD NINON , BLANCO LAURENCE , MOHAMMEDI KAMEL , MONLUN MARIE , RIGALLEAU VINCENT
Published: June 2019

In type 2 diabetes, Diabetic Retinopathy (DR) can worsen with rapid glucose control in specific circumstances. We sought whether DR can be systematically related to a previous dramatic reduction of HbA1c. In patients hospitalized for uncontrolled or complicated type 2 diabetes, we collected values of HbA1c from the previous years. "Rapid declinors" were defined by a reduction of more than -3% between two consecutive HbA1c values, and "sustained moderate declinors" if the HbA1c always declined without reaching -3%. We compared the prevalences of DR according to the previous HbA1c courses, and adjusted the analysis for risk factors for DR. Our 680 patients were mainly men (56.8%), 62±10 years old, with 14±10 year duration of diabetes. Their BMI was 32.1±6.1 kg/m2. Sixty-seven percent had arterial hypertension, 67.5% were treated by a statin and 44.5% had a Diabetic Kidney Disease. They were poorly controlled: mean HbA1c at 8.7±1.7% at admission. One thousand and five hundred previous HbA1c values were available: 9.0±1.9% during the previous year (n=641, time -4±4 months before), 8.7±1.8% during the year before (n=363, time -16±4 months), 8.7±1.8% during the second year before (n=253, time -30±4 months), and 9.0±2.2% for the most ancient (n=243, time -65±27 months).One hundred and sixty-three subjects (24%) had a DR, associated to a longer duration of diabetes, higher previous HbA1c, arterial hypertension, Diabetic kidney disease, and dyslipidemia. A previous rapid decline of HbA1c was related to DR (OR=1.869, 95% CI:1.028-3.401) after adjustment for age, gender, BMI, arterial hypertension and DKD, blood lipids and statin treatment, duration of diabetes and the mean of previous available HbA1c. The relation between DR and a previous sustained moderate reduction of HbA1c as occurred in 193 other subjects (28.3%) was NS (OR=0.798, 95% CI:0.485-1.313). In subjects with poorly controlled T2D, a history of rapid decline of HbA1c was found to predispose to DR in our population, whereas a sustained moderate decline was safe.

Disclosure

A. Larroumet: None. J. Korobelnik: Board Member; Self; Novo Nordisk Inc. Consultant; Self; Allergan, Bayer AG, Novartis France, Roche Pharma. N. Foussard: None. L. Blanco: None. K. Mohammedi: None. M. Monlun: None. V. Rigalleau: None.
611-P: Berberine Prevented High-Fat Diet-Induced Metabolic Disorders via Inhibition of Whole Lipid Metabolism
Authors: YU MUYU , ALIMUJIANG MIRIAYI , YIN JUN
Published: June 2019

Berberine, an alkaloid extracted from coptis and phellodendron, is known to alleviate lipid metabolism disorders, but the precise molecular mechanism remains unknown. This study aimed to investigate whether berberine regulated lipid metabolism by mitochondrial complex I suppression. In this study, the mitochondrial complex I inhibitor rotenone was used parallel to explore whether the lipid-lowering action of BBR was related to complex I. B6 mice were fed with high-fat diet (HFD) with or without berberine or rotenone for 20 weeks. Obesity, hepatic steatosis and insulin resistance were induced by HFD and reversed by berberine. Additionally, berberine reduced HFD induced complex I-dependent oxidative phosphorylation of gut and liver, citrate synthase activity, mtDNA copy number and ATP synthesis in liver. It also inhibited lipid synthesis, fatty acid uptake and oxidation. Furthermore, berberine increased the length and decreased the density of mitochondria to facilitate mitochondrial fusion. Berberine promoted the intestinal lipid excretion as well as reduced the abundance and diversity of gut microbiota remarkably. Nevertheless, no changes in metabolism and mitochondrial function of the recipient mice were observed after transplantation of fecal microbiota from the berberine treated mice. In vitro, berberine normalized oleic acid induced lipid deposition of mouse primary hepatocytes significantly. Oleic acid decreased AMPK activity, which was activated by berberine. The lipid-lowering effects of berberine were unaffected in the presence of compound C, an AMPK inhibitor. In all experiments, rotenone showed similar effects as berberine except for the little alteration of gut bacteria.

In conclusion, these results suggested that mitochondrial complex I of gut and liver is the target of berberine. Berberine and rotenone alleviates obesity and hepatic steatosis independently of gut microbiota and AMPK activity.

Disclosure

M. Yu: None. M. Alimujiang: None. J. Yin: None.

Funding

National Natural Science Foundation of China (81670790)
620-P: Novel Case of Diabetes Mellitus with VLCAD Deficiency
Authors: PRICE CATHERINE E. , MEKALA KAVYA , FAVREAU KACI
Published: June 2019

Objective: To present a novel case of diabetes mellitus (DM) with hypertriglyceridemia in a patient with Very Long Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) Deficiency.

Case: A 37 year old man presented to ER with nausea, emesis, and abdominal pain. He also noted polyuria, polydipsia, and 23 pounds weight loss in the prior 2 weeks, during a rehab program for cocaine abuse. He reported non-adherence to very high carbohydrate, low fat diet prescribed for VLCAD Deficiency, myopathic episodic form. Labs on admission revealed Na 123 mmol/L, K 6.0 mmol/L, BG 1,065 mg/dL, Anion Gap 12 mmol/L, pH 7.377, Triglycerides 2,281 mg/dL, Lipase 46 IU/L, CK 326 IU/L, Urine negative for ketones, Serum Beta-Hydroxybutyrate 0.62 mmol/L, Serum Osmolality 337 mOsm/kg, and HbA1c 13.5%. IV insulin and IVF were used to treat hyperglycemia and hypertriglyceridemia. CK levels remained stable. He was transitioned off IV insulin to subcutaneous insulin once TGL<1000 mg/dL.

Discussion: VLCAD Deficiency is a rare autosomal recessive disease that disables the breakdown of long-chain fatty acids into energy, which can be a significant issue during times of fasting. It is treated primarily with dietary modifications consisting of a high carbohydrate, low fat diet. Prolonged fasting is not recommended in this condition, to avoid risk of rhabdomyolysis. Given these concerns, caution was exercised to avoid hypoglycemia by adding dextrose to IV fluids and initiating complex carb diet thereafter. DM has been reported to occur in patients with medium-chain acyl-coenzyme A dehydrogenase deficiency, but to our knowledge, has not been described in VLCAD Deficiency in literature. In this case, the diagnosis of DM was established in the setting of elevated triglycerides and deviation from prescribed diet. Ketones were low, likely owing to limited fatty acid oxidation. GAD Antibody was undetectable and Tetradecenoylcarnitine, C14:1 elevated to 4.37 was consistent with deficiency of VLCAD. Further investigations will be pursued to determine potential underlying mechanism.

Disclosure

C.E. Price: None. K. Mekala: None. K. Favreau: None.
64-OR: Postprandial Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide in Type 2 Diabetes
Authors: STENSEN SIGNE , GASBJERG LÆRKE S. , KROGH LIVA S. , SPARRE-ULRICH ALEXANDER HOVARD , SKOV-JEPPESEN KIRSA , JENSEN METTE HØY , HARTMANN BOLETTE , VILSBØLL TINA , HOLST JENS J. , ROSENKILDE METTE MARIE , CHRISTENSEN MIKKEL B. , KNOP FILIP K.
Published: June 2019

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1).

In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients.

Disclosure

S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Funding

Novo Nordisk Foundation; European Foundation for the Study of Diabetes