bluuebunny/crossref_metadata_2025 huggingface dataset:
45-OR: The Role of the Angiopoietin-Tie2 Pathway in Microvascular Complications of Diabetes Mellitus
Authors: GONZALEZ VICTOR H.
Published: June 2019

Introduction: The Tie2 pathway is a key regulator of vascular stability. Deactivation of this pathway, caused by hyperglycemia or ischemia, results in pathological vascular inflammation, permeability and neovascularization. AKB-9778 is a small molecule Tie2 activator. The TIME-2 study (NCT02050828) was performed to examine the efficacy of AKB-9778 for the treatment of diabetic retinopathy and nephropathy.

Methods: TIME-2 was a multicenter randomized trial in which 144 diabetic patients with center-involved diabetic macular edema (DME) were randomized (1:1:1) to 3 months of treatment with 15 mg AKB-9778 administered subcutaneously (SC) BID plus monthly intravitreal treatment (IVT) with 0.3 mg ranibizumab (RBZ), 15 mg AKB-9778 plus sham IVT, or RBZ plus placebo SC injections BID. DME was measured by optical coherence tomography (OCT), severity of diabetic retinopathy was measured by grading of 7-field color fundus photos (ETDRS DRSS scale), and kidney function was measured by UACR and eGFR.

Results: Reduction of DME was 50% greater after 3 months of combination AKB-9778 + RBZ treatment than with RBZ treatment alone (-164 µm vs. -110 µm; P< 0.01). Diabetic retinopathy was improved by ≥ 2 steps in 11.4%, 8.8%, and 10% of patients in study eyes of the combination, RBZ, and AKB-9778 treatment groups, respectively. In fellow eyes (no RBZ) 11.4% showed ≥ 2-step improvement in retinopathy with systemic AKB-9778 compared to 4.2% of untreated eyes in the placebo group. UACR geometric mean was improved by 21% in patients with albuminuria at baseline (UACR ≥ 30 mg/g) in patients treated with AKB-9778 for 3 months.

Conclusions: The TIME-2 study provides evidence that restoration of Tie2 activity by AKB-9778 has beneficial effects on retinal and kidney function in patients with diabetes mellitus. AKB-9778 is a promising therapeutic for the prevention of end-organ damage in diabetic patients.

Disclosure

V.H. Gonzalez: Consultant; Self; AbbVie Inc., Alcon/Novartis, Alimera Sciences, Inc., Allegro Ophthalmics, LLC., Allergan, Bausch and Lomb, Bayer US, Clearside Biomedical, Genentech, Inc., PanOptica, Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics, Topcon, Valeant Pharmaceuticals International, Inc. Research Support; Self; 60 Pharmaceuticals, Alcon/Novartis, Allegro Ophthalmics, LLC., Allergan, Apellis Pharmaceuticals, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Chengdu Kanghong Biotechnology Co, LTD, Clearside Biomedical, DRCR NET, EyeGate Pharma, Genentech, Inc., Graybug Vision, Inc., ICON plc., Iconic Therapeutics, Insite Vision Inc, Mallinckrodt Pharmaceuticals, Opthea Ltd., Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics. Stock/Shareholder; Self; Alimera Sciences, Inc., PanOptica.
451-P: SGLT2 Inhibitor Protects Cardiomyocytes against Palmitate-Induced Lipotoxicity by Increasing Activation of AMPK and Lipid Oxidations
Authors: LEE HAN BYEOL , CHOI SUNGE , KANG YUP , KIM TAE HO , LEE NAMI , MOON HYUN UK , HAN SEUNG JIN , KIM DAE JUNG , LEE KWANWOO
Published: June 2019

Aim: This study was designed to evaluate the effects of SGLT2 inhibitor on palmitate-induced lipotoxicity of cardiomyocytes and the underlying mechanism involved with palmitate.

Methods: We checked SGLT2 expression in muscle cells, including H9C2. H9C2 cells were palmitate treated with/without SGLT2 inhibitor. Then, insulin resistance was measured, 2-NBDG uptake, and immunoblotting using insulin signaling pathway antibodies. Inflammation and cardiac metabolism were analyzed several related genes. Cardiomyocyte apoptosis was also detected using DNA fragmentations assay and immunoblotting using cleaved caspase 3.

Results: Low doses of palmitates evoked lipotoxicity in cardiomyocytes. Treatment of SGLT2 inhibitor dramatically reduced palmitate-induced expression levels of inflammatory cytokines. Immunoblotting analysis showed treatment of cardiomyocytes, with SGLT2 inhibitor, recovered impaired insulin signaling, such as phospho-IR and phospho-AKT, but total IR and AKT did not change. SGLT2 inhibitor also restored insulin-stimulated glucose uptake, which was destroyed by lipotoxicity. Treatment with SGLT2 inhibitor decreased the level of ER stress markers as well as inflammatory signaling markers. In particular, SGLT2 inhibitor stimulated phosphorylation of AMPK and fatty acid beta-oxidation. Cardiomyocyte exposure to high doses of palmitates evoked apoptotic features such as caspase 3 activation and DNA fragmentations. But pretreatment of SGLT2 inhibitor significantly protected palmitate-induced apoptotic features.

Conclusions: This data suggests SGLT2 inhibitors protect palmitate-induced cardiomyocytes inflammation, impaired cardiac metabolism, insulin resistance, and cardiomyocyte apoptosis. Therefore, attempts to use treatment of SGLT2 inhibitor might be a useful strategy for preventing diabetes-associated ventricular remodeling and diabetic cardiac complication.

Disclosure

H. Lee: None. S. Choi: None. Y. Kang: None. T. Kim: None. N. Lee: None. H. Moon: None. S. Han: None. D. Kim: None. K. Lee: None.
467-P: Estimation of 10-Year Cardiovascular Risk among Newly Diagnosed Type 2 Diabetes Patients in the “Evaluation of Effectiveness of Treatment Paradigm for Newly Diagnosed Type 2 Diabetes Patients in China (NEW2D)” Study Population
Authors: YAN YU , CAI XIAOLING , XU JIE , MANNER DAVID , BAE JAY P. , HEINE ROBERT J. , JI LINONG
Published: June 2019

Introduction: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). This study aimed to estimate the distribution of 10-year predicted CVD risk among newly diagnosed T2D patients, using China-PAR (Prediction for Atherosclerotic cardiovascular disease Risk in China) model, in the NEW2D population.

Methods: CVD was defined as the first occurrence of acute myocardial infarction, stroke, or death from cardiovascular causes. Risk factors included in the China-PAR model were age, geographic region, urbanization, smoking, waist circumference, systolic blood pressure, total cholesterol, HDL-C, and family history of CVD.

Results: Of the total population of 5770 patients, 2301 fulfilled the inclusion criteria (e.g., no glucose-lowering therapy) and were included in the current analyses. The model-predicted mean CVD risk was 7.4%, with 54% of patients having a medium or high risk to develop CVD within 10 years (Table 1).

Conclusions: Our study demonstrates that the majority of newly diagnosed patients with T2D in China have a medium or high risk to develop CVD. SBP appears to be a prominent driver of this elevated risk. These results underscore the importance of primary prevention and management of CVD in patients with T2D.

Disclosure

Y. Yan: Employee; Self; Eli Lilly and Company. X. Cai: None. J. Xu: None. D. Manner: Employee; Self; Eli Lilly and Company. J.P. Bae: Employee; Self; Eli Lilly and Company. R.J. Heine: Employee; Self; Eli Lilly and Company. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.
469-P: The Scavenging Product of Metformin and Methylglyoxal Improves Endothelial Cell Function in I1R and/or α2R-AKT-ERK1/2-eNOS-NO Dependent Pathway
Authors: NGUYEN HUONG
Published: June 2019

Methylglyoxal (MG) is highly elevated in type 2 diabetes (T2D) patients. MG covalently reacts with proteins to form non-enzymatic advanced glycation end products (AGEs), which cause cellular damage during diabetic cardiovascular complications. The T2D first-line drug therapy, metformin (MF), significantly reduces adverse diabetic endpoints more effectively than other antihyperglycemic agents. However, the exact mechanism(s) is far from well characterized. We previously discovered that MF scavenges MG to form a novel imidazoline (IMZ) metabolite, thus reducing MG-derived AGEs. We hypothesize that IMZ improves endothelial cell function and contributes to the therapeutic effects of MF. In the current studies we examined the in-vitro effects of IMZ on endothelial cell function using HUVECs cells and characterized potential signaling pathways. IMZ at physiological relevant concentrations induces the production of the endothelial derived relaxation factor, nitric oxide (NO), concomitant with an increase in the activation of eNOS. IMZ-induced NO production was blunted by pretreatment with imidazoline 1 receptor (I1R) and alpha-2 receptor (α2R) antagonists, suggesting that IMZ action is receptor mediated. We also observed that IMZ cause the activation of Akt and ERK1/2, in a concentration and time-dependent manner. IMZ-induced activation of Akt, ERK1/2, eNOS was inhibited in the presence of a PI3K inhibitor. ERK1/2 phosphorylation mediated by IMZ was also reduced in the presence of Akt1/2 specific inhibitors, suggesting that ERK1/2 might lie downstream of Akt. The effects of IMZ on angiogenesis function was examined by a tube-formation assay. IMZ treatment significantly increased tube length compared to untreated controls. Collectively, the data demonstrate that IMZ might contribute to the protective effects of metformin on endothelial cell function by activating I1R and/or α2R-Akt-ERK1/2-eNOS-NO pathway.

Disclosure

H. Nguyen: None.
470-P: Combined Use of Sulforaphane and Zinc Provides a Better Protection against Diabetic Cardiomyopathy than Either One Alone in Type 1 Diabetic OVE26 Mice
Authors: WANG JIQUN , WANG WANNING , CAI LU
Published: June 2019

Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetic patients. Oxidative stress is considered to be one of the most important mechanisms. Thus, treatments targeting oxidative stress may represent suitable strategies for the effective prevention of DCM. Nuclear factor-E2-related factor 2 (Nrf2), a transcription factor responsible to oxidative stress, goes to nuclei and binds to antioxidant response elements of promoters of several antioxidant genes. Metallothionein (MT) is a protein that can bind heavy metal ions such as zinc (Zn) and also a potent scavenger of free radicals because of its high thiol contents. Genetically overexpressing either Nrf2 or MT specifically in the heart protects from DCM. In addition, we also showed that induction of MT with Zn or activation of Nrf2 with sulforaphane (SFN) also partially protects from DCM. Here we further explore whether up-regulation of both simultaneously with Zn and SFN combination would provide a better protection against DCM than either alone. OVE26 mouse is one genetic type 1 diabetic model with the diabetes onset at 3 weeks old and survival more than one year without insulin treatment, so it is very good model for diabetic complication study. 5-week old OVE26 mice were confirmed with hyperglycemia and then treated with SFN (0.5 mg/kg) and/or Zn (5 mg/kg) for 18 weeks. 23-week old OVE26 mice showed typical DCM, reflected by cardiac dysfunction and remodeling fibrosis by echocardiography and collagen staining, along significantly oxidative damage, and inflammatory responses using western blotting and real-time PCR. Treatment of OVE26 mice either with SFN or Zn significantly prevented the development of DCM, along with up-regulating Nrf2 function and overexpressing MT protein, respectively, but the best protection from DCM is in the SFN/Zn group. Therefore, combined use of SFN with Zn may provide a better protection against DCM than SFN or Zn alone for diabetic patients.

Disclosure

J. Wang: None. W. Wang: None. L. Cai: None.

Funding

American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.)
474-P: Apabetalone (RVX-208) Attenuates an Inflammatory Milieu that Enhances Adhesion of Monocytes to Endothelial Cells in Type 2 Diabetes Mellitus with Cardiovascular Disease Patients
Authors: TSUJIKAWA LAURA , KULIKOWSKI EWELINA , CALOSING CYRUS , WASIAK SYLWIA , GILHAM DEAN , HALLIDAY CHRISTOPHER , JOHANSSON JAN O. , SWEENEY MICHAEL , WONG NORMAN C.
Published: June 2019

To explore mechanisms underlying a 57% relative risk reduction of major adverse cardiovascular events (MACE) in type 2 diabetes mellitus (T2DM) patients (pts) with CVD given 200 mg apabetalone (APL) by mouth. APL is a small molecule that inhibits bromodomain and extra-terminal (BET) proteins, which are epigenetic readers of acetylated lysine in histones contained within actively transcribing chromatin. Inhibiting BET proteins attenuates transcribed genes that are upregulated in disease states. Studies here used SOMAscan proteomics of patient plasma given placebo (n=30) or APL (n=25) and cultured monocyte (THP-1) or endothelial (HUVEC) cells. Results showed differences in the proteome spanning 4 CVD pathways: acute phase response, intrinsic prothrombin activation, leukocyte extravasation signaling, and coagulation. This data showed TNFα target genes were preferentially upregulated in T2DM+CVD (p<0.001; z-score = 2.270) vs. euglycemic pts, suggesting an inflammatory state that was attenuated by APL (p<0.001; z-score = -2.308). To mimic inflammation in vitro, TNFα (10 ng/ml) added to co-culture of THP-1 and HUVEC induced adhesion 12-fold in euglycemia; APL inhibited it by 44%. HUVECs exposed to TNFα induced IL-1β, E-selectin, VCAM1 and IL-6 mRNA by 1685, 1164, 196 and 9-fold respectively while APL inhibited (50-99%). In THP-1, TNFα induced IL-1β, MYD88 and CD-44 mRNA by 3.5, 2.6, and 1.8-fold respectively; inhibited by APL (39-84%). To mimic T2DM, high glucose (HG, 25.6 mM) induced adhesion of THP-1 to HUVEC by 2.4-fold was blocked by APL. In HG, Very Late Antigen-4 (VLA-4) mRNA, a THP-1 adhesion gene, rose 1.3-fold; APL blocked it >50%. HG induced adhesion genes in HUVECs, E-selectin and MYD88, by 2- and 1.3-fold was lowered by APL.

In summary, APL lowers MACE in T2DM+CVD pts by attenuating expression of genes that mediate adhesion of monocytes to endothelial cells. This hypothesis is being tested in a phase 3 trial BETonMACE.

Disclosure

L. Tsujikawa: None. E. Kulikowski: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. C. Calosing: None. S. Wasiak: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. D. Gilham: Employee; Self; Resverlogix Corp. C. Halliday: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. J.O. Johansson: Employee; Self; Resverlogix Corp. M. Sweeney: Employee; Self; Resverlogix Corp. N.C. Wong: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp.
48-OR: Gut Dysbiosis Promotes Diabetic Retinopathy (DR) through TLR-2 Activation by Peptidoglycan (PGN) in Angiotensin Converting Enzyme 2 (ACE2) Deficient Type 1 Diabetic (T1D) Mice
Authors: PRASAD RAM , DUAN YAQIAN , FLOYD JASON L. , GRANT MARIA B.
Published: June 2019

Purpose: Previously, we demonstrated that ACE2 deficiency increases the severity of DR in Akita mice. In this study, we sought to determine the mechanism where by the gut microbiome, which is typically altered in T1D, contributes to the pathogenesis of DR in ACE2-/-Akita mice.

Methods: Wild type (WT), Akita and ACE2-/-Akita mice were studied at 9 months of diabetes and the gut microbiota was examined using 16S rRNA sequencing and metatranscriptomic analysis. Microbial load in the circulation was assessed by measuring circulating PGN levels along with markers of the gut vascular barrier (GVB). Next, human retinal endothelial cells (HREC) were treated with PGN, a known Toll-like receptor (TLR)-2 agonist, to determine whether PGN enhances permeability.

Results: 16S rRNA sequencing revealed a shift in beta diversity of the gut microbiota with an increase in Firmicutes and Bacteroidetes within the gut of ACE2-/-Akita mice. Metatranscriptomic analysis showed increases in PGN synthesis. Loss of ACE2 promoted gut barrier permeability through decreasing the turnover of VE-cadherin expression (41%, p<0.0001) in the intestine of ACE2-/-Akita mice. Increased vascular permeability was associated with barrier dysfunction, microbial translocation and increase PGN in the circulation (2.5 fold, p<0.007) in ACE2-/-Akita mice compared with Akita mice. Acellular capillaries (2 fold, p<0.05) were significantly higher in ACE2-/-Akita mice compared with Akita mice. PGN treatment caused dissociation of VE-cadherin junctional complexes in HRECs through a MyD88/ARNO/ARF6-mediated signaling pathway. This occurred by depleting p120-catenin (51%. p<0.004) and internalization of VE-cadherin.

Conclusions: These data suggest that microbiota-derived PGN has deleterious effects on retinal endothelial cells to increasing permeability. Strategies aimed at resorting gut health may serve to prevent development of DR.

Disclosure

R. Prasad: None. Y. Duan: None. J.L. Floyd: None. M.B. Grant: None.

Funding

National Eye Institute (EY028858)
483-P: Pioglitazone Suppresses Macrophage Proliferation in Apolipoprotein-e Deficient Mice by Activating PPARγ
Authors: MURAKAMI-NISHIDA SAIKO , MATSUMURA TAKESHI , NISHIDA SHUHEI , SENOKUCHI TAKAFUMI , ISHII NORIO , YAMADA SARIE , MORITA YUTARO , WADA TOSHIAKI , MOTOSHIMA HIROYUKI , KONDO TATSUYA , ARAKI EIICHI
Published: June 2019

Background and Aims: Local macrophage proliferation in the atherosclerotic plaque is linked to the enhanced atherosclerosis progression. Although we reported that troglitazone, a thiazolidinedione (TZD), suppressed oxidized low-density lipoprotein (Ox-LDL)-induced macrophage proliferation, its mechanisms have been unclear. We therefore investigated the mechanism(s) of the inhibitory effect of macrophage proliferation by another TZD, pioglitazone.

Methods: High-fat diet (HFD)-fed, apolipoprotein E-deficient (ApoE KO) mice were treated orally with pioglitazone (10 mg/kg/day). After 8 weeks of treatment, the whole aorta or frozen sections of the aortic sinus were stained with Oil red O. To identify macrophage proliferation and apoptosis, we performed Ki67/Iba-1 double immunohistochemical staining and TUNEL method, respectively.

Results: Atherosclerosis progression was suppressed in aortic sinuses of pioglitazone-treated ApoE KO mice, and they showed fewer proliferating macrophages in the plaques. Pioglitazone suppressed Ox-LDL-induced macrophage proliferation in a dose-dependent manner, which was ameliorated by peroxisome proliferator-activated receptor-γ (PPARγ) siRNA. Low concentrations (less than 100 µM) of pioglitazone, which can suppress macrophage proliferation, activated PPARγ in macrophages, but did not induce macrophage apoptosis. Pioglitazone did not induce TUNEL-positive cells in atherosclerotic plaques in ApoE KO mice.

Conclusions: Pioglitazone suppresses macrophage proliferation through PPARγ without inducing macrophage apoptosis. These findings imply that pioglitazone could prevent macrovascular complications in diabetics.

Disclosure

S. Murakami-Nishida: None. T. Matsumura: None. S. Nishida: None. T. Senokuchi: None. N. Ishii: None. S. Yamada: None. Y. Morita: None. T. Wada: None. H. Motoshima: None. T. Kondo: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.
484-P: Acute Hyperglycemia In Vivo Promotes a Proatherogenic Monocyte Phenotype
Authors: ZHANG RONG MEI , OH JISU , LIN XIAOBO , STONE PAMELA , WHARTON KATHLEEN J. , ARBELAEZ ANA MARIA , BERNAL-MIZRACHI CARLOS
Published: June 2019

Diabetes is a chronic inflammatory disease that accelerate cardiovascular disease (CVD). However, the contribution of hyperglycemia to inflammation and CVD risk is unclear. Animal studies have shown that monocytes carry cholesterol to the atherosclerotic plaque. Thus, it is key to determine if hyperglycemia can exert a pro-atherogenic effect in human monocytes in vivo. We performed octreotide euglycemic-hyperglycemic clamps in 21 healthy subjects, 20-45 yo. Monocytes isolated during euglycemia (90 mg/dl) and after 2h of hyperglycemia (300 mg/dl) were evaluated for cholesterol metabolism and monocyte function (adhesion to fibronectin, transwell migration assays). Also, we assessed the effects of hyperglycemia on monocyte cholesterol metabolism and function from 10 healthy controls cultured in euglycemia or high glucose media with or without 2-deoxyglucose (2DG) at 2 and 6 hours. Acute hyperglycemia in vivo increased 37% total monocyte cholesterol content (TC) (p<0.02), 40% cholesterol ester (CE)(p<0.02) and upregulated oxidized low-density lipoprotein (oxLDL) cholesterol uptake by by 24%(p<0.01). Moreover, acute hyperglycemia increased monocyte adhesion and transwell migration (p<0.01) suggesting cholesterol full monocytes carry cholesterol into the vessel wall. In vitro studies confirmed that hyperglycemia increased monocyte adhesion and migration by 20% and monocyte TC by 20% and CE by 40% at 2 and 6 hours (p<0.03) by increasing oxLDL or LDL cholesterol uptake. Hyperglycemia didn’t affect monocyte cholesterol biosynthesis or cholesterol efflux induced by HDL or APOA1. Addition of 2DG cultured monocytes in both glucose conditions prevented hyperglycemia induced monocyte adhesion migration and monocyte CE and TC content at 2 and 6 hours. Thus, acute hyperglycemia in vivo without hyperinsulinemia induce monocyte glycolysis increasing monocyte cholesterol uptake, total cholesterol content it activates monocytes adhesion and migration, all key components to accelerate atherosclerosis.

Disclosure

R.M. Zhang: None. J. Oh: None. X. Lin: None. P. Stone: None. K.J. Wharton: None. A. Arbelaez: None. C. Bernal-Mizrachi: None.

Funding

National Heart, Lung, and Blood Institute (R01HL094818-06); National Institute of Neurological Disorders and Stroke (P01NS080675)
487-P: The Activation of mTORC1 in Leukocytes of Patients with Cancer and Diabetes
Authors: VATSEBA TAMARA , SOKOLOVA LIUBOV K. , PUSHKAREV VIKTOR V. , KOVZUN OLENA I. , PUSHKAREV VOLODYMIR M. , TRONKO MYKOLA D.
Published: June 2019

Aim: mTOR/p70S6K1 play an important role in the pathogenesis of cancer and diabetes. Macrophages and lymphocytes are involved in the pathogenesis of diabetes, diabetic atherosclerosis, formation of insulin resistance as well as immune response to cancer and tumor maintenance. Thus, the aim was to study the mTORC1 activation by determining the phosphorylation of PRAS40 and p70S6K1 in leukocytes of patients with type 2 diabetes and cancer.

Materials and Methods: The following groups were studied: control group - healthy people, representative by age (n=6), patients with type 2 diabetes (n=12), cancer patients (n=15) and patients with both cancer and diabetes (n=7). For determinations of phospho-PRAS40 (Thr246) and phospho-p70S6K1 (Thr389) amounts ELISA kits КНО0421 and 85-86053 (Invitrogen) respectively were used. The protein concentration in the lysate was determined using BCA protein assay kit. The measurements were carried out on a microplate reader at a wavelength of 450 nm.

Results: The amounts of phosphorylated PRAS40 and p70S6K1 significantly increase in leukocytes of patients with type 2 diabetes and cancer, which indicates the mTORC1 activation. The number of phospho-PRAS40-positive samples in patients with diabetes was 83.3%, and in patients with cancer - 66.7%. The decrease in the amount of phospho-PRAS40 in leukocytes of the patients group both with cancer and diabetes was observed.

Conclusions: Thus, phosphorylation of PRAS40 is generally consistent with the activation of mTORC1, as measured by phosphorylation of p70S6K1. The changes in the activity of mTOR/S6K in severe chronic diseases can be systemic, and the study of the status of these kinases in leukocytes perhaps could be useful for diagnostic and prognostic purposes.

Disclosure

T. Vatseba: None. L.K. Sokolova: None. V.V. Pushkarev: None. O.I. Kovzun: None. V.M. Pushkarev: None. M.D. Tronko: None.
488-P: Effects of Novel Antidiabetic Therapy on Platelet Reactivity in Patients with Type 2 Diabetes Mellitus
Authors: SIASOS GERASIMOS , BLETSA EVANTHIA , STAMPOULOGLOU PANAGIOTA K. , BATZIAS KONSTANTINOS , ANTONOPOULOS ALEXIOS , PASCHOU STAVROULA A. , TSIGKOU VASILIKI , GOULIOPOULOS NIKOLAOS , MAZARIS SAVVAS , VOGIATZI GEORGIA , TSALAMANDRIS SOTIRIS , OIKONOMOU EVANGELOS , ZAROMYTIDOU MARINA , POLITOU MARIANNA , VRYONIDOU ANDROMACHI , THANOPOULOU ANASTASIA , TENTOLOURIS NIKOLAS , TOUSOULIS DIMITRIS
Published: June 2019

Background: Patients with type 2 diabetes mellitus (DM2) exert a higher risk for thrombotic events. Platelet reactivity may be used to assess prothrombotic state in patients with cardiovascular disease. We aimed to investigate whether the administration of novel antiglycemic agents may influence platelet reactivity in these patients.

Methods: We enrolled 99 patients (male=63.3%) receiving metformin for DM2 who did not achieve therapeutic targets under current treatment. Subjects were assigned to age and sex matched groups (n=33 per group) of an additional antiglycemic agent; either DPP-4 inhibitor, SGLT2 inhibitor or a GLP-1 agonist. Platelet reactivity was measured with PFA-200 assay; collagen/epinephrine (CEPI) and collagen/ADP closure time (CADP) were calculated in seconds and HbA1c at baseline and at 3 months.

Results: There was no difference for male gender (p=0.10) or age (64.92 ± 8.30 years, p=0.27) between the study groups. All patients achieved better glycemic control in terms of HbA1c values between baseline and follow-up (7.78% vs. 6.92% for DPP-4, 7.52% vs. 6.73% for SGLT2 and 8.19% vs. 6.85% for GLP-1, p<0.001 for all). Platelet reactivity did not differ significantly at baseline between the study groups (p=0.71 for CEPI and p=0.6 for CADP). Additionally, CEPI (p=0.54) and CADP (p=0.43) did not change significantly at follow-up in all groups. Interestingly, when we conducted a separate analysis for patients not receiving antiplatelet agents, we observed that only CADP was significantly reduced at follow-up time after DPP-4 and GLP-1 treatment, but not after SGLT2 administration (148.50 ± 60.65 vs. 119.75 sec for DPP-4, p=0.01, 104.12 ± 25.68 vs.88.7 ± 22.25 sec for GLP-1, p=0.01 and 101.57 ± 15.26 vs. 88.57 ± 13.26 sec for SGLT2, p=0.73).

Conclusion: The addition of DPP-4 or GLP-1 to metformin influences platelet reactivity and achieves better glycemic control in DM2 patients, providing further insights in the pathophysiology of DM2.

Disclosure

G. Siasos: None. E. Bletsa: None. P.K. Stampouloglou: None. K. Batzias: None. A. Antonopoulos: None. S.A. Paschou: None. V. Tsigkou: None. N. Gouliopoulos: None. S. Mazaris: None. G. Vogiatzi: None. S. Tsalamandris: None. E. Oikonomou: None. M. Zaromytidou: None. M. Politou: None. A. Vryonidou: None. A. Thanopoulou: None. N. Tentolouris: None. D. Tousoulis: None.
491-P: Obesity-Induced Kidney Damage Is Attenuated by Genetic Deletion of miR-379 in Mice
Authors: ABDOLLAHI MARYAM , KATO MITSUO , TUNDUGURU RAGADEEPTHI , LANTING LINDA L. , NATARAJAN RAMA
Published: June 2019

Obesity is significantly associated with diabetes and related complications like kidney disease. Evidence shows dysregulation of certain non-coding RNAs including microRNAs can accelerate diabetic kidney disease (DKD). Recently, we found that miR-379 and its host transcript long non-coding RNA, lncMGC, were regulated by endoplasmic reticulum (ER) stress in glomerular cells, and lncMGC could promote features of DKD in mice. In this study, we examined the in vivo role of miR-379 in obesity-induced kidney disease by testing miR-379-knockout (KO) mice generated by CRISPR-Cas9 editing. Male (M) and female (F) mice were fed with control diet, or high fat diet (HFD) for 24 weeks to induce obesity in wild type (WT) and miR-379KO mice. Kidney function was examined by measuring urinary albumin and creatinine. Expression of miR-379 target genes (Edem3, Fis1), Leptin receptor (LepR) and profibrotic genes (Tgf-β1, Ctgf, Col4a1, Col1a2) was measured in isolated glomerular cells. Cortical sections were stained for histopathology. Blood glucose levels were similar in miR379KO-HFD and WT-HFD. miR379KO-HFD-F mice exhibited significantly lower body weight and body fat composition versus WT-HFD-F. Hyperinsulinemia observed in WT-HFD-F mice was attenuated in miR379KO-HFD-F. LepR expression was significantly decreased in WT-HFD-F but not miR379KO-HFD-F mice relative to controls. Increased expression of profibrotic genes, glomerular hypertrophy and interstitial fibrosis observed in WT-HFD-F were significantly attenuated in miR379KO-HFD-F mice. Similar to females, male miR-379KO-HFD-M mice showed significant reductions in glomerular hypertrophy, fibrosis and ER stress markers vs. WT-HFD-M. However, unlike females, miR379KO-HFD-M mice did not display reduced body weight compared to WT-HFD-M. These results suggest miR-379 deficiency protects mice from HFD-induced obesity and kidney injury, with some gender differences. miR-379 inhibition may be a novel therapy for HFD-induced metabolic disorders.

Disclosure

M. Abdollahi: None. M. Kato: None. R. Tunduguru: None. L.L. Lanting: None. R. Natarajan: None.

Funding

National Institutes of Health
507-P: Influence of Past Information to Precision of Diabetic Nephropathy Aggravation Prediction
Authors: KOSEKI AKIRA , ONO MASAKI , KUDO MICHIHARU , HAIDA KYOICHI , MAKINO MASAKI , SUZUKI ATSUSHI
Published: June 2019

Background: In the presence of large data set of electronic health records (EHRs), predicting the future disease status is of importance for decision making in the medical treatments. Using modern machine learning techniques, it is generally becoming easier to build complex models to predict the future. For those models, a set of past information are used to make explanatory variables, however, we don't have enough knowledge as to how long we should collect data backward. In some cases, very late tendencies are influencing the future status of disease while in the other cases, old events were the importance causes of the change of the disease status. Our interest thus lies in how old data we have to process to make the good prediction models.

Method: In this paper, we discuss a set of machine learning algorithms to predict the diabetic nephropathy stage in the future using sets of input variables which were collected from different time span of past records. To compare the performance of algorithms we used Logistic Regression, AdaBoost, Gradient Boosting, Decision tree, Multi-layer Perceptron, and Random Forest. We then provide different set of variables of EHR that include past 30-, 60-, 90-, 180-, 210-, 240-, 270-, 300-, 330-, and 360-day data sets, from which we extracted several longitudinal statistics for input variables. From about 65 thousand type 2 diabetes patients, the models classify whether the nephropathy stage gets aggravated or stay in 180 days.

Results: For almost all algorithms, AUC is getting improved when using older data, and 360-day data sets gave the best. Among the algorithms, Gradient Boosting gave the best AUC of 0.77 when using 360-day data set. When using 360-day data sets, Decision Tree gave worst AUC of 0.61.

Conclusion: We observed that when using to past data up to 360 days, the oldest data set gave the best prediction performance. Longitudinal statistics in rather long span gives good explanatory information for future nephropathy development.

Disclosure

A. Koseki: Employee; Self; IBM. M. Ono: None. M. Kudo: Employee; Self; IBM. K. Haida: None. M. Makino: None. A. Suzuki: Research Support; Self; Chugai Pharmaceutical Co., Ltd., Dai-ichi Life Insurance Company, IBM, MSD, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Asahi Kasei Corporation, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd.
511-P: The Renoprotective Effect of Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, in a Mouse Model of Renal Fibrosis
Authors: KIM NAYOUNG , LEE IN-KYU , PARK SUNG DON , KIM MIN-JI , KIM JUNG-GUK , CHOI YEON-KYUNG , PARK KEUN-GYU , KIM MI-JIN
Published: June 2019

Background: Renal tubulointerstitial fibrosis is a major pathologic finding of nearly all cause of end-stage renal disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease. This study aimed to investigate possible beneficial effects of evogliptin on renal fibrosis in mice.

Methods: We examined the effects of evogliptin on renal tubulointerstitial fibrosis following unilateral ureteral obstruction (UUO) in mice. We further defined the role of evogliptin on transforming growth factor-β (TGF-β)/Smad signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study.

Results: Through hematoxylin/eosin and sirius red staining, we observed that evogliptin effectively ameliorates UUO-induced renal atrophy and fibrosis. Immunohistochemistry in conjunction with western blot analysis revealed that evogliptin treatment inhibited UUO-induced up-regulation of phosphorylated Smad3, α-smooth muscle actin, plasminogen activator inhibitor 1, fibronenctin, and type 1 collagen. In vitro experiments with proximal tubule epithelial cell suggested that the effects of evogliptin on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway.

Conclusion: The present study demonstrates that evogliptin has a protective effect on UUO-induced renal tubulointerstitial fibrosis, suggesting that its clinical applications could extend to the treatment of nondiabetic origin renal disease.

Disclosure

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

Funding

National Research Foundation of Korea
527-P: Renal Hemodynamic and RAAS Profiles in Patients with Type 2 Diabetes (T2D) and Heart Failure (HF)
Authors: LYTVYN YULIYA , BURNS KEVIN D. , LYTVYN ANDRIY , AMBINATHAN JAYA P. , OSUNTOKUN OLUWATOSIN , GODOY LUCAS C. , CHERNEY DAVID , PARKER JOHN D.
Published: June 2019

HF is associated with decreased renal blood flow and RAAS activation, which may be aggravated in the presence of T2D. The renal arterial-venous gradient for RAAS markers has not been previously reported in HF patients. Our aim was to characterize renal hemodynamic function and renal arterial-venous gradient for RAAS markers in patients with: (1) HF with T2D, (2) HF without T2D, and (3) controls without HF or T2D.

In this post hoc analysis, GFRinulin, ERPFPAH, plasma angiotensin converting enzyme (ACE), ACE2, aldosterone, angiotensinogen, plasma renin activity (PRA) and ACE activity were measured in renal artery and vein samples from 20 HF with T2D, 28 HF without T2D and 24 controls. RAAS inhibitors were used in 90% of HF and 63% of controls.

GFR and ERPF were higher in controls vs. HF with and without T2D (p<0.05). There was a larger renal arterial-venous gradient for PRA and ACE levels in HF patients, regardless of T2D status, compared to controls (p<0.01). There were no arterial-venous differences in HF with T2D vs. HF without T2D (Figure 1).

HF patients exhibited lower renal perfusion vs. non-HF patients regardless of T2D status. A larger renal arterial-venous gradient for the RAAS markers suggests a renal origin for neurohormonal activation in HF patients. T2D status did not impact renal hemodynamics or RAAS markers in patients with HF, highlighting the need to broadly target neurohormonal abnormalities in these patients.

Disclosure

Y. Lytvyn: None. K.D. Burns: None. A. Lytvyn: None. J.P. Ambinathan: None. O. Osuntokun: None. L.C. Godoy: None. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. J.D. Parker: Research Support; Self; Ironwood Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Theracos, Inc. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Servier, Theracos, Inc.
531-P: Weight Change and the Incidences of End-Stage Renal Disease and Proliferative Diabetic Retinopathy in Patients with Newly Diagnosed Diabetes Mellitus: A Nationwide Cohort Study
Authors: KWON HYUK-SANG , SONG KI-HO
Published: June 2019

Aims/Hypothesis: This study aimed to investigate the impact of weight changes on the clinical outcomes of diabetic nephropathy and retinopathy among patients with newly diagnosed diabetes.

Methods: Using nationally representative data from the Korean National Health Insurance System, 181,872 patients newly diagnosed with diabetes who were free of end-stage renal disease (ESRD) and proliferative diabetic retinopathy (PDR) during 2007-2012 were followed to the end of 2016. Weight change was defined as the difference in body weight from the time of diabetes diagnosis to 2 years later.

Results: There were 180 cases of ESRD (0.10%) and 780 cases of PDR (0.43%) followed-up for a median of 5.5 years from the index year at 2 years after diagnosis. Those with moderate weight gain (+5% to +10%) showed a significantly higher hazard ratio (HR) for ESRD, compared with those with modest weight changes (−5% to +5%) after adjusting for several confounding factors, including the baseline estimated glomerular filtration rate (HR, 1.732; 95% CI 1.125-2.667). Those with severe weight loss (−5% to −10%) showed the lowest HR for PDR (HR, 0.591; 95% CI 0.372-0.938), whereas those with severe weight gain (> +10%) showed the highest HR for PDR (HR, 1.732; 95% CI 1.125-2.667).

Conclusion: This study provides direct evidence that a change in body weight affects the risk of diabetic microvascular complications. Strategies to control body weight may reduce the risk of ESRD and PDR in patients with newly diagnosed diabetes.

Disclosure

H. Kwon: None. K. Song: None.
556-P: Noninvasive Measurements of AGE Products in the Crystalline Lens of the Eye Can Distinguish Subjects with Prediabetes and Type 2 Diabetes and Correlated with Severity of Neuropathy
Authors: TAVAKOLI MITRA
Published: June 2019

The accumulation of advanced glycation end products (AGEs) in the body contributes to pathogenesis of many diseases including complications of diabetes including retinopathy and neuropathy. Proteins in the lens of the eye do not turnover and therefore give an indication of the average glucose levels over a very long period of time. AGEs have a unique measurable fluorescence, however non-invasive measurement of AGEs was not available until recently with introducing a new scanning confocal biomicroscope. The main aim of the present study was to investigate if measurement of lens Auto fluorescence (FL) can distinguish subjects with impaired Glucose Tolerance (IGT) and type 2 diabetes (T2DM) from Healthy control subjects and to investigate the relationship between levels of FL. ratio, and corneal nerves morphology. 20 T2DM, 20 IGT and 20 Healthy aged matched control subjects underwent comprehensive medical and neurological assessments including corneal confocal microscopy and measurement of Crystalline Lens Autofluorescence by using a confocal bio microscope. There was a significant difference at the level of fluorescence ratios in Control subjects, IGT patient and T2DM patients. There was a significant correlation between FL. Ratios and level of HbA1C, and CNFL.

The results of this study showed the Lens fluorescence is significantly greater in patients with IGT and T2DM. The level of AGEs products was correlated with HbA1C and alterations in corneal nerves morphology. However, the relationship with HbA1c was rather poor since HbA1c cannot completely reflect long-term glycation process. Lens autofluorescence could be a robust marker of long-term diabetes control predicting future complication risks. This supports the feasibility of lens autofluorescence to screen subjects for undiagnosed type 2 diabetes. However, confirmation of such hypothesis will need larger and long-term clinical studies.

Disclosure

M. Tavakoli: None.
567-P: Influence of Sex on Cardioautonomic Neuropathy in Patients with Type 1 Diabetes
Authors: NATTERO-CHÁVEZ LÍA , DIAZ SARA ALONSO , MONTANEZ LAURA , FERNÁNDEZ ELENA , LOPEZ SANDRA REDONDO , UREÑA MARTA GARNICA , BAYONA ANE , ESCOBAR-MORREALE HÉCTOR FRANCISCO , RAMÍREZ MANUEL LUQUE
Published: June 2019

Objective: Cardiovascular autonomic neuropathy (CAN) is a common complication of type 1 diabetes (DM1). The risk of CAN is lower in middle-aged healthy women than in men, a fact that might be related to a more dominant parasympathetic regulation in the former. This sex-related effect in favor of women appears to disappear beyond 50 year-old. We assessed the effects of age and sex on CAN in patients with DM1.

Research Designs and Methods: Cross-sectional study in 281 consecutive patients (158 males and 123 females) with DM1. CAN was assessed by the Ewing Score using the variability of heart rate (HR) in response to deep breathing, standing, and the Valsalva’s maneuver, and the response of blood pressure to active standing. A composite score ≥ 1 was diagnostic of CAN. CAN was classified as early or mild when the Ewing score was between 1-2, and definitive when ≥ 2.

Results: The mean age of our study population was 36±12 years-old and their average duration of DM1 was 20±11 years. Their mean HbA1cwas 7.6±1.3%. The global prevalence of CAN was 30.6% (25.5-36.2). CAN was categorized as early/mild in 79 (92%) cases and definitive in 7 (8%) cases. CAN prevalence was not significantly different between men and women when analyzing all subjects regardless of age. When age was taken into account, the prevalence of CAN was independent of sex among individuals below 50 year-old, but in subjects aged ≥ 50 years (21 males and 19 females) the prevalence of CAN was larger in women than in men [63.2% (41.0-80.9) vs. 23.8% (10.6-45.1), respectively; χ2: 6.32, p= 0.012]. The OR of having CAN was 5.5 (1.4-21.6) in women aged ≥ 50 years compared to their male counterparts and 3.9 (1.4-10.7) compared to women under 50 years.

Conclusions: The increase in CAN risk in subjects with type 1 DM may be greater in women over 50 years than in men of similar age. Moreover, women aged ≥ 50 years-old associate to a higher risk of CAN than younger women and men. This finding might be related to the menopausal-related decline in sex steroids.

Disclosure

L. Nattero-Chávez: None. S. Alonso Diaz: None. L. Montanez: None. E. Fernández: None. S. Redondo Lopez: None. M. Garnica Ureña: None. A. Bayona: None. H. Escobar-Morreale: None. M. Luque Ramírez: None.

Funding

Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (PI1400649, PI151686, PIE1600050); Fondo Europeo de Desarrollo Regional
569-P: Prefrontal Cortex Brain Damage and Glycemic Control in Patients with Type 2 Diabetes
Authors: CHOI SARAH E. , ROY BHASWATI , KUMAR RAJESH , FREEBY MATTHEW , MULLUR RASHMI S. , WOO MARY A.
Published: June 2019

Cognitive impairments are common in patients with type 2 diabetes (T2DM) and adversely impact self-care and glycemic control. However, brain injury in a site that controls cognition (prefrontal cortices; PFC) and its relationship to glycemic outcomes in T2DM remains unclear.

Methods: We examined 9 T2DM patients (age 58.2 ± 4.6 years; BMI 30.3 ± 5.0 kg/m2;3 males) and 47 healthy controls (age 55.7 ± 4.2 years; BMI 26.4 ± 3.0 kg/m2; 29 males) for cognition (Montreal Cognitive Assessment [MoCA]), glycemic control (hemoglobin A1c [A1C]), and PFC status via brain magnetic resonance imaging (MRI). Two high-resolution T1-weighted images were collected using a 3.0-Tesla MRI scanner to evaluate PFC status with voxel-based morphometry (VBM) procedures.

Results: No significant differences in age and gender emerged between T2DM and control subjects. However, BMI values were significantly higher in T2DM subjects over controls. MoCA scores were significantly lower in T2DM patients compared to controls (24.3 ± 2.4 vs. 26.9 ± 2.3; p = 0.004). Mean A1C was 7.6±0.8% (51-68 mmol/mol) in T2DM patients. Reduced PFC volume was observed in T2DM patients compared to controls (left 0.35±0.02 vs. 0.41±0.03, p<0.001; right 0.31±0.02 vs. 0.38±0.02, p<0.001). PFC volume was positively correlated with cognition; left PFC regions (r= 0.94, p=0.002) and right PFC regions (r= 0.89, p=0.007) with age and gender as covariates. Significant negative correlations were found between PFC volume and A1C; left PFC (r= -0.92, p=0.003) and right PFC regions (r=-0.92, p=0.004) with age and gender as covariates.

Conclusions: T2DM patients have PFC brain damage which is associated with cognitive deficits and poor glycemic control. Further research is needed to identify causal relationships between A1C and brain changes in T2DM and to examine interventions to enhance brain/neurogenesis and its impact on A1C.

Disclosure

S.E. Choi: None. B. Roy: None. R. Kumar: None. M. Freeby: None. R.S. Mullur: None. M.A. Woo: None.

Funding

National Institutes of Health (R01NR017190)
570-P: The Slipping Slipper Sign Predicts Risk of Falling in Patients with Type 2 Diabetes Mellitus
Authors: RAMDATH MOSHANTI M. , NANDLAL RESHAM R. , TEJA BOPPANA LEELA KRISHNA , TEELUCKSINGH SURUJPAL
Published: June 2019

Background: Patients with diabetes, particularly those with peripheral neuropathy, are known to be at increased risk for falls. The objective of this study was to determine if the presence of a positive Slipping Slipper Sign (SSS) - a clinical marker of severe diabetic peripheral neuropathy could be associated with an increase tendency towards falls, recurrent falls and fractures.

Subjects and Methods: Using a case control design, among 78 subjects selected from our diabetic clinic there were 26 subjects with the SSS and 52 controls without the SSS. Questionnaires were administered to obtain data related to the frequency of falls, recurrent falls and fractures which occurred within a one year time period (May 2015 to May 2016), in addition to demographic and medically relevant data.

Results: Overall 33 subjects had experienced a fall giving an incidence of 42% for the entire cohort whereas all 26 (100%) subjects with the SSS had experienced a fall within the one year-period. Only 7 (13·5%) subjects had fallen in the group with a negative SSS, p<0·001. Furthermore, 17 (65·4%) subjects with the SSS were found to have experienced recurrent falls as compared to only 4 (7·7%) non-SSS subjects, p<0.001. Similarly, 10 (38·5%) SSS subjects but only 3 (5·8%) subjects without the SSS were found to have sustained fractures, p = 0·001. Most falls occurred during the act of walking. Multivariate analysis showed the significant predictors of the SSS were: duration of diabetes (p = 0·001), female sex (p = 0·026) and the use of oral hypoglycemic agents (p = 0·047). The relative risks of falls, recurrent falls and fractures were 7·43 (95% CI: 3·73 - 14·79), 8·50 (95% CI: 3·18 - 22·69) and 6·67 (95% CI: 2·005 - 22·16) times greater for subjects with the SSS compared to those without.

Conclusion: A positive SSS among subjects with T2DM predicted the risk of falls, recurrent falls and fractures and has potential as a screening tool to reduce morbidity and mortality from falls among those with diabetic peripheral neuropathy.

Disclosure

M.M. Ramdath: None. R.R. Nandlal: None. L. Boppana: None. S. Teelucksingh: None.