bluuebunny/crossref_metadata_2025 huggingface dataset:
346-OR: In Young People with T1D, Additional Mealtime Insulin Produces a Dose-Dependent Improvement in Glycemia after a High-Fat, High-Protein Meal
Authors: SMITH TENELE A. , SMART CARMEL E. , FUERY MICHELLE E. , KNIGHT BRIGID , HOWLEY PETER , KING BRUCE R.
Published: June 2020

Background: To manage hyperglycemia following high fat and protein (HFHP) meals, T1D guidelines recommend additional mealtime insulin. However, guidance regarding dosing adjustments for HFHP meals is unclear.

Aim: To determine the amount of additional insulin required for a HFHP meal to optimise 6 h postprandial glucose, in young people with T1D using insulin pumps.

Method: This was a 4x4 crossover trial conducted at 2 centers in Australia. On 4 days, participants (n=27) with mean age 14.5 ± 3.6 yrs and HbA1c 53 mmol/mol (7.0 ± 0.7%) ate a HFHP meal [carbohydrate (CHO) 30g, fat 40g, protein 50g]. Insulin based on the CHO: insulin ratio (CIR) was given in random order: 100% (control), 120%, 140%, 160% CIR. Postprandial sensor glucose was measured for 6 h.

Results: Compared to 100% CIR, 140% and 160% CIR resulted in significantly lower mean glucose excursions from 90- 360 min (p≤ 0.018) and mean peak glucose excursions (4.0 and 2.7 v 6.0 mmol/L, p< 0.001). Hypoglycemia for 100%- 160% CIR was 7.7%, 7.7%, 12.0% and 19.2% respectively (p≥ 0.139). With increasing insulin there was a dose-dependent reduction in mean glucose excursions from 60- 360 min (p< 0.01).

Conclusions: Incremental addition of mealtime insulin for fat and protein produces a dose- dependent improvement in postprandial glycemia. For HFHP meals, 140% CIR is advised with titration based on individual glucose response.

Disclosure

T.A. Smith: None. C.E. Smart: None. M.E. Fuery: None. B. Knight: None. P. Howley: None. B.R. King: Other Relationship; Self; Menarini Group.

Funding

Australasian Paediatric Endocrine Group
362-OR: The Biological Variability of the BETA-2 Score in Islet Transplant Recipients
Authors: MILLOTT ROBYN , ORAM RICHARD A. , FORBES SHAREEN , SHAPIRO A.M. JAMES , SENIOR PETER A. , LAM ANNA
Published: June 2020

Background: The BETA-2 score is a validated composite measure of beta cell function in islet transplantation. It is calculated from a fasting sample and lends itself to regular monitoring of islet graft function. To determine whether changes in the BETA-2 score are significant, it is important to understand inherent variability of the score. The aim of this study was to characterize the biological variability (coefficient of variation (CV)) of the BETA-2 score and to define the critical difference (CD) for the score which is the percentage change in score that reflects a significant change in islet function.

Methods: Islet transplant recipients with stable graft function were included in this retrospective study. BETA-2 score was calculated weekly over 8 consecutive weeks and the CV was calculated based on the root mean square method. The CD at the 95% confidence limit was calculated as follows: CD = 2.8 x CV.

Results: 21 transplant recipients were included of whom 6 were insulin dependent and 15 were insulin independent. These patients also varied in terms of kidney function: 10 subjects with eGFR ≥ 60 (76 ± 14 ml/min/1.73 m2) and 11 subjects with eGFR < 60 (44 ± 10 ml/min/1.73 m2). The CV for all patients was 9.3%, 95% CI [8.7, 10.0]. The CV was similar between insulin independent and insulin dependent subjects (9.0%, 95% CI [8.1, 9.9] vs. 10.2, 95% CI [9.3, 11.1], p=0.5), as well as between subjects with eGFR > 60 vs. eGFR < 60 (8.9%, 95% [8.1,9.8] vs. 9.7%, 95% CI [8.7,10.7], p=0.6). The critical difference for the BETA-2 score was 26.2% for all subjects, 25.1% for insulin independent subjects, 28.5% for insulin dependent subjects, 24.9% for those with eGFR>60, and 27.9% for those with GFR <60.

Conclusions: The biological variability of the BETA-2 score appears stable across various clinical scenarios and a minimum difference of 26% between scores appears to constitute a significant change in BETA-2 score. Further analysis including more subjects and a greater range of kidney function is warranted.

Disclosure

R. Millott: None. R.A. Oram: None. S. Forbes: None. A. Shapiro: Consultant; Self; Viacyte, Inc. P.A. Senior: None. A. Lam: None.
38-LB: One- to Six-Month Outcomes Forecasts for Diabetes and Related Conditions
Authors: WEXLER YDO , GOLDNER DAN , MERCHANT GINA , HIRSCH ASHLEY , HUDDLESTON BRIAN , DACHIS JEFF
Published: June 2020

Background: Treatment goals for diabetes and related conditions including hypertension and prediabetes are defined as reductions in health metrics: blood glucose concentration (BG), blood pressure (BP) and weight. Accurately predicting these metrics enables the delivery of timely treatment and lifestyle recommendations, leading to improved outcomes. We used health and self-care data collected in the One Drop app to forecast changes in BG, BP and weight, one to six months in advance.

Method: Data from a sample of over 50,000 app users were used to train a suite of patent-pending supervised learning models, each for a different health metric (weight, BP or BG) and time horizon (1-2, 2-3, 3-4, or 4-6 months). People in the sample were not enrolled in One Drop programs focused on reducing weight or blood pressure. Data collected prior to 2019 were used for training; data from January 2019 through February 2020 were used for testing. Prediction root mean square error (RMSE) was compared to the RMSE that would result from assuming persistence (no change from current values). For each health metric, population subsets were identified, based on information available at prediction time, for whom predictions were more accurate.

Results: The test set comprised over 200,000 predictions. Error reduction relative to persistence varied by metric, forecast horizon, and subset. For weight, persistence RMSE ranged from 2.2-5.4 kg; predictions reduced RMSE by 6.0-9.3%. For 30-day average systolic BP, persistence RMSE ranged from 11.3-16.1 mm Hg; predictions reduced RMSE by 14.2-20.0%. For 30-day average BG, persistence RMSE ranged from 19.4 to 58.8 mg/dL; predictions reduced RMSE by 12.6-40.5%.

Conclusion: Machine learning models based on app-collected health and self-care data can predict changes in BG, BP and weight up to six months in advance. These predictions can contribute to prioritizing interventions and guiding self-care, potentially improving outcomes.

Disclosure

Y. Wexler: Employee; Self; One Drop. D. Goldner: Employee; Self; One Drop. G. Merchant: Employee; Self; One Drop. A. Hirsch: Employee; Self; Informed Data Systems Inc. B. Huddleston: Employee; Self; One Drop. Stock/Shareholder; Self; One Drop. J. Dachis: Board Member; Self; One Drop. Employee; Self; One Drop. Stock/Shareholder; Self; One Drop.
395-P: N-hydroxyethyl-1-deoxynojirimycin (Miglitol) Restores the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Diabetic Rats
Authors: DONOVAN CASEY , JOKIAHO ANNE J.
Published: June 2020

Antecedent hypoglycemia leads to a reduction in the sympathoadrenal response during subsequent hypoglycemia, i.e., HAAF. We’ve shown previously that this can be corrected in nondiabetic rats by portal vein infusion of N-hydroxyethyl-1-deoxynojirimycin (NEOH-DNJ; miglitol). In the current study we examined the efficacy of portal vein NEOH-DNJ infusion in restoring the sympathoadrenal response for diabetic animals.

Diabetes was induced in rats via streptozotocin (STZ) injection (65mg/kg) 4 weeks prior to experiments. Conscious, unrestrained STZ-diabetic rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days with a glycemic nadir of 2.6 ± 0.04 mM. On Day 2 animals received portal vein miglitol infusions (1.45 μmol/kg/min) either upstream, (PORups) or liver adjacent (PORadj), while hypoglycemic controls (HYPO) received normal saline infusion. Serial plasma samples were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE).

On Day1 peak epinephrine (22.7 ± 2.1 nM) and norepinephrine (2.92 ± 0.3 nM) values were not significantly different between HYPO, PORups and PORadj (P>0.38). On Day 2, EPI values for untreated HYPO controls were suppressed by 85% relative to Day 1 (P < 0.0001). In contrast, EPI responses for miglitol infused groups, PORups (21.3 ± 2.2 nM) and PORadj (16.1 ± 2.01 nM) were not significantly different from Day 1 values (P = 0.75 and 0.50, respectively). NE demonstrated similar responses with HYPO suppressed by 63% on Day 2 (P<0.05), while miglitol treated groups, PORups and PORadj, demonstrated Day 2 NE values not significantly different from Day 1 (P>0.85).

Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia is restored in STZ-diabetic rats by miglitol (NEOH-DNJ) treatment during subsequent hypoglycemia. As with nondiabetic rats, STZ-diabetic animals demonstrated no differences between portal miglitol infusion sites.

Disclosure

C. Donovan: None. A.J. Jokiaho: None.

Funding

JDRF (3-SRA-2017-486-S-B)
402-P: Comparison of the Effects of Sodium–Glucose Cotransporter 2 Inhibitor and Thiazolidinedione Treatment on Risk of Stroke among Patients with Type 2 Diabetes
Authors: LEE SEUNG EUN , NAM HYEWON , CHOI HAN SEOK , KIM KYOUNG-AH
Published: June 2020

Background: Influential guidelines recommend using SGLT2i preferentially among antidiabetic drugs in patients with diabetes and ASCVD. Although CVOTs with SGLT2i showed reduction in risk of 3-point major adverse cardiovascular events (MACE), they did not demonstrate beneficial effect on stroke. In addition, a meta-analysis reported adverse effect of SGLT2i for stroke. On the contrary, pioglitazone, a type of TZD, demonstrated the effect in secondary stroke prevention from two large RCTs. The aim of this study was to compare the effect of SGLT2i and TZD on the risk of stroke among patients with type 2 diabetes.

Methods: Using the Korean National Health Insurance Service data, we compared a 1:1 propensity score-matched cohort of patients who were new users of SGLT2i (n = 82,044) and TZD (n = 82,044) from January 2014 to December 2018. The primary outcome was stroke. The secondary outcomes were MI, CV death, and 3-point MACE.

Results: The incidence rates of stroke were 5.2 and 5.3 per 1000 person-years in SGLT2i-treated patients and TZD-treated patients, respectively. The hazard ratio of stroke was 0.955 (95% CI: 0.841-1.084) in SGLT2i-treated patients compared with TZD-treated patients. There was no clear difference in risk of MI (HR: 1.151, 95% CI: 0.914-1.449), CV death (HR: 0.865, 95% CI: 0.660-1.132), 3-point mace (HR: 0.988, 95% CI: 0.894-1.092) between two groups. Results were consistent regardless of prior CV disease.

Conclusions: In this real-world data, the risk of stroke was comparable in patients with type 2 diabetes treated with TZD vs. SGLT2i.

Disclosure

S. Lee: None. H. Nam: None. H. Choi: None. K. Kim: None.
425-P: Mechanisms Regulating VEGF Receptors in Diabetic Angiogenesis
Authors: BHATTACHARJEE SUDARSHAN , WU HAO , XU JIAN , CHEN HONG
Published: June 2020

Diabetes-related vascular complications underlie a number of life-threatening conditions including cardiovascular disease, stroke, and peripheral limb ulcerations, the latter of which can lead to severe infections and a multitude of serious medical issues. Our goal is to understand how chronic hyperglycemia impairs endothelial cell function to identify molecular targets that would form the basis for new therapies to treat the peripheral vascular complications associated with diabetes. Since VEGFRs are critical regulators of both angiogenesis and lymphangiogenesis, we and others have shown that VEGFRs 2 and 3 were significantly reduced in the endothelium of diabetic patients and animals. We demonstrated that loss of the endocytic adaptor proteins epsin 1 and 2 in lymphatic endothelial cells (LECs) prevents VEGFR3 endocytosis and degradation, leading to enhanced lymphangiogenesis in vivo and cell proliferation, migration, and tube formation in vitro. Mechanistically, reactive oxygen species produced in diabetes induced c-Src–dependent VEGFR3 phosphorylation and degradation, and upregulated epsins through the AP-1 transcription factor. Epsins bind to and promote the degradation of newly-synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Here, we show that diabetic conditions induce expression of the autophagosome-specific gene Ulk1, which promotes VEGFR2/3 degradation. Hence, Ulk1 deficiency inhibits autophagosome formation and enhances angiogenic responses under diabetic conditions through upregulation of multiple endothelial-specific pathways that support neovascularization. Loss of endothelial Ulk1 elevated VEGFR2/3 levels and enhanced in vitro angiogenesis as measured by endothelial proliferation, migration, and tube formation and augmented wound healing in diabetes. Collectively, our results show that inhibition of epsins and Ulk1 in diabetes can restore angiogenic and lymphangiogenic responses and provide therapeutic targets.

Disclosure

S. Bhattacharjee: None. H. Wu: None. J. Xu: None. H. Chen: None.

Funding

National Institutes of Health (R01HAO130845)
426-P: Serum Cholesterol Earlier vs. Later in Life as a Predictor of CAD and Cardiovascular Mortality
Authors: LEIHERER ANDREAS , ULMER HANNO , MUENDLEIN AXEL , SAELY CHRISTOPH H. , VONBANK ALEXANDER , FRAUNBERGER PETER , FOEGER BERNHARD , BROZEK WOLFGANG , NAGEL GABRIELE , DREXEL HEINZ , CONCIN HANS
Published: June 2020

We here aim at comparing the value of total cholesterol (TC) earlier versus later in life to predict CAD and cardiovascular mortality. In a cardiovascular observation study (CVOS) we performed coronary angiography and prospectively recorded cardiovascular events over up to 19 years in 1090 patients, of whom 288 had T2DM at baseline. These patients had participated in a health survey 15 years prior to the CVOS baseline. TC was measured both at the health survey and at the baseline of the CVOS. Patients in the highest versus the lowest TC ESC/EAS SCORE category at the health survey had an OR of 6.18 [3.35-11.38]; p=0.001) for significant CAD at angiography and a HR of 9.50 [1.30-69.19]; p=0.026) for cardiovascular death after multivariate adjustment including T2DM. In contrast, TC as measured at the baseline of the CVOS was neither significantly associated with CAD nor with cardiovascular death during follow-up. ESC-SCORES were more powerful in predicting cardiovascular death when using earlier instead of recent TC (Figure), with a net reclassification improvement of 0.250, p=0.02.We conclude that TC assessed earlier in life independently of the presence of T2DM is a better predictor of CAD and of cardiovascular mortality than TC assessed later in life.

Disclosure

A. Leiherer: None. H. Ulmer: None. A. Muendlein: None. C.H. Saely: None. A. Vonbank: None. P. Fraunberger: None. B. Foeger: None. W. Brozek: None. G. Nagel: None. H. Drexel: None. H. Concin: None.
43-LB: Glycemic Control Affects Heart-Rate Variability in Adults with Type 1 Diabetes
Authors: PARK MINSUN , CHU MINSEUNG , SONG YOUNGKWAN , SEVIL MERT , CINAR ALI , QUINN LAURIE T. , BRONAS ULF G.
Published: June 2020

People with type 1 diabetes (T1D) have an increased risk for autonomic dysfunction and those with poorly controlled blood glucose levels have an increased risk for cardiovascular disease. The purpose of this study was to determine heart rate variability (HRV) and glucose variability (GV) parameters in less than optimally controlled patients (Group 2: A1C ≥ 7.0%, n = 6]) compared to well-controlled patients (Group 1: A1C ≤ 6.9% [n = 7]) during steady state treadmill exercise took and rest.

Methods: Thirteen T1D participants, (32.42 ± 10.46 years), performed steady state treadmill exercise (40% VO2Peak) for 30 minutes. Prior to exercise, participants rested for 30-minutes for determination of resting HRV and GV. Participants wore continuous glucose monitors and a Zephyr Bioharness™ to determine GV and HRV, respectively. Nonparametric, paired samples T-tests were conducted using SPSS 24.

Results: In group 2, there were significant differences between the resting period and treadmill exercise in the (1) root mean score of successive differences (RMSSD) (27.71 ± 13.43 vs. 8.01 ± 3.90; z = -2.201, respectively; p <.05); (2) standard deviation of RR intervals (SDNN) (36.54 ± 16.04 vs. 11.68 ± 6.19; z = -2.201, respectively; p <.05); and (3) the stress index (11.17 ± 5.48 vs. 23.07 ± 6.31; z = -2.201, respectively; p <.05). However, during treadmill exercise, there were no significant differences in GV, compared to a resting period. In group 1, there were no significant differences in HRV, during treadmill exercise compared to the resting period. However, there were significant differences in GV (.26 ± .18 vs. .54 ± .38; z = -2.197, respectively; p <.05)., between resting and exercise period.

Conclusion: This study suggests that during steady state aerobic exercise, people with poorer glucose control exhibit a pattern of metabolic inflexibility; however, HRV decreased with steady state exercise in both groups suggesting that exercise training may help to normalize HRV in patients with poorly controlled glucose levels.

Disclosure

M. Park: None. M. Chu: None. Y. Song: None. M. Sevil: None. A. Cinar: Research Support; Self; Dexcom, Inc., JDRF. Stock/Shareholder; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Tandem Diabetes Care. L.T. Quinn: None. U.G. Bronas: None.

Funding

JDRF
44-LB: Training Load and Time-in-Range Affect Sleep Time of Professional Cyclists with Type 1 Diabetes
Authors: SCOTT SAM N. , FONTANA FEDERICO Y. , MARTINEZ-GONZALEZ BORJA , HAYES CHARLOTTE A. , LAGROU PETER H. , MARCORA SAMUELE , ZUEGER THOMAS , STETTLER CHRISTOPH
Published: June 2020

Background and Aims: People with type 1 diabetes (T1D) experience higher rates of sleep disturbances than those without diabetes, and this can have negative implications for glycemic control. Sleep is critical for optimal athletic performance and recovery so it is important to have an understanding of factors that can influence sleep in athletes with T1D. This study investigated whether there is a relationship between i) daily training load and ii) time in glycemic ranges on sleep time of professional cyclists with T1D.

Methods: Sixteen professional cyclists from Team Novo Nordisk (age 27 ± 4 y; HbA1c 6.8 ± 0.5%) used a wrist-worn actigraph device (Actiwatch Spectrum Plus, Philips Respironics, Murrysville, PA) to monitor sleep-wake activity over a 10-day training camp. Training variables (distance (km), elevation (m), work (kJ)) were used to determine a training stress score (TSS) for each day of the camp and glycemia was recorded using Dexcom, G6 (San Diego, CA). Summary statistics and correlations were run over the measured variables.

Results: On average, riders spent 8.6 ± 1 h in bed with a total sleep time of 7 ± 1.3 h (6.0 ÷ 7.8). The riders cycled 115 ± 26 km with 1849 ± 1086 m of elevation gain per day, corresponding to a mean TSS of 221 ± 142. Total sleep time was negatively associated with TSS (-0.29, p=0.01). Greater time in range (4-10 mmol/l) was positively associated with sleep time (r=0.21, p=0.03), with hyperglycemia, particularly level 2 (>14 mmol/l), being negatively associated with sleep time (-0.21, p=0.03).

Conclusions: We provide preliminary evidence that a greater TSS is negatively associated with total sleep time in professional athletes with T1D. Second, greater time spent in euglycemia is associated with greater sleep time, with time above target having a negative association with sleep. Further data should be collected longitudinally to strengthen these results to serve as a basis to promote better sleep hygiene practices to overcome the effects of higher training loads.

Disclosure

S.N. Scott: None. F.Y. Fontana: None. B. Martinez-Gonzalez: None. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. P.H. Lagrou: None. S. Marcora: None. T. Zueger: None. C. Stettler: None.
442-P: Comparative Study of the Effects of GLP-1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms
Authors: EID ELSAYED A. , HUSSEIN ABDELAZIZ , LASHIN LASHIN , TAHA MEDHAT
Published: June 2020

Objectives: In the present study we investigated the possible cardioprotective effects of GLP-1 and SGLTi against diabetic cardiomyopathy (DCM) in type 2 diabetic rats and the mechanisms underlying these effects.

Methods: 32- male Sprague Dawley rats were randomly subdivided into 4 equal groups; a) control group, b) DM group, type 2 diabetic rats received 2ml oral saline daily for 4 weeks, c) DM+ GLP-1, type 2 diabetic rats were treated with GLP-1 analogue (liraglutide) at a dose of 75 µg/kg via S.C. injection for 4 weeks and d) DM+ SGLTi: type 2 diabetic rats received SGLT2 inhibitor (dapagliflozin) at a dose of 1mg/kg via oral gastric gavage. By the end of treatment (4 weeks), serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB) were measured. Also, the cardiac histopathology, myocardial oxidative stress markers (MDA, GSH and CAT) and norepinephrine (NE), myocardial fibrosis, the expression of caspase-3, TGF-β, TNF-α and tyrosine hydroxylase (TH) in myocardial tissues were measured.

Results: T2DM caused significant increase in serum glucose, HOMA-IR index, serum CK-MB and LDH (p< 0.05). This was associated with significant myocardial damage and fibrosis, elevation of myocardial MDA, NE with upregulation of myocardial caspase-3, TNF-α, TGF-β and TH and significant decrease in serum insulin and myocardial GSH and CAT (p<0.05). Administration of either GLP-1 analog or SGLTi caused in significant improvement in all studied parameters (p< 0.05).

Conclusions: GLP-1 and SGLTi exhibited cardioprotective effects against DCM in type 2 diabetic rats. SGLTi showed more cardioprotective effect than GLP-1. The cardioprotective actions of these agents might be due to attenuation of fibrosis, oxidative stress, apoptosis (caspase-3), sympathetic nerve activity and inflammatory cytokines (TNF-α and TGF-β).

Disclosure

E.A. Eid: None. A. Hussein: None. L. Lashin: None. M. Taha: None.
446-P: Skin Autofluorescence, a Measure of Advanced Glycation End Products, and Diabetes Complications: Meta-analysis and Systematic Review
Authors: KOUIDRAT YOUSSEF
Published: June 2020

Background: Chronic accumulation of advanced glycation end products (AGEs) has been suggested as predictor of cardiovascular complications in diabetes mellitus. Tissue AGEs can be measured noninvasively and reproducibly in the skin by Skin autofluorescence (SAF), a clinical tool developed in the 2000s. This study aimed to estimate the relationship between AGEs indicated by SAF levels and the risk of micro- and macro-vascular complications based on data from observational studies.

Methods: A systematic literature search was performed using PubMed, Embase, and the Web of Science databases from their inceptions until December 2018. Two reviewers identified eligible studies that reported the measure of AGEs by SAF in patients with diabetes mellitus. Meta-analyses using random effects models were used to analyze the data.

Results: Twenty-four published studies involving 2715 patients with diabetes (1756 T2D and 959 T1D), 1673 controls with uncomplicated diabetes and 1283 healthy controls were included in the meta-analysis. Five diabetes-related microvascular complications: Nephropathy, Neuropathy, Retinopathy, Erectile dysfunction and Diabetic foot ulcer and 3 main macrovascular complications : Peripheral arterial diseases, Stroke and CVD were identified. Both, in patients with T1D or T2D, SAF levels were significantly higher compared to healthy controls with substantial heterogeneity (I2=78% in T1D and I2=91% in T2D; P<0.0001). Interestingly, patients with complicated diabetes exhibited significantly higher SAF levels compared to patients with uncomplicated diabetes: for T2D: mean difference [MD]: 0.303 AU; 95% CI: 0.237-0.369) with mild heterogeneity (I2=20%; P<0.0001). For T1D: MD: 0.385AU; 95% CI: 0.289-0.480), with moderate heterogeneity (I2=54%; P<0.0001).

Conclusions: Our findings suggest that SAF measure may play an important role as a biomarker for patients with high risk of diabetes-related vascular complications.

Disclosure

Y. Kouidrat: None.
449-P: Impact of Body Mass Index (BMI) and Waist Circumference (WC) on Coronary Artery Disease (CAD) in Japanese with and without Diabetes Mellitus (DM)
Authors: KOMATSU TAKESHI , FUJIHARA KAZUYA , YAMADA MAYUKO H. , SATO TAKAAKI , KITAZAWA MASARU , YAMAMOTO MASAHIKO , SEIDA HIROYASU , YAMANAKA NAUTA , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , SONE HIROHITO
Published: June 2020

BMI ≥25.0 and WC ≥90 are components of the International Diabetes Federation (IDF) definition of metabolic syndrome for Asians. We have investigated more suitable BMI and WC levels for risk of CAD using large-scale nationwide claims data on people with and without DM in the same cohort. The sample included 157,220 Japanese men 18-72 years of age without a known history of CAD at baseline (DM: 15,465 patients, non-DM: 141,755 patients). Multivariate Cox regression model examined the association of BMI/WC categories and their combination with CAD. During the study period (median follow-up 5.3 y), 662 and 332 CAD events occurred in non-DM and DM, respectively. Cox regression model showed that BMI ≥22.5 and WC ≥80 conferred a 1.29 (1.07-1.55), and 1.23 (1.00-1.50) times increased risk of CAD, respectively, in non-DM but that those relationships disappeared in people with DM (HR, 0.96 (0.71-1.29) for BMI and 1.13 (0.78-1.62) for WC. Stratified analysis of 4 groups of combinations of BMI and WC showed that in non-DM with BMI ≥22.5/WC ≥80 the risk of future CAD was significantly increased compared with non-DM with BMI<22.5/WC<80 (Table). Each DM group had an approximately 3-fold increase in CAD events (Table).

In summary, lower BMI and WC values can predict CAD in individuals without DM whereas their influence was modest in people with DM.

Disclosure

T. Komatsu: None. K. Fujihara: None. M.H. Yamada: None. T. Sato: None. M. Kitazawa: None. M. Yamamoto: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
452-P: Exercise-Induced Elevation of MicroRNA-181b Ameliorates Endothelial Dysfunction in Diabetic Mice
Authors: SHANG WENBIN , WANG YU , LUO JIANG-YUN , TIAN XIAO YU , WANG LI , HUANG YU
Published: June 2020

Endothelial dysfunction plays an essential role in the pathogenesis of diabetic vascular diseases. Our previous studies showed exercise improves endothelial function in diabetic mice partially through AMPK pathway. MicroRNA 181b (miR-181b) was reported to inhibit NF-κB activity in endothelial cells. However, it is still unknown whether miR-181b is regulated by AMPK signaling and involved in the vasoprotective effect of exercise. The present study investigated the expression of miR-181b in aortas from diabetic mice with/without exercise and reveals a role of the AMPK in exercise-induced miR-181b expression. We first determined the miR-181b level in the aortas of diabetic db/db mice subjected to treadmill exercise (45 min/day for eight weeks). The results showed that exercise significantly increased miR-181b level in the endothelium of mouse aorta compared to the sedentary mice. To test whether the increased blood flow during exercise affects miR-181b expression, we tested the effect of laminar flow on miR-181b expression in Human Umbilical Vein Endothelial Cells (HUVECs). Laminar flow greatly increases miR-181b expression. To understand the mechanism for flow-induced miR-181b expression, we treated HUVECs with AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and found that AICAR-induced miR-181b expression is reversed by AMPK inhibitors. Furthermore, we infected db/db mice with the adenovirus over-expressing miR-181b. MiR-181b overexpression improved endothelial function in db/db mice accompanied by decreased vascular inflammation and increased eNOS expression in mouse arteries. In summary, exercise increases miR-181b level in mouse endothelium probably via shear stress-induced AMPK activation. MiR-181b improves endothelial function in diabetic mice by inhibiting vascular inflammation and increasing eNOS expression. The present results suggest the therapeutic potential of targeting miR-181b against diabetic vasculopathy.

Disclosure

W. Shang: None. Y. Wang: None. J. Luo: None. X. Tian: None. L. Wang: None. Y. Huang: None.

Funding

Hong Kong Research Grants Council/Collaborative Research Fund (C4024-16W); Hong Kong Health and Medical Research Fund (05161746)
455-P: Pan-ErbB Inhibition Attenuates Diabetes-Induced Vascular Dysfunction in an Experimental Model of Diabetes
Authors: AKHTAR SAGHIR , CHANDRASEKHAR BINDU , BENTER IBRAHIM
Published: June 2020

The underlying mechanisms leading to diabetes-induced vascular complications are not fully understood. We have previously shown that epidermal growth factor receptor (EGFR), which is part of the four membered family of EGFR/ErbB receptor tyrosine kinases, appears to play a detrimental role. However, the role of the other ErbB family members (ErbB2, ErbB3, and ErbB4)- that regulate cell growth, proliferation, differentiation and apoptosis- is not fully known and was further evaluated in this study. In a streptozotocin-rat model of type 1 diabetes, 4-weeks of diabetes induced significant vascular dysfunction, as assessed by abnormally high vasoconstrictor responses to norepinephrine in the mesenteric vascular bed (MVB). Diabetes also led to increased phosphorylation of all ErbB receptors with subsequent increased phosphorylation of downstream ERK1/2 in the MVB. Chronic 4-week in vivo administration of a novel pan-ErbB inhibitor, generation 7 polyamidoamine dendrimer (G7PAMAM; 20mg/kg daily i.p), or the well-established pan-ErbB inhibitor, Genistein (1mg/kg i.p. alt diem) to diabetic rats led to a marked attenuation in the hyperphosphorylation of all ErbBs, ERK1/2 and to a significant correction in NE-mediated hyper-responsiveness of the diabetic MVB. Furthermore, pan-ErbB inhibitors attenuated high glucose-induced ErbBs-ERK1/2 signaling in primary vascular smooth muscle cells grown in high (25mM) glucose. These data show for the first time that pan-ErbB inhibition attenuates diabetes-induced vascular dysfunction in an experimental model of diabetes. Therefore, pan-ErbB inhibition might represent a novel strategy for the treatment of diabetes-induced vascular complications.

Disclosure

S. Akhtar: None. B. Chandrasekhar: None. I. Benter: None.

Funding

Qatar University (QUCG-CMED-19/20-3)
463-P: Deterioration of Atherosclerosis via Dysbiosis in ApoE Null Mice Fed with High-Salt Diet
Authors: KIMURA TOMONORI , HASHIMOTO YOSHITAKA , SENMARU TAKAFUMI , USHIGOME EMI , HAMAGUCHI MASAHIDE , YAMAZAKI MASAHIRO , FUKUI MICHIAKI
Published: June 2020

Recent studies reported that the impairment of gut microbiota (Dysbiosis) cause impairments of gut metabolisms, which induce chronic inflammation in the body. High salt intake not only increases blood pressure, but also causes Dysbiosis. However, the detailed mechanism has not been clarified yet. Here we investigate the mechanism of the atherosclerosis progression through dysbiosis caused by high salt diet. 16-week-old male Apolipoprotein E-deficient (ApoE-/-) mice were fed normal breeding diet (ND group), high-fat high-sucrose diet (HFHSD group), and high-fat high-sucrose high-salt diet (HFHSDNaCl8%, high salt group) for 8 weeks. The concentration of salt in ND and HFHSD is set as 2%. Immune cells in the aorta were extracted and evaluated by FACS CANTII. The metagenome was evaluated by the 16S target sequencing method. Lipidome in the aorta, serum, or intestinal contents were evaluated and quantified by GCMS system (Agilent 7890B/5977B). In high salt group, gene expression levels of inflammatory cytokines and chemokines were upregulated, and M1 macrophages and Group 2 innate lymphoid cells in atherosclerotic lesions increased. The prevalence of Firmicutes decreased and the prevalence of Bacteroidetes increased. Lipidome in the aorta, serum and intestinal contents were significantly different among the HFHSD group and high salt group, although the lipids administered were the same. High salt intake increases M1 macrophages and Group 2 innate lymphoid cells by altering intestinal bacterial lipid metabolisms, and could deteriorate chronic inflammation of arteriosclerosis.

Disclosure

T. Kimura: None. Y. Hashimoto: None. T. Senmaru: None. E. Ushigome: None. M. Hamaguchi: None. M. Yamazaki: None. M. Fukui: None.
465-P: Thrombin Induces SGLT1 and SGLT2 Expression to Promote the AT1R/NADPH Oxidase-Mediated Pro-oxidant Response Inducing Senescence in Atrial Endothelial Cells
Authors: HASAN HIRA , PARK SIN-HEE , BELCASTRO EUGENIA , AUGER CYRIL , LEE HYUN-HO , SCHINI-KERTH VALERIE
Published: June 2020

Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular (CV) disease independently of glycemic control. Although blood-derived coagulation factors are major contributors of CV diseases, their impact on the expression of SGLT1 and 2 in endothelial cells (ECs) has not been studied. This study investigated whether thrombin affects the expression of SGLT1 and 2 and examined their role in the induction of endothelial senescence.

ECs were isolated from porcine atrial tissue (AECs) and used at first passage. Endothelial senescence was assessed by determining senescence-associated beta-galactosidase (SA-beta-gal) activity, oxidative stress using dihydroethidium, and protein level by Western blot analysis and immunofluorescence staining.

Exposure of AECs to thrombin (1 or 3 U/ml) for 24 h induced an upregulation of the low protein expression level of SGLT1 and SGLT2. Thrombin induced a sustained pro-oxidant response and increased the level of SA-beta-gal activity that were both inhibited by antioxidants, an angiotensin-converting enzyme inhibitor and an AT1 receptor antagonist and also by sotagliflozin (a dual SGLT1 and SGLT2 inhibitor) and by empagliflozin (a selective SGLT2 inhibitor). In addition, thrombin upregulated the expression level of angiotensin-converting enzyme and AT1 receptors, VCAM-1 and down-regulated that of endothelial NO synthase.

In conclusion, thrombin up-regulates both SGLT1 and SGLT2 expression in AECs to sustain oxidative stress leading to endothelial senescence and dysfunction. The fact that the AT1R/NADPH oxidase/SGLT1 and 2 pathway acts in a feedforward manner suggests that inhibition of SGLT1 and/or SGLT2 appears as an attractive strategy to perpetuate the protective endothelial function on the cardiovascular system.

Disclosure

H. Hasan: None. S. Park: None. E. Belcastro: None. C. Auger: None. H. Lee: None. V. Schini-Kerth: Research Support; Self; Boehringer Ingelheim International GmbH.
47-OR: A Reference Map of the Human Proinsulin Biosynthetic Interaction Network
Authors: TRAN DUC T. , ARVAN PETER , KAUFMAN RANDAL J. , ITKIN-ANSARI PAMELA
Published: June 2020

The beta-cell protein synthetic machinery is dedicated to insulin production, and recent reports suggest misfolding of its precursor, proinsulin, is a feature of type 2 diabetes (T2D). Despite the critical role of insulin in organismal homeostasis, the precise network of interactions required for proper proinsulin folding and subsequent trafficking through the Golgi and secretory pathway, remains poorly defined. In the present study we conducted unbiased profiling of the proinsulin interactome in human islets, utilizing a human proinsulin-specific monoclonal antibody for affinity purification and mass spectrometry. Stringent analysis identified a central node of interactions between human proinsulin and sequential secretory pathway proteins that is remarkably conserved across both genders and 3 ethnicities. Among the most prominent proinsulin interactions was with the ER localized oxidoreductase peroxiredoxin-4 (PRDX4). A functional role for PRDX4 was demonstrated by knockdown studies in MIN6 beta-cells that rendered proinsulin susceptible to misfolding, particularly in response to oxidative stress. Conversely, exogenous PRDX4 improved proinsulin folding. Notably, oxidative stress and even high glucose treatment alone induced proinsulin misfolding in human islets and MIN6 cells and this was accompanied by sulfonylation of PRDX4, a modification known to inactivate peroxiredoxins. This finding prompted PRDX4 analysis in a panel of human islet samples that revealed significantly higher levels of sulfonylated (inactive) PRDX4 in islets from patients with T2D compared to that of healthy individuals. Taken together, these data provide a detailed reference map of the human proinsulin interaction network and suggest critical unrecognized areas for study in insulin biosynthesis, beta cell function, and T2D.

Disclosure

D.T. Tran: None. P. Arvan: None. R.J. Kaufman: None. P. Itkin-Ansari: None.

Funding

National Institutes of Health (R24DK110973); JDRF (2-SRA-2015-47-M-R)
480-P: Reversal of Diabetic Nephropathy in T2D db/db Mouse Model by Systemic Pyruvate Kinase M2 (PKM2) Activation
Authors: ST-LOUIS RONALD , FU JIALIN , PARK KYOUNGMIN , SHINJO TAKANORI , LUDEKE JOHANNA , YOKOMIZO HISASHI , LI QIAN , WOLFSON EMILY , KING GEORGE L.
Published: June 2020

Mitochondrial abnormalities induced by diabetes have been postulated to cause several complications including nephropathy. Elevated expressions of enzymes for glycolysis and mitochondrial functions in the glomeruli have been associated with protection against the development of diabetic nephropathy of chronic duration. Activation of a glycolytic enzyme, pyruvate kinase M2 (PKM2), by a small molecule selective activator (TEPP-46) or its targeted overexpression to the podocytes in mice reversed glomerular mitochondrial dysfunction and pathology in insulin deficient diabetic mice. However, the effects of PKM2 activation to stop glomerular dysfunction and pathology have not been studied in animal models of type 2 diabetes (T2D). Thus, we studied the effect of activating glycolysis and mitochondrial metabolism with PKM2 activator, TEPP-46, in db/db mice (with obesity and hyperglycemia) and BLKS mice on regular diet (RD) or high fat diet (HFD). HFD feeding induced obesity in BLKS but did not cause changes in glomerular PKM activities or functions as measured by urinary albumin to creatinine ratio (ACR). Oral feeding with TEPP-46 did not affect body weight (BW), glucose tolerance, lipids, ACR, glomerular pathology in BLKS mice on RD or HFD. In contrast, db/db mice on RD had elevated BW and hyperglycemia that were significantly increased by HFD, which also induced loss of glomerular PKM2 protein expression and activities, elevations of gene expression for fibrosis (fibronectin, TGF-b), mesangial expansion and ACR after 3 months. Intervention with oral TEPP-46 treatment for 3 months, but not 1 month, after 3 months of diabetes and HFD, (total of 6 months of diabetes), improved significantly both glomerular PK activities and ACR, without lowering hyperglycemia and hyperlipidemia of the db/db mice. These findings support the idea that systemic activation of PKM2 can improve renal functions in both T1D and T2D.

Disclosure

R. St-Louis: None. J. Fu: None. K. Park: None. T. Shinjo: None. J. Ludeke: None. H. Yokomizo: None. Q. Li: None. E. Wolfson: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
489-P: Energy Status Could Modulate Autophagy through Colocalizations of Fyn, P53, and Tgm2 in the Renal Tubules In Vivo
Authors: UEHARA RYOTA , YAMADA EIJIRO , NAKAJIMA YASUYO , HORIGUCHI KAZUHIKO , ISHIDA EMI , MATSUMOTO SHUNICHI , OKADA SHUICHI , BASTIE CLAIRE C. , YAMADA MASANOBU
Published: June 2020

Diabetic kidney disease (DKD) is one of the major diabetic complications, the leading cause of the end stage renal disease, and recently autophagy was shown to regulate DKD. Previously we reported Fyn functions as a muscle mass regulator by suppressing autophagy. More recently, we demonstrated that Fyn also down-regulates autophagy in HK2 cells, an in vitro cell model of renal proximal tubular epithelial cells (RPTC). Phospho-proteomic analysis revealed that Fyn phosphorylates Transglutaminase 2 (Tgm2), a known autophagic inhibitor, on Y369 and Y617. Fyn dependent phosphorylation of Tgm2 regulates autophagy. Moreover, since Tgm2 was reported to make a complex with p53 and p62, known autophagy regulator/substrate to degrade p53 in autophagosome in cancer cells we examined it in HK2 cells and found that p53 expression was decreased in Tgm2 knock-downed HK2 cells indicating that Tgm2-p62-p53 complex modulating autophagy in RPTC. Those are biochemical studies with in vitro systems, we proceeded it in vivo. Since previously we showed that Fyn could be regulated by energy status, we first examined whether energy status could change the subcellular localization of those molecules in RPTC in vivo using the marker, Aquaporin 1. Confocal microscopic studies revealed that Ad libitum fed mice showed no punctate of p62 in those cells indicating suppressing autophagy. Fyn, Tgm2 and p53 shaped the dotted form mainly in basement membrane. Interestingly, all the molecules changed their localizations into cytoplasm in fasted state where p62 punctations observed indicating increased autophagy. Taken together, these data suggest that Energy status could regulates Fyn to not only phosphorylates Tgm2 and modulates Tgm2-p62-p53 complex but also change their co-localizations of Fyn, p53 and Tgm2 in RPTC to regulate autophagy leading to pathogenesis of DKD.

Disclosure

R. Uehara: None. E. Yamada: None. Y. Nakajima: None. K. Horiguchi: None. E. Ishida: None. S. Matsumoto: None. S. Okada: None. C.C. Bastie: None. M. Yamada: None.
495-P: Risk Factors for Incident T2DM in Patients with Prediabetes by CKD Status
Authors: HENNESSEY KELLY A. , ALICIC RADICA Z. , DARATHA KENN B. , JONES CAMI , NEUMILLER JOSHUA J. , DURU O. KENRIK , NICHOLAS SUSANNE , MCPHERSON STERLING M. , NORRIS KEITH C. , TUTTLE KATHERINE R.
Published: June 2020

Longitudinal data are critical to inform prediction of transition to type 2 diabetes mellitus (T2DM) from prediabetes. This study aimed to ascertain T2DM incidence and risk factors, including chronic kidney disease (CKD), in patients with prediabetes. The CURE-CKD registry of electronic health record data includes >2.6 million patients with and at-risk for CKD (T2DM, hypertension, prediabetes).

Adults with prediabetes were identified by established criteria for % A1C, random and fasting glycemia, and administrative codes. T2DM was defined by corresponding established criteria. CKD was defined by estimated glomerular filtration rate <60 mL/min/1.73m2, urine albumin-to-creatinine ratio >30 mg/g based upon 2 or more measurements >90 days apart, and administrative codes. Cox proportional hazards regression was used to predict T2DM.

From 2006 to 2017, there were 678,493 patients with prediabetes and baseline A1C 5.9±0.3% (mean±SD). Incident T2DM occurred in 185,770 (27%) at a mean of 3.6 years. At baseline, 134,240 (20%) had CKD. Adjusted for age, gender, race/ethnicity, and hypertension, hazard ratios for T2DM were greater in patients with CKD (1.44, 95%CI [1.42, 1.47]) and with increases in 1% A1C (4.59 95%CI [4.47, 4.72]).

CKD was common in prediabetes and, along with higher A1C, demonstrated the greatest hazards for incident T2DM. Presence of CKD identifies patients with prediabetes who are high-risk for transition to T2DM.

Disclosure

K.A. Hennessey: None. R.Z. Alicic: None. K.B. Daratha: None. C. Jones: None. J.J. Neumiller: None. O. Duru: None. S. Nicholas: Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Centers for Disease Control and Prevention, George Institute for Global Health, Goldfinch Bio, Inc., National Institutes of Health. S.M. McPherson: None. K.C. Norris: None. K.R. Tuttle: Consultant; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Goldfinch Bio, Novo Nordisk Inc.
497-P: Abnormal ABI in Association with Nephropathy Is a Risk Factor for CAD in Type 2 Diabetic Patients: A Retrospective Real-World Evidence Study in Indian Population
Authors: TREHAN SIDDHANT , CHAWLA RAJEEV , JAGGI SHALINI , S ANUSHRITA , PALUKURI SRIVANI , DEKA SAURAV , MAKKAR BRIJ M.
Published: June 2020

Objective: To study the association between ankle brachial index (ABI) and microvascular complications in type 2 diabetes (T2DM) patients with coronary arterial disease (CAD).

Methodology: A retrospective study was carried on 3,468 T2DM patients who gave ABI test between 2002 and 2019. ABI status was defined as normal (1.0-1.4) and abnormal (<1.0 and >1.4). The distribution of patients was given in percentages. The logistic regression was used to study ABI status, microvascular complications and CAD risk factors (hypertension, age, BMI, smoking etc) role on CAD, and the resulted odds ratio (OR) was given with 95% CI and p-value.

Results: Patients were classified based on history of CAD, with, G1 (334), and without, G2 (3134). In G1, 69% patients were normal ABI and 31% abnormal. Across G1 and G2, neuropathy was populated with 37% (1279), nephropathy, 8% (293), hypertension, 15% (507) and hypothyroidism, 8% (270). The ABI abnormality was high in nephropathy (G1: 41%; G2: 29%) than neuropathy (G1: 34%; G2: 27%). Age wise, 60 and 70% of patients in neuropathy and nephropathy, respectively, were >60 years and shown increased ABI abnormality with age. The logistic model had revealed that patients with nephropathy, OR-1.8 [1.26-2.58], p-0.001 and abnormal ABI, OR-1.27 [95% CI, 0.99-1.63], p-0.059 were likely to have positive CAD outcome, i.e., both are associated. While neuropathy, OR-0.69, [0.54 - 0.90], and hypertension, OR-0.43 [0.33 - 0.57] were not contributing towards CAD in our study population.

Conclusion: T2DM patients with abnormal ABI were predicted to have 27% of increased odds of CAD outcome and this was increased to 80% in presence of nephropathy. Thus, following the onset of diabetes, albuminuria screening along with ABI measurement are suggested.

Disclosure

S. Trehan: None. R. Chawla: None. S. Jaggi: None. A. S: None. S. Palukuri: None. S. Deka: None. B.M. Makkar: Advisory Panel; Self; Abbott, AstraZeneca, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Eris Lifesciences, Novartis AG, Novo Nordisk Inc., Sanofi, USV Private Limited. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc.