bluuebunny/crossref_metadata_2025 huggingface dataset:
473-P: HDAC Inhibition Augments TGF-ß-Induced JNK Activation, CTGF Expression, and NF-E2 Degradation Promoting Profibrotic Signaling in Renal Proximal Tubules
Authors: LI JIA , RANE MADHAVI JAGDISH , CAI LU , TAN YI
Published: June 2020

The role of TGF-β in diabetes-induced renal fibrosis remains incompletely understood. We showed decreased NFE2 expression in TGFβ-treated renal proximal tubule cells and in diabetic mouse kidneys. TGF-β treatment increased NFE2 mRNA level in HK11 cells suggesting a role for NFE2 degradation. ERK and p38 MAPKs promoted TGFβ-induced NFE2 degradation, CTGF and FN expression. NFE2 over-expression/silencing inhibited exacerbated TGFβ-induced CTGF. Proteasome inhibitor MG132 preserved TGFβ-induced NFE2 expression and inhibited CTGF and FN expression. Current study examined role of JNK MAPK and HDAC inhibition on NFE2 and CTGF expression in TGF-β treated HK-11 cells and effects of MG132 on JNK activation in OVE26 mouse kidneys and in TGFβ-treated HK-11 cells.HK11 cells were pre-treated with/without JNK inhibitor SP600125, HDAC inhibitor trichostatin A, and MG132, for an hour prior to treatment with TGFβ for 24 h.JNK blockade inhibited TGFβ-induced CTGF expression but not NF-E2 expression. MG132 blocked TGFβ-induced JNK activation in HK11 cells and in OVE26 mice. HDAC inhibition exacerbated TGFβ-induced NFE2 degradation and induced CTGF expression. ERK, p38 and JNK pathways contribute to enhanced CTGF expression but only p38 and ERK MAPK pathways contribute to NFE2 degradation. MG132 blocked TGFβ-induced JNK activation, suggesting that proteasome function is necessary for JNK activation and therefore, blocking JNK had no effect on preserving NF-E2 expression. Blocking HDAC activation possibly promoted HAT activity, NFE2 acetylation and enhanced degradation. Thus, proteasome inhibition plus TGFβ preserved NFE2 expression and prevented JNK activation and CTGF. HDAC inhibition plus TGFβ exacerbated NFE2 degradation and enhanced JNK activation and CTGF. We identified NFE2 as a potential anti-fibrotic protein in the kidney.

Disclosure

J. Li: None. M. Rane: None. L. Cai: None. Y. Tan: None.
474-P: Gut Microbiome–Derived Phenyl Sulfate Contributes to Albuminuria in Diabetic Kidney Disease
Authors: KIKUCHI KOICHI , ABE TAKAAKI
Published: June 2020

Diabetic kidney disease is a major cause of renal failure in urgent of breakthrough in disease management. Type 2 diabetes causes significant changes in an array of plasma metabolites, and in the humans, SLCO4C1 is the only transporter contributes to transport them into urine. We generated transgenic (Tg) rats overexpressing SLCO4C1 in the proximal tubule, a typical model for human renal excretion. Using this model, we characterize metabolites that are increased in diabetic wild type rats, but reduced in diabetic Tg rats.PS increase with the progression of diabetes and was decreased in Tg rats with limited proteinuria. In diabetes models, PS administration induced albuminuria and podocyte damage due to the mitochondrial dysfunction. Phenol is synthesized from tyrosine by gut bacterial-specific tyrosine phenol-lyase (TPL) and phenol is metabolized to PS in the liver. Administration of TPL inhibitor reduced not only serum PS level but also albuminuria in diabetic mice. Furthermore, TPL inhibitor significantly ameliorate renal dysfunction in adenine-induced renal failure model. Because TPL inhibitor did not alter the major composition, the non-lethal inhibition of microbial-specific enzymes has a therapeutic advantage with lower selective pressure for the development of drug resistance. We next confirmed whether PS also related with the diabetes and DKD progression in humans. In a diabetic patient cohort (U-CARE study, n=362), serum PS levels related with the basal albuminuria level. In addition, logistic regression analysis showed that among known ACR predictive factors, PS was the only factor which significantly related 2-year progression of albuminuria in patients with microalbuminuria. These data suggested that PS may have a potential as important predictive marker of DKD.PS is a modifiable cause and a target for the treatment of DKD. Chemical reduction of TPL should represent another aspect for developing drugs preventing DKD (Kikuchi et al. Nat. Commun. 10: 1835, 2019).

Disclosure

K. Kikuchi: None. T. Abe: None.
484-P: Abnormal Ketone Body Metabolism Caused by Bdh1 Deficiency Promoted the Progression of Diabetic Kidney Disease by Activating ROS
Authors: WAN SHENGRONG , TENG FANGYUAN , JIANG ZONGZHE , XU YONG
Published: June 2020

Objective: This study was intended to reveal the mechanism of ketone body metabolism abnormality caused by bdh1 deficiency promoting the progression of diabetic kidney disease(DKD) by activating reactive oxygen species (ROS).

Methods: Eight-week-old wild type(n=8) and db/db (n=8) mice were treated with normal diet and high-fat diet for three months, respectively. Then two groups of mice kidney samples were taken for RNA-Seq analysis to select the target gene. It was verified by qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry in mice kidney. A high glucose-induced ROS activation model of HK-2 renal cells was established, and then siRNA was used to interfere with bdh1.

Results: RNA-seq showed that the pathway of ketone body metabolism in DKD changed significantly, and further analysis showed that bdh1, the key protein of ketone body metabolism, decreased significantly. The sequencing result was further confirmed by qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry, and we found that bdh1 was mainly expressed in tubular epithelial cells. In order to identify the molecular mechanism of bdh1 involved in DKD, we constructed the high glucose-induced ROS activation model of HK-2 cells in vitro. It was found that bdh1 was significantly down-regulated in high glucose treated HK-2 cells. The knockdown of bdh1 by siRNA could promote the production of ROS induced by high glucose. Further research found that bdh1 promoted the expression of nrf2 then inhibited ROS through the ketone body metabolism pathway, thus protected HK-2 cells in a high glucose environment.

Conclusions: Bdh1 promoted the expression of nrf2 through the pathway of ketone body metabolism and inhibited the production of ROS to protect HK-2 cells in a high glucose environment. Abnormal ketone body metabolism caused by bdh1 deficiency participated in the progress of DKD.

Disclosure

S. Wan: None. F. Teng: None. Z. Jiang: None. Y. Xu: None.
49-OR: Synergistic Effect of ERAD and Autophagy in Preventing Proinsulin Aggregation and Promoting Beta-Cell Survival
Authors: SHRESTHA NEHA , REINERT RACHEL B. , ARVAN PETER , QI LING
Published: June 2020

Decline of proteostasis in the endoplasmic reticulum (ER) is thought to underlie molecular changes in β cell function and drive the pathogenesis of diabetes. ER-associated degradation (ERAD) and macroautophagy (hereafter “autophagy”) are two principal quality-control mechanisms responsible for the clearance of ER-resident proteins or protein aggregates, respectively, in the cell. However, the physiological significance of ERAD-autophagy crosstalk remains unexplored. Previously, using β cell-specific knockout mouse models, we reported that ERAD deficiency leads to β cell dedifferentiation, while autophagy deficiency leads to β cell loss by 4-5 months of age. Interestingly, we observed that loss of ERAD in β cells triggered activation of autophagy pathways, as monitored by LC3 flux. Furthermore, chloroquine-mediated inhibition of autophagy in ERAD-deficient islets led to an increased proinsulin aggregation. In mice, combined deletion of ERAD and autophagy in β cells caused marked hyperglycemia soon after weaning, with extensive loss of β cells and premature death at 2-3 months of age. Thus, our data demonstrate that ERAD and autophagy act synergistically to prevent proinsulin aggregation and promote β cell survival. This study reveals a critical role for crosstalk between the ERAD and autophagy pathways in preventing diabetes and provides the first evidence for synergism between ERAD and autophagy in vivo.

Disclosure

N. Shrestha: None. R.B. Reinert: None. P. Arvan: None. L. Qi: None.

Funding

JDRF (2-SRA-2018-539-A-B); National Institutes of Health (1R01DK117639-01, 1R01DK111174)
500-P: Renal Function Decline and the Related Risk Factors in a Cohort of Beijing Community Diabetes Study
Authors: YUAN MINGXIA , YUAN SHENYUAN ,   BEIJING COMMUNITY DIABETES STUDY (BCDS) GROUP
Published: June 2020

Objective: To explore the renal function decline and the related risk factors in a cohort of Beijing Community Diabetes Study.

Methods: A multi-center, prospective study with ten-year follow-up was conducted at Beijing communities between 2008 and 2018. The clinical information and physical examination were recorded. Laboratory test including hemoglobin A1c, serum uric acid, fasting blood glucose, serum creatinine, and blood lipid profile were conducted. The patients were divided into two groups according to their age (<65 and ≧ 65). Annual eGFR decline rate≧3ml/min/1.73m2 was defined as rapid renal function decline. The tendency of renal function change over 10 years in different age groups had been described. Logistic multivariable models were employed to investigate the risk factors of rapid renal function decline.

Results: A total of 1655 patients with type 2 diabetes were enrolled. The median (quartile1, quartile3) annual rate of decline in eGFR of T2DM was 0.21(-2.51, 3.06) ml/min/1.73m2. Among them, 25.5% of the patients (n=422) showed rapid GFR decline, with an annual decrease of 5.28(3.85, 7.46) ml/min/1.73m2. Non-rapid decliner was 74.5% (n=1233), and the annual decrease was -0.99(-3.66, 0.82) ml/min/1.73m2. The patients with end-stage renal disease increased from 0.12% to 0.91% compared with the baseline. Uric acid was an independent risk factor for rapid GFR decline in both non-elder (OR=1.01, 95%CI: 1.00-1.01, P=0.001) and elder population (OR=1.01, 95%CI: 1.00-1.01, P=0.002), adjusting for age, sex and duration. Hyperfiltration was another independent risk factor for rapid GFR decline in non-elder (OR=14.72, 95%CI: 8.97-24.15, P<0.001) and elder population (OR=7.91, 95%CI: 4.04-15.48, P<0.001).

Conclusions: A quarter of patients with type 2 diabetes showed rapid renal function decline over 10 years. Serum uric acid and glomerular hyperfiltration are independent risk factors to rapid renal function decline.

Disclosure

M. Yuan: None. S. Yuan: None.

Funding

Capital Health Research and Development (2016-1-2057)
502-P: Tubular Markers and Diabetic Retinopathy Can Predict Early Diabetic Kidney Disease
Authors: ZHANG LIN , LU JING
Published: June 2020

Aim: To evaluate the association of tubular markers and diabetic retinopathy (DR) in 2-DM patients with normal creatinine(Cr) and urinary microalbumin/Cr(ACR).

Methods: In this study, we selected 1164 patients with 2-DM to integrate the clinical biochemical indexes and urinary alpha-1 microglobulin/Cr(A1CR), urinary immunoglobulin G/Cr(IGUCR), urinary transferrin/Cr(TRUCR), ACR and fundus examination. 274 patients underwent nuclear medicine 99mTc-EC to measure renal effective plasma flow (ERPF) and 99mTc-DTPA to measure glomerular filtration rate (GFR). They were divided into 2 groups: 52 cases with DR and 222 cases non-DR. Renal parameters were compared between 2 groups.

Results: In this cross-sectional study, we fund the tubular markers: A1CR, IGUCR, and TRUCR in the DR group were higher (P < 0.001) than non-DR group, while ERPF decreased (P < 0.001). The glomerular parameters: ACR was slightly higher in the DR group, GFR had no significant difference between 2 groups (P > 0.05). Pearson correlation analysis showed A1CR had a better correlation with GFR and ERPF (P < 0.001) than ACR (P > 0.05). In a binary logistic analysis, after adjusting sex, age, course of DM, and other factors, A1CR, IGUCR, and ERPF were still independently associated with DR.

Conclusion: In 2-DM patients, tubular indexes and DR were the sensitive and noninvasive biomarkers for early prediction of diabetic kidney disease.

Disclosure

L. Zhang: None. J. Lu: None.
526-P: Urine Tricarboxylic Acid Cycle Organic Anions and Progression of Diabetic Kidney Disease
Authors: LUNYERA JOSEPH , NGUYEN MAGGIE , DIAMANTIDIS CLARISSA J. , BOSWORTH HAYDEN B. , PATEL UPTAL D. , DAVENPORT CLEMONTINA A. , BAIN JAMES R. , MUEHLBAUER MICHAEL , ILKAYEVA OLGA , SHAH SVATI H. , SCIALLA JULIA
Published: June 2020

Background: Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression.

Methods: We conducted an ancillary study to the Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease (STOP-DKD) Trial - a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014-2015. In this study, we used linear mixed models to assess associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR decline. TCA cycle OAs were measured in 24h urine samples by targeted MS and modeled as: (1) the average of z-scores for each OAs; and (2) factor scores derived by principal component analysis (PCA). We extended follow-up for eGFR to mid-2019 using electronic health records.

Results: Among 132 participants (50% men; 58% Black; mean age 64 years [SD 9]; median eGFR 72 ml/min/1.73m2 [IQR 59-89] and urine albumin-to-creatinine [UACR] 25 mg/g [IQR 9-81]), PCA identified 3 OA metabolite factors (F). Fumarate, malate, α-ketoglutarate, citrate, lactate, and pyruvate loaded positively on F1; succinate, pyruvate, and lactate loaded negatively on F2; and methylsuccinate, ethylmalonate, and methylmalonate loaded positively on F3. Over a median follow-up of 1 year [IQR 1.3], higher average OA z score, F1, and F3 were each strongly associated with higher baseline eGFR after adjustment for age, sex, race, and log(UACR) at baseline (all p<0.01). Higher F2, but not other scores, was associated with faster eGFR decline (p=0.05).

Conclusion: Lower urine TCA cycle OAs, most notably a factor comprising lower succinate, pyruvate and lactate, are potential biomarkers for faster DKD progression.

Disclosure

J. Lunyera: None. M. Nguyen: None. C.J. Diamantidis: None. H.B. Bosworth: Board Member; Self; Preventric Diagnostic. Consultant; Self; Abbott, Medicines Company, Novartis Pharmaceuticals Corporation. Research Support; Self; improved patient outcomes, Novo Nordisk Foundation, Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pharma foundation, Proteus Digital Health, Proteus Digital Health, Sanofi. U.D. Patel: Board Member; Self; Goldfinch Bio. Employee; Self; Gilead Sciences, Inc. C.A. Davenport: None. J.R. Bain: None. M. Muehlbauer: None. O. Ilkayeva: None. S.H. Shah: Research Support; Self; AstraZeneca, Verily Life Sciences LLC. J. Scialla: Advisory Panel; Self; Tricida. Other Relationship; Self; GlaxoSmithKline plc., Sanofi.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK076169)
533-P: Predicting Treatment Response in Painful Diabetic Neuropathy Using Magnetic Resonance Brain Imaging
Authors: TEH KEVIN , WILKINSON IAIN D. , SLOAN GORDON P. , TESFAYE SOLOMON , SELVARAJAH DINESH
Published: June 2020

Background: Painful diabetic polyneuropathy (DPN) is difficult to manage as treatment response is often varied. The aim of this study was to explore the central mechanisms to explain the variance in treatment response.

Methods: Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. All subjects completed a treatment efficacy questionnaire. Twenty-nine patients (responders n=14 and non-responders n=15) along with 26 healthy controls subsequently underwent multimodal brain magnetic resonance (MR) imaging to acquire anatomical and resting state functional data (3T, Achieva, Phillips Healthcare).

Results: There was no significant difference in age (p=0.53), pain duration (p=0.89), diabetes duration (p=0.19) and clinical parameters of neuropathy (TCNS, p=0.16 and NTSS-6, p=0.61) between responders and non-responders to lidocaine treatment. Neither was there a difference in the use of concurrent neuropathic pain treatments. Non-responders to lidocaine had significantly lower mean S1 cortical volumes and mean number of vertices compared to responders and healthy controls (ANOVA p=0.02 and 0.02 respectively). There was no significant difference in S1 cortical volumes or vertices between responders and healthy controls. There was significantly greater resting state functional connectivity in lidocaine responders between the insula cortex [F(4)(13)=10.33; p-FDR=0.01] and the orbital frontal cortex [T(20)=3.88; p-FDR=0.02], amygdala [T(20)=3.65; p-FDR=0.02] and anterior cingulate gyrus [T(20)=4.04; p-FDR=0.01].

Conclusion: To the best of our knowledge, this is the first assessment of CNS mechanisms of treatment response in painful DPN. Key nociceptive processing areas showed decreased grey matter density (S1 cortex) and reduced functional connectivity (insula) relating to treatment response. MR neuroimaging may serve as a Central Pain Signature which could be used to predict treatment response.

Disclosure

K. Teh: None. I.D. Wilkinson: None. G.P. Sloan: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, Wörwag Pharma. Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, Napp Pharmaceuticals, Novo Nordisk Inc., Pfizer Inc. D. Selvarajah: None.

Funding

European Foundation for the Study of Diabetes; University of Sheffield
538-P: Inter-Rater Agreement of Vibration and Pressure Sensation in the Assessment of Sensorimotor Dysfunction in Diabetes
Authors: JUDE EDWARD B. , TENTOLOURIS ANASTASIOS , ELEFTHERIADOU IOANNA , TENTOLOURIS NIKOLAOS
Published: June 2020

Assessment of large fibre dysfunction is based on tuning fork (TF) for vibration perception and on monofilament (MF) for pressure sensation. Herein we examined the inter-rater variability of the MF and TF alongside with the VibraTip™ (VT), a new measure of vibration perception. We recruited 100 subjects with diabetes. Patients with active ulcers or peripheral vascular disease were excluded. A consultant diabetologist (CD) initially performed a general physical and foot examination at each foot which included MF, TF and VT. The tests were then performed by a podiatrist (P) and a diabetes specialist nurse (DSN) and the results were compared among the healthcare professionals (HCP); each examiner was blinded to the results of the other examiners. Inter-rater agreement was determined by weighted kappa (k) statistics. k values 0.41-0.60 represent moderate agreement, 0.61-0.8 good and >0.81 very good agreement. Diagnosis of insensation (%) by the CD, P and DSN were as follows: MF insensation 37.5%, 34.5% and 34.0%, respectively; TF insensation, 48.0%, 31.5% and 45.0%, respectively; VT insensation 39.0%, 35.0% and 35.5%, respectively. The inter-rater agreement (k, 95% confidence intervals) between the CD and the P, the P and the DSN as well as the CD and the DSN were as follows: TF 0.62 (0.52-0.73), 0.62 (0.51-0.72), 0.68 (0.57-0.78), respectively; MF 0.67 (0.57-0.78), 0.70 (0.59-0.80), 0.73 (0.63-0.83), respectively; VT 0.72 (0.62-0.82), 0.70 (0.60-0.81), 0.67 (0.56-0.78), respectively. The k statistics suggested good level (>0.6) of agreement of the three neurological modalities between the HCP. Despite the differences observed in the ability of various tests to diagnose reduced sensation, there is good overall agreement in the results of neurological examination by MF, TF and VT between HCP. Further research is required to examine the performance of these tests in the diagnosis of neuropathy.

Disclosure

E.B. Jude: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk Inc., Sanofi. Other Relationship; Self; Lilly Diabetes, Menarini Group. A. Tentolouris: None. I. Eleftheriadou: None. N. Tentolouris: None.
555-P: Current Status of Diabetic Peripheral Neuropathy in Type 2 Diabetes: Results from a National Health Insurance Service National Sample Cohort, 2006-2015
Authors: KIM CHONG HWA , PARK TAE SUN , MOON SEONG-SU , KIM SUNG RAE , LEE KIYOUNG
Published: June 2020

Objectives: To determine the prevalence and clinical characteristics of diabetic peripheral neuropathy in patients with type 2 diabetes in Korea.

Methods: From the National Health Information database maintained by the Korean National Health Insurance Service (NHIS) a representative sample cohort of 1,201,208 participants was randomly selected, comprising 2.2% of the total eligible Korean population in 2006, and followed until 2015. Data source: NHIS-NSC: National Health Insurance Service-National Sample Cohort.

Results: The annual prevalence of DPN increased from 24.5% in 2006 to 26.3% in 2007 and thereafter it tended to gradually decrease to 21.2% in 2015. DPN medication was administered in 68% to 69% of DPN patients. Drug therapy was prescribed for up to 90% mono therapy, dual combination treatment for up to 10%, and triple combination treatment for up to 1%. Prescribed medications for DPN from 2006 to 2015 were α-lipoic acid (54.7% to 43.2%), anticonvulsant drugs (21.7% to 36.8%), tricyclic antidepressants (21.3% to 12.6%), serotonin-norepinephrine reuptake inhibitors (0.3% to 5.5%), γ-linoleic acid (2.3% to 1.9%). Persistency for pharmacological treatment of DPN was 30.0%- 48.5%, and the rate of persistency was increasing over time. The incidence of lower-extremity amputation was greater in patients with DPN compared with those without and the incidence has been gradually increasing through the follow-up period.

Conclusion: The prevalence of DPN patients is about a quarter of those with diabetes, and medication is about 70 percent, and most medications are administered with mono therapy.

Disclosure

C. Kim: None. T. Park: None. S. Moon: None. S. Kim: None. K. Lee: None.
556-P: 20-Hydroxyeicosatetraenoic Acid: A Prospective Therapeutic Target for Diabetes-Induced Neuropathy
Authors: HADDAD MARY , EID STEPHANIE , EID ASSAAD A.
Published: June 2020

Background: Diabetic Neuropathy is one of the most prevalent complications of diabetes. Clinically, Diabetic Peripheral Neuropathy (DPN) is characterized by reduced electrophysiological recordings and sensorimotor deficits which have been correlated with myelin defects in nerve fibers and limited regenerative potential. Oxidative stress emerged as the final key mediator of diabetic complications. Cytochrome P450 (CYPs) enzymes are major contributors which have been shown to mediate diabetes-induced organ injuries. Yet, no studies have investigated their role in DPN.

Methods: We assessed peripheral nerve functionality in a murine model of type 2 diabetes mellitus (T2D) treated with either a potent and selective inhibitor of 20-HETE synthesizing enzyme, HET0016, or with metformin, an AMPK activator. Behavioral, histological, biochemical and molecular assessments were performed.

Results: Hyperglycemia resulted in CYP4A protein upregulation and 20-HETE overproduction in sciatic nerves of diabetic animals which correlated with alterations in myelin protein levels culminating in sensorimotor deficits. Elevated 20-HETE levels were concurrent with increased ROS production. This was paralleled by AMPK inactivation in addition to alterations in Beclin-1 and LC3B levels. Interestingly, 20-HETE synthesizing enzyme inhibition via HET0016 was shown to normalize myelin protein profiles, p-AMPK levels, ROS production and autophagic defenses, restoring sensorimotor function in diabetic animals. Of interest, mice treated with metformin exhibited a decrease in CYP4A protein expression as well as in 20-HETE levels. Similarly, metformin treatment withdrew the injurious effect of diabetes on Schwann cells and attenuated peripheral neuropathy.

Conclusion: Our study suggest that hyperglycemia leads to oxidative injury via CYP4A alteration and AMPK inactivation, altering autophagy which compromises myelin integrity and peripheral nerve functionality.

Disclosure

M. Haddad: None. S. Eid: None. A.A. Eid: None.

Funding

American University of Beirut
565-P: Diabetic Retinopathy in African-Born Blacks Living In America: Prevalence, Risk Factors, and Diagnostic Tests
Authors: HWANG CHRISTOPHER K. , AGRON ELVIRA , CHEN MICHELLE A. , DUBOSE CHRISTOPHER , SUMNER ANNE E. , CHEW EMILY
Published: June 2020

The prevalence of diabetic retinopathy (DR), risk factors for DR and the best diagnostic tests for prediction of DR in Africans with prediabetes (preDM) and diabetes (DM) are unknown. Evaluation for atrophy of the retinal inner layers may be helpful but has not been studied in Africans. Therefore, African-born blacks (n=249, male 63%, age 40±10y (mean±SD), BMI 27.8±4.5 kg/m2) living in the United States had OGTT and eye exams with spectral-domain optical coherence tomography (OCT) and fundus photos. A validated automated algorithm was applied to OCT images to measure thickness of retinal layers. Both A1C and glucose criteria during the OGTT was used to diagnose glucose tolerance status. Newly diagnosed DM occurred in 9.6% (24/249), preDM in 40.6% (101/249), normal glucose tolerance (NGT) in 49.8% (124/249). Retinopathy was present in 4% (10/249) overall, 20.8% (5/24) in those with DM, 1.9% (2/101) with preDM, and 2.4% (3/124) with NGT. The NGT cases with retinopathy had hypertension, anemia and/or thrombocytopenia and were excluded from DR analysis. Fasting plasma glucose had the highest correlation with DR (P<0.001), followed by 2h glucose from the OGTT (P=0.001). Higher total abdominal adipose tissue (TAT) was associated with DR (P=0.043). Higher waist circumference and age trended towards significance (P=0.054 and 0.075, resp). However, BP, BMI, years in the U.S., GFR, urine microalbumin:creatinine, CHOL, TG, HDL, LDL, hip circumference, % body fat and refractive error were not correlated. No correlations were found with A1C, fructosamine or glycated albumin. Neither DM nor preDM were associated with atrophy of the various retinal layers evaluated. The overall prevalence of DM and preDM combined was high (50.2%), and DR was present in 21% with DM. Higher FPG and 2-hr OGTT could be predictive of DR, and higher TAT was significantly associated with DR, but atrophy at different retinal layers was not. As the study is on-going, analyses will be repeated with a larger sample.

Disclosure

C.K. Hwang: None. E. Agron: None. M.A. Chen: None. C. DuBose: None. A.E. Sumner: None. E. Chew: None.
573-P: Construction and Validation of a Hierarchical-Driven Network for Decoding the Potential Molecular Mechanisms in Diabetic Microvascular Complications
Authors: LI HAICHENG , FU XIANAN , HE XUEMIN , PENG RONGDONG , NIE YUANPENG , LI TING , CHEN YANMING
Published: June 2020

Aim: Diabetic microvascular complications, including diabetic nephropathy (DN) and diabetic retinopathy (DR), lead to poor life quality and increased mortality. Accumulating evidence indicates that the complexity of pathophysiology is controlled by hierarchical molecular factors at the epigenetic, transcriptional and post-transcriptional levels. Yet most studies focus on one of the driven factors, it still lacks a systematic classification model that links hierarchical molecular factors to the precise diagnosis of diabetic microangiopathy. This study aimed to construct driven networks that reveal the potential molecular mechanisms for the precise diagnosis of diabetic microangiopathy.

Methods: By combining multi-regulators, transcriptional kinetics, gene expression, DNA-protein binding signals and lncRNA targets, we based on the hierarchical Bayesian Model, DrivenRN, to construct driven networks for detecting the signature of key function genes. Then we tested this model using public datasets, followed by real-time PCR validation of the identified genes’ expression in the peripheral blood mononuclear cells (PBMCs) from patients.

Results: Through DrivenRN analysis, we identified four genes that are specifically involved in driving DN, including TIMP3, CNDP1, MYH9 and ENPP1. We also identified three genes that are specifically involved in driving DR-, including EDN1, CD34 and CYR61. Furthermore, we validated CNDP1, MYH9 and ENPP1 in DN PBMCs, and CD34 in DR PBMCs.

Conclusion: This study has constructed a novel model, DrivenRN, which effectively maps the driven networks for the prediction of potential pathological factors in diabetic microvascular complications.

Disclosure

H. Li: None. X. Fu: None. X. He: None. R. Peng: None. Y. Nie: None. T. Li: None. Y. Chen: None.
577-P: Choroidal Thickness Is Dependent on BMI and Acute Changes in Blood Glucose
Authors: MEYHOEFER SVENJA , WILMS BRITTA , CHAMORRO RODRIGO , PAGELS ANNA-JOSEPHIN , GREIN HANS-JÜRGEN , SCHMID SEBASTIAN M.
Published: June 2020

Background: Diabetic retinopathy (DR) is a serious complication of diabetes that can lead to blindness. As diagnosis is often made when cell and vision loss are already existing, detecting retinal changes at early stages is crucial. Due to its high vascularization, changes in the choroid play an important role in the pathogenesis of retinal impairment and therefore might be an early diagnostic target.

Aim: The aim of this pilot study was to evaluate BMI- and glucose-dependent changes in choroidal thickness (ChT) of healthy volunteers under standardized conditions.

Methods: 18 healthy volunteers aged 19 to 42 years (mean±SEM: 26.2±1.7 years) with a body mass index (BMI) between 20 to 34 kg/m2 (24.9±0.8 kg/m2) were included. During an intravenous glucose tolerance test (ivGTT), blood glucose profiles were measured by a gold-standard laboratory system. Simultaneously, a second researcher assessed ChT by optical coherence tomography (OCT, company Heidelberg Engineering GmbH). Researchers were blinded to measurements done by the other one.

Results: In general, ChT was positively correlated with BMI (r=0.229; P=0.045). Moreover, the steeper increase of blood glucose up to minute 6 of the ivGTT was significantly associated with greater ChT (r=0.254; P=0.039).

Conclusion: ChT is modulated by BMI and short-term fluctuations in blood glucose in healthy subjects without any history of diabetes. It is tempting to speculate that increased ChT and/or reduced susceptibility to glucose dynamics could be a novel marker for early impairment of posterior eye structures. Ongoing studies evaluate ChT and its glucose-dependent variability in patients with diabetes.

Disclosure

S. Meyhoefer: None. B. Wilms: None. R. Chamorro: None. A. Pagels: None. H. Grein: None. S.M. Schmid: None.

Funding

German Center for Diabetes Research
580-P: Role of Bile Acids in Hepatic Lipid Metabolism: Characterization of the Fasting Lipid and Lipoprotein Profile of Tgr5-/- Hamsters
Authors: ALVARES DANIELLE C.L. , HOFFMAN SIMON S. , ADELI KHOSROW
Published: June 2020

Introduction: A major complication of insulin resistant states is fasting dyslipidemia, a lipid profile characterized by elevated triglycerides, increased small dense LDL and low HDL-cholesterol. Recently, bile acid signaling has been suggested to improve hepatic insulin sensitivity and lipid accumulation through activation of the Takeda G protein-coupled receptor 5 (TGR5). Using CRISPR/CAS9 gene editing, and in collaboration with the Wang laboratory at Utah State University, we have developed a novel Tgr5-/- hamster model. As the role of TGR5 in regulating hepatic lipid and lipoprotein metabolism has not been explored, the present study was performed to characterize the fasting lipid profile of this model in normal and mild insulin resistant states and further examine bile acid signaling within these hamsters.

Methods/Results: Eight-week-old Tgr5+/+ and Tgr5-/- hamsters were fed a high fat, high fructose and low cholesterol (FFLC) diet for 6 weeks. Glucose tolerance and fasting plasma lipids were examined at baseline, and following 6-weeks of FFLC consumption. Unlike the Tgr5+/+ hamsters, who exhibited impaired glucose tolerance following 6-weeks of FFLC-feeding, Tgr5-/- hamsters did not. This alteration in glucose tolerance was not associated with any significant differences in body weight or food consumption, or hepatic triglyceride or cholesterol between genotypes. Lipoprotein profiling was performed via FPLC analysis. Preliminary results suggest that Tgr5-/- hamsters exhibit reduced VLDL-triglyceride and -cholesterol, and HDL-cholesterol. Finally, chow fed hamsters received intraduodenal injections of deoxycholic acid (DCA), a bile acid with a strong affinity for TGR5. DCA administration was associated with reduced VLDL-triglyceride secretion in Tgr5+/+ hamsters, an effect that was blunted in Tgr5-/- hamsters. The present research will set a framework to expand our knowledge of the role of TGR5 signaling in hepatic lipogenesis.

Disclosure

D.C.L. Alvares: None. S.S. Hoffman: None. K. Adeli: None.

Funding

Heart and Stroke Foundation of Canada
587-P: The Relationship between Metabolic Index, Liver Enzyme Index, and the Incidence of Diabetes: The Jinchang Cohort Study
Authors: HUANG PEIYAO , YANG JINGLI , HUANG WENYA , LIU NIAN , WANG RUONAN , ZHANG RUI , BAI ZHAO , BAI YANA , CHENG NING , WANG MINZHEN , ZHENG SHAN
Published: June 2020

Objectives: To explore the incidence of diabetes under different indicator and interaction between metabolic index and liver enzyme index for diabetes mellitus.

Methods: This study based on the Jinchang cohort, which is a prospective cohort included 48,001 subjects at baseline. To compare the incidence of diabetes under different metabolic indexes and liver enzyme indexes; Cox proportional hazard model was used to analysis the risk of diabetes with different metabolic indexes and liver enzymes indexes; The multiplicative model was used to analyze the interaction between different metabolic indexes and liver enzymes indexes for diabetes.

Results: With the increase of TC, TG, ALT and AST, the incidence of diabetes gradually increased(p<0.05), with the increase of HDL-C level, the incidence of diabetes gradually decreased(p<0.05).With the increase of TC, TG, LDL-C, ALT, AST and GGT, the risk of diabetes were rising(p<0.05), and the increase of HDL-C reduced the risk of diabetes. In men, the interaction between TC and TG, TC and ALT, TG and ALT, ALT and GGT are positively and multiply; which HR(95%CI) was 6.71 (1.66∼27.04),20.62(9.50∼44.76),10.23(6.42∼16.29) and 6.63(4.38∼10.04), respectively. In women, TC and TG, ALT and GGT are positively and multiply, they also play a synergistic role in the risk of diabetes, and the HR(95%CI) was 6.75(2.12∼21.50) and 15.93(4.95∼51.25), respectively.

Conclusion: TC, TG, LDL-C,ALT, AST and GGT were risk factors for the incidence of diabetes, and HDL-C was a protective factor for the incidence of diabetes. In the male population, the interaction of TC and TG, TC and ALT, TG and ALT, ALT and GGT were all positively multiplied. In the female population, TC and TG, ALT and GGT were positively multiplied by the interaction.

Disclosure

P. Huang: None. J. Yang: None. W. Huang: None. N. Liu: None. R. Wang: None. R. Zhang: None. Z. Bai: None. Y. Bai: None. N. Cheng: None. M. Wang: None. S. Zheng: None.

Funding

National Institutes of Health (1R01ES02908201A1); Lanzhou University (2018LDBRZD008)
591-P: Macrophage IL-1beta–Dependent VEGF-A Expression Is Required for Inflammatory Arteriogenesis and Wound Healing in Type 2 Diabetes
Authors: MANTSOUNGA CHRIS S.
Published: June 2020

Impaired wound healing in patients with diabetes mellitus (DM) is a major source of morbidity and mortality. Current treatments for diabetic wounds are modestly effective at promoting healing. Recently, we identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/arteriogenesis required for adequate wound healing. We sought to understand the impact of diabetes on inflammatory angiogenesis and consequent healing. We hypothesized that diabetes mellitus (DM) results in reduced inflammatory macrophage VEGF-A expression with consequent impairments in angiogenesis-dependent wound healing. Mice with experimental diabetes demonstrated profound delays both in wound healing using a dermal punch biopsy model and in perfusion recovery using the femoral artery ligation model of hind limb ischemia. VEGF-A expression is highly upregulated in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing macrophages. This is supported by a strong association between IL-1β and VEGF-A expression. In order to understand whether this relationship between IL-1β and VEGF-A was causal, we generated a novel mouse with a LoxP flanked IL-1β allele to create an inducible macrophage deletion of IL-1β. Myeloid IL-β deletion resulted in severely impaired macrophage VEGF-A expression and consequent decreases in angiogenesis and wound healing, consistent with the experimental model of DM. Moreover, macrophages from diabetic mice demonstrated reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A expression. Defining inflammatory macrophages as key, early drivers of angiogenesis supports a paradigm shift away from inflammation-suppression for adequate wound healing, allowing for macrophage reprograming strategies that promote appropriate inflammation-dependent healing responses.

Disclosure

C.S. Mantsounga: None.

Funding

National Institutes Health (1R01HL139795)
599-P: Magnetic Field vs. Calcium Channel Blockade Effect on Microcirculation: Potential Implementation in Diabetic Foot Microvascular Dysfunction
Authors: GMITROV JURAJ
Published: June 2020

The goal was to compare static magnetic field (SMF) vasodilator capacity with verapamil (VER) a potent Ca2+ channel blocking agent infusion, aimed to asses SMF potential implementation in conditions with vascular ischemia. Mean femoral artery blood pressure, heart rate and ear lobe skin microcirculatory blood flow measured by microphotoelectric plethysmogram (MPPG) were simultaneously recorded in conscious rabbits after 40-min carotid baroreceptor exposure to 0.35 T SMF (SMF-Car, n = 14) or 0.25 T SMF, generated by Nd-Fe-B magnets, exposed directly to ear microvascular net (SMF-Ves, n = 20), Fig. 1a, and compared with that after 30 min VER i.v. infusion (20 mg kg-1 min-1, n = 20), Fig. 1b. The principal finding is that SMF-Car, SMF-Ves and VER significantly increased microcirculation by: 22.6 ± 11.11%, 17.9 ± 9.58% and 30.5 ± 14.06% (mean ± SEM) resp. and that was no significant difference between all of three treatments (p = 0.986). Microvascular dilation was accompanied by significant decrease of baroreflex sensitivity in VER and its increase in SMF-Car coupled with enhanced vessel sensitivity to nitric oxide dilatory effect. This suggests SMF strong, comparable with VER vasodilator property tailored to address neural and myogenic component of microvascular dysfunction in diabetic foot and nephropathy especially employing both SMFs vasodilation synergy.

Disclosure

J. Gmitrov: None.
611-P: Splenic Stimulation with Focused Ultrasound Aids in Wound Healing
Authors: MORTON CHRISTINE A. , COTERO-LEFEVRE VICTORIA E. , PULEO CHRIS , ASHE JEFFRAY
Published: June 2020

Wound care in at risk populations is a growing problem. The cost of care of these non-healing wounds is projected to be in the billions with the number of people affected being above 6.5 million and increasing as the population ages. There is significant mortality related with non-healing wounds with 5-year rates being higher than many cancers such as prostate or breast. Chronic inflammation, a comorbidity of type 2 diabetes, when left unchecked may result in non-healing wounds. This study explores the use of non-invasive focused ultrasound (FUS) targeted to the spleen to aid in healing of full thickness excision skin wounds in Obese Zucker Diabetic (ZDF) or Zucker Diabetic Sprague Dawley (ZDSD) rats. Splenic stimulation with FUS has been shown to decrease TNF-α 60 minutes post stimulation in both whole blood and the spleen of animals injected with LPS. By decreasing systemic proinflammatory cytokines, wounds may progress to better outcomes. In the current study, FUS was targeted to the spleen daily while wounds were healing (16 days). Hyperglycemic (fed glucose >250 mg/dL) ZDF stimulated with FUS were predicted (by linear regression) to heal 5 days faster than shams (17.1 ±0.8 days vs. 22.3±1.6 days respectively). Glucose levels remained similar throughout the study. The same FUS conditions were applied to prediabetic ZDSD (fed glucose < 195 mg/dL). FUS stimulated rats were predicted to heal 2 days faster than shams (20 ±1.2 vs. 22.3±1.1 respectively).

Disclosure

C.A. Morton: None. V.E. Cotero-Lefevre: None. C. Puleo: Employee; Self; General Electric. J. Ashe: Employee; Self; General Electric.
613-P: The Needs of Caregivers for Recently Hospitalized Older Adults with Type 2 Diabetes Mellitus
Authors: DANNER ALYSSA , OCONNOR MELISSA , WHITEHOUSE CHRISTINA
Published: June 2020

Background: Caregivers play a crucial role in the management of older adults with type 2 diabetes mellitus (T2DM). Caregivers often lack support and experience caregiver burden.

Purpose: The purpose of the study was to investigate the needs and experience of caregivers of recently hospitalized older adults with T2DM.

Methods: Qualitative interviews were conducted using a semi-structured interview guide with open-ended questions that highlighted the caregivers’ experience caring for a recently hospitalized older adult with T2DM. All interviews were digitally recorded and professionally transcribed. Once transcribed, transcripts were uploaded to ATLAS.ti to organize and retrieve data. Transcripts were analyzed using qualitative content analysis.

Results: A total of 20 caregivers were interviewed. Most of the subjects were caregivers for a family member, with a majority of subjects caring for their parents. Participants were mostly female (75%), above age 50, and non-Hispanic Black (80%). The main themes that emerged from the qualitative data were: (1) the role itself, (2) challenges, (3) role preparation, and (4) additional comorbid diagnoses.

Conclusion: Our findings provide an understanding of experience, tasks, and needs of caregivers for older adults with T2DM. This study revealed that many caregivers feel that care taking is an obligation and a full-time role. A majority of caregivers indicated they did not receive education regarding caring for someone with DM, despite being solely responsible for providing care. Although many of the caregivers did not identify T2DM as the main concern due to additional comorbid conditions, the most pertinent patient and caregiver challenges identified include diet, multiple responsibilities, and time-management. This study identifies the importance of inclusion of family caregivers when providing education.

Disclosure

A. Danner: None. M. OConnor: None. C. Whitehouse: None.
619-P: The Impact of Type 2 Diabetes Mellitus Risk Perception on Adoption of Preventive Strategies in Women with a History of Gestational Diabetes
Authors: VU AMANDA V. , TURK NORMAN , DURU O. KENRIK , MANGIONE CAROL , PANCHAL HEMALI , AMAYA SARAH A. , NORRIS KEITH C. , MOIN TANNAZ
Published: June 2020

Background: Gestational diabetes confers a 3-7 fold higher risk of incident diabetes. However, studies show women with GDM underestimate their personal risk, even when they understand GDM is a risk factor for incident T2DM. The study objectives were to identify predictors of T2DM risk perception in women with GDM and to determine if their level of risk perception impacts adoption of evidence-based health behaviors for T2DM prevention.

Methods: Using electronic health records to identify eligible women between 18-50 years old, we surveyed women with a history of GDM who had not progressed to T2DM.

Results: The study sample (n=264) was racially and ethnically diverse; 37% Hispanic, 29% Asian, 27% non-Hispanic white, and 5% black. About one in five (21%) women were unaware that GDM increases the risk of incident T2DM after pregnancy; almost half (48%) believed their personal risk of T2DM was low. In multivariate analyses adjusting for race, ethnicity, education level, time since index GDM pregnancy, and agreement with GDM diagnosis, family history of T2DM (OR 2.1, 95% CI 1.1-4.0) and knowledge of GDM increasing risk of T2DM (OR 4.5, 95% CI 2.1-9.7) were independent predictors of higher risk perception of T2DM. Higher risk perception was associated with both a higher level of interest in taking metformin (unadjusted OR 2.2, 95% CI 1.1-4.1) and a higher level of interest in attending a National Diabetes Prevention Program (unadjusted OR 2.3, 95% CI 1.3-3.9) compared to women with lower risk perception.

Conclusion: Educating women with a history of GDM about their increased risk of T2DM is important; our study underscores the need to identify ways to effectively convey personal risk of T2DM. Family history of T2DM, which is strongly associated with personal risk perception, may be a key area for discussion with women with GDM to positively impact the adoption of T2DM preventive strategies; this may be relevant for all patients with higher risk of progression to T2DM.

Disclosure

A.V. Vu: None. N. Turk: None. O. Duru: None. C. Mangione: None. H. Panchal: None. S.A. Amaya: None. K.C. Norris: None. T. Moin: None.

Funding

National Institutes of Health (5R18DK105464)
624-P: Primary Care Education Leads to Improved Diabetes Knowledge and Clinical Practice
Authors: WOOLLEY RYAN , COLWELL ELAINE , FORD ERICA , SAXENA ANKITA , BRADLEY SARAH
Published: June 2020

Primary care providers (PCPs) are the initial treatment provider for a majority of the more than 100 million adults in the U.S. now living with diabetes or prediabetes. Constant changes in health care delivery and new diabetes therapies make it challenging for PCPs to stay up to date on the latest diabetes guidelines. In addition, only 14% of PCPs refer all patients with type 2 diabetes to diabetes self-management education and support (DSMES) programs despite their evidence base for improving diabetes-related outcomes. The American Diabetes Association (ADA) developed a professional education program designed to broaden the knowledge and usage of the Standards of Medical Care in Diabetes (SOC) among PCPs and increase referrals to evidence-based interventions for the prevention and management of diabetes. Programs provide 6 hours of case-based, accredited, interactive education built around the realities of primary care to a group of 100-200 PCPs. The program covers treatment options, strategies to improve compliance in diabetes management, and prevention of type 2 diabetes. To assess changes in clinical practice, online surveys are administered before and 6 months following the program. From June 2018 to March 2019, 1,183 PCPs participated in one of 9 in-person programs hosted across the country. Six months after the program, 98% of PCPs reported a gain in knowledge related to their clinical practice, and knowledge of pharmacologic treatment options increased 21%. In addition, 56% of PCPs increased their use of the SOC and PCP referrals to DSMES programs increased 16%. Results from the program demonstrate positive impact on PCP knowledge and clinical practice in the primary care setting. PCPs are learning how to optimize patient care in a changing health care landscape, thus increasing the likelihood of improved patient outcomes. Notably, this program has an estimated reach of 2.7 million patients with diabetes and 1.4 million with prediabetes leading to a widespread improvement in care across the country.

Disclosure

R. Woolley: Employee; Self; American Diabetes Association. E. Colwell: None. E. Ford: None. A. Saxena: None. S. Bradley: None.

Funding

Abbott Diabetes Care; AstraZeneca; Merck & Co., Inc.; Novo Nordisk