bluuebunny/crossref_metadata_2025 huggingface dataset:
2117-P: BET Bromodomain Inhibitors Mitigate Cytokine-Induced Transcription in ß-Cells via Inhibition of Nf-κB
Authors: NORD JOSHUA , WYNIA-SMITH SARAH , SMITH BRIAN C.
Published: June 2020

Type 1 diabetes is an autoimmune disease characterized by chronic inflammation of pancreatic islets, mediated by proinflammatory cytokines, leading to reduced response to glucose and ultimately selective destruction of insulin-producing β-cells. In common with many autoimmune diseases, the exact causes are poorly understood. Although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins suggest an, as yet undetermined, contribution of epigenetic factors. Recent studies have begun to explore the contributions of epigenetic regulatory proteins in onset and progression of autoimmune diabetes. An important class of epigenetic “readers” is the bromodomain and extraterminal domain (BET) family (Brd2, Brd3, Brd4, and Brdt), which has emerged as promising drug targets for a wide variety of diseases. A unique trait of the BET family is that these proteins contain two bromodomains (BD1 and BD2) that afford them the capacity to simultaneously bind two acetylated histones and/or non-histone proteins such as DNA-binding factors to modulate transcription in a cell-type specific manner. Here, we use an insulinoma β-cell line (INS832/13) and primary rat islets to investigate the ability of chemical inhibitors of BET bromodomain proteins to decrease the β-cell response to proinflammatory cytokines. We found that BET inhibitors mitigated cytokine-induced transcription of inflammatory mediators known to damage β-cells. This is mediated through the inhibition of the NF-κB pathway by BET inhibitors. Furthermore, using CRISPR/Cas9 knockout insulinoma β-cell lines of Brd2, Brd3, and Brd4 and BD1 vs. BD2 specific chemical inhibitors, we identified key mechanisms through which this altered transcriptional profile occurs. This work provides important mechanistic insights to disease onset and progression of autoimmune diabetes for which current therapies are ineffective.

Disclosure

J. Nord: None. S. Wynia-Smith: None. B.C. Smith: None.

Funding

American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119359)
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<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<0.005; n=9) and reactive oxygen species production was increased (33 vs. 58 pmols/s/g tissue; P<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 <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<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.
217-LB: A Novel GPR119 Agonist, DA-1241, Improves Hepatic Inflammation and Fibrosis in ob-NASH Mice
Authors: PARK HANSU , LEE BORAM , CHAE YUNA , KIM MI-KYUNG
Published: June 2020

GPR119 activation is known to inhibit de novo lipogenesis in hepatocytes, but it still remains elusive if and how GPR119 agonists can affect the pathogenesis of hepatic inflammation and fibrosis in NASH. Herein, we report the therapeutic potential of DA-1241 for NASH, especially for hepatic inflammation and fibrosis. DA-1241 was given to ob/ob mice with western diet for 10 weeks. Plasma and liver tissue samples were tested for biochemical and histological analyses. Human monocyte cells and primary hepatic stellate cells were used for in vitro proof-of-concept. At the end of experiment, ob/ob NASH mice distinctly exhibited increased plasma total cholesterol and hepatic lipid accumulation, but plasma glucose and triglyceride values were within normal range. After 10-weeks of treatment, DA-1241 significantly blocked the progression of hepatic inflammation and fibrosis compared to the NASH control (-39% and -64% for NAS and fibrosis score; p<0.05), while MBX-2982, a GPR119 agonist under clinical development, failed to reach statistical significance at the same dose (-19.4% and -29%; p>0.05). Moreover, plasma total glucagon-like peptide-1 levels were increased by DA-1241 treatment, but not by MBX-2982. Plasma ALT and AST levels were significantly lower in DA-1241-treated mice, which were much lower than those of MBX-2982-treated mice. Of note, DA-1241 were more efficacious than MBX-2982 in reducing the hepatic expression of fibrotic proteins such as type 1 collagen, α-SMA, and TIMP1, and pro-inflammatory proteins including CCL2, TNFα. To explore its underlying modes of action in vitro, THP-1 macrophages or primary hepatic stellate cells were activated by LPS or TGFβ, respectively. DA-1241 inhibited the differentiation and activation of macrophages and blocked stellate cells activation. Our findings suggest that DA-1241 has a therapeutic potential for NASH, which may be partly attributed to blocking macrophage and stellate cell activation in addition to the inhibition of lipogenesis.

Disclosure

H. Park: Employee; Self; Dong-A ST Co., Ltd. B. Lee: Employee; Self; DONG-A ST Co,Ltd. Y. Chae: Employee; Self; Dong-A ST Co., LTD. M. Kim: Employee; Self; Dong-A ST Co., Ltd.
2172-PUB: Factors Influencing Parent Emotional Functioning after Young Child’s Type 1 Diabetes Diagnosis
Authors: TULLY CARRIE , HILLIARD MARISA E. , MONAGHAN MAUREEN , WANG JICHUAN , STREISAND RANDI
Published: June 2020

Introduction: Young child type 1 diabetes (YC-T1D) diagnosis can cause significant stress. While rates of increased depression have been documented, less is known about parent general emotional functioning (EF). This study aims to evaluate four hypothesized domains that may be related to parents’ EF: family characteristics, diabetes health characteristics, family protective factors (PF), and diabetes-specific functioning.

Method: 157 newly diagnosed YC-T1D (M age=4.43±1.67; M days post diagnosis =28.78±15.10) and their primary caregivers (72% Caucasian, 90% female) were assessed for an RCT evaluating a behavioral intervention. Medical data were extracted from the EHR. Parents completed a psychosocial battery at baseline; selected measures were identified to explore hypothesized domains associated with parents’ EF: family characteristics (Race), PF (Protective Factors Survey, Social Support), diabetes-specific functioning (Self-Efficacy for Diabetes-Parent) and parent EF (Perceived Stress Scale).

Results: Table 1 presents findings from regression analyses.

Conclusion: Preliminary findings demonstrate associations among family characteristics, PF, and diabetes-specific functioning with parent EF. Results provide initial support for a broader model, which may incorporate additional variables; future research may examine a broader model over the first year after diagnosis.

Disclosure

C. Tully: None. M.E. Hilliard: None. M. Monaghan: Research Support; Self; American Diabetes Association. J. Wang: None. R. Streisand: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102561)
218-LB: Liver-Humanized Mice Reveal Similarity and Divergence in Genomic Response between Human and Mouse
Authors: JIANG CHENGFEI , CAO HAIMING
Published: June 2020

Mouse is the most widely used preclinical animal model yet the translational rate is dismal. To understand the molecular underpinnings of the differential pathophysiology between human and mouse, we analyzed similar or discordant gene expression networks regulated by a variety of metabolic conditions under multiple complementary experimental settings, and tested these regulations in humanized mice where the confounding factors are minimized. We first analyzed human and mouse liver transcriptomes derived from conditions ranging from differentially expressed genes in fatty liver disease to genes regulated by transcriptional or posttranscriptional factors. In addition to genes that are exclusively regulated in human or mouse, we identified that a large fraction of commonly regulated genes (up to 50%) exhibit completely opposite regulation. To determine the intrinsic similarity and differences between human and mouse liver biology, we further analyze gene expression in a humanized mouse model in which human and mouse hepatocytes co-exist in the humanized liver and are exposed to identical in vivo metabolic milieu. Strikingly, divergent gene expressions in human and mouse hepatocytes are recapitulated in the humanized mice. By integrating the data of humanized mice, we are able to reveal the intrinsic consistently and oppositely regulated genes and pathways between human and mouse in each condition we analyzed. Although the regulations of these genes are largely condition dependent, the most constant consistently or oppositely regulated pathways can be identified. Furthermore, our analysis suggests that human and mouse lncRNAs might play a critical role in the differential gene regulations in human and mouse. Our work provides a foundation to understand the molecular basis for divergent metabolic responses in human and mouse liver, highlighting the importance of a human or humanized system for translational studies.

Disclosure

C. Jiang: None. H. Cao: None.
2181-PUB: The Patient Characteristics of Contour Diabetes App Users Worldwide
Authors: RICHARDSON JAMES M. , PARDO SCOTT , SHAGINIAN RIMMA
Published: June 2020

Since 2016 more than 600,000 people have been utilizing the CONTOUR®DIABETES app (CDA) in combination with connected CONTOUR® Blood Glucose Monitoring Systems (BGMSs) worldwide. The aim of this analysis was to assess demographic data of CDA users from North America (NA) 42.6%, Europe (EU) 47.9% and Asian Pacific (APAC) region 4.5%. We examined the CDA database of patients that uploaded at least one blood glucose (BG) result during September 2019. BG results were automatically synched from a BGMS to CDA via BLE (Bluetooth Low Energy) or had the capability to enter manually in the app. All other data were self-reported and included age, gender, diabetes type, therapy mode, physical activities, carbs and location. From 625,837 users 19.9% of patients recorded at least one BG result during September 2019. In all three regions the proportion of patients above 60 years old was similar (NA 26.6%, EU 23.8%, APAC 26.5%). There were slightly fewer male users in U.S. than in EU and APAC (NA 49.3%, EU 52.6%, APAC 52.8%). The proportion of T1D and T2D users was as follows in NA: T1D 12.9%, T2D 48.6%, EU :T1D 23.2%, T2D 39.4% and APAC: T1D 15.9%, T2D 48.9%. Analysis of treatment mode demonstrated that T2D patients treated by insulin alone or in combination with other glucose lowering medications (OAM) differed from region to region (NA 28.0%, EU 38.1%, APAC 14.5%). Among them daily BG testing adherence also varied (NA 25.5%, EU 33.3%, APAC 23.9%). The daily BG testing in T1D patients was also different per region (NA 30.3%, EU 33.8%, APAC 26.3%). Around 20% of patients that registered with CDA since 2016 were actively using the app. The majority of them were T2D patients across all regions. The proportion of insulin use in this population varied by region. This analysis showed that real world BG testing frequency in T2D patients treated with insulin alone or in combination with OAM as well as in T1D patients appears lower than current recommendations. Further analysis is planned to identify the profile of patients who would mostly benefit from the use of CDA.

Disclosure

J.M. Richardson: Employee; Self; Ascensia Diabetes Care. Employee; Spouse/Partner; Ascensia Diabetes Care. S. Pardo: Employee; Self; Ascensia Diabetes Care. R. Shaginian: Employee; Self; Ascensia Diabetes Care.
2185-PUB: Once-Weekly Semaglutide 1mg vs. Empagliflozin 25mg as Add-On to Metformin Monotherapy in Patients with Type 2 Diabetes: A Meta-regression Analysis of Individual Patient Data
Authors: LINGVAY ILDIKO , CATARIG ANDREI-MIRCEA , SANDBERG ANNA , LAWSON JACK , CAPEHORN MATTHEW , JOHANSEN PIERRE , SHAW ROBERT D. , PAINE ABBY
Published: June 2020

There are no published head-to-head trials of once-weekly semaglutide 1 mg vs. once-daily empagliflozin 25 mg in type 2 diabetes (T2D). We indirectly compared the pooled semaglutide arms in SUSTAIN 2, 3 and 8 with the empagliflozin arm in PIONEER 2 using individual patient data, for those on metformin monotherapy. Although all trials had similar inclusion criteria and duration, meta-regression analyses adjusting for effect modifiers and prognostic factors further controlled for differences in design and population. Mean baseline characteristics were similar with semaglutide and empagliflozin (age: 56 vs. 58 years, diabetes duration: 7 vs. 8 years, BMI: 33 vs. 33 kg/m2, HbA1c: 8.2% vs. 8.1%, respectively). Semaglutide reduced mean HbA1c by -1.4 vs. -0.8%-point with empagliflozin (p<0.001), and body weight by -5.3 vs. -3.7 kg with empagliflozin (p<0.001, Table). Sensitivity analyses, which were performed to assess robustness of these findings, supported these results. A significantly greater proportion of patients on semaglutide vs. empagliflozin also achieved HbA1c targets and clinically relevant weight-loss targets (Table). In this indirect comparison, pooled semaglutide 1 mg provided significantly greater HbA1c reduction and body weight loss compared with empagliflozin 25 mg in patients with T2D on metformin monotherapy.

Disclosure

I. Lingvay: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk A/S, Sanofi, TARGET PharmaSolutions, Valeritas, Inc. Other Relationship; Self; Novo Nordisk A/S. A. Catarig: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A. Sandberg: None. J. Lawson: Employee; Self; Novo Nordisk A/S. M. Capehorn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. P. Johansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. R.D. Shaw: Consultant; Self; Novo Nordisk A/S. A. Paine: Consultant; Self; Novo Nordisk A/S.

Funding

Novo Nordisk A/S
2193-PUB: Effect of One Month Basal Insulinization in Addition to OADs Initiation on Glycemic Parameters in Newly Diagnosed Treatment-Naïve Type 2 Diabetes Patients Presenting with Osmotic Symptoms or Glucotoxicity: A Long-Term Follow-Up Study
Authors: JAGANMOHAN BALAJI , MATHUR PRAVEER R. , DAS SAMBIT , RM MANIKANDAN , SANJOY P , MANOHAR SUDEEP P. , AHMED AFTAB , BS NARENDRA , SAI JAYAPRAKASH , MC DEEPAK , MANI AKILA , KOLUKULA VAMSI K.
Published: June 2020

Aim: To assess the glycemic outcomes of early basal insulin therapy in newly diagnosed treatment naïve T2DM patients presenting with glucotoxicity.

Methods: A cross-sectional observational retrospective data analysis of T2DM patients visiting diabetes specialty clinic across India from January 2016 to October 2019. Patients initiated on basal insulin for one month along with oral antidiabetes drugs were included in the analysis. The demographic, clinical, and glycemic investigations data were collected from electronic medical records. Patients were followed up for at least 4 clinic visits at 3 months interval.

Results: Total 527 newly diagnosed T2DM patients were included. Males: 352 (67%) and females were 175 (33%). Mean age was 50.5 years and BMI was 27.7 kg/m2. Patients glycemic parameters at the time of initiation of insulin therapy were highly uncontrolled, their mean HbA1c, FBG, and PPBG were 10.9%, 236 mg/dL and 335 mg/dL. Among these patients, only 87 patients regularly followed up to clinic for a year. The average follow-up time period was 250 days. These patients’ glycemic parameter reduced significantly from baseline through last follow up visit. HbA1c reduced from 12.2% to 7.5%; FBG 270 mg/dL to 135mg/dL; PPBG 370 mg/dL to 181 mg/dL (p <0.001). Further, there was clinically significant improvement in the lipid profile of these patients. In addition, TC 199 to 151 mg/dL; TG 222 to 161 mg/dL; low density lipoprotein 122 to 81 mg/dL were also reduced.

Conclusions: Early initiation of basal insulin therapy has shown to reduce glycemic burden and the disease progression suggesting early insulinization should be the treatment option for effective control of diabetes and long term benefits in avoiding the complications. This is even supported by international guidelines as part of an individualized approach to chronic disease management.

Disclosure

B. Jaganmohan: None. P.R. Mathur: None. S. Das: None. M. Rm: None. P. Sanjoy: None. S.P. Manohar: None. A. Ahmed: None. N. Bs: None. J. Sai: None. D. Mc: None. A. Mani: None. V.K. Kolukula: None.
2194-PUB: Structured Basal-Bolus Insulin Injection in Hospitalized Patients with Type 2 Diabetes: Tertiary Teaching Hospital Experience
Authors: MOON SUN JOON , JANG HAN NA , YANG YE SEUL , KWAK SOO HEON , JUNG HYE SEUNG , PARK KYONG SOO , CHO YOUNG MIN
Published: June 2020

Objectives: Although the efficacy of basal-bolus insulin regimen (BBI) in type 2 diabetes (T2D) patients has been demonstrated in clinical studies, few studies have revealed changes in glycemic control following the introduction of BBI in hospital practice. This study was aimed to evaluate the effect of structured BBI in clinical practice for hospitalized patients with T2D.

Methods: We retrospectively analyzed non-critically ill T2D patients treated with insulin, who were hospitalized for glycemic control at Seoul National University Hospital (SNUH) from 2004 to 2018. The effects of BBI in T2D patients after 2007, when the current BBI protocol was introduced to SNUH, compared to that of the other types of insulin in T2D patients until 2007. Patients were propensity-score-matched in a 1:1 ratio.

Results: Among 294 BBI treated patients (age, 60.4 ± 13.8 years; male, 141 [48.0%]; HbA1c, 10.4 ± 1.9%) and 294 other insulin-treated patients (age, 59.9 ± 12.6 years; male, 148 [50.3%]; HbA1c, 10.3 ± 1.9%), mean admission pre-prandial blood glucose level were 181.0 ± 37.7 mg/dl and 200.0 ± 34.0 mg/dl, respectively (P <0.05). Blood glucose target of <140 mg/dl was achieved in 56.1% of patients in the BBI group and in 33.7% of those in the other insulin group on the sixth day of admission. The mean first target achievement day was 3.6 ± 1.3 days in the BBI group and 4.2 ± 1.5 days in other insulin groups, respectively (P <0.05). Events of hypoglycemia (≤70 mg/dL) and severe hypoglycemia (<55 mg/dL) were not different between the groups.

Conclusion: In this study of clinical practice in a tertiary hospital, structured BBI showed significantly improved glycemic control compared to other types of insulin regimens for T2D patients.

Disclosure

S. Moon: None. H. Jang: None. Y. Yang: None. S. Kwak: None. H. Jung: None. K. Park: None. Y. Cho: None.
22-LB: Incident Myocardial Infarction Is Associated with Insulin Resistance and Liver Fibrosis Scores
Authors: M ÖSER CLARA , ZAHARIA OANA P. , ROTHE MAIK , HWANG JONG-HEE , BOBROV PAVEL , BURKART VOLKER , B ÖNNER FLORIAN , JUNG CHRISTIAN , KELM MALTE , RODEN MICHAEL , SZENDROEDI JULIA
Published: June 2020

Insulin resistance and nonalcoholic fatty liver disease associate with increased risk of cardiovascular disease and predict a worse outcome. The underlying mechanisms are yet unclear. We hypothesized that individuals who suffer from their first acute myocardial infarction (MI) already feature not only lower insulin sensitivity (M-value) and ejection fraction (EF), but also higher hepatocellular lipids (HCL) and liver fibrosis scores (MRE) than matched individuals without MI. We compared participants of the DISTEMI (DIabetes and ST-Elevation MI) Study at 6-12 weeks after MI (MI+; n=21, 81% male, 29% type 2 diabetes, age 61±8 years, BMI 26.8±2.8 kg/m2, HbA1c 5.8±1.0%) with humans without MI (MI-; n=34, 71% male, 32% type 2 diabetes, age 57±8 years, BMI 27.8±3.1 kg/m2, HbA1c 5.5±0.6%). Participants were matched by sex, age, HbA1c and body mass index. They underwent a 75-g oral glucose tolerance and hyperinsulinemic-euglycemic clamp tests. HCL, MRE, EF, infarct size and microvascular obstruction (MVO) were measured with 1H-magnetic resonance (MR) spectroscopy and imaging. MI+ had a lower whole-body insulin sensitivity (M-value: 7.3±2.0 vs. MI- 9.0±3.1 mg*kg-1*min-1, p<0.05). HCL was comparable (2.9±2.8% vs. 5.7±6.7%), while MRE was higher in MI+ compared to MI- (2.5±0.4 kPa vs. 2.1±0.4 kPa, p<0.05). EF was lower in MI+ than in MI- (53±16% vs. 65±7%, p<0.05). In MI+, EF correlated negatively with infarct size (r=-0.91) and MVO (r=-0.82) as well as with HbA1c (r=-0.61) and fasting blood glucose (r=-0.61, all p<0.05).

In conclusion, individuals with incident MI have lower insulin sensitivity, reduced ejection fraction and higher liver fibrosis scores, which relate to worse glucose metabolic control and may contribute to increased risk of heart failure after the first MI.

Disclosure

C. Möser: None. O.P. Zaharia: None. M. Rothe: None. J. Hwang: None. P. Bobrov: None. V. Burkart: None. F. Bönner: None. C. Jung: None. M. Kelm: Research Support; Self; Abbott, B. Braun Medical Inc., Philips. Other Relationship; Self; Amgen, Ancora Heart, Dai-ichi Life Insurance Company. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. J. Szendroedi: None.

Funding

SFB 1116
22-OR: Increased Adverse Glycemia and Hospital-Acquired Infection following Withdrawal of the RAPIDS Early Intervention Model for Diabetes Care in Medical and Surgical Inpatients
Authors: KYI MERVYN , WANG JOANNA , WRAIGHT PAUL R. , COLMAN PETER G. , FOURLANOS SPIROS
Published: June 2020

Background: We previously reported an early intervention model of diabetes care, whereby an inpatient diabetes team performed glycemic surveillance and provided proactive management within 24 hours of admission. In the RAPIDS cluster randomized study, early intervention decreased hyperglycemia and hospital-acquired infection (HAI) compared to usual care [Diabetes Care. 2019;42(5):832-40]. We investigated if improvements in ward glucose control and patient outcomes were sustained following the completion of proactive care intervention.

Methods: We performed a 3-month extension observational study on eight medical and surgical wards immediately following the completion of the RAPIDS study, recruiting consecutive inpatients with pre-existing diabetes or new hyperglycemia. Glycemic and clinical outcomes during the three time periods: baseline (usual care), active (proactive care), and extension (usual care) were compared.

Results: We analyzed 1518 inpatients (mean age 71y, 87% type 2 diabetes, 25% insulin-treated) and observed 8610 patient-days. In the intervention wards, during baseline, active and extension periods, patient-day mean glucose were: mean 9.4 (SD 3.3), 9.0 (2.7), and 9.4 (3.1) mmol/L (p<0.001); and proportion of patient-days with mean glucose >15 mmol/L were 7.3%, 3.3%, and 5.7% (p<0.001). HAI rates paralleled hyperglycemia: 6.4% during baseline period, 2.4% active period (p=0.022 vs. baseline), and 5.4% extension period (p=0.056 vs. active). In the control wards there was no change in hyperglycemia or HAI rates.

Conclusion: Following withdrawal of proactive care with early intervention, hyperglycemia and HAI rates increased to baseline levels. Ongoing intervention with specialist diabetes care teams may be required to achieve sustained glycemic and clinical improvements in hospital.

Disclosure

M. Kyi: None. J. Wang: None. P.R. Wraight: None. P.G. Colman: None. S. Fourlanos: Advisory Panel; Self; Medtronic, Mylan, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk Inc.

Funding

Australian Diabetes Society; Sanofi; National Health and Medical Research Council of Australia (APP1093152); Royal Melbourne Hospital (GIA-030-2019, GIA-027-2016)
2201-PUB: The Combined Effect of Gender and Age on Remission Rate in Patients with Newly Diagnosed Type 2 Diabetes after Intensive Insulin Therapy
Authors: XUESI WAN , HUANG ZHIMIN , LIU LIEHUA , LI YANBING
Published: June 2020

According to our previous study, short-term intensive insulin therapies(SIIT) can induce long-term remission from T2DM in half of the patients. It’s interesting that young male patients seem to recover better. In order to examine the combined effect of gender and age on remission of T2DM, an observation of 160 patients with newly diagnosed T2DM (n=160, 103 male, aged 50±10 ys, HbA1C 11±2.1%) after 2-week therapy were studied. Men and women differed in age with T2DM onset (47±10 ys vs. 54 ±9ys, Fig A.). The average remission time in a 5-year follow-up was 30 months for men and 21 months for women(Fig B.). But in the same age stage, the remission time was similar between male and female, as well as the improvement of HOMA-B and HOMA-IR by this therapy(Fig C., D., E.).There were no statistical gender differences in each age stage.

In conclusion, the gender differences in age of onset for T2DM affected the remission rate from T2DM after SIIT. The male often has diabetes earlier and was better to recover.

Disclosure

W. Xuesi: None. Z. Huang: None. L. Liu: None. Y. Li: None.

Funding

National Key Research and Development Program of China (2018YFC1314100)