bluuebunny/crossref_metadata_2025_split huggingface dataset:
2119-P: Deep Profiling of Phosphorylation Dynamics in Human Islets in Response to Inflammatory Cytokines
Authors: SWENSEN ADAM C. , YE YINYIN , DIRICE ERCUMENT , KULKARNI ROHIT , QIAN WEIJUN 
Published: June 2020

Human islets, particularly beta cells, are sensitive to their environment and face many types of stressors. These stressors may stem from intense demand for hormone production, viral insult, impaired intra-islet signaling, immune activation, or a combination of any/all of the previously mentioned stressors. How islets respond to these stressors is vital to the continued function and whole-body cooperation of these important cells, especially in patients which are already carry predisposed risk. It is well understood that once immune invasion occurs, islets face a veritable barrage of cytokine/chemokine chemical stressors. Elucidating the early cellular response to these stressors is paramount to understanding the complex interconnected balance at play between the immune system and the islet. The initial response is critical and must occur quickly; this is why we chose to look at changes in phosphorylation-based dynamics which occur at these short time scales. Islet samples from 10 donor patients were harvested and cytokine treated ex vivo and subsequently collected over a time course of 10 min, 30 min and 2 hours. Samples were then prepared for mass-spectrometry-based proteomics analysis using the newly-developed BASIL (Boosting to Amplify Signal using Isobaric Labeling) method for small-scale enriched phosphoproteomics. This technique allowed for unprecedented deep phosphoproteome coverage and signaling network reconstruction of cytokine-induced stressed human islets; thereby allowing us to observe a molecular-level response to this kind of stress in this critical phase of disease pathogenesis.

Disclosure
A.C. Swensen: None. Y. Ye: None. E. Dirice: None. R. Kulkarni: None. W. Qian: None.

Funding
National Institutes of Health (UC4DK104167, R01DK122160)
2126-P: Investigating the Regulation of Autophagy and the Antioxidant Response by IL-6 Family Cytokines
Authors: MARASCO MICHELLE , AKBAR ZAIN , CROWDER JUSTIN , NOVAK ALISSA , MURALIDHARAN CHARANYA , ARVIN MATTHEW , LINNEMANN AMELIA K. 
Published: June 2020

Pathways that mitigate cellular stress are critical for pancreatic beta cell function and survival. We have reported that the cytokine interleukin-6 (IL-6) coordinately activates two such pathways, autophagy and the antioxidant response, resulting in decreased oxidative stress and increased beta cell survival under diabetogenic conditions. Our investigation of this protective effect of IL-6 on the beta cells subsequently revealed that members of the IL-6 family of cytokines stimulated the mitochondrial translocation of NRF2, the central antioxidant regulator. This was surprising since NRF2 is well-characterized as a transcription factor. Under these conditions, we also observe translocation of another transcription factor, STAT3, to the mitochondria, consistent with previously published observations. Here, we present data to validate these findings in the islet in vivo and investigate the downstream events associated with NRF2 mitochondrial translocation. We used a mouse model where animals were intraperitoneally injected with either IL-6 or another IL-6 family member, leukemia inhibitory factor (LIF), and pancreata were collected at 30 minutes post-injection. We then used immunofluorescence analysis of paraffin tissue sections. We observed that both IL-6 and LIF rapidly elicit a reduction in the autophagy receptor p62 both in the cytosol and at the mitochondria when compared to saline-injected mice. This suggests that both global autophagy and selective mitophagy are stimulated in the beta cell by both IL-6 and LIF. Furthermore, as both IL-6 and LIF selectively stimulate mitochondrial but not nuclear translocation of NRF2, our data suggests that NRF2 may play a role in the stimulation of mitophagy by IL-6 family cytokines. Further studies investigating the requirement of NRF2 for beta cell mitophagy under conditions of beta cell stress response will shed light on this novel pathway of the cellular antioxidant response.

Disclosure
M. Marasco: Employee; Spouse/Partner; Eli Lilly and Company. Z. Akbar: None. J. Crowder: Employee; Spouse/Partner; Eli Lilly and Company. A. Novak: None. C. Muralidharan: None. M. Arvin: None. A.K. Linnemann: None.

Funding
National Institutes of Health (T32DK064466-16, R03DK115990)
2129-P: Glucagon Secretion from Pancreatic Islets Is Regulated by Beta-Arrestin-1
Authors: DATTAROY DIPTADIP , BARELLA LUIZ F. , PYDI SAI PRASAD , CUI YINGHONG , KAESTNER KLAUS H. , WESS JÜRGEN 
Published: June 2020

Glucagon, a hormone released from alpha cells of pancreatic islets, plays a key role in maintaining proper glucose homeostasis. Substantial evidence suggests that inappropriately elevated plasma glucagon levels contribute to the pathophysiology of type 1 and 2 diabetes. Therefore, it is of great importance to understand the signaling pathways that regulate glucagon release from alpha cells. As is the case with virtually all cell types, the function of pancreatic alpha cells is modulated by the activity of cell surface receptors known as G protein-coupled receptors (GPCRs). GPCR signaling is regulated by two intracellular proteins, β-arrestin-1 and -2 (barr1 and barr2, respectively), which can terminate GPCR signaling. Interestingly, barr1 and barr2 can also act as signaling molecules in their own right. Studies with whole body knockout mice have shown the two β-arrestins regulate many important physiological functions. The potential roles of barr1 and barr2 in modulating alpha cell function in vivo remain unknown at present. To address this issue, we used Cre-lox technology to delete barr1 in a conditional fashion in pancreatic alpha cells of adult mice (alpha-barr1 KO mice). Alpha-barr1 KO mice showed significantly decreased plasma glucagon levels and impaired glucose-stimulated insulin secretion. Studies with hamster alpha cells demonstrated that the ability of forskolin and arginine vasopressin to stimulate glucagon secretion was significantly decreased after knockdown of barr1 expression. We also found that the islets prepared from alpha-barr1 KO mice showed a significant reduction in glucagon content and mRNA expression, while insulin content and mRNA expression remained unaltered. In future studies, we will explore the molecular/cellular mechanisms through which barr1 regulates alpha cell function and glucagon content. This work may identify novel signaling pathways modulating glucagon secretion that can be targeted for therapeutic purposes.

Disclosure
D. Dattaroy: None. L.F. Barella: None. S. Pydi: None. Y. Cui: None. K.H. Kaestner: None. J. Wess: None.
2130-P: Transcription Factor NF-kB Regulates Thermogenic Function of Brown Adipocytes in UCP1-Independent Manner
Authors: YE JIANPING 
Published: June 2020

NF-kB is a transcription factor that is activated upon cellular response to endotoxin, TNF-a or oxidative stress, etc. The transcription factor is formed by two subunits, p65 and p50, in most cells. The transcription activity is mainly determined by the p65 subunit for the transactivation domain. The p50 subunit does not contain a transactivation domain in the protein structure. NF-kB is expressed in brown adipocytes and the expression of p65 is increased by differentiation of the adipocytes. However, the activity of NF-kB remains unknown in brown adipocytes, especially in the thermogenic function of the adipocytes. To address this issue, we generated brown adipocyte-specific NF-kB transgenic mice with gain-of-function and loss-of-function using the Cre-LoxP strategy. The gain-of-function was achieved by over expression of the p65 subunit in a knockin mice, and the loss-of-function was made by inactivation of p65 subunit in a floxed mice. The gene modification was achieved by crossing the p65 mice with UCP1-CreER mice. The gain-of-function led to an elevation of mitochondrial function in brown adipocytes with an increase in uncoupling activity. The gene alteration preserved the brown fat function in DIO mice. In contrast, NF-kB loss-of-function made the mice intolerant to cold exposure in the lean condition and obese condition. The thermogenic function was significantly decreased in the mice. UCP-1 is a dominant uncoupling protein in the mitochondria of brown adipocytes to mediate the cold-induced heat production. UCP-1 expression and post-translational modification were not altered in brown adipocytes of the two lines of transgenic mice. These results suggest that NF-kB is required for the thermogenic function of brown adipocytes, and its activity is not associated with regulation of UCP-1.

Disclosure
J. Ye: None.
214-LB: Brain Mitochondrial Function and Cognition Are Impaired in Brain Insulin Receptor Knockout Mice
Authors: PATAKY MARK W. , RUEGSEGGER GREGORY , KLAUS KATHERINE , STARSKI PHILLIP , SREEKUMARAN NAIR K. 
Published: June 2020

Insulin resistance has been linked to cognitive dysfunction and increased risk for Alzheimer’s disease and other dementias. It is unclear if cognitive decline during insulin resistance is due to systemic or brain-specific insulin resistance. Previous studies demonstrated that brain mitochondrial function is reduced concurrent to diminished insulin signaling in high fat-fed mice. However, it remains to be determined whether insulin signaling in the brain directly impacts brain mitochondrial function and cognition. Therefore, we developed a tamoxifen inducible brain-specific insulin receptor knockout (BIRKO) mouse by breeding C57/BL6J mice with a floxed insulin receptor gene with mice that express a tamoxifen-inducible Nestin-Cre. These BIRKO mice were used to identify if brain insulin signaling is required for maintenance of brain mitochondrial function and cognition. Four weeks after tamoxifen administration, we confirmed using western blotting that the insulin receptor was completely absent in all regions of the brain, but not the muscle, heart, liver, kidney, or adipose from the BIRKO mice. Spatial learning was reduced (P&lt;0.05; n=8 so far) and short-term memory trended to be reduced (P=0.18; n=8 so far) in BIRKO mice compared to controls. Further, ATP production rate was reduced (64 vs. 42 pmols/s/mg tissue; P&lt;0.005; n=9) and reactive oxygen species production was increased (33 vs. 58 pmols/s/g tissue; P&lt;0.005; n=9) in isolated mitochondria from the cerebrum in BIRKO mice versus controls. These changes were not accompanied by altered body weight, fat mass or lean body mass. Because the clearly pronounced mitochondrial deficits in the brain of BIRKO mice are accompanied by cognitive decline, our results suggest a link between cognition and brain mitochondrial function. Thus, these novel and important findings warrant further studies to provide molecular insights into the mechanisms governing the link of brain insulin resistance to Alzheimer’s disease and other dementias.

Disclosure
M.W. Pataky: None. G. Ruegsegger: None. K. Klaus: None. P. Starski: None. K. Nair: None.

Funding
National Institutes of Health (T32DK07352)
2142-PUB: Major Limb Amputation Decreased Plasma DPP-1 Activity in Diabetes Patients
Authors: CHEN LEE-WEI 
Published: June 2020

Metabolic syndrome and diabetes mellitus (DM) are associated with increasing DPP-4 level. In recent researches, DPP-4 inhibitor, besides from glycemic control, was found to have benefit in inflammation and cardiovascular disease. The changes of DPP-4 level in metabolic syndrome or DM patients with peripheral arterial occlusive disease (PAOD) have not been clarified. We collected 30 patients with metabolic syndrome and 30 patients without metabolic syndrome, who were scheduled to receive operation. The patients in acute disease status, in pregnancy or breast-feeding, with coagulopathy were excluded. Smoking, BMI (body mass index), underlying disease were extracted from medical record. The blood sample and the fat tissue near the surgical wound were collected. Serum DPP-4, GLP-1, HbA1c, TG, LDL level, and cytokines in fat tissue (TNF-⍺, IL-1β, IL6) were examined. This research has been approved by IRB of VGHKS. The serum DPP-4 level was significantly higher in overweight (BMI≧24) patients, and slightly higher in patient with metabolic syndrome, DM or PAOD. Among patients with metabolic syndrome, the DPP-4 level was significant lower in patients who received amputation for DM foot and/PAOD. However, this condition was not observed in traumatic amputation patients. The DPP-4 inhibitor only lower serum DPP-4 level in patients with metabolic syndrome. Serum DPP-4 level decreased after amputation for severe infection with poor peripheral perfusion, but not in traumatic amputation. This finding supports that DPP-4 was associated with inflammation and vascular disease.

Disclosure
L. Chen: None.
2143-PUB: Beneficial Impact of a Routine Clinical Practice Multifactorial Approach on the Progression of Subclinical Arterial Disease in Type 2 Diabetes: 3.2 Years Follow-Up Study
Authors: MAKRILAKIS KONSTANTINOS , KONSTANTONIS GEORGIOS , ARIDA AIKATERINI , AISSOPOU EVAGGELIA , ARGYRIS ANTONIOS , PROTOGEROU ATHANASE , SFIKAKIS PETROS P. , TENTOLOURIS NIKOLAOS 
Published: June 2020

Diabetes is associated with higher incidence of cardiovascular (CV) disease complications due to accelerated arterial damage. The beneficial effect of multi-factorial treatment of CV risk factors in type 2 diabetes is well established from randomized clinical trials. We prospectively examined the impact of such a treatment in a real-world setting, on the development of subclinical arterial damage (SAD), as determined by structural and functional non-invasive biomarkers of vascular pathology (atheromatosis [presence of atheromatous plaques in carotid/femoral arteries, ankle-brachial index], arteriosclerosis [carotid-femoral pulse wave velocity, carotid distensibility], carotid hypertrophy [intima-media thickness, cross-sectional wall artery area]). We prospectively studied 116 persons with type 2 diabetes, treated with a multi-factorial approach of CV risk factors in routine clinical practice at a tertiary medical center, and 324 individuals without diabetes, for 3.2 years. The primary outcome was changes in vascular biomarkers related to SAD. At baseline, participants in the diabetes group had higher prevalence of subclinical arterial disease. At study end, changes in clinical, biochemical and lifestyle characteristics, as well as antihypertensive and lipid-lowering treatments, were comparable between the two groups. During follow-up, classical CV risk factors (smoking, blood pressure, LDL-cholesterol, triglycerides), and behavioral features were significantly improved in both groups. Multivariate analysis, after adjusting for all classical CV risk factors and use of anti-hypertensive/lipid-lowering therapies, demonstrated that all evaluated SAD biomarkers were similarly changed between the two groups. Implementation of a multi-modality approach of type 2 diabetes treatment is feasible and effective in decelerating progression rates of SAD in routine clinical practice.

Disclosure
K. Makrilakis: None. G. Konstantonis: None. A. Arida: None. E. Aissopou: None. A. Argyris: None. A. Protogerou: None. P.P. Sfikakis: None. N. Tentolouris: None.
2146-PUB: Features of Acute Myocardial Infarction in Patients with Diabetes Mellitus of the Buryat Population
Authors: BARDYMOVA TATIANA , BELOKHVOSTIKOVA TATIANA , TSYRETOROVA SESEG 
Published: June 2020

The inflammatory processes that develop in patients with type 2 diabetes mellitus (T2DM) vary in different ethnic groups. The level of cytokines in the peripheral blood characterizes the severity of the disease and the dynamics of the pathological process in the acute period of myocardial infarction. The study included 34 individuals of the Buryat population. The Buryats are the main northern group of Mongolians, they are a core population of Siberia with a compact residence close to Lake Baikal. The first group included 14 patients with T2DM and ST-elevation acute myocardial infarction (STEMI) (5 men and 9 women), with a median age was of 62.5 years. The second group consisted of 20 individuals of the control group without diabetes and STEMI (11 men and 9 women), a median age was of 62 years. We studied levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP) admitted within 24 h after the symptoms onset (Table 1). In Buryat patients with T2DM and STEMI, production of pro-inflammatory cytokines IL-1β and IL-6 relative to the control group without diabetes and STEMI (p &lt;0.05) is reduced. In addition, in Buryat patients with T2DM and STEMI, a significant increase in the level of hs-CRP was registered relatively to the control group (p&lt;0.05).

Disclosure
T. Bardymova: None. T. Belokhvostikova: None. S. Tsyretorova: None.
2148-PUB: Relationship between SGLT2 Inhibitor, ACEI/ARB, and Pioglitazone to Renal Function in Patients with Type 2 Diabetes Mellitus
Authors: LEE TAO-CHUN 
Published: June 2020

Background: Despite the recent evidence of SGLT2-inhibitors (SGLT2i) in renal function protection, the treatment of ACEI/ARB and pioglitazone may also be promising to diabetic kidney disease progression. This study aims to discuss the interplay between SGLT2i, ACEI/ARB and pioglitazone to changes of renal function in patients with type 2 diabetes (T2DM).
Materials and Methods: Patients with T2DM who initialized SGLT2i over six months and had at least two serum creatinine examinations were included in the present study. We categorized our participants into three groups according to their ACEI/ARB and pioglitazone status. GEE was used to analyze significant factors for subsequent EPI changes.
Results: A total of 253 patients with T2DM were included in the present study. Their SGLT2i treatment duration was 23.7±9.6 months and serum creatinine was followed 4.1± 1.6 times during the study period. After SGLT2i initiation, A1C reduced 0.5%, body weight decreased 2.2 kg, systolic blood pressure dropped 6 mmHg and LDL-C lowered 7 mg/dl; however, EPI showed a J-curve improvement as treatment duration increased (P=0.021). To disclose the interaction between ACEI/ARB and pioglitazone in these SGLT2i users, we categorized our participants into three groups, and the number of patients in the ACEI/ARB(-)/pioglitazone(-), ACEI/ARB(+)/or pioglitazone(+) and ACEI/ARB(+)/pioglitazone(+) group was 83, 133 and 37, respectively. In the consideration of the effect of age, gender, body weight, A1C, albuminuria status, treatment duration, systolic and diastolic blood pressure and LDL-C, we found SGLT2i users who simultaneously under ACEI/ARB and pioglitazone therapy had a significant renal function deterioration by 5.77 mL/min/1.73m2 (P=0.011) as compared with other two group.
Conclusions: Our study suggested that the encouraging renal effect brought by SGLT2i may be lessened in patients with T2DM who simultaneously under ACEI/ARB and pioglitazone treatment.

Disclosure
T. Lee: None.
2152-PUB: Cardiac Autonomic Dysfunction in Patients with Psoriasis and without Metabolic Syndrome
Authors: CASELLINI CAROLINA M. , PARSON HENRI , BAILEY MICHAEL D. , BARNEY ABBY , VAN VOORHEES ABBY S. , VINIK AARON I. , SIRAJ ELIAS S. 
Published: June 2020

Background: Studies have shown a connection between psoriasis (PsO) and metabolic syndrome (MS), diabetes mellitus and cardiovascular disease. In addition, MS is associated with autonomic dysfunction (AD). AD has also been associated with chronic arthritis including psoriatic arthritis, but there is lack of similar evidence in patients with PsO. The aim of this study was to look for an association between PsO and AD, independent of the presence of MS.
Methods: Cross-sectional study of subjects with PsO without MS; age, sex and BMI matched healthy controls (HC); and age and sex matched subjects with MS. Subjects underwent skin evaluation by dermatologist, blood work for HbA1c, insulin, glucose, and lipids, sudomotor function testing with SudoscanTM device (Impeto Medical-Paris, France) and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc. Philadelphia).
Results: We included 47 subjects (13 PsO, 16 HC and 18 MS). PsO subjects had worse cardiac autonomic function compared to the other groups, although glucose and insulin parameters were similar to the HC group (Table 1). No differences were seen in sudomotor function between the groups.
Conclusions: PsO seems to have an association with cardiac autonomic dysfunction, independent of its relationship with insulin resistance and MS. Further studies are needed to clarify the significance of these findings and how they relate to MS and diabetes.

Disclosure
C.M. Casellini: None. H. Parson: None. M.D. Bailey: None. A. Barney: None. A.S. Van Voorhees: Consultant; Self; Celgene. Other Relationship; Self; AbbVie Inc., Lilly Diabetes. A.I. Vinik: None. E.S. Siraj: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc.
2161-PUB: Determinants of Digital Divide among Older Adults with Diabetes Mellitus
Authors: PARK SUNHEE 
Published: June 2020

Background: Access to the internet has grown dramatically over the past two decades. However disparities in internet use, the second level of the digital divide, persist.
Objective: This study examined the opportunity-, motivation-, and health-related factors to determine variables that might predict the digital divide among older adults with DM.
Methods: Data for this study came from a nationally representative sample of people aged 65 years or older (N=1919). The dependent variable, digital divide, is designated by use or nonuse of internet or mobile searching for information. Dependent variables are opportunity (demographic and socioeconomic), motivation (participation in *ICT skill education, voluntary work, and intention of education) and health related factors (self-rated health, physical and cognitive functions). Logistic regression was used to explore potential differences in predictor variables between users and nonuser groups.
Results: Only 16.0% of older adults with DM currently used the internet for information searching and they are more likely to be younger, have a higher level of education, and more leisure activity expenditure. Most of all, they were more likely to have had experience of ICT skill, and more motivated to education than nonuser. They also were more likely to do volunteer work, be healthier in in terms of physical and cognitive functions, and perceived better health status.
Conclusions: Our results suggest the experience of ICT skill education and better physical and cognitive functions are more predictive of internet use than education or economic level in older adults with DM. Lest the frailest and vulnerable older adults, such as DM sufferers, be left behind with the move towards online and digital first health care, health care providers should offer them digital health interventions including digital competency training programs.*Information and communication technology.

Disclosure
S. Park: None.