bluuebunny/crossref_metadata_2025 huggingface dataset:
292-OR: Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets
Authors: TRAN DUC T. , LOGUERCIO SALVATORE , LEE KOUTA , POTTEKAT ANITA , BALCH WILLIAM E. , ARVAN PETER , KAUFMAN RANDAL J. , ITKIN-ANSARI PAMELA
Published: June 2021

It has become increasingly appreciated that inflammatory cytokines promote islet dysfunction in both type 1 and type 2 diabetes. Aberrant secretion of the insulin precursor proinsulin is observed in patients with both types of diabetes and may contribute to proinsulin autoimmunity in T1D, yet the mechanisms responsible for proinsulin release remain obscure. To investigate the effects of inflammation on proinsulin trafficking, human islets were treated ex vivo with the diabetes associated cytokines, Interleukin-1-beta and Interferon-gamma, provoking a four-fold release of proinsulin. To identify proinsulin interacting proteins responsible for aberrant trafficking, intracellular proinsulin was affinity purified and its interactome defined by mass spectrometry. Cytokines altered the identify or magnitude of proinsulin’s engagement with binding partners at every stage of the canonical proinsulin biosynthetic pathway that we recently defined in normal human islets. Of particular relevance to potential avenues of proinsulin escape, cytokines promoted proinsulin interactions with: 1) antigen presentation loading complex components TAP2 and calnexin 2) stress granule assembly factors G3BP1, Ataxin-2 and IGF2BP2, that are also found in secreted exosomes, and 3) the immature insulin granule marker and T1D autoantigen ICA1/ICA169. Pathway analysis further revealed that cytokine treatment increased proinsulin binding, even if indirectly, to multiple KIF family microtubule motor proteins. Given that stress granules and immature granules are sensitive to microtubule dynamics we tested the role of microtubules in cytokine induced proinsulin release. Microtubule destabilization with Nocodazole significantly increased proinsulin release above that provoked by cytokines alone. Together, the data quantitatively map the cytokine reshaped proinsulin interactome and provide new insight into how an inflammatory environment can promote proinsulin escape from human islets.

Disclosure

D. T. Tran: Employee; Self; Encodia Inc. S. Loguercio: None. K. Lee: None. A. Pottekat: None. W. E. Balch: None. P. Arvan: None. R. J. Kaufman: None. P. Itkin-ansari: None.

Funding

JDRF (2-SRA-2015-47-M-R); National Institutes of Health (R24DK110973)
300-OR: Association of Raised Lipoprotein(a) Levels with Micro- and Macrovascular Complications in Patients with Type 1 Diabetes
Authors: VAN HAARE HEIJMEIJER SOPHIE , HERMANS MICHEL P.
Published: June 2021

Background: Raised levels of lipoprotein(a) [Lp(a)] are causally associated with incident macroangiopathy and aortic valvular calcification in (non)diabetic subjects.

Objective: In type 2 diabetes (T2DM), there is an inverse, J-shaped relationship between elevated Lp(a) and prevalent microangiopathies. This work assessed whether this inverse association also exists in type 1 diabetes (T1DM).

Methods: The cardiometabolic phenotype of 357 patients with T1DM was determined, alongside routine lipids, Lp(a), non-Lp(a)-LDL-C, apolipoprotein B100, apolipoprotein A-I, and atherogenic dyslipidemia. Patients in the 1st tertile of Lp(a) ([TI]; n=119; median Lp(a) 6 nmol/L) were compared to those in the 3rd tertile of Lp(a) ([TIII]; n=119; median Lp(a) 100 nmol/L).

Results: There were no significant differences between [TI] and [TIII] patients regarding gender, diabetes duration, HbA1c, smoking, BMI, hypertension, GFR, (micro)albuminuria, cerebrovascular disease, routine lipids (total C; LDL-C; HDL-C; TG), apolipoprotein B100, apolipoprotein A-I, non-Lp(a)-LDL-C, and frequency/intensity of statin use. Compared to [TIII], [TI] patients were younger (48 vs. 53 years), had lower body fat (24 vs. 27%), and higher muscle mass (36 vs. 34%; all p<0.05). After adjusting for age, [TIII] had more overall microangiopathy (+37%; 57 vs. 45%) and diabetic retinopathy (+34%; 51 vs. 38%; 0.0441). They also had an increased prevalence of overall macroangiopathy (+211%; 19 vs. 9%; p 0.0265) and coronary artery disease (+250%; 15 vs. 6%; p 0.0238). Among [TIII] patients, 35% were in the highest CV risk category, vs. 16% of [TI] (p 0.0008).

Conclusion: In addition to the risk of macrovascular complications, a high level of Lp(a) is associated with an increased frequency of retinal microangiopathy in T1DM patients, contrary to what was observed in T2DM. On the other hand, the frequency of macroangiopathy was increased in T1DM just like in T2DM and nondiabetic patients.

Disclosure

S. Van haare heijmeijer: None. M. P. Hermans: None.
301-OR: Effect of Vitamin D Supplementation on Insulin Sensitivity and Beta-Cell Function in Prediabetes
Authors: RASOULI NEDA , BRODSKY IRWIN , CHATTERJEE RANEE , KIM SUN H. , PRATLEY RICHARD E. , STATEN MYRLENE , NELSON JASON P. , PITTAS ANASTASSIOS G. ,   D2D RESEARCH GROUP
Published: June 2021

Vitamin D is believed to regulate pathways in glucose homeostasis, but effects of vitamin D supplementation on insulin sensitivity and β-cell function in humans remain uncertain. We completed a secondary analysis of the Vitamin D and type 2 diabetes (D2d) study to investigate the effects of vitamin D supplementation on insulin sensitivity and β-cell function. Participants at high risk for type 2 diabetes, meeting at least 2-out-of-3 ADA criteria for prediabetes, were randomly assigned to 4000 IU/day of vitamin D3 or placebo. Insulin sensitivity and β-cell function were estimated using data from 75-gram oral glucose tolerance tests (OGTT). We used the University of Oxford HOMA2 Calculator to estimate insulin sensitivity from simultaneously measured fasting plasma glucose and C-peptide values. Early C-peptide and insulin responses were calculated as the ratio of C-peptide or insulin increment to glucose level changes during the first 30 minutes of the OGTT. The disposition index (DI) as an estimate of β-cell function was calculated as the product of C-peptide response and HOMA2%S. The response to vitamin D3 was evaluated in 1,774 participants over 24 months. Baseline characteristics [mean age 60.5±9.8 years, BMI 31.9±4.4 kg/m2, 56.4% male, 69.1% white, 25-hydroxyvitamin D (25-OH D) 28.2±10.2 ng/ml, HbA1c 5.9%±0.2, FPG 107.7±7.2 mg/dl, 2hrOGTT glucose 137.1±34.1 mg/dl] were similar between the vitamin D and placebo groups. Serum 25-OH D increased from 27.9±10.3 ng/ml to 54.9±14.4 ng/ml at 24 months in the vitamin D group and remained unchanged with placebo (p<0.05 between group changes from baseline). There were no significant differences in changes in HOMA2%S, C-peptide or insulin responses and DI between the two groups.

In conclusion, in this pre-specified analysis from the D2d study, supplementation with vitamin D for 24 months did not alter insulin sensitivity or β-cell function in people with prediabetes who were not selected based on their baseline vitamin D levels.

Disclosure

N. Rasouli: Consultant; Self; Novo Nordisk, Research Support; Self; Allergan plc, Lilly Diabetes, Novo Nordisk. I. Brodsky: None. R. Chatterjee: Research Support; Self; Bristol-Myers Squibb Company, Epigenomics AG, Verily Life Sciences. S. H. Kim: Advisory Panel; Self; Bayer U. S., GI Dynamics, Stock/Shareholder; Spouse/Partner; Dexcom, Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Staten: None. J. P. Nelson: None. A. G. Pittas: None. D2d research group: n/a.

Funding

American Diabetes Association (1-14-D2d-01 to A.G.P.); National Institute of Diabetes and Digestive and Kidney Diseases (U34DK091958); Office of Dietary Supplements (U01DK098245)
313-OR: Disparities in Preventive Care Utilization among Patients with Diabetes in the Diabetes Belt and Surrounding Areas
Authors: SOHN MIN-WOONG , KANG HYOJUNG , MCMURRY TIMOTHY L. , KIM SOYOUN , LOBO JENNIFER M.
Published: June 2021

Objective: Preventive care has been shown to reduce both the incidence and progression of diabetic complications. American Diabetes Association treatment guidelines recommend annual preventive care such as annual doctor visits and A1c tests. Our objective is to compare utilization rates of four annually recommended preventive services for persons with diabetes in the Diabetes Belt and those in the surrounding area.

Methods: We used 2015 Medicare claims data to identify preventive service utilization using ICD9/10 and CPT/HCPCS codes. Diabetes Belt consists of 644 counties in the Appalachian region and southeastern part of US that had diabetes prevalence over 11% in 2008 compared to ~8.5% in the rest of the country. Surrounding counties include 118 counties that are adjacent but not contiguous to the Diabetes Belt counties.

Results: Patients in the Belt had significantly lower utilization than those in surrounding counties for all four preventive services: foot exam, 81% vs. 88%; eye exam, 53% vs. 58%; microalbuminuria test, 31% vs. 34%; one or more A1c tests, 73% vs. 74%. After adjusting for age, sex, and race/ethnicity, patients in the Diabetes Belt had 38%, 18%, 16%, and 11% lower odds of using foot exams, microalbuminuria tests, eye exams, and A1c tests, respectively, compared to those in the surrounding counties (p for all comparisons < 0.001). Even after adjusting for socioeconomic, access-to-care factors, and service availability, patients in the Diabetes Belt had consistently lower rates of utilization for these four services than surrounding counties.

Conclusion: Patients with diabetes in the Diabetes Belt are doubly jeopardized for diabetic complications because of higher prevalence diabetes and lower preventive care utilization than surrounding counties. Health policy makers may want to pay more attention to the Diabetes Belt in reducing the regional differences in the utilization of these services.

Disclosure

M. Sohn: None. H. Kang: None. T. L. Mcmurry: None. S. Kim: None. J. M. Lobo: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113295)
315-OR: Trends in Racial and Ethnic Difference in Glucose-Lowering Medication (GLM) Use, Out of Pocket (OOP) Payment, and HbA1c Control in U.S. Adults with Diabetes, 2005-2018
Authors: LI PIAOPIAO , GUAN DAWEI , GUO JINGCHUAN , WINTERSTEIN ALMUT G. , ZHANG PING , SHAO HUI
Published: June 2021

Fast escalating price of insulin and introductions of high-cost new GLMs in the last decade could affect racial/ethnic groups differently. This study examined trends in GLM uses, OOP payments for GLMs, and HbA1c control by racial/ethnic group among US adults with diabetes from 2005 to 2018. Data were from the Medical Expenditure Panel Survey and the National Health and Nutrition Examination Survey. Persons with diabetes were identified by self-report or lab test. GLM uses were identified by national drug code. We compared trends in the three study outcomes among non-Hispanic White perons, non-Hispanic Black perons, and Hispanic perons. Between 2005 and 2018, the use of newer GLM (dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose transport protein 2 inhibitors) was higher in non-Hispanic White persons (0% to 24.9%) than non-Hispanic Black persons (0% to 19.9%,) or Hispanic persons (0% to 19.5%, all p<0.05). Use of insulin analogue increased from 43.4% to 87.3% in Non-Hispanic White persons, 22.3% to 78.4% in non-Hispanic Black persons and 32.8% to 77.9% in Hispanic persons. Significant falls in annual OOP payments for GLMs were seen among Hispanic perons ($350 in 2005 to $205 in 2018) and non-Hispanic Black persons ($350 to $210), but not among non-Hispanic White persons ($355 to $345). In 2005, a higher proportion of non-Hispanic White persons achieved the HbA1c goal of <7.0%, compared with Hispanic persons and non-Hispanic Black persons (68.4% vs. 47.2% vs. 52.3%, p<0.05). Non-Hispanic White persons also had a lower average HbA1c level than Hispanic persons or non-Hispanic Black persons (6.7% vs. 7.8% vs. 7.4%, p<0.05). These differences remained throughout the study period. Our findings providevidence on racial/ethnic differences in GLM and insulin usage over time and could assist decision-makers in identifying the means to reduce racial/ethnic disparities in HbA1c control.

Disclosure

P. Li: None. D. Guan: None. J. Guo: None. A. G. Winterstein: Research Support; Self; Merck Sharp & Dohme Corp. P. Zhang: None. H. Shao: Research Support; Self; Sanofi.
331-OR: Joint Exposure to Various Ambient Air Pollutants, Obesity, and Incident Type 2 Diabetes: A Prospective Study in UK Biobank
Authors: LI XIANG , WANG MENGYING , MA HAO , ZHOU TAO , HEIANZA YORIKO , QI LU
Published: June 2021

Background: Air pollution has been related to type 2 diabetes (T2D). However, little is known about the relation between long-term exposure to multiple ambient air pollutants and the risk of T2D. We aimed to prospectively assess the joint association of various air pollutants with the risk of T2D and examine the modification effect by obesity status on the relationship.

Methods: A total of 449,006 participants from UK Biobank who were free of T2D at baseline (2006-2010) were included in the current study and followed up to March 2020. Ambient air pollutants, including particulate matter (PM) with diameters ≤2.5 µm (PM2.5), between 2.5 µm and 10 µm (PM2.5-10), nitrogen oxides (NO2), and nitric oxide (NO) were estimated by a Land Use Regression model. An air pollution score was created to assess the joint exposure to the four air pollutants.

Results: During a median of 11 years follow-up, we documented 18,239 incident T2D cases. The hazard ratios (95% confidence interval) for T2D associated with the extreme quintiles of PM2.5, PM2.5-10, NO2, and NO were 1.12 (1.05 to 1.18), 1.06 (1.00 to 1.11), 1.11 (1.04 to 1.18), and 1.12 (1.06 to 1.18), respectively. We also found that the air pollution score was significantly associated with an increased risk of T2D. Compared to the lowest quintile of air pollution score, the multivariate-adjusted hazard ratio for T2D was 1.05 (0.99 to 1.10), 1.06 (1.00 to 1.11), 1.09 (1.03 to 1.15), and 1.12 (1.06 to 1.19) for the second to fifth quintile, respectively. In addition, we found a significant interaction between the air pollution score and obesity status on the risk of T2D (p-interaction <0.001). The observed association was more pronounced among overweight and obese participants than in the normal-weight people.

Conclusion: Our results indicate that an air pollution score, which incorporated PM2.5, PM2.5-10, NO2, and NO, is associated with an increased risk of T2D, and such association is strengthened by higher adiposity.

Disclosure

X. Li: None. M. Wang: None. H. Ma: None. T. Zhou: None. Y. Heianza: None. L. Qi: None.
352-P: Assessment of a Deep Learning Model Based on Three-Year Longitudinal Electronic Health Record Data for Predicting Severe Hypoglycemia in Patients with Type 2 Diabetes
Authors: LEE GARAM , KO SEUNG-HYUN , AHN YU-BAE , LEE EUN YOUNG , CHA SEON-AH , KIM DOKYOON , YUN JAE-SEUNG
Published: June 2021

Background: This study aimed to investigate the ability of a deep learning model to predict the outcome of severe hypoglycemia (SH) using longitudinal electronic medical records data.

Methods: Structured data were extracted from the clinical data warehouse, including demographics, laboratory, medications, and diagnostic information. Between January 2010 and December 2012, 17,670 adult patients were enrolled; participants had type 2 diabetes, were aged over 30 years, and visited the diabetes centers of two hospitals. The primary outcome was SH, defined as diagnostic codes for hypoglycemia (E16.x, E11.63, E13.63, E14.63) in hospitalization or emergency room records. The performance of the longitudinal deep learning model (gated recurrent units) in predicting SH was quantified using the area under the receiver operating characteristic curve (AUROC) and evaluated in terms of net reclassification improvement (NRI) versus a traditional logistic regression model. Based on predicted risk of SH, we stratified patients into four risk groups: low (<1.0%), intermediate (1.0% to <2.0%), high (2.0% to <5.0%), and very high (≥5.0%).

Results: Of 17,670 patients, 528 patients developed SH events during the follow-up period (mean of 6.4 years). The performance of the longitudinal deep learning model was superior to the logistic model for predicting SH (AUROC of logistic model, 0.788 [95% CI 0.781-0.793] vs. longitudinal deep learning model, 0.858 [0.853-0.863]). The very high-risk group of SH categorized using the deep learning model had 73 times higher risk of SH than the low-risk group. The deep learning model improved case reclassification (NRI, 13.4%).

Conclusion: We found that the longitudinal deep learning model showed better performance and classification ability for predicting than the conventional logistic model.

Disclosure

G. Lee: None. S. Ko: None. Y. Ahn: None. E. Lee: None. S. Cha: None. D. Kim: None. J. Yun: None.

Funding

Korean Diabetes Association (2018-F to J-S.Y.)
362-P: Punicalagin Promotes Mitochondrial Fusion and Alleviates Diabetic Cardiomyopathy via Regulating PTP1B-Stat3-Opa1 Pathway
Authors: DING MINGGE , LI MAN , FU FENG , LIU CHAOYANG
Published: June 2021

This study aims to explore the efficacy of punicalagin on diabetic cardiomyopathy, with a specific focus on the mechanisms underlying the effects of punicalagin on mitochondrial fusion/fission dynamics. Diabetes was induced by a single intraperitoneal injection of streptozotocin intraperitoneally in Sprague-Dawley rats. Cardiac structural and functional abnormalities were ameliorated in diabetic rats receiving punicalagin administration as evidenced by increased ejection fraction and attenuated myocardial fibrosis and hypertrophy. Punicalagin promoted mitochondrial fusion and enhanced mitochondrial function in both diabetic hearts and high glucose-treated cardiomyocytes. Punicalagin-induced increases in Opa1 expression were responsible for the above mitochondrial enhancements, and these changes could be blocked by knockdown of Opa1. Inhibitor screening and chromatin immunoprecipitation analysis showed that Stat3 directly regulated the transcriptional expression of Opa1 by binding to its promoter and was responsible for punicalagin-induced Opa1-mediated mitochondrial fusion. Moreover, pharmmapper screening and molecular docking studies revealed that punicalagin embedded into the activity pocket of PTP1B and inhibited the activity of PTP1B. Overexpression of PTP1B blocked the promoting effect of punicalagin on Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, our study has provided the first evidence that punicalagin protects against diabetic cardiomyopathy and uncovered the precise mechanisms on how punicalagin promotes Opa1-mediated mitochondrial fusion under hyperglycemic condition, a process in which punicalagin interacts with PTP1B and inhibits its activity that in turn increasing Stat3 phosphorylation and then enhancing the transcriptional expression of Opa1.

Disclosure

M. Ding: None. M. Li: None. F. Fu: None. C. Liu: None.

Funding

National Natural Science Foundation of China (81970316, 82070387)
407-P: Long-Term Effect of Intensive Lifestyle Intervention on Incidence of Nephropathy in Adult Patients with Diabetes: A Post-hoc Analysis of a 10-Year Longitudinal Study
Authors: TOMAH SHAHEEN , ZHANG HONGXIA , GARDNER HANNAH , AL-BADRI MARWA , HAMDY OSAMA
Published: June 2021

We previously reported that, in patients with diabetes, intensive lifestyle intervention (ILI) in real-world clinical practice could lead to significant weight loss that was attainable for up to 10 yrs and had favorable impact on glycemic control and lipid profile. These improvements were predicted by achieving ≥7% weight loss at 1 yr. In this secondary analysis, we investigated whether initial weight loss at 1 yr is associated with incidence of nephropathy over 10 yrs. This analysis included 128 patients with diabetes enrolled in a 12-wk ILI (age 53.7±10.1 yrs; 66.4% females; duration of diabetes 9.6±9.4 yrs; body mass index [BMI] 38.3±5.3 kg/m2; and 9.3% had type 1 diabetes). At 1 yr, we divided participants into 2 groups: group A (n=61, 47.7%) maintained <7% weight loss and group B (n=67, 52.3%) maintained ≥7% weight loss. Data on incidence of nephropathy were collected from electronic health records over 10 yrs of follow-up. Cox proportional hazard models were used to calculate hazard ratios after dichotomizing the incidence of nephropathy. After a median of 10 yrs of follow-up, the incidence rate of nephropathy in group A was 3.58 cases per 100 person-years vs. 1.42 cases per 100 person-years in group B (difference 2.16 cases per 100 person-years, sex-adjusted hazard ratio for group B: 0.33, 95% CI: 0.12, 0.94, p=0.039). Moreover, in a multivariable model fitted with terms for age, diabetes type, diabetes duration, BMI, plus group assignment and sex, the group-effect retained independent significance (fully adjusted hazard ratio for group B: 0.32, 95% CI: 0.11, 0.9, p= 0.007). We conclude that adult patients with diabetes who maintained ≥7% weight loss at 1yr after the initial ILI had a 68% lower risk of nephropathy for up to 10 yrs. These data support the essential role of weight reduction in preventing or delaying the progression of chronic kidney disease in patients with diabetes and overweight or obesity.

Disclosure

S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. H. Zhang: None. H. Gardner: None. M. Al-badri: None. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC.
412-P: Increased Peripheral Neutrophil Count Is Closely Associated with the Incidence and Progression of Chronic Kidney Disease in Older Type 2 Diabetic Patients
Authors: ZHANG RUI
Published: June 2021

Preventing and managing chronic kidney disease (CKD) is the primary task of the overall management of T2DM. An increasing number of studies has indicated that low-grade chronic inflammation plays a crucial role in the pathophysiology of CKD. A total of 3345 subjects were recruited in this study of whom 1257 derived from one centre and served as case-controls and 2088 with T2DM derived from two other centres and were followed up annually for 4 years and entered into a retrospective cohort study. In the case-control study, neutrophil count performed best as an independent risk factor for CKD even after 1:1 case-control matching for age, gender, and history of high blood pressure (HBP). Spline regression revealed a significant linear association between CKD incidence and continuous neutrophil count in excess of 3.6 × 109/L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil-to-lymphocyte ratio (NLR), respectively. COX regression analysis showed that only neutrophil count demonstrated an increased HR for estimated glomerular filtration rate (eGFR) reduction greater than 30% (the highest group vs. the lowest group, 1.604 (1.029 - 2.501), P < 0.05) after fully adjusting for potential confounders. The cumulative incidence of CKD in T2DM patients gradually increased with increasing neutrophil count. This study suggested that neutrophil count is associated with the incidence and progression of CKD in T2DM patients.

Disclosure

R. Zhang: None.

Funding

Medical Key Faculty Foundation of Shanghai (ZK2019B15)
421-P: Genetically Reduced Chondroitin Sulfate Prevents the Progression of Diabetic Neuropathy via Pericyte Functions
Authors: ISHIGURO HAJIME , USHIKI TAKASHI , HONDA ATSUKO , MIKAMI TADAHISA , KITAGAWA HIROSHI , SANGO KAZUNORI , MASUKO MASAYOSHI , IGARASHI MICHIHIRO , SONE HIROHITO
Published: June 2021

Background: The extracellular matrix is associated with diabetic complications; however, chondroitin sulfate (CS) role remains unclear. Herein, genetically engineered mice lacking the rate-limiting CS-synthesizing enzyme, CS N-acetylgalactosaminyltransferase-1 (T1), were used to clarify CS effects on diabetic neuropathy. Diabetes was induced by streptozotocin injection in 6-week-old male T1 knockout (T1KO) and wild-type (WT) mice.

Results: Previously reported preliminary data at the former ADA meeting revealed that thermal nociception and the number of plantar peripheral nerve fibers were disrupted in diabetic WT mice, whereas in diabetic T1KO were preserved. Moreover, conduction velocity in the sciatic nerve was significantly declined in diabetic WT than in T1KO mice. [A1] Immunohistochemical data revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, whereas those neurons were protected in diabetic T1KO mice. Moreover, DRG gene expression analysis showed that caspase-3 and -9 were reduced in T1KO compared with WT mice. To investigate the mechanisms underlying these events, the role of pericytes, which are important CS-expressing components of the blood-nerve barrier (BNB), was explored. Assessment of the retinal vessels, which represent a good model to evaluate pericyte functions and easier to access than peripheral nerves, revealed a higher proportion of pericyte-deficient retina blood vessels in diabetic WT than in T1KO mice upon administration of a platelet-derived growth factor receptor (PDGFR) β antibody. Therefore, pericytes in T1KO mice were more resistant against PDGFRβ antibody than those of WT mice. Thus, it is possible that the BNB in T1KO mice may be more resistant against external stress, including diabetes.

Conclusions: Reduced CS production may induce beneficial effects to prevent diabetic neuropathy by improving pericyte function.

Disclosure

H. Ishiguro: None. T. Ushiki: None. A. Honda: None. T. Mikami: None. H. Kitagawa: None. K. Sango: None. M. Masuko: None. M. Igarashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
433-P: Hyperglycemia-Induced Oxidative Stress Prevents REDD1 Degradation by Chaperone-Mediated Autophagy
Authors: MILLER WILLIAM P. , TORO ALLYSON , SUNILKUMAR SIDDHARTH , GIORDANO JOSEPH , DENNIS MICHAEL D.
Published: June 2021

Upregulation of the stress response protein REDD1 (regulated in development and DNA damage response 1) has been implicated in diabetes-induced retinal defects in both preclinical models and diabetic patients. In fact, intravitreal administration of a siRNA targeting the REDD1 mRNA has demonstrated promise for improving visual function in patients with diabetic macular edema. However, the mechanism responsible for increased retinal REDD1 protein content in the context of diabetes has never been established. Herein, we investigated the hypothesis that diabetes promotes REDD1 expression by reducing the rate of REDD1 degradation. In the retina of streptozotocin-induced diabetic mice, REDD1 protein content was increased in the absence of a change in REDD1 mRNA. When diabetic mice were administered antioxidants, neither oxidative stress nor REDD1 expression were increased in the retina. In human MIO-M1 retinal Müller cells, the rate of REDD1 degradation was reduced upon exposure to hyperglycemic conditions. Antioxidant addition to culture medium prevented both the increase in oxidative stress and REDD1 stability in cells exposed to hyperglycemic conditions. Surprisingly, the suppressive effect of oxidative stress on REDD1 degradation was independent of the ubiquitin-proteasome pathway. Rather, REDD1 was rapidly degraded upon activation of chaperone-mediated autophagy (CMA) and exposure to hyperglycemic conditions prevented the suppressive effect of CMA activation on REDD1 expression. Additional mechanistic details of this new regulatory pathway will be presented. Overall, the findings provide evidence that diabetes promotes retinal REDD1 protein content via a post-transcriptional effect and potentially identifies superior therapeutic targets for preventing the pathological increase in REDD1.

Disclosure

W. P. Miller: None. A. Toro: None. S. Sunilkumar: None. J. Giordano: None. M. D. Dennis: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.); National Institutes of Health (R01EY029702 to M.D.D.), (F31EY031199-01 to W.P.M.)
440-P: Dual Long-Term Effects of Free Fatty Acid on Human Endothelial Barrier In Vitro Are Mediated by NO, Mitochondrial ROS, and Dicarbonyl Stress
Authors: SAMSONOV MIKHAIL , PODKUYCHENKO NIKITA , KHAPCHAEV ASKER Y. , VLASIK TATIANA , LANKIN VADIM , SKULACHEV MAXIM , STAFEEV IURII , VOROTNIKOV ALEXANDER V. , SHESTAKOVA MARINA V. , SHIRINSKY VLADIMIR P.
Published: June 2021

In diabetes-associated hyperlipidemia, free fatty acids (FFAs) are thought to induce insulin resistance and endothelial dysfunction leading to vascular injury and cardiovascular T2DM complications. However, evidence is scarce regarding the effects of FFA on vascular endothelial barrier. We used human umbilical vein endothelial cells (HUVEC) to model, in vitro, the endothelial barrier and reveal its responses to experimental hyperlipidemia induced by long-term treatment with palmitic acid in complex with albumin. Palmitate was continuously present in the growth medium at 0.8 mM to reproduce FFA levels typical for T2DM. We developed conditions to maintain the HUVEC monolayers in the presence of the high palmitate concentration for up to 2 weeks by adding exogenous carnitine to facilitate mitochondrial β-oxidation of FFA. In this model system, palmitate readily augmented the transendothelial electric resistance (TER) of HUVEC via increased NO production by endothelial NO-synthase (eNOS). Western blots showed that palmitate neither disturbed insulin signaling cascade towards eNOS nor upregulated eNOS expression. After the initial 3-4-day rise in TER, further treatment with palmitate led to barrier stabilization and attenuation as compared to FFA-free conditions. This later phase was associated with increased ROS and malondialdehyde (MDA) accumulation, both prevented by the mitochondria-targeted antioxidant SkQ1. Treatment of HUVEC with exogenous MDA impaired the TER and barrier suggesting that accumulation of MDA-modified proteins may contribute to the barrier dysfunction upon long-term experimental hyperlipidemia. Altogether, obtained evidence suggests that prolonged exposure of vascular endothelium to high levels of palmitate compromises endothelium barrier capacity and insulin-mediated eNOS regulation turning the enzyme permanently active.

Disclosure

M. Samsonov: None. V. P. Shirinsky: None. N. Podkuychenko: None. A. Y. Khapchaev: None. T. Vlasik: None. V. Lankin: None. M. Skulachev: Other Relationship; Self; Mitotech LLC. I. Stafeev: None. A. V. Vorotnikov: None. M. V. Shestakova: None.

Funding

Russian Science Foundation (19-15-00361)
462-P: Factors Associated with Health Literacy among Patients with Type 2 Diabetes in China
Authors: ZHAO XIAOYAN
Published: June 2021

Background: Health literacy is vital for self-care activities and quality of life among patients with type 2 diabetes. However, no study has been conducted to determine health literacy using Health Literacy Scale in patients with type 2 diabetes in China. Therefore, this study aims to identify factors associated with health literacy in patients with type 2 diabetes.

Methods: A cross-sectional study was performed among 310 patients with type 2 diabetes in the department of endocrinology of four hospitals in China. Health literacy was measured using the Health Literacy Scale. A series of structured questionnaires were used to measure sociodemographic and clinical variables, social support, diabetes knowledge. EpiData 3.1 was used to establish the database. Univariate analysis and multiple linear regression analysis were applied to examine factors associated with health literacy using SPSS 25.0.

Results: The patients’ mean (SD) score of health literacy was 2.82 (0.28) on a range from 1.71 to 3.50. In univariate analysis, health literacy was associated with age, educational level, marital status, complications, income, health education, social support, diabetes knowledge. Multiple linear regression analysis showed that health literacy was positively associated with educational level (β=0.32, 95% CI: 0.26, 0.38), diabetes knowledge (β=0.41, 95% CI: 0.20, 0.62). Similarly, patients who hadn’t received health education (β=-0.14, 95% CI: -0.22, -0.06), divorced or widowed (β=-0.18, 95% CI: -0.30, -0.05) had lower health literacy level. 54.40% of the variability in health literacy can be predicted by educational level, diabetes knowledge, health education, and marital status.

Conclusions: Health professionals should pay attention to the improvement of diabetes knowledge and health education among patients with type 2 diabetes and take corresponding measures. Patients divorced or widowed or with low educational level may need special attention to improve their health literacy level.

Disclosure

X. Zhao: None.
48-LB: Associations between Health Literacy and Patient Perceptions of Care in Poorly Controlled Diabetes
Authors: KOBE ELIZABETH A. , GERMAN JASHALYNN , SOLIMAN DIANA , ALEXOPOULOS ANASTASIA-STEFANIA , JEFFREYS AMY S. , EDELMAN DAVID , COFFMAN CYNTHIA , CROWLEY MATTHEW
Published: June 2021

Background: Low health literacy (HL) is a barrier to improving health outcomes in patients with type 2 diabetes (T2DM). The Newest Vital Sign (NVS) is a validated, short questionnaire for assessing HL. The relationship between NVS HL and patient-reported diabetes behavioral and patient-provider interaction measures, particularly among patients with poor glycemic control, is currently unknown.

Methods: Cross-sectional analysis of baseline data of 248 Veterans with poorly controlled T2DM (maintenance of hemoglobin A1c (HbA1c) ≥8.5% despite engagement with diabetes care) from a randomized trial of a telehealth intervention. NVS was collected at baseline, along with other demographic, clinical, and psychosocial metrics. We used multivariable regression with restricted cubic splines for continuous covariates to explore associations between baseline NVS and four measures (Diabetes Knowledge Questionnaire (DKQ), Diabetes Self-Management Questionnaire (DSMQ), Perceived Competence Scale (PCS), and Healthcare Climate Questionnaire (HCCQ)).

Results: The sample had a mean age of 58.1 (SD = 8.3) years, was 78.6% male and 76.2% non-White. Average HbA1c was 9.8 (SD = 1.5) and average NVS was 3.4 (SD = 2.0). After adjusting for demographic, clinical, and psychosocial factors, NVS was significantly associated (linearly) with DKQ and PCS scores, but not DSMQ or HCCQ scores. For every 1-point increase in NVS, the DKQ score increased by 0.33 (95% CI 0.13, 0.52, P = 0.0010) and PCS score decreased by 0.11 (95% CI -0.21, -0.0081, P = 0.034), indicating that higher HL is associated with higher diabetes knowledge and lower perceived competence.

Conclusions: The direct association of NVS HL with DKQ scores is consistent with literature using other HL metrics among general T2DM populations; however, the indirect association of NVS HL with PCS scores is less intuitive, suggesting a possible misplaced confidence among patients with higher HL yet poor glycemic control despite diabetes care engagement.

Disclosure

E. A. Kobe: None. J. German: None. D. Soliman: None. A. Alexopoulos: None. A. S. Jeffreys: None. D. Edelman: None. C. Coffman: None. M. Crowley: None.

Funding

National Center For Advancing Translational Sciences (TL1TR002555 to E.A.K.); U.S. Department of Veterans Affairs (IIR 16-213 to M.C.)
483-P: Remote Diabetes Care, Education, and Support Encounters in Adults with Type 1 Diabetes
Authors: GREENFIELD MARGARET , STUBER DIANA L. , STEGMAN-BARBER DANIELLE , KEMMIS KAREN , WELLS BETH A. , MCARTHUR TERESA S. , MATTHEWS BELINDA , MORLEY CHRISTOPHER P. , WEINSTOCK RUTH S.
Published: June 2021

Aim: To understand how remote Certified Diabetes Care and Education Specialists (CDCES) helped adults with type 1 diabetes (T1D) transition from provider in-person to tele-visits.

Methods: Adults with T1D were referred to remote CDCES to fulfill needs from 4/16/2020 - 8/14/2020. Pertinent information from the EMR was provided to the CDCES who were not previously known to the patients. A summary of the remote CDCES encounter was communicated to the provider. Data analysis used t-tests to assess differences in means and Pearson correlation coefficients to assess relationship between the number of encounters and insurance and age. SPSS v. 27 was used.

Results: Adults (n=1089) with T1D [mean age 46 (range 18-90 yrs); 50% female; 20% Medicaid, 23% Medicare, 54% private coverage; mean A1c 8.4% (range 4.6 to >14.0%); 52% pump and 61% CGM users], had 1662 encounters with remote CDCES. Of those referred, 232 (21%) could not be reached or did not receive education/support. Older age was associated with more encounters (r=0.126, p<0.001) as was coverage with Medicare (mean 1.9) vs. private insurance (mean 1.3; p<0.001) vs. Medicaid (mean 1.6; NS). A1c was negatively correlated with age (r=-0.195, p<0.001). During remote encounters the most frequently discussed topics were CGM (64%), insulin pumps (48%), tele-visit preparation (37%) and hypoglycemia (24%); device download training (46%) and CGM education/data review (58%) was provided to participants. Lack of access to a computer, tablet, smartphone or internet was seen in 14%; mean age of those without vs. with access was 51 vs. 45 yrs (p<0.001).

Conclusions: Most remote CDCES encounters in adults with T1D were successfully completed, assisting the majority with CGM education/data review and nearly half with device download training in preparation for their provider tele-visit. Older adults and those with Medicare required more encounters to fulfill needs. Future study could assess whether remote encounters result in improved glycemic control or quality of life.

Disclosure

M. Greenfield: None. D. L. Stuber: None. D. Stegman-barber: None. K. Kemmis: None. B. A. Wells: None. T. S. Mcarthur: None. B. Matthews: None. C. P. Morley: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust; T1D Exchange QI Learning Collaborative
489-P: Facilitating Collaboration through TeleECHO Education in Diabetes
Authors: ALLEN RUSSIE , WELCH LAUREN K.
Published: June 2021

Project ECHO is a collaborative model of medical education that engages clinicians in a continuous learning system via real-time, interactive videoconferencing. During TeleECHO sessions, expert specialist teams at an academic ‘hub’ are linked with care teams in local communities throughout the world. Each session is case-based, with learners and faculty presenting their patient experiences in a HIPAA compliant manner, promoting collaboration and competence building. As an official ECHO hub, MLG recently completed a large-scale, TeleECHO series on treating to guidelines and managing cardiovascular and renal risk in patients with T2DM, consisting of 47 sessions that reached 1976 healthcare professionals. With the ongoing COVID-19 pandemic, these sessions provided a unique way to facilitate a case-based dialogue among community-based practitioners and a national expert, sharing best practices that to apply to the care of individual patients. MLG recorded each session and used the most informative cases to create an enduring activity that is available for one year online. To further support the translation of education into practice and encourage HCP-patient dialogue, MLG also provided learners access to an online Personalized Poster Portal. Learners could choose a variety of images and design a poster that was shipped to their practice setting. There have been 613 poster orders thus far. The outcomes that MLG has collected regarding this unique program and its point-of-care tools indicate how CME can lead to not only improved knowledge but can also translate to practice behavior. While learners demonstrated significant gains across learning objectives, baseline knowledge of the latest data on the use of GLP-1 receptor agonists and SGLT2inhibitors to reduce cardiovascular events demonstrated a need for such education. MLG proposes to partner with Project ECHO to share these results via a poster at the ADA Scientific Sessions.

Disclosure

R. Allen: None. L. K. Welch: None.
490-P: Success of a Multidisciplinary Approach Strategy to Reach Target Glycemic Control in Patients with Uncontrolled Diabetes in a Rural Hospital in Thailand
Authors: LIMPIJANKIT VARISA , CHOTTHUNYAPAT SASINUN , KRUACHAI PETCH , KHAMPETDEE SUNANTA , OP-UN PANIDA , WANTHONG DUANGRAT , AUNLAMAI NUTTAYA , PETCHAI DONLAYA , NOORAPAN JUTARAT , MATIDTO SUNISA , TECHATHAWEERIT PATTARAPORN , LIMPIJANKIT THOSAPHOL
Published: June 2021

Background: To prevent the late complications, achieving a target glycemic control is crucial and challenging, especially in a remote area with limited resource. We aimed to evaluate the efficacy of a multidisciplinary approach strategy to control blood sugar in these uncontrolled diabetes patients.

Method: During July 2019, we set up a team of volunteer including a diabetic educator and local healthcare providers such as doctors, nurses and pharmacists at a hospital in Northeast of Thailand. Forty patients with uncontrolled diabetes (HbA1c >7%) were selected to participate. Baseline characteristic, background knowledge and blood tests were obtained. All patients participated in a one day program learning hands on using blood sugar meter (Contour plus™) to monitor during diet control, medication issue, foot care and complication prevention. Two weeks later, we revisited and reviewed the daily blood sugar record at home and gave more advice. At 1 year, we collected the blood tests, medication list, and complication from medical records.

Results: Most participants were female (89.7%), age <60 years (61.5%) and overweight with BMI>23 kg/m2 (53.8%). Comorbid disease including hypertension, dyslipidemia and chronic kidney disease were found in 66.7%, 23.1% and 25.6%, respectively. At 1 year, there was a significant improvement of blood sugar control (HbA1c <7%) compared to the baseline (18.2% vs. 64.9%, p<0.0001). The number of medication use mostly unchanged (64.4%), with 20.5% decrease and 12.8% increase. Of noted, there was improvement of renal function (GFR> 60 mL/min/1.73 m2) after better glycemic control (71.8% vs. 74.4%, p=0.032) and no new complication at 1 year.

Conclusions: Applying a short program of multidisciplinary approach strategy in uncontrolled diabetes patients at a rural hospital has proven an efficacy to improve target glycemic control. To make it sustainable is feasible by the local healthcare providers.

Disclosure

V. Limpijankit: None. S. Matidto: None. P. Techathaweerit: None. T. Limpijankit: None. S. Chotthunyapat: None. P. Kruachai: None. S. Khampetdee: None. P. Op-un: None. D. Wanthong: None. N. Aunlamai: None. D. Petchai: None. J. Noorapan: None.
502-P: Introduction of a Gluten-Free Diet in Children with Type 1 Diabetes and Coeliac Disease Did Not Impact Glycemic Control, Nutrient Intake, or Quality of Life at Three Months
Authors: MARLOW ALEXANDRA L. , KING BRUCE R. , JOHNSON SHAUN E. , BINKOWSKI SABRINA K. , FAIRCHILD JAN , DAVIS ELIZABETH A. , SMART CARMEL E.
Published: June 2021

Studies on how a gluten free (GF) diet in youth with T1D and CD impacts glycemic control, quality of life (QoL) and nutrient intake are limited. The study aim was to determine the effects of the introduction of a GF diet in children with T1D and newly diagnosed CD on glycemic control, nutrient intake, QoL and body mass index (BMI). Subjects wore a continuous glucose monitor for 12 days and completed a 4-day food record at baseline and 3 months after implementing a GF diet. Participants and one parent completed the PedsQL questionnaire at baseline and 3 months. Ten children participated (age 10.8y ± 3.3, 40% male, BMI Z-score 0.5 ± 0.6, diabetes duration 2.2y ± 2.6 (50% with diabetes duration of <12 months), 60% on multiple daily injections, 20% on insulin pump therapy and 20% on twice-daily injections, HbA1c 6.0 ± 1.1%). BMI Z-score (0.4 vs. 0.5, p=0.73), glycemic variability % CV (40.4% vs. 40.2%, p=0.94), HbA1c (6.0% vs. 5.8%, p=0.56), percentage glucose time above target range >180mg/dL (30.3% vs. 36.1%, p=0.09) and below target range <70mg/dL (7.2% vs. 7.9%, p=0.76) did not change significantly from baseline to 3-months, however time in range (TIR) 70-180mg/dL (62.6% vs. 56.0%, p=0.02) was significantly lower at 3 months. Intake of fibre (18g vs. 16g, p=0.40), iron (9g vs. 8g, p=0.35), calcium (826mg vs. 791mg, p=0.75) and saturated fat (13.5% vs. 14.0%, p=0.77) were not significantly different from baseline to 3 months. QoL score was not significantly different for parents (63.2 vs. 67.4, p=0.08) or children (56.8 vs. 63.5, p=0.08) from baseline to 3 months. This study suggests that implementation of a GF diet in children with T1D does not adversely impact glycemic control, nutrient intake, QoL or BMI Z-score. The only change in glycemic control reduced TIR at 3 months which may represent changing insulin requirements with gut healing and the end of the remission phase of T1D.

Disclosure

A. L. Marlow: None. B. R. King: None. S. E. Johnson: Consultant; Self; Medtronic. S. K. Binkowski: None. J. Fairchild: None. E. A. Davis: None. C. E. Smart: None.

Funding

Australasian Paediatric Endocrine Group; Pfizer Inc. (WI205278)
52-OR: Risk Factors and Incidence over Time for Lower Extremity Amputations in Persons with Type 1 Diabetes: An Observational Cohort Study of 46,008 Patients from the Swedish National Diabetes Registry
Authors: HALLSTRÖM SARA , SVENSSON ANN-MARIE , PIVODIC ALDINA , OLAFSDOTTIR ARNDIS F. , LONDAHL MAGNUS , WEDEL HANS , LIND MARCUS
Published: June 2021

Background: Lower extremity amputations in people with diabetes is a major source of disability and distress and it constitutes a significant financial burden for the healthcare system. Risk factors and current risks for amputation in persons with type 1 diabetes have not been extensively studied.

Methods: Persons with type 1 diabetes registered in the Swedish National Diabetes Registry with no previous amputation from 1998 and followed until 2019 were included. Time-updated Cox regression and gradient of risk per SD were used to evaluate the impact of risk factors on the incidence of amputation. Age and sex adjusted incidences were estimated over time.

Findings: Of 46,008 persons with type 1 diabetes with no previous amputation and a mean age of 32.5 years (SD 14.5) and 25 354 (55%) male, 1,519 (3.3%) underwent amputation. Median follow-up was 12.4 years. The age and sex adjusted incidence for any amputation decreased over time. The standardized incidence was 1998-2001 2.84 (95% CI 2.32-3.36) per 1000 patient years and decreased to 1.64 (95% CI 1.38-1.90) in 2017-2019 along with improved glycaemic control (0.02% [95% CI 0.02-0.02] per year) and renal function (0.23 ml/min/1.73m² [95% CI 0.21-0.24] per year). Risk factors for amputations were hyperglycemia, renal dysfunction, older age, male gender, cardiovascular comorbidities, smoking and hypertension.

Interpretation: Prognosis has improved considerably regarding the risk of amputations in persons with type 1 diabetes while glycaemic control and renal function improved which were the most prominent risk factors.

Disclosure

S. Hallström: None. A. Svensson: None. A. Pivodic: None. A. F. Olafsdottir: None. M. Londahl: Advisory Panel; Self; Abbott, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi. H. Wedel: None. M. Lind: Consultant; Self; AstraZeneca, Eli Lilly and Company, Other Relationship; Self; Novo Nordisk, Research Support; Self; Dexcom, Inc.

Funding

Novo Nordisk Foundation; Swedish State