bluuebunny/crossref_metadata_2025 huggingface dataset:
2186-P: Circulating Exosomes from Simple Obese Humans Inhibited Islet ß-Cell Proliferation through Increasing Cellular Inflammation
Authors: XIE XINXIN , GE QIAN , HUANG RONGFENG , XIAO XIAOQIU , LI XI
Published: June 2019

The progressive decline of the β cell function is one major pathogenesis of type 2 diabetes mellitus. The obese people with normal glucose have already had β cell dysfunction. We aim to investigate whether the circulating exosome vesicles (EVs) could be a new mechanism linking obesity to β cell dysfunction. A total of 43 healthy lean and 44 simple obese volunteers were recruited from June 2017 to February 2018. Compared to lean subjects, obese subjects had lower glucose disposition index (DI) and Secretion-sensitivity index (ISSI-2). Compared to EVs isolated from circulations of lean subjects (L-EVs), EVs from obese subjects (O-EVs) inhibited β cell proliferation while did not affect its apoptosis. Moreover, the O-EVs induced β cell inflammation via activating the NF-kB and increasing the gene expression of chemokine CCL-2. By Quantitative Proteomic Analysis, we further explored that 29 proteins were differentially regulated in O-EVs compared to L-EVs. Among them, the Rapamycin-insensitive companion of mTOR (Rictor) and the Omentin-1 were downregulated by 65% (P<0.01) and by 27% (P=0.03) respectively. The existences and downregulations of both the total and phosphorylated forms of the Rictor, as well as the omentin-1, were verified by Western blot and ELISA (total Rictor: 0.21±0.04 vs. 0.15±0.05, P<0.01; phosphorylated Rictor: 0.33±0.09 vs. 0.25±0.08, P=0.02; Omentin-1: 33.5±5.2 vs.16.3±2.5, P<0.01). Both the phosphorylated Rictor and the Omentin-1 in EVs correlated negatively with the visceral fat mass, the HOMA insulin resistance index, and the fasting insulin secretion. Additionally, the Omentin-1 correlated positively with the DI and the ISSI-2. Thus, circulating EVs from simple obese humans inhibited β cell proliferation through increasing cellular inflammation. This effect may result from the changed protein cargos of EVs during obesity. The two newly identified exosomal proteins may be new therapeutic targets for improvingβcell function.

Disclosure

X. Xie: None. Q. Ge: None. R. Huang: None. X. Xiao: None. X. Li: None.
219-OR: Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing Total Pancreatectomy and Autologous Islet Transplantation
Authors: MCDOWELL RUTH , ALI KHAWLA F. , SAN MARTIN VICENTE T. , BOTTINO RITA , KIRWAN JOHN P. , HATIPOGLU BETUL
Published: June 2019

Rationale: Although autologous islet transplantation aims to prevent surgically-induced insulin-dependent diabetes in patients undergoing total pancreatectomy, only approximately one third of patients achieve insulin independence. To test the hypothesis that reducing nonspecific inflammation improves graft function post-AIT, we conducted a pilot clinical study using oral hydroxychloroquine (HCQ), an FDA-approved anti-malarial that inhibits thrombosis and a broad spectrum of inflammatory cytokines.

Methods: We used a phase II, randomized, double-blinded, placebo-controlled trial to determine the effect of peri-transplant HCQ on individuals (n=8) undergoing total pancreatectomy with autologous islet transplantation (TPAIT). In vivo islet function was assessed via Mixed Meal Tolerance Test (MMTT) before and 6-12 months after surgery. We found that islet grafts were viable for at least 24 hours in culture and we optimized conditions for in vitro assessment of islet graft metabolic function via Seahorse Extracellular Flux.

Results and Conclusions: Islet grafts from HCQ-treated patients showed a 4.7-fold greater mitochondrial spare respiratory capacity compared with placebo-treated patients (64.9 ± 20.7 vs. 13.7 ± 7.1% basal respiration, p = 0.058), suggesting that HCQ may improve metabolic function in the islet graft. We also found that the insulin incremental area under the curve after MMTT was 8.2-fold greater in HCQ-treated patients 6-12 months after surgery compared to that of placebo-treated patients (1154 ± 290 vs. 185 ± 180 mU/L, p = 0.026), suggesting that HCQ may also improve islet engraftment and/or function. Our results warrant further investigation into HCQ using a larger-scale clinical trial with the goal of reducing inflammatory islet destruction and enhancing mitochondrial function to improve metabolic outcomes in TPAIT.

Disclosure

R. McDowell: None. K.F. Ali: None. V.T. San Martin: None. R. Bottino: Research Support; Self; Imagine Pharma. J.P. Kirwan: None. B. Hatipoglu: Advisory Panel; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Merck & Co., Inc.

Funding

Cleveland Clinic Foundation
2190-P: Sex-Based Differences in Nr4a1 Beta-Cell Activity
Authors: TESSEM JEFFERY S. , HERRING JACOB , SMITH COURTNEY J. , AUSTIN MATTHEW C. , WYNN ADAM G.
Published: June 2019

The orphan nuclear hormone receptor Nr4a1 plays a critical role in maintaining and expanding functional beta cell mass. Overexpression of Nr4a1 is sufficient to induce beta cell proliferation in primary beta cells by upregulating cell cycle progression, while maintaining glucose-stimulated insulin secretion. Full body deletion of Nr4a1 results in decreased beta cell mass, while resulting in modified fuel utilization in liver and muscle. Knock down of Nr4a1 decreases glycolytic and TCA cycle gene expression, impairs mitochondrial respiration, decreases cellular ATP levels, and ultimately decreases glucose-stimulated insulin secretion. While Nr4a1 is currently considered an orphaned nuclear hormone receptor, recent findings suggest that unsaturated fatty acids may function as a ligand, and that exposure to these fatty acid’s changes Nr4a1 affinity for promoters of genes involved in fuel utilization. To determine the effect of Nr4a1 presence of absence in the beta cell, and the effect of fatty acid exposure, we developed a beta cell specific, inducible, Nr4a1 knock out mouse. Male and female mice, deficient for Nr4a1 beginning at 3 months of age, were fed a normal chow or high fat diet for an additional four months. Here we present data demonstrating a sex specific difference in phenotype. Male mice demonstrated improved glucose tolerance at four months of feeding, while female mice demonstrated impaired glucose tolerance as early as one month of feeding. Here we present data regarding differences in beta cell mass, glucose stimulated insulin secretion, as well as Nr4a1 DNA binding from in islets from male and female mice exposed to unsaturated and saturated fatty acids. These data begin to demonstrate the role of Nr4a1 in controlling gene expression as a function of nutrient exposure, as well as sex-based differences in Nr4a1 activity.

Disclosure

J.S. Tessem: None. J. Herring: None. C.J. Smith: None. M.C. Austin: None. A.G. Wynn: None.

Funding

American Diabetes Association (1-17-IBS-101 to J.S.T.)
2191-P: PPM1K Regulates ß-Cell Proliferation, Insulin Content, and GSIS
Authors: DELEYE YANN , HERRING JACOB , HESS KAVAN H. , LEININGER BRENNAN R. , HANNOU SARAH A. , ASTAPOVA INNA , HERMAN MARK A. , TESSEM JEFFERY S. , WHITE PHILLIP J.
Published: June 2019

A single nucleotide polymorphism in the gene encoding the protein phosphatase m1K (PPm1K) is associated with increased risk for the development of type 2 diabetes but not insulin resistance in humans. We recently discovered that expression of the PPM1K gene in liver is suppressed by the carbohydrate response element binding protein (ChREBP) which controls transcriptional responses to changes in carbohydrate availability. Taken together these findings suggest that PPM1K might play an important role in the glucose responsive pancreatic β cell; however, little is known about the role of PPm1K in this cell type. Here we studied how changes in glucose concentration affect PPm1K expression in β cells and explored the effect of modulating PPM1K expression on β cell proliferation, insulin content and glucose stimulated insulin secretion. Studies were carried out in INS1-832/13 β cells in culture and key findings were validated in isolated rat islets. In line with our previous observations in liver, we found that increasing glucose concentrations in INS1 cells results in elevated ChREBP activity, measured by expression of the ChREBP β isoform, and lower PPM1K mRNA expression (P<0.01). Treatment of INS-1 cells with adenovirus expressing recombinant human PPM1K for 96h increased β cell proliferation (P<0.05) but robustly lowered GSIS (P<0.001). This effect was due to substantially lower insulin content in the Ad-PPm1K treated cells (P<0.01). Importantly, there was no effect of the control GFP adenovirus compared to non-transfected cells for any of these measures. Moreover, siRNA mediated knock down of PPM1K resulted in increased expression of INS1 and INS2 mRNA suggesting that altered transcription of the insulin gene likely accounts for the effect of PPm1K on β cell insulin content and release.

In conclusion, our data clearly demonstrate that PPM1K plays an important role in the regulation of β cell insulin production and proliferation.

Disclosure

Y. Deleye: None. J. Herring: None. K.H. Hess: None. B.R. Leininger: None. S.A. Hannou: None. I. Astapova: None. M.A. Herman: None. J.S. Tessem: None. P.J. White: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-16-INI-17 to P.J.W.)
2192-P: Extracellular Vesicles as Novel Mediators of Proinflammatory Cytokine-Induced ß-Cell Dysfunction
Authors: JAVEED NAUREEN , HER TRACY K. , VANDERBOOM PATRICK M. , LANZA IAN R. , MATVEYENKO ALEKSEY
Published: June 2019

The presence of a proinflammatory islet microenviroment and consequent dysregulation of glucose-stimulated insulin secretion (GSIS) is a hallmark feature of both type 1 and type 2 diabetes. Recent evidence has implicated islet cell-derived extracellular vesicles (EVs) as novel mediators of cytokine-derived inflammatory stress in diabetes, however the mechanisms governing this process remain largely unknown. Therefore, we set out to test the hypothesis that cytokine-mediated β-cell dysfunction is mediated in part through β-cell autocrine release of proinflammatory EVs which promote inflammation and inhibit GSIS. Particle size analysis of EVs from conditioned media of cytokine treated (IL-1β, TNF-α, and IFNγ) Min6 β-cells (CytoEV) showed an overall increase in β-cell EV secretion (∼2 fold increase, P<0.05) and a decrease in the average size of secreted EVs (P<0.05) implicating a shift towards a more exosomal EV profile. Subsequently, functional assessment of isolated mouse islets treated (48h) with CytoEVs resulted in a significant suppression of GSIS (∼80%, P<0.05 vs. control). Moreover, acute exposure to CytoEVs also recapitulated the transcriptional signature of β-cell failure in diabetes characterized by increased expression of key proinflammatory genes (e.g., Cxcl10, Tlr1, Tlr4), and a decrease in Insulin and Pdx-1 expression (∼40%, P<0.05 for CytoEVs vs. control). Finally, proteomics analysis of CytoEVs from Min6 and INS-1 832/13 lines (compared to control EVs from each line) revealed a distinct proinflammatory profile consisting of proteins implicated in type 1 diabetes and dendritic cell maturation pathways (e.g., HLA-A, STAT1, INS, CPE etc., P<0.05). Taken together, this work provides a novel mechanism of β-cell dysfunction in diabetes mediated by the autocrine exchange of proinflammatory EVs which has implications for the detection and treatment of β-cell failure in diabetes.

Disclosure

N. Javeed: None. T.K. Her: None. P.M. Vanderboom: None. I.R. Lanza: None. A. Matveyenko: None.
220-LB: Early-Life Famine Exposure and Hyperuricemia in Adulthood
Authors: WANG YUYING , ZHANG WEN , WAN HENG , CHEN CHI , CHEN YI , XIA FANGZHEN , HAN BING , LI QIN , GUO YUYU , WANG NINGJIAN , LU YINGLI
Published: June 2019

Background and Aims: Hyperuricemia is a pathological condition associated with hypertension, metabolic dysfunctions, renal, and cardiovascular diseases. Epidemiologic studies indicated that early life famine exposure influences later risk of chronic disorders. But evidence in the association between famine exposure and hyperuricemia were limited. We aimed to investigate whether the association existed between famine exposure in early life and hyperuricemia in adulthood.

Methods: 12666 participants were enrolled in China based on SPECT-China study (ChiCTR-ECS-14005052, www.chictr.org.cn). Hyperuricemia was defined as UA >420 μmol/L for men and >360 μmol/L for women. The associations of famine exposure with hyperuricemia were assessed via logistic regression.

Results: For famine exposed women, fetal famine exposure was significantly associated with hyperuricemia (1.63 (95% CI 1.04-2.54), P=0.031). Early life famine exposure was only associated with hyperuricemia in lean women (fetal exposed: 1.9 (95% CI 1.11-3.24); childhood exposed: 1.91 (95% CI 1.05-3.47), P<0.05), but not in obese subjects. Moreover, the insulin resistant female had a marginal significance of the association between fetal famine exposure and hyperuricemia (1.85 (95% CI 0.92-3.72), P=0.082). Significant association between fetal and childhood famine exposure and hyperuricemia was observed in lean and insulin resistant female (fetal exposed: 3.32 (95% CI 1.13-9.76); childhood exposed: 3.57 (95% CI 1.06-12.01), P<0.05). However, no association was observed in male subjects.

Conclusions: Exposure to famine in early life period may lead to hyperuricemia in female, which indicates malnutrition in early life period may offer a modifiable factor for hyperuricemia development.

Disclosure

Y. Wang: None. W. Zhang: None. H. Wan: None. C. Chen: None. Y. Chen: None. F. Xia: None. B. Han: None. Q. Li: None. N. Wang: None. Y. Lu: None.

Funding

National Natural Science Foundation of China (91857117, 81570726, 81600609, 81600614, 81800694]; Science and Technology Commission of Shanghai Municipality (18410722300, 16411971200, 16410723200); Commission of Health and Family Planning of Pudong District (PWZxq2017-17, PW2015D-5); Shanghai Municipal Commission of Health and Family Planning (15GWZK0202, 20164Y0079); Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ053); Clinical Research Plan of SHDC (16CR3076B)
2205-PUB: Temporal Patterns of Inpatient Hypoglycemia and Predictors of Recurrent Hypoglycemia in a Singapore Tertiary Medical Center
Authors: LIM PAIK SHIA , GOH SU-YEN , BEE YONG MONG , XIN XIAOHUI , ANG LI CHANG , SALLEHA NUR A. , TEH MING M.
Published: June 2019

Background: Inpatients hypoglycemia has adverse impacts on patient outcomes and healthcare resources use. While recurrent hypoglycemia is largely preventable, limited studies were done within the Asia-Pacific context. We sought to determine whether temporal distributions of hypoglycemia exist between insulin and/or sulfonylureas (SU) treated patients and identify predictors of recurrent hypoglycemia at a tertiary medical center in Singapore.

Methods: We analyzed data of 420 hypoglycemic episodes (capillary blood glucose (CBG) ≤ 70mg/dL) in 207 diabetes patients at general medical wards over a 2-month period from 1st May 2017. This was analyzed by 4 time frames coincided with blood glucose monitoring times. Time periods associated with hypoglycemia were compared using the Chi-square test. Multivariate logistic regression estimated risk factors of recurrent hypoglycemia.

Results: Most frequent hypoglycemia episodes occurred between 04:00 and 09:59 (41.7%). Greater frequency was seen in insulin- and SU-treated than insulin-treated patients between 04:00 to 09:59 (58.3% vs.37.9% of readings for respective treatments, p<0.05). It was also more frequent in insulin-treated than SU-treated patients between 10:00 to 15:59 (19.2% vs. 10.9%, p<0.05). Nearly a third of patients had recurrent hypoglycemia (32.9%). Longer length of stay, treated with premixed insulin, age < 65 years, HbA1C > 7% and repeated CBG checking > 30 minutes interval emerged as predictors of recurrent hypoglycemia with odds ratio of 1.07 (95% CI 1.03-1.11), 8.07 (95% CI 2.82-23.08), 3.71 (95% CI 1.59-8.65), 3.12 (95% CI 1.26-7.74) and 3.54 (95% CI 1.59-7.91), respectively.

Conclusions: Hypoglycemic episodes were more frequent in the early hours of the day in insulin and SU-treated inpatients. This may have implications for the continuing use of SU at inpatients. Recurrent hypoglycemia can be prevented by developing strategies targeting the modifiable iatrogenic risk factors.

Disclosure

P. Lim: None. S. Goh: None. Y. Bee: None. X. Xin: None. L. Ang: None. N.A. Salleha: None. M.M. Teh: None.
2208-PUB: Prevalence of Type 2 Diabetes Is Higher in Patients with Heart Failure than in Patients with Stable Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN-PURIN DANIELA , LARCHER BARBARA , MADER ARTHUR , STERNBAUER SIMON , SAID ABDURAHMAN , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2019

High prevalence rates of type 2 diabetes (T2DM) have been reported both in stable coronary artery disease (CAD) and in heart failure (HF) patients, but data directly comparing T2DM prevalence between these patient populations are not available. Here, we therefore aimed at comparing the prevalence of T2DM and of prediabetes in 195 patients with angiographically proven stable CAD who had no history, signs or symptoms of heart failure, and in 183 patients with a diagnosis of HF according to current European Society of Cardiology criteria. Using ADA criteria for the diagnosis of diabetes, T2DM prevalence was significantly higher in HF than in CAD patients (48.6% vs. 22.6%; p<0.001). Also, the proportion of patients reporting a history of diabetes was significantly higher in HF than in CAD patients (37.7% vs. 16.9%; p<0.001). HF remained associated with a higher prevalence of T2DM after multivariate adjustment (OR 2.89 [1.77-4.72]; p<0.001). In contrast, among the patients who did not have diabetes, the prevalence of prediabetes (FPG 100-125 mg/dl or HbA1c 5.7-6.5%) was similar in HF as in CAD patients (66.0 vs. 62.3% =0.558). We conclude that the prevalence of T2DM is even higher in patients with HF than in patients with stable CAD.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin-Purin: None. B. Larcher: None. A. Mader: None. S. Sternbauer: None. A. Said: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
2222-PUB: Type 2 Diabetes as a Predictor of Cardiovascular Events in Peripheral Artery Disease vs. Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN-PURIN DANIELA , LARCHER BARBARA , MADER ARTHUR , SCHINDEWOLF MARC , BAUMGARTNER IRIS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2019

Patients with established cardiovascular disease (CVD) are at a very high risk of cardiovascular events, and cardiovascular risk is considered extremely high in those with the combination of CVD and diabetes. However, the impact of type 2 diabetes (T2DM) on cardiovascular event risk may differ between different manifestations of CVD. To address this issue, we prospectively recorded cardiovascular events over 10 years in 1472 patients with angiographically proven stable coronary artery disease (CAD), of whom 454 had T2DM as well as in 465 patients with sonographically proven peripheral artery disease (PAD), of whom 204 had T2DM. Both among CAD and among PAD patients, those with T2DM were at a significantly higher risk of cardiovascular events than those who did not have diabetes (56.0% vs. 44.5%; p<0.001 and 68.5% vs. 50.6%; p<0.001, respectively). Cardiovascular risk was significantly higher in PAD than in CAD patients, both among those with T2DM (68.0% vs. 56.0%; p=0.003) and among those who did not have diabetes (50.6% vs. 44.5%; p=0.047). In multivariate analyses, T2DM (HR 1.48 [1.13-1.70); p<0.001) and presence of PAD versus that of CAD (HR 1.93 [1.64-2.28];p<0.001) were mutually independent predictors of cardiovascular events. An interaction term T2DM by PAD vs. CAD was non-significant (p=0.146), indicating that the relative risk increase conferred by T2DM did not differ significantly between PAD and CAD patients. We conclude that T2DM increases cardiovascular event risk among patients with PAD as well as among those with CAD and that PAD confers a higher risk of cardiovascular events than stable CAD irrespective of the presence of T2DM.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin-Purin: None. B. Larcher: None. A. Mader: None. M. Schindewolf: None. I. Baumgartner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
2242-PUB: Retinal Biomarkers Indicative of Diabetic Peripheral Neuropathy
Authors: NEMETH SHEILA C. , BURGE MARK R. , WIGDAHL JEFFREY , CARMICHAEL JUSTIN C. , GUO XIAOSHAN , JOSHI VINAYAK , SOLIZ PETER
Published: June 2019

The purpose of this study was to identify biomarkers that are indicative of diabetic peripheral neuropathy (DPN). From a cohort of 21 DPN and 18 controls, optic disc- and macula-centered images were taken. Sixty vascular parameters were measured using computer-assisted software. Statistically significant differences in vascular parameters between subjects with DPN and controls showed that DPN subjects could be differentiated from controls using retinal biomarkers. Statistical significance (p < 0.05) was obtained for 13 retinal features, including fractal dimension, vein width, number of 1st branching vessels, and vessel tortuosity. The reduced fractal dimensions in DPN patients indicate a deterioration of the retinal vascular architecture. The reduced total number of vessels, as well as the total number of venules, contribute to the lower fractals in the DPN patients and supports the findings of a sparser retinal vascular network for DPN subjects. A difference in standard deviation for vessel width may suggest a greater loss of vascular tone and regulation in DPN subjects. A difference in the number of 1st branching vessels in venules was observed, which may indicate that the DPN subjects had fewer numbers of these first bifurcations. This feature would also contribute to the lower fractal dimension as well as a sparser retinal vascular network. Similarly, the statistical difference in the angle of the first daughter vessel suggests that the retinal vascular architecture has deviated from its optimal flow and/or function due to the disease process. The increased difference in curvature tortuosity in the arterioles in DPN correlates with chronic hypertensive retinopathy. We found statistically significant differences in 13 out of 60 retinal vascular features (22%) between control and DPN subjects. As such, the retina reflects the widespread vascular structural abnormalities occurring in diabetic patients with DPN.

Disclosure

S.C. Nemeth: None. M.R. Burge: None. J. Wigdahl: None. J.C. Carmichael: None. X. Guo: None. V. Joshi: None. P. Soliz: Stock/Shareholder; Self; VisionQuest Biomedical LLC.

Funding

National Institutes of Health (R43DK104578-01)
2243-PUB: Impact of Sudomotor Impairment on Physical Fatigue after 16 Weeks of Aerobic Exercise
Authors: GRAY COREY M. , YAHYA ABDALGHANI , ALENAZI AQEEL M. , ALSHEHRI MOHAMMED , RUCKER JASON L. , PASNOOR MAMATHA , KLUDING PATRICIA
Published: June 2019

Introduction: Sudomotor impairment (SI) is common in people with diabetic peripheral neuropathy (DPN) and could potentially influence the effects of exercise. Exercise is known to improve outcomes such as physical fatigue (PF); however, the impact of SI on PF is not clear. Thus, our objective was to examine the impact of sudomotor function on PF change after 16-weeks of moderate intensity aerobic exercise (AEx).

Methods: People with DPN (n=17) who participated in 16-weeks of AEx were included in this secondary analysis. Sudomotor function was evaluated at baseline via a quantitative sudomotor axon reflex test and classified as normal (n=6), mild (n=6), moderate (n=3), or severe (n=2). Self-reported PF was assessed at baseline and post-intervention via a fatigue questionnaire. A Kruskal-Wallis test evaluated the impact of baseline sudomotor function on change in PF after exercise. Dunn’s tests were used to evaluate multiple comparisons. Association between sudomotor function and PF change was evaluated via a Spearman’s correlation. Alpha was set at 0.05.

Results: Changes in PF are reported as negative (↓in PF) and positive (↑in PF) values. Median PF changes of -29%, -30%, 0%, and 14% were observed for normal, mild, moderate, and severe groups, respectively with a significant between-group difference (p=0.039). Pairwise comparisons revealed significant differences between normal and moderate (p=0.025), normal and severe (p=0.047), and mild and moderate (p=0.04) groups. A moderate correlation between SI and PF change (r=0.630, p=0.007) was observed.

Conclusions: Our results indicate that change in PF following 16-weeks of AEx may be influenced by SI. SI can limit the body’s ability to dissipate heat during exercise, potentially exacerbating PF through disruptions in the thermoregulatory negative feedback loop. This could influence response to exercise, and future research should examine the effects of underlying mechanisms of SI on PF in this population.

Disclosure

C.M. Gray: None. A. Yahya: None. A.M. Alenazi: None. M. Alshehri: None. J.L. Rucker: None. M. Pasnoor: Advisory Panel; Self; Alexion Pharmaceuticals, Inc., Terumo BCT. Consultant; Self; Momenta Pharmaceuticals. P. Kluding: None.

Funding

National Center for Advancing Translation Sciences (UL1TR000001); Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD057850)
225-LB: Demographic and Clinical Comparisons of South Asians with Type 2 Diabetes vs. Caucasians and African Americans in an Urban Clinical Setting
Authors: AHMED AMIYA , RAHMAN WEDAD , MUNIR KASHIF M.
Published: June 2019

Background: The incidence of type 2 diabetes (T2D) is rising worldwide. South Asians are at higher risk, nearly 2-4 times greater than white Europeans, and tend to develop T2D at an earlier age and lower BMI. Prior studies have shown a potential advantage of incretin-based therapies in South Asians. The purpose of this study is to compare baseline characteristics of South Asians with T2D with those of other ethnic groups and to determine whether South Asians have a better glycemic response to incretin-based therapies in an urban United States diabetes center.

Methods: Retrospective chart review of patients with T2D at the University of Maryland Center for Diabetes and Endocrinology from 2010-16 was performed. Adult patients (ages 18-85) with T2DM were included. A total of 43 South Asians (India, Bangladesh, Pakistan, Sri Lanka) and 182 non-South Asians (further subclassified into black or Non-Hispanic white) were enrolled. Data on age of T2DM diagnosis, family history, BMI, diabetic medications, exercise, blood pressure, and presence of micro- or macrovascular complications were collected. Baseline characteristics were compared and tested for statistical significance by Chi-square test and student t-tests.

Results: South Asians were diagnosed with T2D at a lower BMI (29 vs. 34; p<0.0001) compared to their non-south Asian counterparts. In the South Asian group, there was a trend towards lower age at diagnosis, higher incidence of CAD and nephropathy compared to non- South Asians. No differences in hemoglobin A1c between South Asians vs. non-South Asians were noted at 3-month follow-up after initiation of incretin-based therapy.

Conclusion: South Asians are more likely to have T2D at a lower BMI than black or Non-Hispanic white patients in an urban United States setting. No significant difference in T2DM complications was noted among ethnic groups, and incretin-based therapies did not have a significant effect on in South Asians vs. non-South Asians.

Disclosure

A. Ahmed: None. W. Rahman: None. K.M. Munir: None.
2251-PUB: Relationship between Type 2 Diabetes and Dyslipidemia in Adult Residents of Minhang District, Shanghai: A Multistage, Stratified Cluster Sampling Survey
Authors: LIANG TONGTONG , XU DONGLI , YAO BAODONG
Published: June 2019

Objective: To investigate the relationship between type 2 diabetes and dyslipidemia in adult residents of Minhang District, Shanghai.

Methods: A multistage, stratified cluster sampling survey were conducted among 3099 adult residents aged 35 and above in Minhang District. The prevalence rate should be adjusted according to the population distribution of the Sixth National Population census data in this area. Logistic regression analysis was used for multivariate analysis.

Results: The adjusted prevalence rate of type 2 diabetes and dyslipidemia were 18.18% and 50.61%, respectively. The increased rates of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were 28.03%, 19.56% and 3.56%, respectively, and the decreased rate of high-density lipoprotein cholesterol (HDL-C) was 14.32%. TC, TG and LDL-C were positively correlated with fasting blood glucose (FBG) with linear correlation coefficients 0.068, 0.190 and 0.049, respectively. While HDL-C was negatively correlated with FBG with linear correlation coefficient -0.076. The relationship between the TC, TG, LDL-C and HDL-C and the 2-hours blood glucose (2hBG) after oral glucose tolerance test (OGTT) was the same as that between the TC, TG, LDL-C and HDL-C and the FBG and the linear correlation coefficients were 0.121, 0.166, 0.116 and -0.045, respectively. Dyslipidemia and higher TG were independent risk factors of type 2 diabetes (OR=1.69, 95% CI:1.32-2.17; OR=1.53, 95% CI:1.21-1.94), adjusting sex, age, education level, occupation, smoking, drinking, BMI and hypertension.

Conclusion: Dyslipidemia is closely associated with type 2 diabetes among adult residents in Minhang District. Comprehensive prevention and control measures for dyslipidemia and type 2 diabetes should be carried out.

Disclosure

T. Liang: None. D. Xu: None. B. Yao: None.
2256-PUB: Fixed-Ratio Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus Treatment in Type 2 Diabetic (T2DM) Patients with Diabetic Foot Ulcers (DFU) and Critical Limb Ischemia (CLI)
Authors: FALCETTA PIERPAOLO , INDOVINA FRANCESCO S. , GIANNARELLI ROSA , PIAGGESI ALBERTO , PENNO GIUSEPPE , MICCOLI ROBERTO , PRATO STEFANO DEL , COPPELLI ALBERTO
Published: June 2019

We report results from the clinical use of IDegLira compared to basal-bolus (BB) insulin regimen in T2DM patients admitted to our department because of DFU and CLI. We retrospectively identified 44 consecutive T2DM patients admitted to our diabetes ward because of DFU (M/F: 24/20; age: 67.3±9.5 years; BMI: 30.6±5.2 Kg/m2; diabetes duration (DD): 23.5±9.9 years; HbA1c 71.7±24.5 mmol/mol). During hospitalization, 28 patients (Group A: M/F: 15/13; age: 65.7±8.9 years; BMI: 32.6±4.8 Kg/m2; DD: 21.1±9.9 years; HbA1c 76.1±25.2 mmol/mol) previously on BB (63.7±33.9 U/day), were started on IDegLira (IDeg 22.8±7.8 U/day, liraglutide 0.82±0.3 mg/day) while the remaining 16 (Group B; M/F: 9/7; age: 70.4±10.1 years; BMI: 30.3±2.2 Kg/m2; DD: 27±9.2 years; HbA1c 63.9±22.0 mmol/mol; all p=NS vs. Group A) continued BB (43±18 U/day), allowing comparison over a mean follow-up period of 3 months. Patients were comparable with respect to distal lesions, pain-relieving, antibiotic therapies, revascularization procedures and surgical treatments performed. In Group A, BMI, HbA1c and LDL-C improved significantly (26.4±10.1 Kg/m2; 54±11 mmol/mol; 61.5±32 mg/dl; p<0.05 vs. baseline) during the follow-up period. No change occurred in Group B whereas Group A also had significant improvement of inflammatory markers (Fibrinogen: 635±178 vs. 437±121 mg/dl; ESR: 74±34 vs. 48±13 mm/h; CRP: 5.2±1.7 vs. 0.8±1.0 mg/dl; all p<0.05 vs. baseline). Ulcer healing was achieved in 17 patients in Group A (61%), and in 3 patients (19%) in Group B (p<0.05). These data suggest that treatment with IDegLira can have positive effects on metabolic and inflammatory parameters of complicated T2DM patients with DFU and CLI, probably contributing to greater ulcer healing observed in this category of patients.

Disclosure

P. Falcetta: None. F.S. Indovina: None. R. Giannarelli: None. A. Piaggesi: None. G. Penno: None. R. Miccoli: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. A. Coppelli: None.
2257-PUB: Evidence-Based Basal Insulin Use in T2D: Extensive Knowledge and Confidence Increases with CME
Authors: LARKIN AMY , HEALY COLLEEN S. , LE ANNE
Published: June 2019

We assessed baseline knowledge of PCPs and diabetologists/endocrinologists (D/Es) and determine if an online continuing medical education (CME) could improve individualized treatment of patients with T2D. A 3-question knowledge and 1-question confidence linked pre-/post assessment study designed with McNemar’s chi-squared test (5% significance level P <.05) and Cramer’s V (<0.05 no effect; 0.06-0.15 small effect; 0.16-0.30 medium effect; >0.30 large effect) assessed educational effect. The activity launched December 19, 2017 and data collected through January 19, 2018. PCPs (N=585) demonstrated a lower baseline knowledge level compared to D/Es (N=118): • 29% of PCPs compared to 81% of D/Es correctly identified which basal insulin had a lower risk for hypoglycemia • 52% of PCPs compared to 75% of D/Es correctly identified the regimen needed to decrease the risk for hypoglycemia and maintain glucose control • 42% of PCPs compared to 62% of D/Es accurately distinguished between basal insulin and longer-acting basal insulin. Overall improvements were seen after participation in the CME activity for both PCPs (N=585, P<.0001, large effect V=0.343) and D/Es (N =118, P<.0001, medium effect V=0.290). • 48% of PCPS (P <.0001) and 15% of D/Es (P=.0008) improved related to risk of hypoglycemia with longer-acting basal insulin • 25% of PCPs (P<.0001) and 20% of D/Es (P=.0011) improved on selecting a regimen to minimize hypoglycemia risk • 40% of PCPs (P<.0001) and 35% of D/Es (P<.0001) improved related to differences in basal versus longer-acting basal insulin • 27% of PCPs and 15% of D/Es reported increased confidence in prescribing basal insulins for patients with T2D. This study demonstrates the success of CME online activity on improving clinical knowledge and confidence of PCPs and D/Es related to evidence-based use of basal insulin for T2D. PCPs especially would benefit from further education on differences between traditional and newer, longer-acting basal insulins.

Disclosure

A. Larkin: None. C.S. Healy: None. A. Le: None.

Funding

Novo Nordisk
2258-PUB: Online CME Improves Clinical Knowledge and Confidence Related to Use of GLP-1 Receptor Agonists in Combination with Basal Insulin
Authors: LARKIN AMY , LACOUTURE MICHAEL , LE ANNE
Published: June 2019

Introduction: We sought to assess baseline knowledge related to GLP-1 receptor agonist (GLP-1RA) use in combination with basal insulin and determine if an online, video-based, continuing medical education (CME) activity could improve the clinical knowledge of primary care physicians (PCPs) and diabetologists/endocrinologists (D/Es).

Methods: A 3-question knowledge and 1-question confidence linked pre-/post-assessment study design with McNemar’s chi-squared test (5% significance level, P <.05) and Cramer’s V (<0.05 no effect; 0.06-0.15 noticeable effect; 0.16-0.30 considerable effect; >0.30 significant effect) assessed educational impact. The activity launched August 23, 2018, and data collected through September 19, 2018.

Results: Overall improvements were seen after participation in the CME activity for both PCPs (n = 254, P<.0001, noticeable effect of V= 0.115) and D/Es (n = 95, P=.0284, noticeable effect of V= 0.091). Improvements include: 11% more PCPs (P=.013) and 5% more D/Es (P=.3597) accurately identified the profound effect of combining a GLP-1RA with basal insulin; 9% more of PCPs (P=.0327) and 14% more D/Es (P=.0311) correctly identified the effect of adding exenatide once weekly to insulin glargine in patients with T2D failing basal insulin; 14% more of PCPs (P=0.0016) and 3% more of D/Es (P=.545) accurately identified which combination of therapy resulted in significantly greater reductions in HbA1c, blood glucose (fasting and postprandial), weight, and systolic blood pressure; 28% of D/Es and 41% of PCPs reported increased confidence in recommending a GLP-1RA or SGLT2 inhibitor for a patient failing basal insulin.

Conclusion: This study demonstrates the success of online, video-based CME on improving clinical knowledge and confidence of PCPs and D/Es related to using GLP-1RA in combination with basal insulin.

Disclosure

A. Larkin: None. M. LaCouture: None. A. Le: None.

Funding

AstraZeneca
226-LB: HOMA-ß and ß-Cell Activity in Early and Late Phase during an OGTT Are Independent Risk Factors of Type 2 Diabetes in Japanese Americans
Authors: SHIMOJO TAKU , IZUMI CHIHAYA , SATO KYOKO K. , LEONETTI DONNA L. , KAHN STEVEN E. , FUJIMOTO WILFRED Y. , BOYKO EDWARD J. , HAYASHI TOMOSHIGE
Published: June 2019

The β-cell plays a major role in type 2 diabetes (T2DM). HOMA-β reflects fasting β-cell activity. Insulin responses during an OGTT reflect β-cell activity during glucose loading, which has two phases, early and late. HOMA-β, early, and late β-cell activity have different pathophysiologies. However, no research has examined whether HOMA-β and early and late phase β-cell activity during an OGTT are independently associated with the risk of T2DM. In a prospective cohort study, 415 nondiabetic Japanese-American men and women were followed for 10-11 years. β-cell activity was assessed by HOMA-β [fasting insulin × 360/(fasting glucose − 63)] as fasting activity, the insulinogenic index (IGI) [?insulin (30-0 min)/?glucose (30-0 min)] during an OGTT as early phase activity, and (area under the curve (AUC) of insulin 60-120 min)/(AUC glucose 60-120 min) as late phase activity. Insulin sensitivity was estimated by Matsuda index [10000/square root of ((fasting glucose) × (fasting insulin) × (AUC glucose 0-120 min/120) × (AUC insulin 0-120 min/120))]. T2DM was diagnosed as fasting plasma glucose level ≥126 mg/dL, 2-hour glucose level ≥200 mg/dL, or taking glucose-lowering medications. During the 10-11 year follow-up, 95 cases of T2DM occurred. HOMA-β, IGI, and late phase β-cell activity were all independently associated with the risk of T2DM. Multiple-adjusted odds ratios of T2DM for tertile 1, 2, and 3 of HOMA-β were 1.00 (reference), 0.25 (95% CI, 0.11-0.57), and 0.14 (0.05-0.37), respectively; those of IGI were 1.00, 0.35 (0.17-0.75), and 0.19 (0.07-0.47), respectively; and those of late phase β-cell activity were 1.00, 0.34 (0.14-0.82), and 0.16 (0.05-0.53), respectively, in the model that included HOMA-β, IGI, late phase β-cell activity, Matsuda index, age, BMI, sex, and family history of T2DM.

In conclusion, higher β-cell activity while fasting and in both the early and late phase during an OGTT were all independently associated with a lower risk of T2DM.

Disclosure

T. Shimojo: None. C. Izumi: None. K.K. Sato: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. W.Y. Fujimoto: None. E.J. Boyko: None. T. Hayashi: None.
2281-PUB: Family Impact Module in NYC: Diabetes vs. Community Sample
Authors: ILKOWITZ JENIECE , ZELENIUCH-JACQUOTTE ANNE , LOIS BECKY , PREZIOSO PAULA J. , GALLAGHER MARY PAT
Published: June 2019

Introduction: We previously reported parents of a child with diabetes (CWD) score poorly on the Pediatric Quality of Life (QoL) Family Impact Module (FIM). Use of the FIM in parents of a CWD is limited and comparison to a control group in or similar to NYC has not been explored. The objective of this study is to compare FIM scores between a PCP office and a diabetes center in NYC.

Method: Parents of children at a diabetes and PCP office in NYC completed the FIM and Holmes and Rahe Stress Scale (HRSS) to assess stressful events.

Results: Parents of 66 CWD (47% Male) and 97 of a child without (45% Male) (controls) enrolled. Compared to controls, CWD were older (median 13.7 vs. 8.3 years; p<0.0001), included more white subjects (86 vs. 63%; p<0.0001) and scored higher on HRSS (median 128.5 vs. 68; p<0.001). Adjusting for age, sex, race, and HRSS, difference in total FIM scores between groups was statistically significant (p=0.002) with higher impact on the CWD group. Statistically significant differences were found in total Parent Health Related QoL (PHRQoL) (p=0.003), physical function (p=0.0009), cognitive function (p<0.0001), communication (p=0.0003), worry (p<0.0001), and daily activity (p=0.04). None were found in total Family Function, emotional or social function, and family relations.

Conclusion: Results show NYC parents of a CWD have higher levels of family impact compared to a community sample. They have worse PHRQoL stress, worry, cognitive and physical function, communication, and daily activity. It is unknown why there is no difference between the groups in all subscales. Previously we reported having a CWD has impact on, communication if CWD is male, worry if multiple CWD, and cognitive function if additional illness. HbA1c, age, and disease duration were not predictors. It should be noted, families from a diabetes clinic are given support which may buffer stress and being in NYC may increase stress regardless. Future study must recruit a larger sample, create normative data, and explore other illnesses.

Disclosure

J. Ilkowitz: None. A. Zeleniuch-Jacquotte: None. B. Lois: None. P.J. Prezioso: None. M. Gallagher: Consultant; Self; Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc.
229-OR: GLP-1 Infusions during Postprandial Insulin Clamps Enhance Muscle Microvascular Flow, Glucose Uptake, and Protein Anabolism in Older Men
Authors: ABDULLA HAITHAM , PHILLIPS BETHAN E. , LIMB MARIE C. , WILKINSON DANIEL J. , JANDOVA TEREZA , CEGIELSKI JESSICA , BASS JOSEPH J. , RANKIN DEBBIE , LEWIS JONATHAN S. , WILLIAMS JOHN , SMITH KEN , IDRIS ISKANDAR RAUF , ATHERTON PHILIP J.
Published: June 2019

Introduction: Ageing skeletal muscle becomes insulin resistant and atrophic. This is largely due to a failure in sequestering of amino acids and glucose from dietary intake into muscle protein and glycogen. GLP-1 possesses pleiotropic multi-organ properties and its receptor is expressed and exert effects in muscle tissue(s) e.g., endothelium. We hypothesized GLP-1 infusion would enhance muscle glucose uptake and bolster the trophic effects of an anabolic stimulus i.e., feeding.

Methods: Eight men (71±1y) were studied in a cross-over trial. Basal measures were taken (first 3 h) prior to insulin (i.e., postprandial (fed-state)) and glucose (euglycaemic) clamps. Participants received I.V co-infusions of octreotide, Vamin 14-EF ±GLP-1. Four muscle biopsies were taken at 90-120 min intervals. Muscle protein turnover was quantified via A-V balance and direct incorporation of 13C6 phenylalanine via mass spectrometric techniques. GLP-1 and insulin were measured using Milliplex Map, ELISA kits. Muscle microvascular blood flow (MBF) was assessed via contrast enhanced ultrasound. Glucose handling was assayed by infusion rates and leg A-V balance.

Results: GLP-1 (vs. -GLP-1 condition) augmented muscle protein synthesis (basal: 0.058±0.004%.h-1 vs. fed: 0.102±0.005%.h-1, p<0.01), net protein balance (p<0.0001 and p=0.03 vs. basal at 1.5h and 3h postprandial, respectively) and MBF (5±2 vs. 1.9±0.7 fold-change from basal respectively, p<0.01) - while increasing whole-body glucose uptake (AUC 17.0±1.7 vs. 11.4±1.8 mg.kg-1.180 min-1, p=0.02 with and without GLP, respectively). Muscle protein breakdown was equally suppressed with and without GLP-1. Leg glucose uptake was unchanged by GLP-1.

Conclusions: The beneficial effects of GLP-1 upon whole-body glycaemic control are seemingly independent of muscle under fed-conditions. The pro-anabolic effect of GLP-1 in ageing is striking and requires further clinical and mechanistic research.

Disclosure

H. Abdulla: None. B.E. Phillips: None. M.C. Limb: None. D.J. Wilkinson: None. T. Jandova: None. J. Cegielski: None. J.J. Bass: None. D. Rankin: None. J.S. Lewis: None. J. Williams: None. K. Smith: None. I.R. Idris: None. P.J. Atherton: None.

Funding

Medical Research Council UK; Arthritis Research UK
2295-PUB: Novel Use of Continuous Glucose Monitoring in Transitioning a Patient with Suspected Monogenic Diabetes from Insulin to Oral Antidiabetic Agent
Authors: NAJERA OMAR , WISSE BRENT E. , TRENCE DACE
Published: June 2019

37-year-old Hispanic female with diagnosis of T1DM at age 18, uncontrolled on MDI with complications of mild non-proliferative diabetic retinopathy and CKD V presented giving additional history of a son just diagnosed with MODY 3. Multiple other family members were reported as having diabetes- diagnosed as both type 1 and type 2. Patient’s GAD 65 antibodies previously checked were negative. A sulfonylurea challenge test was performed. Baseline labs obtained included insulin 18.7 u(IU)/dL, C-peptide 1.9 ng/dL, glucose of 98 ml/dL. Patient was then advised to hold her morning insulin doses. One and a half hours after receiving glipizide and ingesting a meal, insulin level was 18.7 u(IU)/dL, C-peptide 10.3 ng/dL, glucose 141 ml/dL. MODY 3 was strongly suspected and decision made to transition from insulin to sulfonylurea. Given her advanced renal disease, there was significant concern with the potential of hypoglycemia despite cautious initiation of low dose glipizide. A continuous glucose monitoring system- the Freestyle Libre- was procured to allow for the close monitoring of glucose trends, to both guide ability to reduce insulin doses, as well as to judge sulfonylurea dosing in the setting of significant renal disease. The patient was able to decrease insulin doses and transition to sulfonylurea without hypoglycemia. MODY 3 is a form of monogoneic diabetes, and is a rare form of diabetes that should be suspected in patients diagnosed with diabetes mellitus in their early years along with a strong family history and negative GAD65 antibodies. Although not traditionally described in Hispanic populations, MODY3 has been reported in various minority populations. Continuous glucose monitoring should be considered in MODY 3, to aid in the safety of transitioning patients from multiple dose insulin regimens to sulfonylurea therapy, especially in the setting of severe renal disease.

Disclosure

O. Najera: None. B.E. Wisse: None. D. Trence: Stock/Shareholder; Self; Medtronic, Sanofi-Aventis.