bluuebunny/crossref_metadata_2025 huggingface dataset:
2184-P: Foxo1-CoF Repressor (FCoR) Regulates Pancreatic Alpha- and Beta-Cell Identity by both DNA and Histone Methylation
Authors: KODANI NORIKO , KOBAYASHI MASAKI , KIKUCHI OSAMU , KITAMURA TADAHIRO , ITOH HIROSHI , NAKAE JUN
Published: June 2019

We have previously identified a Foxo1 binding protein, FCoR, which suppresses Foxo1 activity by increasing acetylation. FCoR is expressed in pancreatic α- and β-cells. FCoR expression is decreased in high-fat fed mice and in Leprdb/db mice, and FcorKO mice exhibited decreased insulin secretion, increased α-cell mass and β to α-cell conversion, suggesting FCoR involvement in the pathophysiology of diabetes. In FcorKO islets, nucleus localization of Foxo1 was increased, and Foxo1 acetylation was significantly decreased compared to WT. These data suggest that FCoR regulates acetylation and activity of Foxo1 in islets. The qPCR in isolated islets from FcorKO showed increased Arx, Mafb and Gcg expression compared to WT, supporting the phenotype of increased α-cell mass. Interestingly, expression level of Mafa and Neurod1, which are the β-cell markers and target genes of Foxo1, were also significantly increased, confirming activation of Foxo1 in the absence of FCoR. FCoR suppresses the expression of Aristaless related homeobox (Arx), which is essential for α-cell differentiation, via increased methylation of the CG rich promoter region of Arx. One of the epigenetic modifications of histone, the tri-methylation at H3K4 (H3K4me3), is an important marker of Arx expression in α-cells. Chromatin immunoprecipitation assay revealed that H3K4me3 was significantly decreased in αTC cells transduced with Flag-FCoR compared to LacZ-transduced-cells, suggesting that FCoR suppresses Arx expression through epigenetic regulation involving both DNA and histone methylation. Our data show that FCoR regulates Foxo1 activity in islets, and that FCoR regulates pancreatic α- and β-cell identity by epigenetic regulation of DNA and histone methylation.

Disclosure

N. Kodani: Research Support; Self; Lilly Diabetes, Novartis Pharmaceuticals Corporation. M. Kobayashi: None. O. Kikuchi: None. T. Kitamura: None. H. Itoh: None. J. Nakae: None.
2188-P: Altered Transcription Factor Binding and Gene Bivalency May Contribute to Long-Term Gene Dysregulation in Intrauterine Growth-Retarded Rat Islets
Authors: LIEN YU-CHIN , LU XUEQING MAGGIE , WANG ZHIPING , SIMMONS REBECCA A.
Published: June 2019

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR induced by bilateral uterine artery ligation, we performed ChIP-Seq and RNA-Seq to assess the association of genome-wide histone modifications and gene dysregulation in islets from 2 and 10 week rats. IUGR induced significant changes in enrichment of H3K4me3 and H3K27me3 marks in both 2-week and 10-week islets, which were correlated with expression changes of multiple genes critical for normal islet function in IUGR islets. HOMER analysis showed that IUGR-induced histone mark changes were enriched at transcription factor binding motifs, such as Nkx2-1, Nkx2-5, FoxL2, Pax7, Sox4, Mitf, and Oct4-Sox2-Nanog. These transcription factors were also identified by Ingenuity Pathway Analysis of islet transcriptomes as top upstream regulators that regulate the changes in gene expression and biological activities. In addition, our ChIP-seq data revealed more than 1,000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. No expression or very low expression of these genes was consistent with a poised state of transcription. The poised state of many potential bivalent genes was altered by IUGR. Interestingly, 3 genes important for islet function, Acod1, FGF-21, and Serpina11, which were poised in 2-week control islets, lost their poised state in 10-week control islets, but gained bivalency in 10-week IUGR islets. In contrast, another 3 genes, Cdh16, Lrrc27, and Lrrc66, which were not poised in control 2-week islets, gained de novo bivalency in 10-week control islets, but lost their poised state in 10-week IUGR islets. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes which may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

Disclosure

Y. Lien: None. X.M. Lu: None. Z. Wang: None. R.A. Simmons: None.

Funding

National Institutes of Health
2193-P: SREBP1c-PAX4 Axis Mediates Pancreatic Beta-Cell Compensatory Responses upon Metabolic Stress
Authors: KIM JAE BUM
Published: June 2019

Sterol responsive element-binding protein 1c (SREBP1c) is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic beta cells are largely unknown. In this study, we demonstrate that SREBP1c regulates beta cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic beta cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated beta cell proliferation through its novel target gene, PAX4. Compared to SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, beta cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating beta cell compensatory responses in obesity.

Disclosure

J. Kim: None.

Funding

Korean National Research Foundation (2011-0018312)
2197-P: SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation Is Required for Maintaining Glucagon Production in Pancreatic Alpha Cells
Authors: REINERT RACHEL B. , SHRESTHA NEHA , JI YEWEI , QI LING
Published: June 2019

Endoplasmic reticulum-associated degradation (ERAD) is a key component of cellular protein quality control, an essential process for pancreatic islet endocrine cells, which synthesize peptide prohormones in high quantities. Two highly conserved ER membrane proteins comprise the core ERAD machinery: HRD1, a ubiquitin ligase that retrotranslocates and ubiquitinates misfolded proteins for proteasomal degradation, and SEL1L, an adaptor protein that identifies ERAD target proteins and is required for HRD1 stability and function. Pancreatic alpha cells, intestinal L-cells, and certain neurons synthesize and differentially cleave proglucagon into tissue-specific hormones, including glucagon and glucagon-like peptide 1 (GLP-1). To investigate the role of ERAD in these cells, we targeted SEL1L deletion with the Cre-lox system, using mice expressing Cre recombinase under the proglucagon promoter. We found that Sel1LGcg mice showed normal growth and glucose homeostasis in vivo. Oral glucose tolerance was equally impaired by administration of the GLP-1 receptor antagonist exendin 9-39 in both Sel1LGcg and control mice, suggesting intact GLP-1 signaling in Sel1LGcg mice. Glucagon secretion in vivo was not significantly different following a 24 hour fast or insulin-induced hypoglycemia. Interestingly, pancreatic glucagon content was reduced by half in Sel1LGcg mice, despite unchanged pancreatic weight. By immunofluorescence, pancreatic islet morphology in Sel1LGcg mice was normal, though α-cells demonstrated increased expression of the ER chaperone BiP and ERAD-associated proteins OS9 and XTP3-B. By transmission electron microscopy, a large subset of α-cells showed significant ER dilation and fewer, smaller glucagon granules. Our data demonstrate that SEL1L-HRD1 ERAD is required for maintaining normal glucagon expression and ER morphology in pancreatic α-cells but does not entirely disrupt proglucagon signaling in vivo.

Disclosure

R.B. Reinert: None. N. Shrestha: None. Y. Ji: None. L. Qi: None.

Funding

National Institutes of Health (5T32DK007245)
2213-PUB: Management Practices in Indian Type 2 Diabetes Mellitus (T2DM) Participants With or Without Comorbidities in Real-World LEADD (Learnings with Experts to Advance Diabetic Dyslipidemia Management) Study
Authors: UNNIKRISHNAN AMBIKA GOPALAKRISHNAN , DAS ASHOK KUMAR , SABOO BANSHI D. , KALRA SANJAY
Published: June 2019

Background: Diabetes is India’s major health concern due to its high disease burden.

Objective: Evaluate management practices in Indian T2DM participants with/without co-morbidities and risk factors based on ADA/AACE guidelines.

Methods: A real world, prospective, cross sectional, observational LEADD study in T2DM participants conducted at 226 sites. Participants with informed consent, were enrolled. Demographics, disease family history, comorbidities, lab data, and treatment as available was analyzed with descriptive statistics. “n” signifies number of participants analyzed for each parameter.

Results: A total of 4002 participant’s records were evaluated. Mean age was 55.7 ± 11.5 years (n=3822), 52.5% males (n=1697/3230) and 66.5% had BMI of ≥25 kg/m2 (n=1868/2808). Average duration of T2DM was 7.6± 6.0 years (n = 2855) with mean values of Hb1Ac 8.15± 1.7% (n=2577), LDL 117.7±37.6mg/dl (n = 2545) and serum creatinine 1.34 ± 2.5 mEq/L (n= 2086). LDL-C levels (≥100mg/dl), 69.3% (n = 1764/2545), non-HDL C high (≥ 160mg/dl) in 42.6% (n= 1039/2438) was analyzed. Most common comorbidities were: Hypertension (68.3%, n = 1826/2673), dyslipidemia (52.3%, n = 1399/2673). Rosuvastatin was given in 87% (n=2419/2757) participants. Hb1Ac ≧7% was in 77.7% (n=2003/2577), blood pressure >140/90mmHg (n = 596/1826) in 32.6% participants. In ≥80% participants with ASCVD/ASCVD risk factors were not prescribed antihyperlipidemic drugs per recommendation by AACE/ADA guidelines.

Conclusion: Significant participants with Diabetes had hypertension, hyperlipidemia as co-morbidities. T2DM participants have high ASCVD risk, many participants with co-morbidities were not optimally treated to goal. A need to strive for stringent control of Hb1Ac, hypertension and hyperlipidemia, as per AACE/ADA guidelines, is desired for better patient outcome.

Disclosure

A. Unnikrishnan: Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dr. Reddys Laboratories, Eli Lilly and Company, Eris Pharmaceuticals, Ipca Laboratories Ltd., MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. A.K. Das: None. B.D. Saboo: None. S. Kalra: None.

Funding

Dr. Reddy's Laboratories; Diabetes Care India
2219-PUB: Antioxidant Protective Effect and Mechanism of Selenoprotein S in Diabetic Vascular Endothelium-Mimicking Microenvironment
Authors: YU SHANSHAN , ZHONG YINGSHUO , MEN LILI , YAO JUNJIE , DU JIANLING
Published: June 2019

Endothelial dysfunction is an initiating key step for diabetic macrovascular complications, and it is closely related to the hemodynamic microenvironment in vivo. However, diabetic patients usually coexist with other cardiovascular risk factors, and the more powerful targeting strategy for protecting endothelium is still limited. Selenoprotein S (SelS) was found in our previous study that could increase vascular endothelial cells resistance to oxidative stress associated with protein kinase C α (PKCα). Thus, in this study, we constructed a diabetic vascular endothelial bionic microenvironment mimicking hyperglycemia and/or hyperlipidemia based on microfludic chip through modulating the concentration of medium glucose and oxidized low density lipoproteins. Our results showed that under diabetic vascular endothelial bionic microenvironment, the upregulation of SelS enhanced nitric oxide synthase (eNOS) expression and reduced endothelin-1 level in human aortic endothelial cells (HAECs), accompany with increase in cell viability and SOD1 and SOD2 activity, and decrease in ROS. Furthermore, SelS overexpression attenuated the activation of PKCα, which subsequently promoted the activation of PI3K/Akt/eNOS pathway. Conversely, the knockdown of SelS resulted in an enhancement of endothelial injury. These findings suggest that SelS could protect endothelial cells from oxidative stress injury under diabetic vascular endothelial bionic microenvironment through PKCα and PI3K/Akt/eNOS pathway. Our results offer a promising and biomimetic platform for investigation on endothelial protection, and provide evidence of SelS as potential novel target to treat diabetic macrovascular complications.

Disclosure

S. Yu: None. Y. Zhong: None. L. Men: None. J. Yao: None. J. Du: None.

Funding

National Natural Science Foundation of China (81570727)
222-OR: BETA-2 Calculated Based on Single Fasting Blood Sample Allows to Define and Discriminate between Optimal and Suboptimal Islet Allograft Function Prior to the Clinical Need for Insulin Support
Authors: BACHUL PIOTR J. , GOLEBIEWSKA JUSTYNA E. , ANTIC FILIP , PARA MONICA , BASTO LINDSAY , GOLAB KAROLINA , PEREA LAURENCIA , WANG LING-JIA , TIBUDAN MARTIN L. , THOMAS CELESTE C. , WITKOWSKI PIOTR
Published: June 2019

Introduction: The goal of the study was using BETA-2 to define suboptimal islet allograft function, which precedes clinical need of the insulin support and to discriminate it from the optimal function which allows for persistent insulin independence after islet allotransplantation.

Material: Thirty five islet transplants were performed in 16 patients with T1DM. BETA-2 trends over the time were assessed in 3 transplant groups depending on the clinical outcome: Group 1 (N=9) persistent insulin independence; Group 2 (N=13) insulin independence loss preceded by the gradual islet graft decline; Group 3 (N=13) no insulin independence. Day 75 was a surrogate day of accomplished islet engraftment.

Results: None of the transplants with BETA-2 < 17.4 on Day 75 resulted in persistent insulin independence (ROC AUC=17.4 for BETA-2 Group 1 vs. Group 2+ Group 3 with 100% sensitivity). Moreover, afterwards BETA-2 always oscillated above 17.4 and never dropped below after each transplant from Group 1 with up to 12 years follow-up. In contrast BETA-2 dropped below 17.4 in every case from Group 2, 9 months (3-24) prior to the loss of insulin independence (Kaplan-Meyer, p=0.03). Based on above, we defined that optimal islet function at any time point was represented by BETA-2 >=17.4, whereas suboptimal when BETA-2 was below that. Once BETA-2 dropped below 17.4 at any time point, islet function never recovered, instead gradually deteriorated with subsequent need for insulin support in every patient from group 2. Optimal vs. suboptimal islet graft function could be also discriminated based on individual fasting glucose, c-peptide or A1c values but with lower sensitivity and specificity. BETA-2 values never reached 17.4 at any time point after each transplant from Group 3.

Conclusion: BETA-2 with cut off 17.4 allowed to define and discriminate optimal vs. suboptimal islet allograft function before need for insulin support.

Disclosure

P.J. Bachul: None. J.E. Golebiewska: None. F. Antic: None. M. Para: None. L. Basto: None. K. Golab: None. L. Perea: None. L. Wang: None. M.L. Tibudan: None. C.C. Thomas: None. P. Witkowski: None.

Funding

State of Illinois; Dompé
2223-PUB: Association of Vitamin D Metabolites with Type 2 Diabetes Complications in Qatar
Authors: ATKIN STEPHEN , BUTLER ALEXANDRA E.
Published: June 2019

Aims: Vitamin D deficiency is a major issue worldwide, and particularly in Middle Eastern countries where full body coverage is standard cultural practice. Epidemiology studies have suggested that vitamin D deficiency is associated with the development of type 2 diabetes. The relationship between diabetes complications and 1,25-dihydroxyvitamin D (1,25(OH)2D3), 25-hydroxyvitamin D3 (25(OH)D3), 24,25-dihydroxyvitamin D (24,25(OH)2D3) and 25-hydroxy-3epi-Vitamin D3 (3epi25(OH)D3) is unclear.

Methods: 750 Qatari subjects, 460 (61.3%) with type 2 diabetes and 290 (38.7%) nondiabetic, participated in the study. Plasma levels of vitamin D and its metabolites were measured by LC-MS/MS analysis.

Results: The type 2 diabetic subjects had lower levels of all vitamin D metabolites except 3epi25(OH)D3. Males had higher levels of all vitamin D metabolites (p < 0.001) versus females. In the type 2 diabetic subjects. 1,25OHD3 deficiency was associated with hypertension, diabetic retinopathy and coronary artery disease (p<0.01), whilst 25OHD3 and (24,25(OH)2D3) levels were only associated with dyslipidemia (p<0.005); 3epi25(OH)D3 was not associated with diabetic complications.

Conclusions: The active 1,25OHD3 correlated to diabetic complications, but 25OHD3 levels did not, other than for dyslipidemia. Vitamin D3 metabolites were lower in type 2 diabetic subjects in this Qatari population, where full body coverage is standard, particularly in Qatari females. The role of 24,25(OH)2D3 in dyslipidemia requires clarification, but 3epi25(OH)D3 appears not to be associated with diabetes complications.

Disclosure

S. Atkin: None. A.E. Butler: None.
223-OR: Pioglitazone Discontinuation in Patients with Nonalcoholic Steatohepatitis (NASH) Is Associated with Disease Recurrence
Authors: BRIL FERNANDO , LOMONACO ROMINA , KALAVALAPALLI SRILAXMI , LAI JINPING , CUSI KENNETH
Published: June 2019

Pioglitazone (PIO) therapy results in a ∼60% resolution of NASH in patients with prediabetes or T2DM. However, the effects of treatment discontinuation have not been carefully examined. To this end, we assessed plasma aminotransferases (LFTs) after study drug discontinuation among patients who had completed 36 months (n=63) of our randomized, controlled trial (RCT) of PIO for NASH (Cusi, et al. Ann Intern Med 2016). This was an 18 month RCT of PIO 45mg QD vs. placebo (and dietary counseling in all), followed by 18 months of open label PIO. We retrospectively assessed LFTs for 18 months following study discontinuation. PIO normalized plasma ALT, an indicator of hepatocyte injury in NASH, within 3 months of therapy initiation (from 61±5 to 35±2 U/L; p<0.001) and for the duration of treatment (Figure 1).

However, PIO discontinuation resulted in a rapid rebound of LFTs after 3 months (from 30±2 to 42±7 U/L, p=0.02), and continued to increase over time, reaching the highest levels 18 months after discontinuation (59±12 U/L, p<0.001 vs. end of the trial). Plasma AST followed a similar pattern during treatment and after discontinuation.

Conclusion: PIO rapidly normalizes LFTs in NASH and improves liver histology, but its discontinuation results in an abrupt increase in LFTs, likely reflecting NASH recurrence. Therefore, PIO therapy for NASH should be considered as a long-term management approach.

Disclosure

F. Bril: None. R. Lomonaco: None. S. Kalavalapalli: None. J. Lai: None. K. Cusi: Consultant; Self; Allergan, AstraZeneca, Genentech, Inc., Novo Nordisk Inc., Poxel SA, ProSciento. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk Inc.

Funding

American Diabetes Association (1-08-CR-08 to K.C.); Burroughs Wellcome Fund; National Center for Research Resources (M01-RR-01346); University of Texas Health Science Center at San Antonio; U.S. Department of Veterans Affairs
2230-PUB: The Role of Baseline Urine ACR and Estimated GFR in the Development of Advanced CKD after 8.4 Years of Follow-Up in Type 2 Diabetic Patients
Authors: AN LINGWANG , HSU HUI-CHUN , CHANG YU HUNG , LEE TAO-CHUN
Published: June 2019

Background: There is discordance between the presence of albuminuria and the decline in renal function. This study aimed to assess the role of baseline Urine Albumin-to-Creatinine Ratio (UACR) and the estimated glomerular filtration rate (eGFR) in the development of advanced chronic kidney disease (CKD; GFR < 60 mL/minute per 1.73 m2) in type 2 diabetic patients.

Methods: A total of 2424 patients who had participated in a comprehensive diabetic care program were studied and were stratified into progressor (n=578) and non-progressor groups (n=1846) according to the status of progression to advanced CKD during the mean 8.4 years follow-up period.

Results: By Cox regression analysis, the risk of CKD progression [hazard ratio, HR (95% CI)] for patients with microalbuminuria and eGFR >90, non-albuminuria and eGFR 60~89 or microalbuminuria and eGFR 60~89 were 2.215 (1.592~3.081), 3.091 (2.354~4.059) and 4.351 (3.253~5.820), respectively (P<0.001 for all). By Kaplan-Meier survival curve, the progression rates were 9.4% in patients with non-albuminuria and eGFR >90, 25.6% in patients with microalbuminuria and eGFR >90, 28.0% in patients with non-albuminuria and eGFR 60~89 and 38.5% in patients with microalbuminuria and eGFR 60~89.

Conclusions: Our study demonstrated that type 2 diabetic patients with microalbuminuria and eGFR >90 or patients with non-albuminuria and eGFR level of 60~89 were associated with similar risk of progression to advanced CKD.

Disclosure

L. An: None. H. Hsu: None. Y. Chang: None. T. Lee: None.
2244-PUB: Role of B Vitamins (B1, B6, B12) in Managing Diabetic Peripheral Neuropathy (DPN): A Systematic Review
Authors: LIEW JASS , BARLOW ASHLEY , LIM LEE-LING , SUASTIKA KETUT , YASAHARDJA YOSKA , CHAN SIEW PHENG , SOH ABEL , LI LEONARD S.W. , TAN ALEXANDER T.
Published: June 2019

Introduction: DPN affects approximately 50% of diabetic individuals worldwide1. B Vits are used in DPN management although evidence supporting treatment outcomes vary.

Objective: Evaluate the evidence supporting B Vits usage in DPN.

Methods: Literature search: Medical Subject Headings and text words in Pubmed/EMBASE identified 226 clinical trials published between 1978 - Nov 2018. Using PRISMA guidelines, data was extracted from eligible studies and risk of bias assessed was assessed by 2 authors.

Main Results: Fifty-one studies involving 4621 patients were selected [40 RCTs (Placebo-controlled: 7; Active-control: 34) and 10 single-arm study]. Results from placebo-control studies involving daily B vitamin(vit) monotherapy [benfotiamine 300- 600mg OR methylcobalamin 1500μg (MC)] OR Superoxide Dismutase (SOD), Alpha Lipoic Acid (ALA), Acetyl L-Carnitine (AC) and Vit B12 combination showed significant improvement in neuropathy-related scores/symptoms vs. control. One study (150mg pyridoxine daily) showed no improvement in nerve conduction was noted vs. placebo. Vit B6 80mg + 800mg ALA/day showed no inflammatory marker improvement.

When Mono- or combination B Vits was compared to active controls[e.g.: micronutrients/herbs(ALA; ALC; Traditional Chinese Medicine), drugs (pregabalin; nortriptyline; venlafaxine) and lifestyle interventions (moxibustion; low-fat plant-based diet)], 29 studies showed improvements in DPN symptoms relative to control. Two studies showed less effectiveness compared to venlafaxine and cytidinie triphosphate. All single arm B Vit studies (IM MC 500μg 1/day OR 3/week OR benfotiamine/Vit B1/B12) showed improvement in nerve function.

Conclusion: B Vits had positive effect on neurophysiological symptoms and/or functions compared to baseline in 38 studies. RCTs evaluating the efficacy of B Vits in standardized combination/doses are limited. Further studies are required to elucidate optimum treatment combination/doses and duration.

Disclosure

J. Liew: None. A. Barlow: None. L. Lim: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. K. Suastika: None. Y. Yasahardja: None. S. Chan: None. A. Soh: None. L.S. Li: None. A.T. Tan: None.
2264-PUB: Status of Self-Monitoring of Blood Glucose and Its Influencing Factors among Patients with Diabetes in Shanghai
Authors: WEI LI , ZENG YUANYUAN , XIAO YUANYUAN , JI LINLIN , LIU MENGDAN
Published: June 2019

Objective: To investigate the status of self-monitoring of blood glucose (SMBG) among patients with type 2 diabetes mellitus in Shanghai and analyze the factors affecting the frequency of SMBG.

Methods: A total of 987 Chinese subjects with type 2 diabetes mellitus aged 20 to 80 years old was included in the present study from August 2017 to December 2017. A standard questionnaire was completed. The frequency of SMBG and related factors of hyperglycemia were analyzed. The subjects were divided into two groups according to the frequency of SMBG. The relatively high frequency group (RHF) (more than twice a week) and the relatively low frequency group (RLF) (one and twice a week).

Results: Among all the subjects, 337 (34.2%) of them were in the RHF group, and 648 (65.8%) were in the RLF group. The number of patients who monitored blood glucose three times a day and more than three times a day was less (16 and 43, 1.6% and 4.4% respectively). Majority of patients adjusted their blood glucose levels through exercise (38.9%) and diet (38.1%), rather than drug (7.7%) after SMBG. Other methods (15.2%) were also used to alleviate hyperglycemia. Multivariate logistic regression analyses showed that age, duration of diabetic history, glycated hemoglobin, educational levels, insulin usage were factors influencing the frequency of SMBG in patients.

Conclusions: The current status of SMBG among diabetic patients in Shanghai is not optimistic, in which the frequency of SMBG is relatively low. It is of great importance to increase the frequency of SMBG in controlling blood glucose levels.

Disclosure

L. Wei: None. Y. Zeng: None. Y. Xiao: None. L. Ji: None. M. Liu: None.

Funding

National Natural Science Foundation of China (81570778)
2265-PUB: Education in T2D: What Else Can We Do to Improve Patients' Quality of Life?
Authors: MARTINS AMANDA , ABRÃO PAULA , SEGAWA JULIE , CAVALCANTI CATARINA , NITATORI MARCOS , CARIRI FRANCISCO ANDRE , BRITO ROBERTA , ABRUSIO FABIANA , LABA ISABELLA
Published: June 2019

Brazil has more than 13 million people with diabetes, 4th place among top 10 countries for number of adults with diabetes. One of our main problems regarding T2D is lack of patients’ understanding about disease severity and its complications. Considering this, in 2017 we carried out a theater-experience for T2D education. There were 20 presentations for 1.400 patients all over the country, and a great result. Considering Brazil is huge and heterogeneous, in 2018 we decided to go beyond and listen what patients have to say, conducting Regional Patients Advisory Boards, so that we could understand the different scenarios of our 5 geographic regions and the main unmet needs, to design new effective educational programs for both patients and health care professionals. So, we had 5 meetings with patients from public and private health systems, and a local T2D leader conducting the discussion, to find out their journey, perceptions, treatment patterns and what is important for them. All patients and HCPs involved in this project were very impressed and satisfied with this action. Patients felt important and really the center of the discussion, and somebody was carrying about them. HCPs could learn a lot and think about what they are doing for patient’s education and to change this worrying scenario. Interestingly, they are now actively sharing this experience with other HCPs and spreading this way of bringing patients to the center of the decisions. The main Brazilian medical societies are interested in establishing partnerships to conduct educational and disease awareness actions. We have participated on the first T2D patients’ national conference, and have organized a big action in and also a symposium in 2 regions, impacting almost 2.000 people. Now we are preparing the next meetings addressing specific regional needs, also drafting a scientific manuscript for T2D awareness, and planning more actions together with medical societies to spread the importance of education for improving patients’ treatment and quality of life.

Disclosure

A. Martins: None. P. Abrão: None. J. Segawa: None. C. Cavalcanti: None. M. Nitatori: None. F.A. Cariri: None. R. Brito: None. F. Abrusio: None. I. Laba: Employee; Self; AstraZeneca.

Funding

AstraZeneca Brazil
2273-PUB: Translational Analytics Clustering Type 2 DM Patients Treated on Wholesome Millet in Reducing HbA1c
Authors: VAIRAMUTHU SEKAR , SEKAR BRAHATHESHWAR , MARAPPAN SIVAPRAKASH , ANANTHASUBRAMANI RAJAGOPAL
Published: June 2019

Aim: To study the effect of whole grain millet based food in type 2 DM patients on HbA1c reduction.

Methodology: The contexts of the datasets of patients were studied as they arrive at Coimbatore Diabetes Foundation for over a period of 3 years, were classified based on initial visit according to the HbA1c results. High risk > 8%, moderate risk 7% ≤ 8% and low risk < 7%, among 100 patients, were further clustered (as 1,2 and 3 containing 41, 49 and 10 patients respectively) based on age, BMI, FBS, PPBS, and HbA1c, using K-Mean cluster. The translational analytics focus on the conclusions of the datasets from the passive deduction scope to active prescriptive scalability for real time practice on the effect of wholesome millet diet (WMD), millets are small seeded grasses grown as a cereal crops. This approach of real time application of clinical practice in fundamental research that can be easily practiced for treatment of DM, despite the natural limitation of hereditary and aging process. The patients who were following WMD were tested for HbA1c periodically. The Translational analytics: The Interval Plot and individual control chart with the analysis of variance examines the significance of the reduction in the average level of HbA1c% for each cluster.

Findings: 1. Significant reduction of HbA1c between first and second visit from 11.7 to 7.4% (at P value = 0) for cluster group 3 after a lapse of 106 days. This was sustained in the 4th visit up to 480 days 2. In cluster 2 the average reduction from 8.9 to 7.1% in the interval of 79 days and further significant reduction was visible in 4 th visit at 6.6% (at P value 0) up to 335 days. 3. In cluster 1 the significant reduction of HbA1c was noticed at the fourth visit at 6.8% from 7.4% after a lapse of 361 days (P value at 0.007).

Disclosure

S. Vairamuthu: None. B. Sekar: None. S. Marappan: None. R. Ananthasubramani: None.
228-OR: Cerebral Glucose Transport and Metabolism in Obesity
Authors: GUNAWAN FELONA , JIANG LIHONG , LEVENTHAL JESSICA , PACH JOLANTA J. , RANGEL ELIZABETH SANCHEZ , BELFORT-DEAGUIAR RENATA , COPPOLI ANASTASIA , ROTHMAN DOUGLAS L. , SHERWIN ROBERT , MASON GRAEME F. , HWANG JANICE J.
Published: June 2019

Metabolic derangement triggered by a high fat diet has been associated with decreased brain glucose uptake in mice through downregulation of GLUT-1 expression at the blood-brain barrier. Likewise, a prior study by our group using 1H magnetic resonance spectroscopy (MRS) showed diminished change in brain glucose level during acute hyperglycemia in patients with obesity and diabetes. However, whether this reflected differences in absolute brain concentrations remains unknown. We utilized 13C MRS scanning at 4 Tesla to compare the rate of glucose transport (Tmax) and cerebral metabolic rate of glucose (CMRgl) in the occipital lobe during a 2-hour hyperglycemic clamp. Plasma glucose concentration of ∼180mg/dl was achieved using a variable 1-13C-glucose infusion. The study included 8 healthy lean (1M/7F, age 29 ± 5 years, BMI 21 ± 2 kg/m2, HgbA1c 5.4 ± 0.2%) and 6 obese participants (4M/2F, age 30 ± 3 years, BMI 33 ± 3 kg/m2, HgbA1c 5.5 ± 0.2%). Insulin and free fatty acids (FFA) levels were measured during the clamp. Despite nearly identical plasma glucose concentrations at steady state (lean 182.5 ± 9.0 mg/dL, obese 186.5 ± 13.5 mg/dL, P=0.55, averaged over time 60-120 minutes), the absolute brain glucose concentrations were 30% less in obese compared to lean participants (P=0.02). Moreover, using previously reported Michaelis-Menten Kt of 1.1 mM, the calculated Tmax/CMRgl at steady state were 37% less in obese participants (P=0.01), suggesting reduced glucose transport. A trend of higher insulin and FFA levels in obese participants during hyperglycemia was observed. In addition, FFA levels at steady state were negatively correlated with absolute brain glucose concentrations (r= -0.575, P=0.05). We conclude that obesity is associated with diminished absolute concentration of brain glucose during acute hyperglycemia, likely explained by reduced cerebral glucose transport capacity. These findings may have implications for understanding the impact of obesity on central regulation of feeding behavior as well as neurocognitive function.

Disclosure

F. Gunawan: None. L. Jiang: None. J. Leventhal: None. J.J. Pach: None. E. Sanchez Rangel: None. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. A. Coppoli: None. D.L. Rothman: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. G.F. Mason: None. J.J. Hwang: None.

Funding

American Diabetes Association (1-17-ICTS-013 to J.J.H.)
2280-PUB: Impact of Diabetes-Related Family and Social Discomfort on Diabetes Self-Management (DSM)
Authors: CAMPBELL JENNIFER A. , GARACCI EMMA , WALKER REBEKAH J. , EGEDE LEONARD E.
Published: June 2019

Background: DSM is key to diabetes care and critical for optimal outcomes. Understanding whether diabetes related discomfort with family or friends impacts DSM may have important implications for patient care.

Methods: Data from 1,901 adults from the Health and Retirement Survey (HRS) 2003 diabetes cohort was used. The outcome, DSM behaviors included medication adherence, diet, and blood sugar testing. The primary independent variable was perceived family or social discomfort with diabetes. Survey logistic regression models tested the likelihood of performing recommended DSM behaviors, and whether perceived family or social discomfort with diabetes was associated with DSM behaviors. The model controlled for age, gender, race, education, and marital status.

Results: Mean age of the population was 70 years. Overall, 21% reported experiencing diabetes related discomfort with family or friends. Compared to those who did not report any diabetes related discomfort with family or friends, reporting discomfort was related to higher odds of medication non-adherence (OR 2.33; CI 1.56-3.47). Ethnic minorities were more likely to be non-adherent to medications when reporting experiences of family discomfort compared to Whites (OR 2.36; CI 1.50-3.73). Reporting discomfort was also significantly related higher odds of diet non-adherence for fruits/vegetables (OR 1.72; CI 1.20-2.48). Eating high fat foods, junk food, and testing blood sugar were not statistically significant.

Conclusions: Patients with diabetes who report diabetes discomfort in their family and social relationships were more likely to be non-adherent to medications and more likely to be non-adherent to diet recommendations for fruits/vegetables. These results suggest that unique barriers to DSM behaviors may exist as a result of familial and social pressures related to living with diabetes, particularly for minority populations, necessitating tailored diabetes self-management education, support, and interventions.

Disclosure

J.A. Campbell: None. E. Garacci: None. R.J. Walker: None. L.E. Egede: Consultant; Self; Novo Nordisk Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.

Funding

National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases
2291-PUB: Web Application for In-Depth Analysis of Oral Glucose Tolerance Test
Authors: SHINDE SURESH N. , JOSHI ASHWINI S. , SHINDE RITUPARNA S.
Published: June 2019

OGTT can be used to calculate various indexes of insulin secretion, resistance and beta cell function and to stratify the dysglycemic stage. Since calculating these indexes involves complex mathematical calculations, they are less commonly used. Realizing this, we created a single page web-based computer application to calculate these OGTT indexes. The values obtained during standard 75 gm, two-hour OGTT were entered in an Excel worksheet using standard formulas. This was then converted into a web-based calculator. The app can be used on all platforms and devices including smartphones. Once downloaded into a browser, the user needs to replace the default values with patient values obtained during OGTT. The app calculates and prints fasting, post glucose indexes and generates graphical charts showing the comparison between the patient and the expected normal values. It can email a copy for record and works in offline mode also. This app is in public domain and can be freely downloaded from www.ogtt.in. Even though less sensitive, HOMA indexes are commonly used due to their simple formulas. This calculator makes it very easy to calculate the post-glucose indexes which help in early recognition of specific organ resistance and clinical conditions such as obesity, prediabetes, fatty liver, PCOS, gestational diabetes, T2DM. Clinicians can use this rapid and easy tool for risk stratification of dysglycemia and to assess the response to therapy.

Disclosure

S.N. Shinde: None. A.S. Joshi: None. R.S. Shinde: None.
2293-PUB: Evaluation of Utility of Flash Glucose Monitoring (FGM) in People with Type 2 Diabetes in an Urban Indian Setting
Authors: CHAWLA MANOJ , CHAWLA PURVI M. , SHAH AMI
Published: June 2019

The scientific utility of Self-Monitoring of Blood Glucose (SMBG) has been recently challenged by scientific reports. Therefore, we aimed to understand the utility of FGM in Indian setting. FGM is a standard care of practice at our center to deliver effective metabolic care. We analyzed the FGM reports (Libre Pro) from the LINA cohort (n=102; males 67, females 35), to understand the impact of measures adopted for glycemic control. We compared the baseline HbA1c with the repeat HbA1c when the patients reported for at least one follow-up within six months, of undergoing the FGM and being recommended changes in lifestyle with appropriate therapeutic changes, on the basis of FGM findings. Statistical analysis was performed by student t test. The mean age was 60 years (SD±13, 95% CI 57-62). Mean duration of diabetes 13 years (SD±9.2, 95% CI 11-15). The mean baseline HbA1c 8.5% (SD±1.5, 95% CI 8.2-8.8) significantly reduced to mean HbA1c 8% (SD±1.4, 95% CI 7.7-8.3) (p=0.144). Mean reduction in HbA1c was -0.5% (SD±1.4, 95% CI -0.78 to -0.22). Out of 102 patients for HbA1c comparison for change in HbA1c, 68 reported reductions in HbA1c of which 47 (69%) reported HbA1c reductions greater than 0.5%. We corroborated the reported estimated HbA1c (eHbA1c) from Libre Pro with conventional HbA1c reports at follow-up. The higher mean difference in HbA1c of 0.82%, does not justify the utility of eHbA1c in FGM. This often is a misleading tool and a deterrent to efficacious glycemic care. The greater adoption of FGM in our setting empowered patients to choose a healthy lifestyle and the health care professionals to judiciously customize the therapy, with reduction in glycemic variability and increasing the time in range. The rationality of the utility of eHbA1c, which has been questioned in our real-world data, need to be addressed through a higher level of evidence by a larger, nation- wide prospective multicentric study.

Disclosure

M. Chawla: None. P.M. Chawla: None. A. Shah: None.
2296-PUB: Serum Metabolome Reflects the Status of Glucose Metabolism of Japanese Pregnant Women
Authors: SAKURAI KENICHI , EGUCHI AKIFUMI , WATANABE MASAHIRO , YAMAMOTO MIDORI , MORI CHISATO
Published: June 2019

Objective: We reported that some metabolites during early pregnancy could predict subsequent development of gestational diabetes. In this study, to elucidate the metabolic status of pregnant women associated with glucose metabolism, we examined the association of the metabolomic profile and the glycohemoglobin (A1c) levels in Japanese pregnant women.

Research Design and Methods: This study was conducted with participants enrolled by the Center of Chiba Unit of the Japan Environment and Children’s Study. Of those, 237 participants were enrolled in this study. Metabolite levels of their serum obtained during early pregnancy were analyzed using hydrophilic interaction chromatography tandem mass spectrometry. To examine the association between A1c levels and metabolic profiles, we performed least absolute shrinkage and selection operator (lasso) regression. The study protocol was approved by the Biomedical Research Ethics Committee of the Graduate School of Medicine, Chiba University.

Results: Characteristics of participants were followed: age 32.0 (5.0) years, pre-gestational BMI 22.7 (4.6) kg/m2, A1c 5.09 (0.37) %. The association between their A1c levels and the metabolomic profiles, analyzed using lasso regression showed that nineteen metabolites were associated with A1c levels. Enrichment analysis revealed that the metabolites associated with A1c were related to ABC transporters, aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glycine, serine and threonine metabolism, and metabolic pathway.

Conclusion: Our results suggest the association of the serum metabolomic profile with the level of glycemia during pregnancy.

Disclosure

K. Sakurai: None. A. Eguchi: None. M. Watanabe: None. M. Yamamoto: None. C. Mori: None.

Funding

Japan Society for the Promotion of Science; Japan Ministry of the Environment
230-LB: Intraindividual Variability of Measures of Beta-Cell Response
Authors: ANNA NEYMAN , EVANS-MOLINA CARMELLA , DIMEGLIO LINDA , MIRMIRA RAGHAVENDRA , MATHER KIEREN J. , HANNON TAMARA S. , SIMS EMILY K.
Published: June 2019

Diabetes intervention study designs require knowledge of within-subject variability of outcome measures. We evaluated the variability of measures of β-cell response assessed across 9-12 weeks in 3 nondiabetic adult populations relevant to type 1 diabetes (T1D) research: relatives of individuals with T1D who are single islet autoantibody (Ab) +, first degree relatives (FDR) with TID who are Ab -, and Ab- adults with no family history of T1D.

C-peptide and glucose levels were measured in repeated mixed meal tolerance tests (MMTT) and hyperglycemic clamps separated by means of 2.8 months and 3.0 months. The 12 participants (22-49 y; 50% male) included 3 single Ab + FDRs, 5 Ab-FDRs, and 4 with no family history of T1D. Fasting proinsulin:C-peptide (PI:C) ratios were calculated as molar ratios. For MMTTs and clamps, stimulated C-peptide measures were calculated. Between-visit coefficients of variation and intraclass correlations were calculated.

Test-retest variability differed between measures (Table). Test-retest correlations were highest for fasting PI:C and first-phase C-peptide response measures.

In nondiabetic adults with or without known T1D risk factors, test-retest variability ranged from 10-30% for measures of β-cell response. These observations will inform study design including choice of methodology and sample sizes needed to detect treatment effects using these methods.

Disclosure

A. Neyman: None. C. Evans-Molina: None. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research & Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. R. Mirmira: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. E.K. Sims: None.

Funding

JDRF (2-SRA-2017-498-M-B)
2305-PUB: Effects of Dulaglutide on Renal Function, Glycemic Control, and Weight Outcomes in Indian Patients with Type 2 Diabetes: A Real-World Study
Authors: PATANGE SONALI A.
Published: June 2019

Objective: This study aims to evaluate the changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA1c) together with waist-to-hip ratio (WHR) and body weight (BW) in Indian patients with type 2 diabetes (T2D) treated with once weekly dulaglutide in a real-world setting.

Methodology: Patients with inadequately controlled T2D (N = 41) from a tertiary care center in India were treated with once weekly dulaglutide as an add-on medication to oral antidiabetics (OADs) with or without insulin (mean eGFR [standard deviation [SD]]: 76.11 [20.23] mL/minute in patients with <120 mL/min/1.73 m2; mean HbA1c [SD]: 9.33 [1.18] %; mean WHR [SD]: 0.96 [0.06]; mean BW [SD]: 82.44 [14.55] kg; mean BMI [SD]: 31.19 [4.29] kg/m2). A total of 5 patients presented with glomerular hyperfiltration (eGFR>120 mL/min). Improvements in eGFR, HbA1c, WHR, and BW from baseline to 6-month follow-up were analyzed using paired t test.

Results: Follow-up of 6 months with dulaglutide therapy was associated with a significant increase (P<.001) in eGFR (for patients with baseline eGFR ≤120 mL/min) with a mean increase ± standard error of the mean (SEM) of 10.39 ± 1.58 mL/min. Moreover, patients with glomerular hyperfiltration demonstrated a reduction in eGFR with a mean reduction (MR) ± SEM of 37.20 ± 1.64 mL/minute that was statistically not significant. A significant reduction (P<.001) in HbA1c, 2.45 ± 0.11% was demonstrated. In addition, a significant reduction in WHR, BW, and BMI with MR ± SEM of 0.050 ± 0.004, 6.30 ± 0.39 kg, and 2.90 ± 0.22 kg/m2, respectively was demonstrated. Adverse events (AEs) reported include nausea (n = 9), loose stools (n = 2), and loss of appetite (n = 2) that were managed with probiotics and rabeprazole as required.

Conclusion: In a real-world setting, dulaglutide as add-on therapy was well tolerated and significantly improved renal function and glycemic control along with WHR and BW in Indian patients with T2D.

Disclosure

S.A. Patange: None.
2306-PUB: Long-Term Effect of Liraglutide on the Prevention of Progression of Diabetic Nephropathy in Elderly Patients with Type 2 Diabetes
Authors: YOSHIDA MAMI , YOSHIDA AI , OH ERIKO , YAMAMOTO NAOMUNE , SASAKI EUN , SAEKI AKIO , YOSHIDA SHIGERU , KUZUYA TAKESHI , OHSAWA NAKAAKI , SUGINO MASAKAZU
Published: June 2019

Purpose: The aim of this study was to assess the long-term efficacy of liraglutide on diabetic nephropathy in elderly patients with type 2 diabetes.

Methods: Liraglutide was administrated to elderly patients with poorly controlled type 2 diabetes in Aino Hospital. We recruited and retrospectively reviewed 31 patients who were treated with liraglutide for 5 years (Group L: 7 males/24 females, 75.4±8.1 years old of age, 16 with cerebrovascular and 8 patients with cardiovascular diseases at baseline) and 25 patients who were not treated with liraglutide (Group N, 9 males/16 females, 74.6±11.6 years old of age). Daily dose of liraglutide was 0.9mg except 2 patients (0.6 mg).

Results: After 5 years of treatment, HbA1c, FPG, and 2h-PPG significantly decreased in both groups (7.5±0.4 to 6.8±0.5 vs. 7.4±0.6 to 6.9±0.4%, 138±19 to 120±11 vs. 132±16 to 113±13, 206±31 to 173±18 vs. 186±23 to 163±18mg/dl, respectively(p<0.01)). Triglycerides significantly decreased in Group L but not in Group N. Body mass index (BMI) significantly decreased in Group L but not in Group N (25.5±4.1 to 24.8±3.8 (p<0.05) vs. 24.1±3.8 to 24.8±3.8kg/m2 (NS)). Estimated glomerular filtration ratio (eGFR) significantly increased in Group L but significantly decreased in Group N (45.6±17.8 to 49.9±18.5 (p<0.05) vs. 48.7±18.9 to 46.3±21.7 ml/min/1.73m2 (p<0.05). When results were stratified according to eGFR at baseline in Group L (Group A(n=6): eGFR >60, Group B (n=18): eGFR = 30-60, Group C (n=7): eGFR<30), eGFR level increased in Group B (43.6±7.6 to 50.8±8.2 (p<0.01)) and in Group A (73.0±10.5 to 76.8±11.1 (NS)), but not in Group C(24.0±3.4 to 23.0±6.3 (NS)). No hypoglycemia requiring medical care was observed. During the treatment period, no newly onset cerebro- and cardiovascular disease were observed.

Conclusion: Liraglutide improved glycemic control, lipid profile and BMI of elderly patients with type 2 diabetes. Liraglutide also demonstrated its beneficial effect on renal function.

Disclosure

M. Yoshida: None. A. Yoshida: None. E. Oh: None. N. Yamamoto: None. E. Sasaki: None. A. Saeki: None. S. Yoshida: None. T. Kuzuya: None. N. Ohsawa: None. M. Sugino: None.