bluuebunny/crossref_metadata_2025 huggingface dataset:
51-OR: Loss of Critical ER Chaperone GRP78 Leads to Beta-Cell Death by a JNK Dependent Mechanism
Authors: SHARMA ROHIT B. , DARKO CHRISTINE O. , GABLASKI BRIAN , LEE AMY S. , ALONSO LAURA C.
Published: June 2020

Endoplasmic reticulum (ER) health is an important determinant of pancreatic beta cell function or failure. Adaptive ER stress leads to expansion of beta cell number through proliferation, but decompensated ER stress results in beta cell loss and contributes to both T1D and T2D. Therefore, understanding the mechanisms of ER-stress-induced beta cell death could help identify novel strategies for the prevention or treatment of diabetes. Glucose responsive protein GRP78/HSPA5 is a key ER chaperone. Loss of GRP78 causes cell death in many cell types; including, in our own prior work, the beta cell. To study the mechanism by which GRP78 loss leads to beta cell death we devised an ex vivo model of GRP78 knockdown by transducing Grp78-flox mouse islets with adenovirus expressing Cre recombinase. To study human islets, we used adenovirus expressing shRNA against GRP78. Using these tools, we successfully reduced GRP78 RNA and protein in primary mouse and human islet cells. Loss of GRP78 strongly activated the ATF6, IRE1 and PERK pathways of the unfolded protein response (UPR). GRP78 knockdown decreased beta cell number due to increased cell death as measured by Annexin V and TUNEL staining. Probing the mechanisms of cell loss, we found that loss of GRP78 activated multiple death-related pathways, notably autophagy and apoptosis; cell death effectors Chop, caspase 9 and cleaved caspase 3 were increased. Additionally, GRP78 deletion increased stress kinase JNK (c-Jun-N-terminal kinase) which has been implicated in cellular proliferation as well as cell death. Inhibition of JNK kinase using JNK-IN-8 inhibitor during GRP78 loss conditions decreased phosphorylation of JNK and rescued beta cells from cell death as measured with Annexin V and TUNEL. Therefore, we conclude that ER stress related cell death induced by loss of GRP78 (ER stress) involves JNK activation, and that modulation of JNK under certain circumstances may help maintain beta cell mass to protect against diabetes.

Disclosure

R.B. Sharma: None. C.O. Darko: None. B. Gablaski: None. A.S. Lee: None. L.C. Alonso: Consultant; Self; Fairbanks Pharmaceuticals Inc. Research Support; Self; American Diabetes Association.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK113300-02)
523-P: Different Effect on UACR According to Predetermined Treatment Schedule Groups (GLP1RA or SGLT2i) Therapy in T2DM
Authors: GOMEZ JUANA CARRETERO , ENA JAVIER , SEGUI-RIPOLL JOSE MIGUEL , CARRASCO-SÁNCHEZ FRANCISCO JAVIER , AREVALO LORIDO JOSE CARLOS , TEMBRA MANUEL SUAREZ , VARELA JOSE MANUEL , GOMEZ-HUELGAS RICARDO
Published: June 2020

Aim: To analyze changes on UACR in T2DM patients according to treatment schedule groups (GLP-1RA or SGLT2i).

Methods: Observational, prospective, multicenter study. Patients were stratified according to predetermined treatment schedule groups (successively vs.simultaneously).

Results: 178 patients (58.6% males, age 61.9+/-10.0 years). Table 1 shows baseline findings by groups. Initial UACR was 19.6+/-52.5 mg/g and initial UACR >30 mg/g (n=68) was 95.1+/-222 mg/g. At 26 weeks significant % change in UACR and UACR>30mg/g was found (4.35+/-30** and 48.8+/105.5**), greater when SGLT2i is added (90.5+/-276.5 *) (Table 2).

Discussion: Our results shows that the combination GLP-1ra-SGLT2i reduces UACR, especially if macroalbuminuria is present and is correlated to improvement in either HbA1c, weight and SBP.

Disclosure

J. Carretero Gomez: None. J. Ena: None. J. Segui-Ripoll: None. F. Carrasco-Sánchez: None. J. Arevalo Lorido: None. M. Suarez Tembra: None. J. Varela: None. R. Gomez-Huelgas: None.
53-LB: Health-Related Quality of Life and Its Associated Factors among Persons with Diabetes in Kathmandu, Nepal
Authors: ACHARYA SUJATA , DHAKAL AMRIT
Published: June 2020

Health- Related Quality of Life (HRQoL) among persons with diabetes is an important public health issue throughout the world. As per the information available, no study has been conducted till date to determine HRQoL using EQ-5D-5L in person with diabetes in Nepal. Therefore, this study was conducted to assess HRQoL in persons with diabetes and to identify factors associated with it. Hospital based cross sectional study was conducted in two diabetes centers of Kathmandu district. Study population included persons already diagnosed with diabetes from diabetes centers. We recruited 225 participants and they were interviewed using the standard Nepali version of the EQ-5D-5L questionnaire and some additional questionnaire based on extensive literature review. Independent t-test was used to find the bivariate association of HRQoL and other factors. Variables with p-value<0.05 in bivariate analysis were fitted into linear regression after fulfilling the assumptions. Ethical approval was obtained from the Institutional Review Board (IRB) of the Institute of Medicine. The study found that HRQoL among persons with diabetes was 0.53. Study found significant association with self-reported complications, age, insulin use, employment, education and duration of diabetes in bivariate analysis. In the multivariate analysis using the linear regression, study found that HRQoL was positively associated with education (β= 0.03), employment (β= 0.11). Similarly, study found that health related quality of life was negatively associated with self-reported complications (β= -0.10), insulin use (β= -0.11) and age (β= -0.09). Fitting the equation in linear regression revealed that 40% of change in HRQoL in persons with diabetes can be predicted by self-reported complications, employment, education, age, and insulin use. Our study findings were similar to other studies conducted in Southeast Asian region. HRQoL was lower compared to studies conducted in most of the developed countries.

Disclosure

S. Acharya: None. A. Dhakal: None.
53-OR: Deletion of YTHDF2 in Beta Cells Results in Glucose Intolerance
Authors: REN DECHENG , SUN JUAN
Published: June 2020

N6-methyladenosine (m6A) is the most common and abundant mRNA modification. However, the role of m6A in regulating β-cell function is unclear. YTHDF2 is a ’reader’ protein that recognizes m6A-containing mRNAs and targets them for degradation. To address the functional role of YTHDF2 in β-cells, we generated an Ythdf2 β-cell knockout mouse using RIP-Cre transgenic mice. At the 3-month old age, the feeding and fasting glucose of βKO mice were similar to that in control mice (RIP-Cre mice). However, both male and female βKO mice are glucose intolerant after glucose challenge. The AUC was increased by 44.6% in male βKO mice and 71.1% in female mice, respectively (both P<0.01). The response to insulin was similar between βKO and control mice. Interestingly, although the fasting insulin levels were comparable between βKO and control mice, the feeding insulin levels in both male and female βKO mice were increased. The serum insulin levels from βKO mice were significantly lower at 15 min after glucose challenge. In addition, the insulin secretion from βKO islets was less due to decreased insulin protein. Surprisingly, β-cell mass in βKO mice was significantly higher than that in control mice (P<0.05). Both islets number and size were increased in βKO mice. To understand the molecular mechanism, we performed RNA-seq to detect the gene expression in βKO and control islets isolated from male mice. Among 626 altered genes in βKO islets, 421 genes were upregulated and 205 genes were downregulated. The genes response to ER stress were among the top up-regulated genes. The genes related to insulin secretion were downregulated. We applied m6A-seq in MIN6 cells and confirmed that Ire1α was indeed modified by m6A in its last exon and 3’ UTR region. We further confirmed that both mRNA and protein levels of Ire1α and spliced XBP-1 were significantly increased in βKO islets.

In conclusion, YTHDF2 plays an important role in regulating insulin secretion, and YTHDF2 deficiency in β-cells induces glucose intolerance by regulating insulin secretion and ER stress.

Disclosure

D. Ren: None. J. Sun: None.

Funding

The University of Chicago (P30-DK020595)
531-P: Metabolomics Identifies Novel Plasma Metabolomic Signatures Associated with Diabetic Neuropathy in a Cohort with Screen-Tested Type 2 Diabetes: ADDITION-Denmark
Authors: RUMORA AMY E. , ALAKWAA FADHL , ANDERSEN SIGNE T. , JØRGENSEN MARIT E. , CHARLES MORTEN , CALLAGHAN BRIAN C. , JENSEN TROELS S. , FELDMAN EVA L.
Published: June 2020

Peripheral neuropathy (PN) is a common complication of diabetes that develops in up to 50% of people with diabetes. Obesity and the metabolic syndrome are risk factors for PN in patients with type 2 diabetes (T2D). However, the lipid metabolites associated with PN development are unknown. We compared the metabolomic profile of plasma from T2D patients with and without PN compared to lean control patients to identify metabolic changes that underlie PN associated with T2D. PN was evaluated in a cohort of T2D patients from the Danish portion of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION). The Toronto criteria was used to assess PN based on symptoms of neuropathy and abnormal nerve conduction studies. To identify metabolomic signatures that associate with PN, plasma samples from 9 lean control, 49 T2D, and 48 T2D patients with PN were submitted to Metabolon® for a global metabolomics analysis. We used least absolute shrinkage and selection operator (LASSO) and Welch’s two-sample t-test to identify metabolites that differed between PN and non-PN subjects. Metabolomics identified plasma lipid metabolites that were dysregulated in T2D including cholesterol, sphingolipids, and acylcarnitines. Cholesterol and three classes of sphingolipid metabolites (dihydrosphingomyelin, glucosylceramide, and sphingomyelin) were significantly lower in plasma from T2D patients irrespective of PN compared to lean controls. Interestingly, long-chain and very long-chain acylcarnitines were also reduced in T2D patients while short-chain acylcarnitines were unchanged. Only a small number of metabolites were uniquely regulated by PN; of these, two very long-chain acylcarnitine species (C26:1 and C24) were significantly diminished in T2D patients with PN compared to those without. These results suggest an association with lipid markers of impaired mitochondrial β-oxidation and PN in T2D.

Disclosure

A.E. Rumora: None. F. Alakwaa: None. S.T. Andersen: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. M. Charles: Other Relationship; Self; Novo Nordisk A/S. B.C. Callaghan: None. T.S. Jensen: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation.

Funding

American Diabetes Association (7-12-BS-045 to E.L.F.); Novo Nordisk Foundation (NNF14OC0011633); National Institutes of Health (1R24082841, 1DP3DK094292); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101357, F32DK112642, K99DK119366); NeuroNetwork for Emerging Therapies; A. Alfred Taubman Medical Research Institute
532-P: The Longitudinal Determinants of Diabetic Complications in the Pima Indians of Arizona
Authors: REYNOLDS EVAN L. , NELSON ROBERT G. , AKINCI GULCIN , HENN ROSIE , PATTERSON ADAM , FELDMAN EVA L. , CALLAGHAN BRIAN C.
Published: June 2020

The 5 components of the metabolic syndrome (MetS) increase the likelihood of developing diabetes, heart disease, and stroke, but their association with neuropathy and diabetic kidney disease (DKD) is less understood.

We examined the longitudinal association between the components of the updated National Cholesterol Education Program criteria for MetS, neuropathy and DKD in Pima Indians with type 2 diabetes, after substituting BMI for waist circumference. The primary outcome for neuropathy was the Michigan Neuropathy Screening Instrument index, for cardiovascular autonomic neuropathy (CAN) was the expiration/inspiration ratio, and for DKD was the Glomerular Filtration Rate. At baseline and during annual follow-up exams, participants underwent metabolic phenotyping and outcome measurements.

Linear mixed effects models with a random patient effect were used to evaluate the associations between the number of MetS components and neuropathy, CAN, and DKD outcomes. We also examined mixed models for each outcome with individual MetS components.

Between 11/1/2013 and 7/1/2019, we studied 141 Pima Indian subjects, who were followed an average of 3.2 years. The mixed effects models revealed a significant interaction between the number of MetS components and follow-up time for neuropathy (point estimate (PE): 0.07, CI: 0.02-0.11), indicating that the rate of neuropathy increases as the number of MetS components increases. Additionally, we found that neuropathy (year PE: 0.30, CI: 0.24,0.35) and DKD (PE: -14.2, CI: -16.8,-11.4), worsened over time, but CAN did not. The mixed models with individual MetS components revealed SBP was associated with each complication: neuropathy (PE: 0.23, CI: 0.07,0.39), CAN (PE: -0.02, CI: -0.03,-0.02) and DKD (PE: -10.2, CI: -15.4,-5.1).

Neuropathy progression was the complication most affected by the number of MetS components. Neuropathy and DKD worsened during follow-up, emphasizing how quickly these complications can change within this population.

Disclosure

E.L. Reynolds: None. R.G. Nelson: None. G. Akinci: Advisory Panel; Spouse/Partner; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. R. Henn: None. A. Patterson: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation. B.C. Callaghan: None.

Funding

National Institutes of Health (R24DK082841, T32NS0007222, R01DK115687); Program for Neurology Research & Discovery; Robert and Katherine Jacobs Environmental Health Initiative; Robert E. Nederlander, Sr. Program for Alzheimer’s Research; Sinai Medical Staff Foundation
54-OR: Nitric Oxide Attenuates Viral Replication in Pancreatic ß-Cells through an Inhibition of Mitochondrial Oxidative Metabolism
Authors: STAFFORD JOSHUA , CORBETT JOHN A.
Published: June 2020

Viral infection has been identified as an environmental factor that may play a role in initiating the destruction of pancreatic β-cells during the development of autoimmune diabetes. We have identified a pro-inflammatory response activated in pancreatic islets in response to infection with encephalomyocarditis virus (EMCV). In response to the local production of cytokines such as IL-1 by resident islet macrophages, β-cells produce nitric oxide, a free radical with known antiviral activity. Nitric oxide has been characterized both as a potent antiviral molecule and as a mediator of β-cell dysfunction and damage and so we investigated the role of nitric oxide in controlling β-cell viability in the context of EMCV infection. We find that nitric oxide, either supplied exogenously with donor compounds or produced endogenously in response to cytokine treatment, attenuates EMCV replication and protects β-cells against EMCV-mediated death. These protective actions of nitric oxide are restricted to conditions in which nitric oxide is produced at low micromolar levels (consistent with the levels of nitric oxide generated by iNOS) and are associated with the ability of nitric oxide to impair mitochondrial oxidation and decrease ATP levels in β-cells. Treatment with rotenone, an inhibitor of complex I of the electron transport chain, likewise attenuates EMCV replication in β-cells, which are reliant on oxidative metabolism for ATP generation, but not in fibroblasts, which can sustain ATP levels via glycolysis alone. These findings suggest a mechanism of protection restricted to β-cells where nitric oxide production attenuates viral replication by inhibiting oxidative metabolism and depleting cellular stores of ATP, supporting a protective role for nitric oxide in the response of β-cells to viral infection.

Disclosure

J. Stafford: None. J.A. Corbett: None.

Funding

American Heart Association (17PRE3253000); National Institutes of Health (DK052194, AI44458)
545-P: Posttranslation Control Mechanisms (miRNAs) in Type 1 Diabetic Patients with and without Cardiac Autonomic Neuropathy
Authors: TOBOR EWA , POLUS ANNA , GASTOL JOANNA , MATEJKO BARTłOMIEJ , PAWLINSKI LUKASZ , KIEC-WILK BEATA
Published: June 2020

Introduction: Type 1 diabetes (T1DM) is a chronic disease with multifactor pathogenesis. Large number of studies confirmed that epigenetic, microRNA (miRNA)- mediated, regulation mechanisms of gene expression are associated with both pathogenesis of T1DM and the progression of its complications. Cardiac autonomic neuropathy (CAN), the microvascular complication, is one of the strongest risk factor of cardiac mortality among T1DM patients. Circulating miRNA might be a prediction marker for development and progression of this diabetic complication but studies concerning connection between miRNA and CAN in T1DM patients are still missing.

Materials and methods: The study included 54 T1DM subjects with and without CAN and 27 healthy, age-correlated volunteers, as a control group. The CAN prevalence was assessed using Ewing test. Expression analysis of human miRNAs was performed using the TaqMan Low-Density Arrays (TLDAs) Panel v3.0 (Applied Biosystems). Differentially and significant (p<0.05) expressed miRNA were uploaded into the DIANA-mirPath v.3, for Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis.

Results: Our study revealed a significantly upregulated expression of miR-190b, miR-520d-3p and miR-30a-5p in both CAN and T1DM groups comparing to control. Nevertheless, the miRNAs expression within T1DM group between CAN and T1DM groups did not differ.

Discussion: All of significantly altered miRNA are involved in axon guidance pathway, playing a role in neuron regeneration and, as a result of impaired function, neuropathy. Additional significantly regulated miR-30a-5p downregulates the expression of Beta/NeuroD gene, which role in the pathogenesis of diabetes mellitus is well documented.

Conclusion: Our study, for the first time, showed the potential correlation between epigenetic mechanisms and CAN, stressing that mi-30a-5p might be a new tool for early diagnosis and potentially therapeutic target of T1DM.

Disclosure

E. Tobor: None. A. Polus: None. J. Gastol: None. B. Matejko: Other Relationship; Self; Dexcom, Inc., Roche Diabetes Care. L. Pawlinski: Other Relationship; Self; Boehringer Ingelheim International GmbH. B. Kiec-Wilk: None.

Funding

National Science Centre in Poland (2014/13/B/NZ4/00149)
55-OR: Cerebral Blood Flow Is Lower in Youth with Type 2 Diabetes Compared with Obese Controls
Authors: REDEL JACOB M. , DIFRANCESCO MARK W. , LEE GREGORY R. , DOLAN LAWRENCE M. , SHAH AMY S.
Published: June 2020

A causal link between youth-onset type 2 diabetes (T2D) and vascular complications is well-established. The brain, as a highly vascular structure, may also be susceptible to the adverse effects of T2D. Brain structural and cognitive differences have been demonstrated in adolescents with T2D, and vascular disease is hypothesized to be a mechanism. We sought to evaluate cerebral blood flow (CBF) in youth with T2D vs. obese, euglycemic controls, and to explore the association between CBF and a non-invasive measure of atherosclerosis, carotid intima medial thickness (IMT). We compared global and regional CBF between 20 youth with T2D (mean T2D duration 2.8 ±2.1 years and mean hemoglobin A1C 7.9 ±2.1%) and 19 age, race, and sex similar obese controls (mean hemoglobin A1C 5.2 ±0.2%), adjusted for socioeconomic status. CBF data were obtained using arterial spin labeling (ASL) MRI. We compared mean CBF values, voxel-wise and globally averaged, between groups using two-sample t-tests. Voxel-wise results were evaluated for statistical significance (p<0.05) after adjustment for multiple comparisons. Carotid IMT in the T2D group was measured using ultrasound and correlated with CBF, both globally and voxel-wise. Compared to obese controls, the T2D group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ±11.5 mL/gm/min, p<0.01). There were seven voxel clusters with ≥100 voxels identified with significantly lower CBF in the T2D group, and no clusters with higher CBF. In the T2D group, IMT of the common carotid artery was inversely correlated with CBF, both globally (r= -0.7, p<0.01) and in regional voxel clusters. Global and regional cerebral blood flow is lower in youth with T2D compared to obese controls. Further work is needed to determine whether these CBF findings are related to brain structural or cognitive differences previously reported in youth-onset T2D. The association found between carotid IMT and CBF suggests this may represent a practical way to track CBF in youth with T2D.

Disclosure

J.M. Redel: None. M.W. DiFrancesco: None. G.R. Lee: None. L.M. Dolan: None. A.S. Shah: None.

Funding

Cincinnati Diabetes and Obesity Center Pilot Grant Program; Endocrine Fellows Foundation; National Institute of Environmental Health Sciences (ES010957-16); Cincinnati Children’s Hospital
56-OR: Degree of ß-Cell Function (ßCF) Impairment and Glycemic Alterations in Obese Youth (OY) Spanning from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D): Does Race Matter?
Authors: KIM JOON YOUNG , TFAYLI HALA M. , BACHA FIDA , GEBARA NOUR , ARSLANIAN SILVA A.
Published: June 2020

In OY it is not clear what degree of βCF impairment translates to increases in OGTT glucose area under the curve (G-AUC) commensurate with transition from NGT to IGT to T2D, and whether there are racial differences. Given the high rates of T2D in Black (BY) vs. White youth (WY), we hypothesized that βCF decline in BY is more detrimental and results in larger increases in G-AUC than in WY. Here we report the quantitative relationship between differences in clamp disposition index (DI=insulin sensitivity [IS] by a 3-hr hyperinsulinemic (80 mu/m2/min)-euglycemic clamp x 1st-phase insulin by a 2-hr hyperglycemic (225 mg/dL) clamp) and OGTT G-AUC in 152 OY. Two-way ANOVA (race x glycemic status) showed that in BY vs. WY larger decrements in DI from NGT to IGT and from NGT to T2D (all p<0.05) correspond to comparable increments in G-AUC (p=NS, Table), with no significant race interaction from IGT to T2D. Contrary to our hypothesis, loss of βCF in IGT and T2D is less detrimental in BY because a ∼2-3 fold greater impairment in βCF corresponds to a similar increase in G-AUC to that of WY. Such observations of preserved glucose regulation in BY compared with WY in the face of larger declines in βCF suggest an adaptive glucose-stimulated glucoregulatory mechanism protecting against dysglycemia consequent to insulin deficiency.

Disclosure

J. Kim: None. H.M. Tfayli: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. N. Gebara: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24-HD01357, R01HD27503); National Center for Advancing Translational Sciences (UL1TR000005); National Center for Research Resources (UL1RR024153)
566-P: Sulodexide Suppresses NLRP3 Inflammasome Activation via NOX4/ROS Signaling in the Retinal Microvasculature
Authors: LI TING , HE XUEMIN , PENG RONGDONG , FU XIANAN , SHI GUOJUN , CHEN YANMING
Published: June 2020

Aims: Sulodexide (SDX) protects endothelial cells via restoring endothelial glycocalyx, but the effect of SDX on endothelial inflammation remains unknown. We showed that SDX potently inhibited the activation of NLRP3 inflammasome in diabetic retinas, but the underlying mechanism was not clear. As reactive oxygen species (ROS) activates NLRP3 inflammasome, and NADPH oxidase 4 (NOX4) is a key generator of ROS in endothelial cells, this study thus investigated if NOX4/ROS signaling mediates the effect of SDX on NLRP3 inflammasome, hoping to provide novel insights into SDX in treating diabetic retinopathy (DR).

Methods: Diabetes was induced in mice by high fat diet and streptozotocin, followed by i.p. injection of SDX (10mg/kg) every other day for 3 months. Human retinal microvascular endothelial cells were exposed to high glucose, accompanied with overexpression or knocking down of NOX4 and a serial concentration of SDX. The retinal levels of NOX4, NLRP3 inflammasome, inflammatory factors, junction components, vascular leakage and ROS levels were determined.

Results: SDX treatment dramatically suppressed the hyperglycemia-induced overexpression of NOX4 and activation of NLRP3 inflammasome in retinas compared to controls. Moreover, SDX preserved the levels of ZO-1, VE-cadherin and ameliorated the retinal vascular permeability. In addition, SDX significantly ameliorated high glucose-induced NOX4 up-regulation, ROS production and NLRP3 inflammasome activation, and restored the reduction of ZO-1 and VE-cadherin in endothelial cells. Conversely, overexpression of NOX4 exacerbated endothelial inflammation through over production of ROS and subsequent activation of NLRP3 inflammasome, which was rescued by SDX treatment.

Conclusion: Our study suggests that SDX protects the retinal microvasculature by inhibiting NOX4/ROS-induced NLRP3 inflammasome activation, thus provides novel evidence of utilizing SDX for the treatment of DR.

Disclosure

T. Li: None. X. He: None. R. Peng: None. X. Fu: None. G. Shi: None. Y. Chen: None.

Funding

Research and Development Plans in Key Areas of Guangdong Province (2019B020227003); National Natural Science Foundation of China (81770826); National Key Research and Development Program of China (2017YFA0105803)
57-LB: The 4 I’s of Adolescent Transition in Type 1 Diabetes Care: A Qualitative Study
Authors: LEUNG JOSEPH M. , TANG TRICIA S. , LIM CATHERINE , LAFFEL LORI M. , AMED SHAZHAN
Published: June 2020

Introduction: Adolescents with type 1 diabetes have worsening glycemic control as they transition from pediatric to adult care. The most effective clinical interventions for this population remain elusive. The aim of this study was to gain adolescent perspectives on the transition preparation experience and the preferred approaches to the transition process in type 1 diabetes care.

Methods: We conducted 5 focus groups with a total of 22 adolescents with type 1 diabetes. Participants also completed an embedded survey where they rated various transition interventions. Transcriptions of audio recordings were analyzed with 3 iterations of thematic content analysis using the grounded theory approach and we determined that saturation was reached.

Results: Four themes related to transition of care were identified: (1) Identity - how the world relates to my diabetes (stigma of type 1 diabetes, confusion with type 2 diabetes, diagnosis disclosure, and resilience); (2) Interconnection - how my support system can help me with my diabetes (peer support, near peer support, parental support, loss of bond with pediatric team, and fear of not having a bond with adult team); (3) Impediment - how my diabetes limits me (self-care takes work and time, unpredictability and restrictiveness, and emotional burden); and (4) Individualization - how to personalize the transition experience (having choices in the transition experience, meeting adult provider before transition, and specific transition preparation). The top interventions rated by adolescents on the survey were: good communication between the pediatric and adult teams, medical summary of past diabetes care, and having pediatric and adult teams in the same building.

Conclusions: The design of future transition interventions for adolescents with type 1 diabetes should address the issues of Identity, Interconnection, Impediment, and Individualization. Adolescents also identified collaborative processes between pediatric and adult providers as most important.

Disclosure

J.M. Leung: Research Support; Self; Lilly Diabetes. T.S. Tang: None. C. Lim: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. S. Amed: None.

Funding

Eli Lilly and Company
574-P: Antioxidant Defence and Long Noncoding RNA in Diabetic Retinopathy
Authors: KOWLURU RENU , RADHAKRISHNAN RAKESH
Published: June 2020

Retinal oxidative stress is increased and the antioxidant defence system is compromised in diabetic retinopathy. Expression of many key antioxidant genes is regulated by a master regulator, nuclear factor erythroid 2-related factor (Nrf2). The transcriptional activity of Nrf2 is mediated by an intracellular inhibitor Kelch-like ECH-associated protein 1 (Keap1), which regulates its nuclear movement. In diabetes, Nrf2 transcriptional activity is decreased and Keap1 levels are increased. A long noncoding RNA (IncRNA), Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), plays a role in regulating Keap1 expression, and retinal MALAT1 levels are upregulated in diabetes. Our aim is to investigate the role of MALAT1 in maintaining the antioxidant defence system in diabetic retinopathy. Human retinal endothelial cells (untransfected or transfected with MALAT1-siRNA) were incubated in 20mM glucose for 96 hours. MALAT1 expression was analysed by q-RTPCR and RNA sequencing, and role of MALAT1 in Keap1 transcription was quantified using MALAT1 RNA pull down assay. Simultaneous occupancy of MALAT1 and transcription factor Sp1 on Keap1 promoter was quantified by Chromatin Isolation by RNA Purification (ChIRP)-reChIP technique, nuclear translocation of Nrf2 by immunofluorescence imaging, and Nrf2-responsive genes superoxide dismutase 2 (Sod2) and heme oxygenase 1 (HO1) by q-RTPCR. Compared to cells in 5mM glucose, high glucose increased co-occupancy of MALAT1 and Sp1 at Keap1 promoter. MALAT1-siRNA ameliorated glucose-induced increase in co-occupancy of MALAT1-Sp1 at its promoter and decreased Keap1 expression. MALAT1-siRNA also restored nuclear localization of Nrf2 and the transcription of Sod2 and HO1. Thus, IncRNA MALAT1, via Keap1, modulates the transcriptional activity of Nrf2 and the antioxidant defence system in diabetic retinopathy. Regulation of MALAT1 can protect the retina from oxidative damage, and prevent/slow down the development of diabetic retinopathy.

Disclosure

R. Kowluru: None. R. Radhakrishnan: None.

Funding

EY014370, EY017313, EY022230
575-P: Improvement in HbA1c after Flash Monitoring Is Not Associated with Risk of Retinopathy Progression in Type 1 Diabetes
Authors: LINTON KATHRYN , GIBB FRASER W.
Published: June 2020

Background: Rapid improvement in HbA1c has been associated with significant short-term worsening of diabetic retinopathy. Flash monitoring (FM) is associated with significant improvement in HbA1c, particularly in those with high HbA1c at baseline.

Methods: We identified all adults with type 1 diabetes, using NHS reimbursed FM, attending our center. This assessment was limited to those with high microvascular risk defined as duration of diabetes > 3 years and pre-FM HbA1c >9%. From this cohort 40 individuals were selected with the largest post-FM fall in HbA1c (responders) and compared with a further 35 with the smallest change in HbA1c (non-responders). Information on retinopathy status and laser photocoagulation was derived from electronic patient records.

Results: Baseline HbA1c was significantly higher in the responder category (10.5 vs. 9.8%, P = 0.002). Median change in HbA1c, following FM, was -2.5% in responders and +0.2% in non-responders. At baseline, 32% had retinopathy classed as more severe than background (25% had proliferative retinopathy). Median duration from FM commencement to next ophthalmological assessment was 36 weeks (IQR 16 - 50). The percentage with worsening retinopathy did not significantly differ between responders (18%) and non-responders (11%) (P = 0.458). The percentage requiring laser photocoagulation after FM commencement did not differ between responders (17.5%) and non-responders (14.3%) (P = 0.704). Logistic regression analysis identified previous laser (OR 19.9, P = 0.001) but not baseline HbA1c (P = 0.139), age (P = 0.115) or HbA1c response after FM (P = 0.473) as predictive of requiring laser photocoagulation after FM commencement.

Discussion: These data suggest that rapid improvement in HbA1c following FM, in a high-risk population, is not independently predictive of subsequent requirement for laser photocoagulation.

Disclosure

K. Linton: None. F.W. Gibb: None.
582-P: Triglycerides, Uric Acid, and Incidence of Type 2 Diabetes Mellitus in Northwest China: The Jinchang Cohort Study
Authors: HUANG WENYA , YANG JINGLI , LIU NIAN , HUANG PEIYAO , ZHANG RUI , WANG RUONAN , BAI ZHAO , CHENG NING , WANG MINZHEN , ZHENG SHAN , BAI YANA
Published: June 2020

Objective: To study the association of triglycerides(TG), uric acid and incidence of type 2 diabetes mellitus(T2DM), evaluate whether there would be an additive interaction between two factors.

Methods: Based on the follow-up population of Jinchang cohort, an ongoing occupational-based prospective cohort study of 48,001 participants at baseline, the nested-case control study was used to explore the relationship of TG, uric acid and incidence of T2DM, and calculate the odds ratio(OR) and 95% confidence intervals(CI). The interaction additive model was used to evaluate whether there would be an additive interaction between two factors.

Results: Among 18,195 participants with normal fasting plasma glucose(FPG) at baseline, there were 267 incident diabetes cases during a median of 2.2 years of follow-up. With the increase of serum TG and uric acid, the cumulative incidences of diabetes in people with normal FPG at baseline were all rising (P for trend<0.05). After multivariable adjustments, the risk factors of diabetes were overweight/obesity(OR=2.30, 95%CI:1.72-3.08), hypertension(OR=2.42, 95%CI:1.78-3.29),hypertriglyceridemia(OR=1.49,95%CI:1.11-2.00), hyperuricemia(OR=2.32,95%CI:1.62-3.30), hypo high density lipoprotein cholesterolemia(OR=2.35, 95%CI:1.60-3.46). There was a positive additive interaction between hypertriglyceridemia and hyperuricemia on the development of diabetes from normal FPG. When they were co-existing, the risk of diabetes(OR, 95%CI) in the total, male and female population were 7.13 (4.70-10.83), 8.42 (5.13-13.83) and 7.09 (2.94-17.14),respectively.

Conclusion: Increased triglycerides and uric acid were strong risk factors of diabetes. Furthermore, there was a positive additive interaction between hypertriglyceridemia and hyperuricemia on the development of diabetes from normal fasting plasma glucose.

Disclosure

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

Funding

National Institutes of Health (1R01ES02908201A1); Lanzhou University (2018LDBRZD008)
590-P: Modulation of Adenine Phosphoribosyltransferase-Mediated Purine Salvage to Accelerate Diabetic Wound Healing
Authors: YOUNG GUANG-HUAR , LIN JIUN-TSAI , CHENG YI-FANG , CHEN HAN-MIN
Published: June 2020

Aim: Adenine phosphoribosyltransferase (APRT) is the key enzyme in purine salvage by the incorporation of adenine and phosphoribosyl pyrophosphate to provide adenylate nucleotide. Our aim was to evaluate the role of APRT in diabetic wound healing.

Methods: The molecular mechanism of APRT-mediated cell survival was validated by the haploid HAP1 cell. The adenylate nucleotides in NIH-3T3 fibroblast response to adenine was monitoring by HPLC-MS/MS method. The effects of cell behaviors were evaluated by mice NIH-3T3 fibroblast and human epithelial keratinocytes. Genetically diabetic mice received surgery for full-thickness of the cutaneous wound and the adenine addition as the substrate for APRT on the wound.

Results: In the wild type and APRT knockout HAP1 cell, our data revealed that APRT utilized adenine to rescue cellular ATP levels and proliferation against hydrogen peroxide-induced oxidative damage. The time-course of monitoring the total adenylate nucleotides in NIH-3T3 fibroblast showed that adenine addition enlarged the cellular adenylate pool, reduced the adenylate energy charge, and provided more AMP for the generation of ATP in further. In mice NIH-3T3 fibroblasts and human NHEK keratinocytes, adenine elevated cellular ATP levels in a dose-dependent manner and facilitated cell migration. The up-regulated APRT found in wound skin was correlated with the demands of wound repair in diabetic mice. Administration of adenine on the wound of diabetic mice exhibited elevated ATP levels in organismic skin and accelerated wound healing.

Conclusions: Our data indicated the role of APRT during diabetic wound healing by regulating the nucleotide pool after injury and demonstrated the improvement by topical adenine, which highlights its value as a promising agent in therapeutic intervention. This study provided an explanation for the up-regulation of APRT in tissue repair and adenine supplement resulted in an enlargement of the adenylate pool for ATP generation.

Disclosure

G. Young: Employee; Self; Energenesis-Biomedical. J. Lin: Employee; Self; Energenesis-Biomedical. Y. Cheng: Employee; Self; Energenesis-Biomedical. H. Chen: Board Member; Self; Energenesis-Biomedical.
62-OR: Childhood Adipokine Profiles Predict the Incidence and Trajectory of Obesity in Young Adults: The BCAMS Study
Authors: GAO SHAN , LI MING , WILLI STEVEN M. , GROUP BCAMS
Published: June 2020

Adipokine dysregulation is an early biomarker of adipose tissue dysfunction, which has been shown to relate to metabolic health. We aimed to investigate whether the profiles of certain adipokines in childhood might predict the incidence of obesity and contribute to BMI trajectory from childhood to young adulthood. A total of 3211 children aged 6-18ys from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study were evaluated at baseline, and 989 of these participants were assessed at 10-year follow-up. Physical activity, dietary and sleep information were collected by questionnaires. Baseline plasma adiponectin, leptin, resistin, retinol binding protein 4, osteonectin and fibroblast growth factor 21 (FGF-21) were measured by ELISA. The sex-adjusted z scores for adipokine levels were examined for their association with adiposity measures (BMI and waist circumference). Only 10.4% of the children who were non-obese at baseline developed obesity at 10-year follow-up, while over 65% of children presenting with obesity remained obese at follow-up, suggesting a well-established obesity trajectory over time. After adjusting for age, tanner stage, diet, exercise and sleep, decreased adiponectin and FGF-21 levels, as well as increased leptin, were associated with obesity risk both at baseline and 10-year follow-up (all P < 0.05). Multivariate analysis showed that after adjusting for confounding factors, each 1-SD increment in the leptin : adiponectin ratio was associated with a 3.26-fold (95% CI:2.08 - 5.10) higher risk for obesity at 10-year follow-up, while each 1-SD increment in FGF-21 level reduced the risk of obesity by 30% (95% CI: 0.48 - 0.96). Finally, among children with obesity at baseline, each 1-SD of elevation in resistin increased the risk of persistent obesity by 1.41-fold (95% CI: 1.13 - 1.77). These findings suggest that certain aberrant patterns of adipokine regulation during childhood may serve as biomarkers for the subsequent development of obesity.

Disclosure

S. Gao: None. M. Li: None. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Tolerion, Inc. Other Relationship; Self; Caladrius Biosciences, Inc.

Funding

National Natural Science Foundation of China (81970732); National Key Research Program of China (2016YFC1304801); Key Program of Beijing Municipal Science and Technology Commission (D111100000611001, D111100000611002); Beijing Natural Science Foundation (7172169); Beijing Science and Technology Star Program (2004A027), Novo Nordisk Union Diabetes Research Talent Fund (2011A002); National Key Program of Clinical Science (WBYZ2011-873); Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32020, 2018PT32001); Beijing Chaoyang Hospital (JXPY201606)
620-P: Improving Glycemic Control in Patients with T2D in Brazil through Tech-Enabled Low-Cost Virtual Monitoring
Authors: CARRICA MARTIN , VALENTE FERNANDO , MIGLIANO LUCIANA , LORDA DUMONT YVES SEBASTIAN , SALLES JOAO E.
Published: June 2020

T2D remains a global epidemic and has become a major public health concern in Brazil, with almost 17M people living with T2D. Poor glycemic control leads to severe loss in life expectancy, quality of life and increased healthcare expenses. The main challenges to support patients with T2D in developing countries are geographical dispersion and limited budgets.

The primary objective of this study is to determine whether the use of a low-cost, 100% virtual patient monitoring program, can improve disease control in patients with T2D in Brazil, using remote diabetes support through Appia’s digital platform connected to a smart BGM, coupled with remote coaches.

Methods: Thirty-one participants aged 36-69 years old previously diagnosed with T2D that measure their BG levels at least 2 times per week, were recruited online and enrolled in the program. Most of them were just receiving oral medication treatment. HbA1c was measured at the beginning and at the end of the program. During the 12-week lifestyle modification program, the patients were given an intelligent BGM connected to a mobile app that stores BG measurements in the cloud. Additionally, patients were given access to a remote diabetes coach for personalized content, weekly goals setting and support. Patients did not receive medical intervention outside of their PCP.

Results: The mean HbA1c was significantly reduced by 1.11% (95% CI: -1.5754 - -0.7446, p<0.0001) from a starting mean of 8.5% to 7.39% at the end of the program. Total average BG levels dropped from 169 mg/dL to 138 mg/dL with n=2439 readings. Also, the severe hyperglycemic events (>300 mg/dL) were reduced by 51.55%, without increasing level 2 (<54 mg/dL) and 3 hypoglycemic events. Finally, the total number of BG measurements during the program increased by 8.43% in 90 days (from 0.8/day to 0.9/day per patient).

Conclusion: The combination of remote diabetes coaching with a smart BGM connected to an app was effective for improving glycemic control in patients with T2D in Brazil.

Disclosure

M. Carrica: Stock/Shareholder; Self; Appia. F. Valente: Consultant; Spouse/Partner; Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk Inc. L. Migliano: Employee; Self; Appia. Y. Lorda Dumont: None. J.E. Salles: Board Member; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc.
652-P: Patients with Diabetes at High Cardiovascular Risk with Chronic Kidney Disease: Online Virtual Simulation Improves Clinical Decisions
Authors: TRIER JOACHIM , GUNESEKERA DAYAN
Published: June 2020

Purpose: Assess if simulation-based online education improves performance of cardiologists (C), diabetologists/endocrinologists (D/E) and primary care physicians (PCP) in managing patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk with chronic kidney disease (CKD).

Methods: Two patient cases were presented in an immersive, virtual patient simulation (VPS) platform designed to replicate the real-life decision-making process allowing learners to order lab tests, assess patients, make diagnoses, and prescribe treatments. Tailored clinical guidance (CG) was provided for each clinical decision (CD) so learners could modify their CDs and indicate their rationale. Physicians who fully completed each case were evaluated. Each learner’s pre-/post CDs were analyzed using a paired t-test. The activity posted on 1/31/2019; data were collected through 10/1/2019.

Results: Upon completion of this educational activity C (n=296/154, cases 1 and 2), D/E (236/128) and PCP (228/157) demonstrated improved performance in making appropriate, evidence-based CDs (all p<0.05) with respect to • Ordering a suitable diagnostic workup to establish elevated reno-vascular risks resulting in a significantly higher proportion of correct diagnoses of CKD and hypertension • Tailoring a comprehensive risk management plan including increased patient education, weight management, foot examination and SGLT2 inhibitor or GLP-1 receptor agonist Rx. Predominant reasons for selecting an SGLT2i • Proven CV risk reduction • Recommended by guidelines. Main reasons for not choosing an SGLT2i • Economic considerations • Unfamiliarity with use.

Conclusion: Immersive VPS-based education improves evidence-based CDs related to the crucial aspects of managing T2D in patients at high CV risk with CKD. Collection of learners’ decision-making rationale data provides insight into the decision-making process of physicians in actual clinical practice.

Disclosure

J. Trier: Consultant; Self; WebMD LLC. D. Gunesekera: None.

Funding

Boehringer Ingelheim Global; Eli Lilly Global
666-P: Predictors and Effects of Participation in Peer Support: A Prospective Structural Equation Modeling Analysis
Authors: AYALA GUADALUPE X. , CHAN JULIANA C. , CHERRINGTON ANDREA , ELDER JOHN P. , FISHER EDWIN B. , HEISLER MICHELE , HOWARD ANNIE GREEN , PARADA HUMBERTO , SAFFORD MONIKA , SIMMONS DAVID , TANG TRICIA S. ,   WRITING GROUP OF PEERS FOR PROGRESS INVESTIGATORS
Published: June 2020

Peer support provides benefits across varied health concerns. As opposed to simple offer of support, however, predictors of and importance of levels of participation are not well understood. Analyses of 7 peer support interventions, with 1,612 participants address these questions, first identifying characteristics that predict participation, and then examining whether, controlling for those characteristics, participation itself predicts benefit, using reduced HbA1c as an indicator of benefit.

From the U.S. (5 sites), Hong Kong, and the UK, interventions shared emphases on peer supporters helping adults with type 2 diabetes improve disease management. Common data included pre/post hemoglobin A1c (HbA1c), contacts of participants with peer supporters, health literacy, availability/satisfaction with support for diabetes management from family/clinical team, and gender, age, education, and years with diabetes.

From structural equation modeling, significant findings indicated 1) older age and lower levels of support for diabetes management predicted more contacts with peer supporters, and 2) more contacts predicted lower levels of final HbA1c. Effects of contacts on HbA1c included those with baseline HbA1c > 7.5% or > 9%. No contacts and tertiles of low, moderate, and high contacts showed a linear, dose-response relationship with final HbA1c (p < 0.001). Baseline and covariate-adjusted, final HbA1c was 8.19% versus 7.85% for those with no and high contacts, respectively. Among those using insulin (29.7%), only those in the high group achieved greater benefit than those with no contacts.

Reflecting other findings that peer support reaches/benefits those at greater disadvantage, those reporting less social support for diabetes management were more likely to participate in peer support. Participation in turn predicted better glycemic control across levels of baseline glycemic control and in a dose response relationship across levels of participation.

Disclosure

G.X. Ayala: None. J.C. Chan: None. A. Cherrington: None. J.P. Elder: None. E.B. Fisher: Research Support; Self; Merck Foundation, Sanofi China. M. Heisler: None. A. Howard: None. H. Parada: None. M. Safford: None. D. Simmons: None. T.S. Tang: None.

Funding

Merck Foundation; Eli Lilly and Company Foundation; Bristol-Myers Squibb Foundation