bluuebunny/crossref_metadata_2025_split huggingface dataset:
211-OR: Hypothalamic Slug Couples Overnutrition States to Epigenetic Reprogramming of Leptin Neural Circuits, Obesity, and Type 2 Diabetes
Authors: KIM MIN-HYUN , JIANG LIN , MYERS MARTIN G. , RUI LIANGYOU 
Published: June 2020

Leptin protects against obesity and metabolic disease mainly through leptin neural circuits in the hypothalamus. Leptin binds to and activates hypothalamic leptin receptors (LepR), thereby suppressing food intake and increasing energy expenditure. Counterintuitively, obesity is associated with hyperleptinemia in rodents and humans. Moreover, leptin therapies fail to ameliorate obesity in humans. These observations support a notion that obese subjects develop leptin resistance. Multiple positive and negative regulators of LepR signaling have been identified to influence leptin sensitivity, including Sh2b1, SOCS3, and PTP1b. However, factors, which couple overnutrition states to leptin resistance, are not fully understood. Here, we observed that high fat diet (HFD) feeding markedly upregulates Slug, a nuclear epigenetic regulator, in the hypothalamus. Remarkably, LepR neuron-specific deletion of Slug (SlugΔLepR) reversed HFD-induced hyperleptinemia, energy imbalance, obesity, insulin resistance, glucose intolerance, and liver steatosis. Conversely, overexpression of Slug (MBHSlug) but not an epigenetic-defective Slug mutant in the mediobasal hypothalamus resulted in obesity, insulin resistance, glucose intolerance, and fatty liver disease in mice. We found that Slug physically binds to the LepR promoter and suppresses LepR promoter activity; accordingly, hypothalamic LepR expression was high in SlugΔLepR mice and low in MBHSlug mice. Furthermore, Slug increased the levels of LepR promoter H3K27 methylation, a repressive epigenetic mark, in the hypothalamus, presumably by recruiting H3K37 methytransferase Ezh2 to the LepR promoter. Indeed, Ezh2 inhibitor treatment blocked Slug suppression of LepR promoter activity. Collectively, we unravel a previously unrecognized Slug-elicited epigenetic reprograming of LepR pathways that couple overnutrition states to leptin resistance, obesity, and metabolic disease.

Disclosure
M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.

Funding
National Institutes of Health (F32DK120111)
2128-P: 12/15-Lipoxygenase Regulates Macrophage Migration during Islet Inflammation
Authors: KULKARNI ABHISHEK , PINEROS ANNIE , IBRAHIM SARA , HERNANDEZ-PEREZ MARIMAR , TERSEY SARAH A. , MIRMIRA RAGHAVENDRA , ANDERSON RYAN M. 
Published: June 2020

Pancreatic islet inflammation is a shared characteristic of type 1 and type 2 diabetes pathogenesis, and macrophage infiltration has been shown to exacerbate this inflammation. The enzyme 12/15-Lipoxygenase (12/15-LOX) which is involved in polyunsaturated fatty acid metabolism, has also been implicated in islet inflammation. Based on its established roles in cellular migration in other contexts, we hypothesized that 12/15-LOX promotes macrophage infiltration. To test this hypothesis, we used two complementary model systems: zebrafish and mice. First, we knocked down 12/15-LOX in Tg(ins:NTR) zebrafish with an antisense morpholino. When these zebrafish are treated with the prodrug metronidazole (MTZ), β cells are specifically injured, and macrophages accumulate in the islet. After a 6-hour incubation with MTZ, we observed a significant reduction in the number of infiltrating macrophages in the islets of 12/15-LOX knockdown larvae as compared to control larvae (2.7±0.8 vs. 1.17±0.7, P&lt;0.05). Similarly, injured β cells in zebrafish treated with the 12/15-LOX inhibitor ML355 showed a significant reduction in the number of islet-infiltrating macrophages compared to vehicle-treated larvae (3.67±0.7 vs. 1.2±0.3, P&lt;0.05). Next, using transwell assays, we measured the migration of peritoneal macrophages that were isolated from 12/15-LOX knockout mice in media that was conditioned by islet culture. Again, we observed a significant reduction in macrophage migration with 12/15-LOX deficiency compared to controls (162.8±15.5 vs. 108.4±15.1, P&lt;0.05). Mechanistically, we found that the expression of the chemokine receptor CXCR3 was significantly downregulated in 12/15-LOX-knockout macrophages. Taken together, our data reveal a role for 12/15-LOX in macrophage migration that is conserved across species. Importantly, our study indicates that the signaling pathways downstream from 12/15-LOX are potential therapeutic targets for the resolution of inflammation-induced damage in the islets.

Disclosure
A. Kulkarni: None. A. Pineros: None. S. Ibrahim: None. M. Hernandez-Perez: None. S.A. Tersey: None. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. R.M. Anderson: None.
2149-PUB: The Changes in the Panel of Circulating Cytokines Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes
Authors: KORBUT ANTON I. , ORLOV NIKOLAI B. , FAZULLINA OLGA , KLIMONTOV VADIM 
Published: June 2020

Aim: To estimate the differences in the panel of circulating cytokines mediating low-grade inflammation and fibrosis in patients with type 2 diabetes (T2D) and chronic kidney disease.Methods: We examined 130 patients with T2D duration ≥10 years. Among them, 65 individuals had reduced estimated glomerular filtration rate (eGFR; 15-59 ml/min/1.73 m2) and 64 patients had increased albuminuria. Thirty healthy subjects were acted as control. Serum IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17A, bFGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF were assessed by multiplex analysis. Urinary nephrin and podocin, as podocyte injury markers, and WFDC-2, a marker of tubulointerstitial fibrosis, were assessed by ELISA.
Results: Patients with T2D and reduced eGFR had increased levels of IL-1ra, IL-8, IL-13 and decreased IL-7, IL-9 and IL-15 concentrations when compared to those with preserved renal function and control (all p&lt;0.05). Excretion of WFDC-2, but not podocyte markers, was increased in these patients (p≤0.02). The elevation of albuminuria was associated with enhanced excretion of nephrin and podocin (p&lt;0.0001), but no differences were found in the levels of all measured cytokines between patients with normal and elevated albuminuria. The levels of IL-2, IL-4, IL-5, IL-17A, bFGF, G-CSF, IP-10 and MIP-1α correlated negatively with eGFR. No correlations were found between measured cytokines and glomerular markers. There was positive correlation between WFDC-2 and MIP-1α. The levels of IL-10 and IL-15, two anti-inflammatory cytokines, correlated negatively with WFDC-2.
Conclusion: The obtained results demonstrate that decreased eGFR and increased urinary excretion of WFDC-2, a marker of tubulointerstitial fibrosis, are associated with a predominance of pro-inflammatory and fibrogenic molecules in the panel of circulating cytokines in T2D subjects.

Disclosure
A.I. Korbut: None. O. Fazullina: None. V. Klimontov: None.
2173-PUB: Assessment of the Knowledge and Perception of Diabetic Symptoms among Patients in a Poor Environment
Authors: ADZIKA VINCENT A. 
Published: June 2020

Introduction/Background: Diabetes mellitus is an endocrine disorder characterized by sustained hyperglycaemia due to loss of insulin secretion and/or impairment of insulin sensitivity at target tissues. More than 15.9 million people have diabetes accounting for more deaths in addition to infectious diseases in low income countries in Africa. Despite the alarming statistics the etiology and prognosis leading to the prevention and management of diabetes still lacks the needed attention and comprehensive education among patients in low income countries.
Aim: The aim of this study is to examine the knowledge of causes and effects of diabetic symptoms among patients in a low income country.
Method: A qualitative methodological framework focusing on participant’s illness experiences and personal beliefs about diabetes was used. We purposely recruited 30 diabetic patients who exhibited diabetic symptoms. After demographic information, each respondent completed the LANSS to ascertain neuropathy after which a semi structured interview guide was used to elicit each respondent’s view regarding diabetes. Data was transcribed and analyzed using a thematic approach.
Results: Most respondents did not know their diabetic type and the precipitating factors for their diabetic symptoms. However some reported that their diabetes was spiritual and might have been contracted through bewitchment and other supernatural means. Others traced their condition to hereditary but the main causes of diabetes were generally lacking. Majority didn’t know their medications but requested for the need to have a much potent medication.
Conclusion: Effective education and knowledge on the etiology, causes and prognosis of diabetes is generally lacking among patients living in poor countries.

Disclosure
V.A. Adzika: None.
2174-PUB: Profiling of Young Diabetes in India: A Cross-Sectional Analysis Report
Authors: NK NARAYANAN , DWARAKANATH CS , S VENKATARAMAN , RM MANIKANDAN , BS NARENDRA , DAS SAMBIT , DASH KALPANA , PALADUGU SRIDEVI , SESHADRI KRISHNA 
Published: June 2020

Aim: The purpose of this study was to profile young-onset (defined as up to age 40 years) diabetes patients in India.
Methods: The current analysis is a retrospective data analysis of young-onset diabetes patients. Young age diabetes is defined as patients diagnosed with diabetes between 18 to 40 years of age. T1DM and other secondary diabetes were excluded while profiling these patients. Patient’s data was extracted from EMRs of Apollo Sugar Outpatient clinics (n=35) from January 2018 to October 2019. Descriptive statistics were applied to analyze the data and report the results.
Results: Of the total 85568 diabetes patient’s records, 4152 (5%) young diabetes patients were identified as fulfilling the criteria of T2DM of early-onset. Males were 2495 (60%) and females were 1657(40%). Mean blood pressure was 122/78 mmHg, average BMI was 28.4 kg/m2, 15% had hypertension, 39% had dyslipidemia and 1% had CAD. Positive family history was recorded in 5% of patients, and 1% were recorded to have current or past smoking. Mean HbA1c was 8.4%, FBG and PPBG were 190 mg/dL and 273mg/dL. Mean cholesterol 179mg/dL, HDL 40mg/dL, LDL 111 mg/dL, and TG 232 mg/dL and creatinine 0.9mg/dL. The average no of antidiabetes drugs prescribed was 2. Nearly 36% of the patients were on oral agents and insulins, 30% were on statins.
Conclusions: In our cross-sectional analysis 5% of patients over 18 month’s period had a diagnosis fulfilled the criteria for early-onset diabetes. There was a male preponderance. The average BMI was considerably higher. The majority had poor control and greater than a third of patients were on insulin. Other comorbidities such as hypertension and dyslipidemia were also prevalent. The higher BMI poor control and presence of comorbidities are ominous predicting a higher progression to complications given the longer disease burden in these patients. Our data indicate the need for further efforts in preventing detecting and treating diabetes in this young group of patients.

Disclosure
N. Nk: None. C. Dwarakanath: None. V. S: None. M. Rm: None. N. Bs: None. S. Das: None. K. Dash: None. S. Paladugu: None. K. Seshadri: None.
2182-PUB: Feasibility of Extended Calibration Intervals with a Long-Term, Implantable CGM System
Authors: GUPTA PIYUSH , BUTLER ANTHONY , BERTSCH KRISTA , JONES HANNAH , LEE MELISSA H. , OBEYESEKERE VARUNI R. , MARTHA SANDRA L. , JENKINS ALICIA , ONEAL DAVID N. 
Published: June 2020

Background: Continuous Glucose Monitoring (CGM) technology has improved glycemia in people with diabetes. However, user burden including frequent calibration, and reinsertion of short-term devices limits adoption of this technology.
Aim: Our objective was to retrospectively analyze CGM data from a fully implanted prototype sensor to assess feasibility of an extended calibration interval.
Methods: The Eclipse® ICGM® System was surgically inserted in the lower abdomen, superficial to the rectus muscle sheath (Figure 1) in 6 adults with T1 diabetes, Mean (SD) age 42(12) years; 33% Females, HbA1c 7.1% (1.2)%/54(13) mmol/mol. For 6 months participants self-monitored blood glucose 4 times/day and wore a Dexcom G5 CGM. In addition, monthly clinic visits include meal-tests with frequent sampling YSI plasma glucose for paired analyses. Analyses of investigational device CGM data was retrospective against benchmark measurements.
Results: There were no device associated adverse events. Data from three participants demonstrate intervals of 30, 48 and 85 days between calibrations without impacting overall performance. Preliminary measures show clinically relevant accuracy of &gt;95 % within the A+B ranges.
Conclusion: Interim data supports extended interval calibration for the fully implanted prototype Eclipse® ICGM® System which holds promise of CGM with fewer device interactions and enhanced patient experience.

Disclosure
P. Gupta: Employee; Self; GlySens Incorporated. A. Butler: Employee; Self; GlySens Incorporated. K. Bertsch: None. H. Jones: None. M.H. Lee: Research Support; Self; Medtronic. Speaker’s Bureau; Self; AstraZeneca, Medtronic. V.R. Obeyesekere: None. S.L. Martha: None. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. D.N. ONeal: None.
221-OR: Does Cell Therapy Improve the Quality of Life of Patients with Chronic Limb-Threatening Ischemia? A Randomized Controlled Trial
Authors: HUSÁKOVÁ JITKA , BEM ROBERT , NEMCOVA ANDREA , FEJFAROVA VLADIMIRA , JIRKOVSKA ALEXANDRA , DUBSKY MICHAL 
Published: June 2020

Background: Autologous cell therapy (ACT) is the last option for patients with no-option chronic limb-threatening ischemia (NO-CLTI) and severe pain. The aim of our study was to assess the impact of ACT on a patient’s quality of life, chronic pain and depression using standardized questionnaires.
Methods: Forty patients with NO-CLTI were randomized and divided into groups treated initially with ACT (iACT, n=20) or standard conservative therapy (iST, n=16); 4 patients dropped out of the study. After 3 months, those in the standard therapy (ST) group were switched to (cell therapy crossover). All patients filled out the standardized EQ-5D questionnaire assessing their quality of life. Pain was evaluated using a special questionnaire including the Visual Analogue Scale (VAS) and Wong-Baker Faces (WB). The questionnaires were evaluated before randomization; in the iST group at 3 months after ST and then at 3 months after ACT.
Results: Pain was significantly reduced in the iACT group after 3 months compared to baseline in both VAS and WB scores (both p&lt;0.001); in the iST group, we observed even worsening of both pain scores without a significant difference (NS). After the cell therapy crossover of in the iST group, both pain scores increased significantly after 3 months (both p&lt;0.001). Quality of life measured by EQ-5D was improved after 3 months of ACT (p&lt;0.001) while not changing in the iST group after 3 months of ST (NS). After the crossover to ACT, quality of life was significantly improved also in the iST group (p&lt;0.001). We observed a trend in towards a decrease in depression rate after 3 months of iACT from 45 to 33%, whereas the depression rate was slightly increased after 3 months of ST (from 56 to 61%) to decrease from 56 to 18% in the iST group after cell therapy crossover (all NS).
Conclusion: Our study showed significant pain reduction in NO-CLTI patients after ACT; this treatment also led to a decrease in depression rate and overall improvement in their quality of life.

Disclosure
J. Husáková: None. R. Bem: None. A. Nemcova: None. V. Fejfarova: None. A. Jirkovska: None. M. Dubsky: None.

Funding
Ministry of Health of the Czech Republic (16-27262A); Project for Development of Research Organization (00023001); IKEM, Prague, Czech Republic
2233-PUB: Electronic Delivery Mode for Completing PROMs in the Norwegian Diabetes Register for Adults (NDR-A)
Authors: HAUGSTVEDT ANNE , HERNAR INGVILD , STRANDBERG RAGNHILD B. , COOPER JOHN G. , LØVAAS KARIANNE F. , MADSEN TONE VONHEIM , REKDAL MAGNE , IVERSEN MARJOLEIN M. , GRAUE MARIT 
Published: June 2020

Background: The NDR-A is a national diabetes quality register. Norwegian health authorities specify that quality registers must include data from Patient-Reported Outcome Measures (PROMs) in addition to biomedical data. NDR-A retrieves data from electronic patient records (EPR). This raises the possibility of utilizing PROMs in clinical consultations. The main PROM included in NDR-A is the Problem Areas in Diabetes scale (PAID).
Aim: To test the feasibility of using electronic delivery mode to collect PROMs and examine how patients and health care providers experience the electronic PROMs and the EPR’s interfaces.
Methods: We invited 441 adults (&gt;18 yrs) with type 1 diabetes to complete PROMs via 1) a web interface from their home (n=304) or 2) a kiosk (touch-screen computer) in the outpatient clinic (n=137). Using a paper questionnaire and qualitative interviews, we examined patients and health care providers experiences with the electronic PROMs and the EPR’s interfaces.
Results: Through the web interface, we reached out to 215 (71 %) of the patients of which 114 (38 %) responded. On the kiosk in the clinic, 69 (50 %) patients completed the PROMs, 24 (18 %) did not attend scheduled consultations, 5 (4 %) did not participate due to technical problems, 20 (15 %) declined participation, and 19 (14 %) did just not approach the kiosk as instructed (when a researcher was not present to remind them). Patients who completed the paper questionnaire experienced the PROMs to be relevant and were in high degree willing to complete PROMs annually. In the qualitative interviews, health care providers reported the PROMs and the EPR’s interfaces to be appropriate to improve the focus on patients’ diabetes-related psychological and emotional challenges and needs.
Conclusion: The tested modes for electronic capture of PROMs have limitations in reaching patients. However, both patients who completed the PROMs and the health care providers were satisfied with the electronic PROMs and the EPR’s interfaces.

Disclosure
A. Haugstvedt: None. I. Hernar: None. R.B. Strandberg: None. J.G. Cooper: None. K.F. Løvaas: None. T. Madsen: None. M. Rekdal: Employee; Self; DIPS AS. M.M. Iversen: None. M. Graue: None.
2247-PUB: Shared Education Visits for Adolescents with Type 1 Diabetes
Authors: WILKES MEREDITH , MURPHY TAYLOR , ALUF ANNA , SPERBER DANA , SHERRY AMELIA , SETHURAM SWATHI , CHOLEVA LAURYN , RAPAPORT ROBERT 
Published: June 2020

Introduction: Deterioration in glycemic control often occurs during adolescence in children with type 1 diabetes (T1D). Shared appointments have been shown to improve quality of life scores and treatment adherence in children with chronic illnesses.
Objective: To examine the impact of combined individual visits and shared education appointments in adolescents with T1D on diabetes control, self-management, and diabetes related distress.
Methods: Adolescents ages 11-19y with T1D for over 1y and poor control/adherence defined by HbA1C &gt; 9%, 2 or more DKA episodes in the past year or 2 missed appointments were enrolled in a 6 month DKA prevention program consisting of monthly individual visits followed by an hour long shared education visit. HbA1C levels were obtained every 3 mo. Participants completed a diabetes distress score (DDS) and diabetes self-management questionnaire (DMSQ) prior to participation and at the 6th visit. Participants were followed for an additional 6 months after completion of the program. Those who attended 2 or more session were included in the analysis.
Results: Ten adolescents (8 female, average age 13.9 y, diabetes duration from 1-11 y, average A1C 10.6% SD 2.0) were enrolled. None of the 10 participants had DKA during the program. There was no statistically significant change in A1C. No changes were noted in the DDS; however there was improvement in dietary control on DMSQ from 4.0 to 5.7 (p value 0.058). Six attended 5 or more of the sessions. Those 6 participants had a decrease in average A1C by 0.3% over 6 mo with no DKA episodes within 6 mo of completion. The 4 participants who attended 2-4 sessions had an increase in average A1C of 0.85% over the same period and 3 had DKA episodes within 6 mo after completion.
Conclusions: Shared education visits may be a valuable approach to the care of adolescents with diabetes. No episodes of DKA and no significant changes in glycemic control were noted in 6 mo; however larger long-term studies are needed to explore whether continued shared visits can improve glycemic control.

Disclosure
M. Wilkes: None. T. Murphy: None. A. Aluf: None. D. Sperber: None. A. Sherry: None. S. Sethuram: None. L. Choleva: None. R. Rapaport: None.
2263-PUB: Consideration of Insulin Resistance Improves HbA1c-Based Type 2 Diabetes Risk Assessment
Authors: MEIGS JAMES B. , PORNEALA BIANCA C. , LEONG AARON , SHIFFMAN DOV , DEVLIN JAMES , MCPHAUL MICHAEL J. 
Published: June 2020

Background: T2D risk assessment is typically based on fasting glucose (FG) and HbA1c levels. We tested the hypothesis that HbA1c-based T2D risk assessment is improved by also considering another physiological axis, insulin resistance (IR), assessed using a fasting insulin (FI) homeostasis model (HOMA-IR).
Methods: We followed 2,205 white individuals from the Framingham Heart Study without T2D (medication use or FG &gt;=126 mg/dL) at baseline for a mean of 16 years. We used age-sex adjusted regression to model incident T2D as a function of baseline HbA1c and IR tertile of HOMA-IR (FI x FG/22.5).
Results: Of 266 incident T2D cases, 205 (77%) were in HOMA-IR tertile 3, and of these, 135 (66% of 205) had HbA1c &lt;5.7 (Table). Individuals in HOMA-IR tertile 3 had 16-year T2D CI rates of 20-35%. Both HbA1c and IR were independently associated with elevated incident T2D risk. We saw similar patterns in the 1,583 individuals with baseline FG &lt;100 mg/dL.
Conclusion: HbA1c and fasting insulin are commonly available clinical diagnostic tests. Combined consideration of high levels of both identifies the great majority of white individuals at highly increased risk for future T2D.

Disclosure
J.B. Meigs: Consultant; Self; Quest Diagnostics. B.C. Porneala: None. A. Leong: None. D. Shiffman: Employee; Self; Quest Diagnostics. J. Devlin: Employee; Self; Quest Diagnostics. M.J. McPhaul: Employee; Self; Quest Diagnostics.