bluuebunny/crossref_metadata_2025 huggingface dataset:
2055-P: The Effect of Transcranial Direct Current Stimulation Associated with Hypocaloric Diet on Glucose Homeostasis in Overweight or Obese Adults
Authors: ARAUJO CARINA DE , FITZ RAQUEL C. , NATIVIDADE GABRIELLA RICHTER , OSÓRIO AMANDA F. , MERELLO PAULA NUNES , SCHESTATSKY PEDRO , GERCHMAN FERNANDO
Published: June 2019

Aims: To test the effect of repetitive active transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) associated with a hypocaloric diet (HD) on glucose homeostasis in overweight or obese adults.

Method: We selected in a RCT double-blind study, overweight or obese adults with different degrees of glucose tolerance to complete a 4-week (20 sessions; five consecutive weekdays) of fixed-dose tDCS (2mA, 20min) delivered over the right DLPFC associated with a standard HD. Subjects were randomly assigned (1:1) and stratified by sex to active tDCS group (AG) or sham tDCS group (SG). Changes on the glycemic and insulinemic response were assessed in a 4h liquid meal tolerance test (LMTT), performed before (t0) and after (t20) the 4-week intervention. Plasma glucose and insulin concentrations were used to determine glucose and insulin AUCs, indices of insulin sensitivity (MISI, Matsuda Insulin Sensitivity Index), insulin secretion (ISI, Insulin Secretion Index), and pancreatic β-cell function (DI, Disposition Index). Data were analyzed with generalized estimating equations adjusted for age, carbohydrate intake, and weight loss (%).

Results: Twenty-eight participants were randomized (79% obese; 29% IGT, 4% T2D; 37.6 [5.8] years). Changes over the time (mean [95% CI]) for FPG was higher in AG than in SG (∆t20-t0 = −7.8 [−14.0, −1.6] vs. ∆t20-t0 = −0.9 [−4.0, 2.1] mg/dL; p = 0.043) after the intervention. Likewise, the MISI was improved in AG compared with SG (∆t20-t0 = 3.2 [1.5 to 4.9] vs. ∆t20-t0 = 0.5 [−1.5, 2.5] pmol-1x mmol-1; p = 0.044). There were no significant differences between groups in fasting insulin, glucose and insulin AUCs, ISI, or DI over the study.

Conclusions: Repetitive active tDCS over the right DLPFC may be a promising non-invasive technique that could be used to improve glucose homeostasis in overweight or obese individuals on a low-calorie diet. ClinicalTrials.org: NCT02683902.

Disclosure

C. de Araujo: None. R.C. Fitz: None. G.R. Natividade: None. A.F. Osório: None. P.N. Merello: None. P. Schestatsky: None. F. Gerchman: Speaker's Bureau; Self; Novo Nordisk Inc. Other Relationship; Self; Sanofi-Aventis.

Funding

Hospital de Clínicas de Porto Alegre (FIPE15-0119, 16-0417)
2067-P: Interrelationship between Serum Bone-Derived Factors and Obesity and Visceral Fat Accumulation in Chinese Middle-Aged Men and Women
Authors: BAO YUQIAN , XU YITING , MA XIAOJING , PAN XIAOPING , HE XINGXING , XIAO YUNFENG
Published: June 2019

Aims: This study was designed to investigate the interrelationships between three bone-derived factors [serum osteocalcin (OCN), fibroblast growth factor (FGF) 23, and neutrophil gelatinase-associated lipocalin (NGAL) levels] and body fat content and distribution, in order to reveal the potential endocrine function of bone in the development of obesity.

Methods: We recruited 1179 people (aged 59.5 ± 6.2 years) from communities in Shanghai. Serum OCN levels were determined using an electrochemiluminescence immunoassay, and thus serum FGF-23 and NGAL levels were determined using a sandwich enzyme-linked immunosorbent assay. The abdominal fat distribution, including visceral fat area (VFA), was assessed by magnetic resonance imaging. Visceral obesity was defined as a VFA ≥ 80 cm2.

Results: Serum OCN levels were inversely correlated with body fat parameters, while FGF-23 and NGAL were positively correlated (P < 0.05). After adjusting for confounders, waist circumference (W) and VFA had a closer relationship with serum OCN, FGF-23, and NGAL levels than body mass index (BMI) and body fat percentage (fat%, all P < 0.05). The risk of visceral obesity significantly increased with higher FGF-23 and/or NGAL levels, as well as with reduced OCN levels (all P < 0.05). In addition, serum OCN, FGF-23, and NGAL levels were independently associated with visceral obesity (all P < 0.01). The relationships persisted among subjects with normal glucose tolerance or subjects with hyperglycaemia (both P < 0.05).

Conclusions: Compared to overall adiposity, visceral adiposity was more closely related to serum OCN, FGF-23 and NGAL levels. There was no interaction among the relationship of three bone-derived factors with visceral obesity, which suggested the independent relationship of endocrine function of skeleton with body fat.

Disclosure

Y. Bao: None. Y. Xu: None. X. Ma: None. X. Pan: None. X. He: None. Y. Xiao: None.
209-LB: Is the Abdominal Aorta Diameter a Novel Marker of Diabetes Risk in Elderly Women?
Authors: DąBROWSKI MARIUSZ , DEREZINSKI TADEUSZ , URUSKA ALEKSANDRA , ZOZULINSKA-ZIOLKIEWICZ DOROTA
Published: June 2019

Diabetes mellitus (DM) prevalence increases worldwide. Elevated BMI, waist circumference (WC), blood pressure (BP), fasting plasma glucose (FPG) and triglycerides (TGs), as well as low HDL cholesterol level are known risk factors of DM incidence. We analyzed the association of these parameters, with the addition of abdominal aorta diameter (AAD) and estimated glomerular filtration rate (eGFR) using CKD-EPI equation, with DM incidence among 200 women aged 65-74, nondiabetic at baseline assessment in 2012. After 6.5 years of follow-up 36 new DM cases occurred. Women with incident DM had significantly higher baseline FPG, 108.6±18.0 vs. 97.2±10,9 mg/dL, P<0.001 and TGs, 142.2±54,6 vs. 115,6±49,7 mg/dL, P=0.002, while they had lower AAD, 18.1±4,7 vs. 18.4±2,5 mm, P=0.019; HDL cholesterol 58.7±12.7 vs. 68.9±17.3 mg/dL, P<0.001 and eGFR, 77.4±14.5 vs. 83.1±17.2 mL/min/1.73 m2, P=0.045. WC, BP and BMI were not significantly different between groups. Relative risk (RR) of DM incidence was significantly higher for AAD <18 mm, RR (95% CI) 2.66 (1.41-5.01), P=0.003; FPG ≥100 mg/dL, RR 2.89 (1.51-5.55), P<0.001; TGs ≥150 mg/dL, RR 2.26 (1.26-4.03), P=0.013 and eGFR <75,0 ml/min/1,73 m2, RR 2.11 (1.18-3.77), P=0.020. Other variables did not attain statistical significance limit. In the multiple logistic regression analysis including all variables, only AAD <18 mm, FPG ≥100 mg/dL, and eGFR <75,0 ml/min/1,73 m2 were independently associated with DM risk (P=0.005, P=0.010 and P=0.018 respectively). In the backward stepwise regression analysis DM incidence could be predicted from a linear combination of the independent variables: AAD <18 mm (P=0.005), FPG ≥100 mg/dL (P=0.009), eGFR <75,0 ml/min/1,73 m2 (P=0.017) and TGs ≥150 mg/dL (P=0.034). Thus, AAD <18 mm seem to be a novel, independent marker of DM risk in elderly women, and AAD assessment during routine abdomen ultrasound may be helpful, together with other DM risk factors, in identifying elderly females at very high risk of DM incidence.

Disclosure

M. D?browski: Other Relationship; Self; Ascensia Diabetes Care, AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk Inc., Sanofi-Aventis, Servier, WöRWAG Pharma. T. Derezinski: None. A. Uruska: None. D. Zozulinska-Ziolkiewicz: Advisory Panel; Self; Roche Diabetes Care. Other Relationship; Self; Ascensia Diabetes Care, AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, Servier, WöRWAG Pharma.
2096-P: Real-World Examination of Lorcaserin Treatment in Patients with Type 2 Diabetes, Prediabetes, and Metabolic Syndrome
Authors: HARRIS SAMANTHA R. , KNOTH RUSSELL L. , LI XUAN , KHILFEH IBRAHIM , CHOI JIYOON , PHILIS-TSIMIKAS ATHENA , FUJIOKA KEN
Published: June 2019

Background: Lorcaserin is a serotonin 2C receptor agonist approved in the U.S. as adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in patients with a BMI ≥ 30 or ≥ 27 with at least one weight-related comorbidity. To date, there is limited data on the real-world use of lorcaserin for weight management, including in patients diagnosed with T2DM, prediabetes, and metabolic syndrome.

Methods: A retrospective chart review was performed at the Scripps Clinic Weight Management Center. Patients were identified if they had at least one prescription for lorcaserin and were ≥ 18 years old. Weight change at 90 days and reason for discontinuation were assessed for patients with at least one day on pharmacotherapy. Patients with weight loss of ≥ 5% at 90 days were defined as medication “responders.”

Results: A total of 118 overweight and obese patients filled a prescription for lorcaserin. Of these, 69 (58%) remained on lorcaserin ≥ 90 days (median follow-up was 306 days). Mean age was 53 years old, 73% were female, and mean baseline weight was 102 kg (BMI= 36). For patients who had follow-up weight information available (N=65), overall mean weight loss at 90 days was -3.5 kg (-4%) from baseline, responders had a decrease -7 kg (-7%, n=24) versus -1 kg (-2%) for non-responders (n=41). For patients diagnosed with metabolic syndrome (n=25), mean weight loss for responders (n=10, 40%) was -6.7 kg (-7%) versus -2.1 kg (-2%) for non-responders (n=15). Similar weight loss was observed in patients with T2DM and prediabetes.

Conclusion: These "real world" results represent a group of commercially insured overweight and obese patients and demonstrate that weight loss programs can use lorcaserin and expect to get significant weight loss when used according to the label.

Disclosure

S.R. Harris: Consultant; Self; Sanofi. Research Support; Self; Eisai Inc. R.L. Knoth: Employee; Self; Eisai Inc. X. Li: Employee; Self; Eisai Inc. I. Khilfeh: Employee; Self; Eisai Inc. J. Choi: Employee; Self; Eisai Inc. Stock/Shareholder; Self; Johnson & Johnson. A. Philis-Tsimikas: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc., Glooko, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. Stock/Shareholder; Spouse/Partner; Ionis Pharmaceuticals, Inc., Novo Nordisk Inc. K. Fujioka: Consultant; Self; Eisai Inc.

Funding

Eisai Inc.
2102-P: Upregulation of Adipose Tissue APOE Expression by ω3PUFA Supplementation Associates with Decreased Plasma FFA Levels and Improves Insulin Sensitivity in Obese Subjects
Authors: RAU CASSANDRA , LI TING , HERNANDEZ JAMES D. , MASUDA MIA Y. , ZHANG XIAODONG , WANG PANWEN , COLETTA DAWN K. , DEFILIPPIS ELEANNA
Published: June 2019

Inflammation of adipose tissue (AT) is key for the development of insulin resistance (IR) in obesity. We previously showed that 3 months supplementation of fish oil (FO, 4g/day), a well-known anti-inflammatory agent, induced 25% improvement in glucose disposal during euglycemic-hyperinsulinemic clamp in 13 obese, insulin resistant subjects (ADA abstract Hernandez J., et al 2017). To explore the mechanism(s) linked to this improvement, we first performed a microarray analysis of subcutaneous (SC) AT samples pre and post FO supplementation. Functional analysis indicated anti-inflammatory pathways as the principal pathways to be enriched after FO supplementation. We identified APOE (1.87 Fold Change (FC) Post vs. Pre-FO, P=0.004) among the most significantly enhanced genes, as APOE was common to the top 5 enriched anti-inflammatory pathways. RT-PCR analysis confirmed the changes in expression levels of several genes in these pathways including APOE, APOC1, MS4A6E, MMP9, MMP7, DEFB132, C1QTNF7, and POPDC3, thereby validating the microarray findings. Plasma and SC AT RT-PCR analysis showed significantly decreased inflammatory markers (IL1B: -0.28 FC, P=0.04, MCP1: -0.44 FC, P=0.04, CD68: -0.36 FC P=0.01) post vs. pre-FO. Additionally, mRNA adiponectin levels increased (FC +0.45 Post vs. Pre, P=0.02), while leptin decreased (FC -.030 Post vs. Pre, P=0.02).

Furthermore, ω3PUFA supplementation significantly reduced plasma FFA levels (Post-FO: 0.578+0.061mM vs. Pre-FO: 0.719 +0.055mM P<0.05). Taken together, our data suggests that ω3PUFA supplementation-induced improvement of insulin sensitivity in obese, insulin resistant subjects is attributed to the reduction of plasma FFA levels. This then associates with inhibition of inflammatory processes mediated by APOE. Additional studies are needed to further analyze the mechanism(s) linking FO to AT APOE gene expression, inflammation and insulin sensitivity.

Disclosure

C. Rau: None. T. Li: None. J.D. Hernandez: None. M.Y. Masuda: None. X. Zhang: None. P. Wang: None. D.K. Coletta: None. E. DeFilippis: None.

Funding

Arizona Department of Health Services (14-00003606); Kathryn H. and Roger Penske Career Development Award
2107-P: The Association between Metabolic Syndrome, Obesity Phenotype, and the Risk of Thyroid Cancer
Authors: KIM EUN SOOK , HAN KYUNGDO , KWON HYUK-SANG
Published: June 2019

Background: Current evidence suggest that obesity and metabolic unhealthy status may be linked to a higher risk of several cancers. This study investigated whether thyroid cancer risk is increased by metabolic syndrome (MetS) and obesity phenotypes.

Methods: A total of 23151947 adults who participated in health screening between 2009-2014 were enrolled from the Korean National Health Insurance Database. Body mass index (BMI), waist circumference, fasting glucose, lipid profiles, and blood pressure were measured. Obesity status was subdivided into being metabolically healthy or unhealthy according to MetS besides BMI. Cox proportional hazards models were used to estimate the risk of thyroid cancer.

Results: During the average 5.6-years of follow-up, 158788 cases of thyroid cancer were newly identified. In multivariate models adjusted for age, smoking, drinking, exercise, and income status, the risk of thyroid cancer was increased with increasing BMI and presence of any MetS components. MetS was associated with 1.30-fold higher risk for thyroid cancer in men and 1.12-fold in women. Compared to metabolically healthy non-obese subjects, metabolically unhealthy non-obese subjects had a higher risk of thyroid cancer in both genders. However, metabolically unhealthy obesity versus metabolically healthy obesity were at greater risk for thyroid cancer only in men.

Conclusions: Components of Mets, especially obesity, and MetS were significantly associated with increased risk of thyroid cancer in Korean men and women. Moreover, metabolically unhealthy subjects were at higher risk of thyroid cancer despite normal BMI. Management of metabolic disorders may give additional benefit of thyroid cancer prevention.

Disclosure

E. Kim: None. K. Han: None. H. Kwon: None.
2111-P: Effect Modification of Vitamin D Intervention by Obesity-Related Metabolites
Authors: BAGHERI MINOO , ASLIBEKYAN STELLA , DJAZAYERY ABOLGHASSEM , FARZADFAR FARSHAD
Published: June 2019

Background: Effects of vitamin D on biomarkers of cardiometabolic disorders among obese individuals are highly variable between studies. Comparing the effects of vitamin D supplementation in metabolically healthy (MHO) vs. metabolically unhealthy (MUHO) obesity using metabolomics may yield mechanistic insights into the observed heterogeneity.

Objective: To quantify small molecular changes shortly after vitamin D intervention in MHO and MUHO individuals with sub-optimal levels of vitamin D (<75 nmol/L) using a targeted metabolomics approach.

Methods: In two randomized double-blind clinical trials, 110 MHO and 105 MUHO individuals were separately and randomly assigned to receive a daily dose of vitamin D supplement (4000 IU) or placebo. These MHO/MUHO phenotypes were defined using the Adult Treatment Panel-III criteria. Obesity-related metabolites (n=104) were measured at baseline and after four months of supplementation, using liquid chromatography coupled to a triple quadrupole mass spectrometry. Multiple linear regression models were fit to assess changes in metabolite levels, adjusting for appropriate covariates as well as controlling for multiple testing.

Results: In the MUHO group (n=78), we identified ten metabolites (citrulline, acyl-lysophosphatidylcholines C16:0, C16:1, C18:0 and C18:1, diacyl-phosphatidylcholines C32:0, C34:1, C38:3 and C38:4 and sphingomyelin C40:4) that were significantly altered (P=4.9×10-4 to P=0.007) in response to vitamin D therapy. In the MHO group (n=82), no significant metabolite changes were observed after the intervention.

Conclusion: Findings from our study contribute to the understanding of biological variation in Vitamin D metabolism across different obesity phenotypes. Upon successful validation, these insights can increase precision of clinical approaches to metabolic derangements in obesity. This study was registered at www.irct.ir as IRCT2015061522762N1.

Disclosure

M. Bagheri: None. S. Aslibekyan: Employee; Self; 23andMe. A. Djazayery: None. F. Farzadfar: None.

Funding

Tehran University of Medical Sciences
2118-P: Evidence of GIP-Induced Regulation of Fatty Acid Desaturase 2 (FADS2) Gene Expression in Subcutaneous Adipose Tissue
Authors: RAMICH OLGA , PFEIFFER ANDREAS F. , RUDOVICH NATALIA N.
Published: June 2019

The incretin glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of postprandial metabolism by stimulating insulin secretion and inhibiting lipolysis in the adipocytes. GIP is also involved in the development of the low-grade tissue inflammation upon high-fat and high-sucrose diet, but complete mechanisms of this action remain poorly understood. Fatty acid (FA) composition affects the obesity-associated low-grade inflammation. Recently human studies showed that fatty acid desaturase 2 (FADS2) gene polymorphism is associated with FA metabolism and adipose tissue inflammation. Here we aimed to investigate the effect on GIP infusion on the FADS2 gene expression in subcutaneous adipose tissue (SAT) and FA composition in humans. Eleven male subjects without diabetes (age: 36.9 ± 1.9 years; body mass index 32.2 ± 1.0 kg/m2) underwent saline infusion (0.9% NaCl), GIP infusion at an infusion rate of 2.0 pmol kg−1min−1, lipid infusion (Intralipid 20% emulsion for infusion) or combined GIP and lipid infusion of 4 hours duration. SAT biopsies were taken at −40 min and 240 min of infusions and FADS2 mRNA levels were detected by real-time PCR. FA compositions were measured in plasma at 0 and 240 minutes of each test by LCMS. FADS2 desaturating activity was calculated as a ratio of 18:3n-6 to 18:2n-6 FA, 20:3n-6 to 20:2n-6 FA, 22:4n-5 to 22:4n-6 FA and C22:6n-3 to C22:5n3 FA. FADS2 gene expression was increased after GIP, lipid and combined GIP and lipid infusion (p<0.01) compared to saline infusion. 18:3n-6 to 18:2n-6 FA ratio was significantly down-regulated at the end of GIP+lipid and lipid infusion but did not change after the GIP infusion alone. The observed GIP-dependent upregulation of FADS2 gene in adipose tissue may influence regulation of adipose tissue inflammation in postprandial state and in obesity. The observed down-regulation of 18:3n-6 to 18:2n-6 ratio reflects the saturation of enzyme capacity by substrate overload during the experiments

Disclosure

O. Ramich: None. A.F. Pfeiffer: Advisory Panel; Self; Abbott, Berlin-Chemie AG, Novo Nordisk A/S. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG, Sanofi-Aventis Deutschland GmbH. N.N. Rudovich: None.
2119-P: AKR1B10 Is Upregulated in Nonalcoholic Fatty Liver Disease and Is Regulated by Fatty Acid Loading in Hepatocytes and Hepatic Stellate Cells
Authors: DAVIS BETHANY , WILHELMSEN DANIELLE M. , HANSON AMANDA , DISTEFANO JOHANNA
Published: June 2019

Type 2 diabetes (T2D) and obesity are associated with fat accumulation in the liver, which is commonly diagnosed as nonalcoholic fatty liver disease (NAFLD). Not only do individuals with T2D have an increased risk of developing the disease, but patients with NAFLD are also at greater risk for developing T2D, and the majority of patients with NAFLD are overweight or obese. Hepatic lipid accumulation has been proposed as a cause, rather than a consequence, of hepatic insulin resistance, but the molecular mechanisms by which this occurs are not yet known. We previously observed abundant expression of aldo-keto reductase family 1 member 10 (AKR1B10) in obese NAFLD patients with advanced liver fibrosis using RNA-sequencing. The goals of this study were to measure AKR1B10 expression across the histological spectrum of NAFLD and elucidate factors that regulate AKR1B10 expression in cultured liver cells. We found that hepatic AKR1B10 expression was increased 6-fold, 19-fold, and 50-fold in NAFLD patients with steatosis, inflammation, and fibrosis compared to those with normal liver histology (P<0.05). We next treated human hepatocytes and hepatic stellate cells with 100 µM palmitate for 24 hours and found a 1.5-fold and 8-fold upregulation, respectively, in AKR1B10 expression compared to vehicle-treated cells. These results show that AKR1B10, which functions to reduce retinals to retinols in the liver, is increased across the NAFLD spectrum and upregulated in key liver cells in response to lipid loading. Studies to investigate the relationship between AKR1B10 expression and lipid-loading in NAFLD are ongoing.

Disclosure

B. Davis: None. D.M. Wilhelmsen: Stock/Shareholder; Self; Not sure of company name. Stock/Shareholder; Spouse/Partner; Not sure-. A. Hanson: None. J. DiStefano: None.

Funding

National Institutes of Health (DK091601)
212-LB: Reporting History of Diabetes Symptoms and Random Blood Glucose Testing to Detect Presymptomatic Type 1 Diabetes (T1D) in the General Pediatric Population
Authors: WAUGH KATHLEEN , FROHNERT BRIGITTE I. , REWERS MARIAN , BAXTER JUDITH , GENO RASMUSSEN CRISTY R.
Published: June 2019

Objective: Detection of pre-symptomatic T1D by islet autoantibody (IA) screening prevents hospitalization and diabetic ketoacidosis at clinical onset. It is unknown if presence of diabetic symptoms and random blood glucose predict islet autoantibodies. We report the efficacy of random blood glucose (RBG) measurement, among those who reported multiple symptoms for T1D, for detecting T1D autoimmunity.

Methods: In 2017-18, the Autoimmunity Screening for Kids (ASK) study screened 14,418 Denver children 1-17 y old for autoantibodies to insulin, GAD, IA-2, and ZnT8. At the time of screening, the parent and/or child were asked whether or not the child had increased urination, thirst, weight loss or vomiting in the last 3 months. If two or more symptoms were reported, RBG was tested using a glucometer and IA testing was fast-tracked with results available in <7 days.

Results: Of the children screened, 0.9% were positive for multiple IA or a single high-affinity IA conferring, respectively, a 44% and 29% 5-year risk of clinical T1D. A fast-track protocol with RBG testing was applied to 501/12,726 children screened between 6/2017-12/2018, flagged for priority testing. Ten (2%) of the 501 fast-track participants had multiple or single high-affinity IA, compared to 91/12,050 (0.8%) IA in those with one or no symptoms (p=0.002). At screening, children found later to have multiple or high-affinity IA more often reported ≥2 symptoms: 9.6% (10/104) compared with low-affinity IA, 4.3% (11/254, p=0.05), or negative, 4.9% (602/12,368, p=0.03). Among those with increased thirst and polyuria, 16/358 (4.5%) had IA. For IA positive, none reported all symptoms (12 IA neg reported all symptoms). RBG>140 mg/dl was detected in 1/14 (7.1%) children with multiple symptoms and IA vs. 15/440 (3.4%) children with symptoms and no IA (p=0.5). None had RBG>200.

Conclusions: Symptoms history is helpful but RBG is not, in finding children with pre-symptomatic T1D.

Disclosure

K. Waugh: None. B.I. Frohnert: None. M. Rewers: None. J. Baxter: None. C.R. Geno Rasmussen: None.

Funding

JDRF
2122-P: System x(c)- Is a Key Molecule in Oxidative Stress-Induced ß-Cell Damage
Authors: YOO SOYEON , BAE JUYOUNG , CHIN HYOUNJUNG , KOH GWANPYO
Published: June 2019

Pancreatic β-cells are vulnerable to oxidative stress, which is related to β-cell failure in type 2 diabetes. System x(c)- is a sodium-independent cystine/glutamate antiporter that mediates the exchange of extracelluar L-cystine and intracellular L-glutamate. The import of L-cystine through this transporter is the limiting state of intracellular glutathione (GSH) synthesis that has a major role in defends against oxidative stress. Our previous study reported that 2-deoxy-D-ribose (dRib) induces oxidative damage through GSH depletion in pancreatic β-cells. The aim of the present study was to elucidate the mechanism underlying oxidative stress-induced β-cell damage. We measured intracellular L-[14C] cysteine uptake, GSH content and reactive oxygen species (ROS) levels, cytotoxicity and apoptosis in rat insulinoma cell line (RINm5F cells). Stimulation with dRib dose- and time-dependently decreased intracellular L-[14C] cystine uptake and GSH content and increased intracellular ROS levels, cytotoxicity and apoptosis. The addition of 2-mercaptoethanol (2-ME), a cystine uptake enhancer, sodium-independently recovered the dRib-induced decreases in L-[14C] cystine uptake, GSH content and cell viability. To determine clearly whether system x(c)- deficiency mediate the oxidative stress-induced β-cell damage, we overexpressed xCT, the substrate-specific subunit of the system x(c)-, by using a lentiviral vector in RINm5F cells. Overexpression of xCT fully recovered the dRib-induced decreases in L-[14C] cystine uptake and GSH content and prevented the dRib-induced ROS rises, cytotoxicity and apoptosis.

In summary, overexpression of xCT showed protective effects against oxidative damage in RINm5F cells. It suggests that system x(c)- deficiency play a critical role in oxidative stress-induced β-cell damage.

Disclosure

S. Yoo: None. J. Bae: None. H. Chin: None. G. Koh: None.
2125-P: Increased StAR (Steroidogenic Acute Regulatory Protein) Is Detrimental to ß Cells and Promotes Mitochondrial Dysfunction
Authors: HOGAN MEGHAN F. , ESSER NATHALIE , TEMPLIN ANDREW T. , ZRAIKA SAKENEH , HULL REBECCA L. , EL-OSTA SAM , KAHN STEVEN E.
Published: June 2019

StAR is a cholesterol transport protein that transports cholesterol from the cytoplasm into the mitochondrial matrix for further metabolism by CYP enzymes. Depending on the CYP expressed, this results in production of corticosteroids, gonadal steroids, neurosteroids or oxysterols. These products generally exert positive effects on cellular health and function but can also be harmful. We previously showed that StAR is produced in β cells and is increased under conditions of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic mouse islets, a model of human islet amyloidosis in type 2 diabetes (T2D). Further, CYP11A1, CYP11B1, CYP7A1 and CYP17A1 are not expressed in mouse islets, and CYP27A1 is expressed but decreases with amyloid deposition. Therefore, we hypothesized that increased StAR in islets is deleterious to β-cell health as the downstream CYP enzymes are not present to metabolize mitochondrial cholesterol.

We first demonstrated (by immunoblot) that StAR is expressed in human islets, a requirement if it is to play a role in T2D. Also in human islets, only CYP27A1 is detectable, while CYP11A1 and CYP7A1 are not (n=4). We next used a lentivirus to increase StAR expression (or a control lentivirus) in INS-1 cells, which resulted in reduced mitochondrial membrane potential (100±2.0% vs. 78.1±1.2%, n=2, p<0.05) and cell viability (100±4.1% vs. 89.7±7.7%, n=3, p<0.05). Finally, we determined whether reducing StAR expression with an siRNA oligonucleotide in hIAPP transgenic islets had beneficial effects. A 40% knockdown in StAR expression did not alter amyloid deposition, but tended to increase islet viability (100±3.1% vs. 134.7±12.2%, n=2, p=0.1).

In summary, StAR is expressed in human islets and increasing its expression is deleterious due to changes in mitochondrial function and β-cell survival. Thus, reducing StAR expression and/or increasing expression of downstream CYP enzymes may be a novel strategy to protect β cells in T2D.

Disclosure

M.F. Hogan: None. N. Esser: None. A.T. Templin: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. El-Osta: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S.

Funding

American Diabetes Association (1-18-PDF-174 to M.F.H.); National Institutes of Health (T32HL007028, F32DK109584); U.S. Department of Veterans Affairs (BX001060); University of Washington
2127-P: Reduced Islet Parasympathetic Nerve Density Correlates with Decrease in Beta-Cell Volume of Islet in Lean Type 2 Diabetic Goto-Kakizaki Rat
Authors: MIZUKAMI HIROKI , GUO DANYANG , TAKAHASHI KAZUHISA , OSONOI SHO , KUDO KAZUHIRO , YAGIHASHI SOROKU
Published: June 2019

Pancreatic branch of vagus nerve (pvn) signaling plays a pivotal role in the maintenance of islet β cell volume density (Vβ). In type 2 diabetes (T2D), small fibers in the epidermis is decreased by diabetic insult. It is not still uncovered yet, however, that the reduction of terminal pvn fibers is associated with Vβ in T2DM. Herein, we explored the association between islet pvn fiber density and Vβ. We recruited non-obese spontaneous T2D Goto-Kakizaki (GK) rats and control Wistar rats (W) at 5 weeks of age. GK was divided into DPP-4 inhibitor (DPi)-treated group (GTe) (10mg/kg teneligliptine), SGLT2 inhibitor (SGi)-treated group (GCa) (10mg/kg canagliflozin) and both treated group (GTeCa). During experimental period, 2g/kg oral glucose tolerance test (OGTT) and glucose-stimulated insulin secretion test (GSIS) was performed. At end, pancreata were underwent for the pathological evaluation. OGTT in GK was attenuated (p<0.01 vs. W). Although DPi and SGi in each significantly improved OGTT compared to GK, the effect was the most robust in GTeCa. Low GSIS in GK (p<0.01 vs. W) was significantly improved in GTe and GCaTe (p<0.05 and p<0.01 vs. GK, respectively), although it was comparable between GK and GCa. Pathological evaluation disclosed a significant decrease in Vβ in GK (p<0.01 vs. W). Vβ was the most well-preserved in GCaTe (p<0.05 vs. GTe), followed by GTe (p<0.05 vs. GK), while it was comparable between GK and GCa. The density of pvn fibers labeled by the antibody for vesicular acetylcholine transporter (VachT) were significantly decreased in the islet of GK (p<0.01 vs. W). It was significantly improved in GCa, GTe and GCaTe compared to GK (p<0.05 vs. GCa and GTe; p<0.01 GCaTe, respectively). pvn fiber density in the islets significantly correlated with Vβ (r=0.53, p<0.01). Our results shed light on the association between terminal fiber density of pvn in the islet and Vβ, and the maintenance of the fibers may be beneficial for the prevention from Vβ loss in T2D.

Disclosure

H. Mizukami: None. D. Guo: None. K. Takahashi: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.
213-LB: Developing a Prognostic Model to Assess Dysglycemia Risk in Canadians Aged 18-39
Authors: SRUGO SEBASTIAN A. , JIANG YING , MORRISON HOWARD I. , DEGROH MARGARET M.
Published: June 2019

In Canada, the prevalence of diabetes has seen the greatest relative increase in young adulthood, where the disorder is severely pathological compared to later-onset. Still, few prognostic models have been developed to screen young adults for dysglycemia risk and boost early identification and intervention. We sought to establish predictors of dysglycemia risk among young Canadian adults (aged 18-39) and evaluate their utility in identifying high-risk individuals. The Canadian Diabetes Risk Questionnaire (CANRISK) study collected questionnaire, anthropometric, and oral glucose tolerance test (OGTT) data from a large, multiethnic convenience sample of Canadians over two phases. Young adults with diagnosed diabetes, missing OGTT data, or pregnant were excluded. Potential factors that modestly predicted (p<0.20) dysglycemia status (FPG≥6.1mmol/L or 2h-PG≥7.8mmol/L) were entered into a lenient stepwise function, producing a young adult-specific model; risk scores were developed from adjusted odds ratios. Discriminatory ability was assessed by optimism-corrected area under the curve (AUC) via bootstrapping and goodness-of-fit by Hosmer-Lemeshow (H-L) test and calibration plot. More than half of the 3334 participants were female (62.4%), non-white (79.2%), less than 25kg/m2 (50.7%), and reported a family history of diabetes (55.4%); based on OGTT results, 7.3% were dysglycemic. The young adult-specific model displayed an adjusted AUC of 72.9%, and reasonable goodness-of-fit (H-L p=0.49). Model performance was similar when run sex-specifically (males: unadjusted AUC of 72.1%, H-L p=0.67; females: 73.6%, p=0.67). Employing a cut-point of 22, the tool displayed high sensitivity (78.8%) but low specificity (54.0%). Only 3% of those identified as low risk by the tool were misclassified.

This young adult-specific risk score shows promise to identify high-risk individuals in a multiethnic Canadian sample. Additional studies are needed to assess its generalizability to new datasets.

Disclosure

S.A. Srugo: None. Y. Jiang: None. H.I. Morrison: None. M.M. deGroh: None.
2132-P: Islet Amyloid Deposition Is Cytotoxic to Islet Endothelial Cells
Authors: CASTILLO JOSEPH J. , HOGAN MEGHAN F. , APLIN ALFRED , HACKNEY DARYL J. , HULL REBECCA L.
Published: June 2019

Islet endothelial cells [ECs] produce numerous factors that support normal β-cell function and survival. Under diabetic conditions, islet ECs develop an activated (pro-inflammatory, pro-adhesive) phenotype which contributes to β-cell failure. In human type 2 diabetes [T2D], aggregation of the β-cell product, islet amyloid polypeptide [IAPP], results in amyloid deposition in the islet perivascular space. The toxic effects of IAPP aggregation on the β-cell are well established, however, whether islet ECs are also susceptible to IAPP toxicity remains unknown. We hypothesized that aggregation of amyloidogenic human IAPP (hIAPP) contributes to islet EC activation in T2D. To test this hypothesis, we performed 24h treatments of primary rat islet ECs with hIAPP [0-20 µM] for 24h, along with non-amyloidogenic rat IAPP [rIAPP; 20 µM] as a control, and, subsequently, the MS1 islet EC line with hIAPP [0-20 µM] ± the amyloid inhibitor Congo Red [CR; 100 µM]. In primary islet ECs, hIAPP, but not rIAPP, reduced cell viability and increased activation markers (interleukin-6, endothelin-1, vascular cell adhesion molecule; Table). A similar effect was seen in MS1 cells, and this was abrogated with CR (Table). Our data suggest that islet ECs are susceptible to hIAPP-induced toxicity. The resulting EC activation may interrupt the cross talk between the EC and β-cell, and thereby contribute to the β-cell toxicity of IAPP in T2D.

Disclosure

J.J. Castillo: None. M.F. Hogan: None. A. Aplin: None. D.J. Hackney: None. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088082); National Heart, Lung, and Blood Institute (T32HL007028); U.S. Department of Veterans Affairs (BX004063)
2136-P: Effects of Cytokine Exposure on the Proteome of Human Islets as Evaluated by Shotgun and 2DE Analysis
Authors: GRANO FRANCESCA , CIREGIA FEDERICA , RONCI MAURIZIO , MAZZONI MARIA ROSA , OVERBERGH LUTGART , LUCA CARMELA DE , SULEIMAN MARA , MARSELLI LORELLA , SIMONE PAOLO DE , BOGGI UGO , MATHIEU CHANTAL , EIZIRIK DECIO L. , LUCACCHINI ANTONIO , GIUSTI LAURA , MARCHETTI PIERO , BUGLIANI MARCO
Published: June 2019

Pro-inflammatory cytokines (CYT) lead to several changes in human islet (HI) protein expression, but few data are available on CYT-induced alterations at the whole proteome level, including post-translational modifications (PTM). We used label-free shotgun analysis (SG) and bi-dimensional gel electrophoresis (2DE) to explore how CYT modify the proteome of isolated HI. For this purpose, HI were isolated from the pancreas of 5 nondiabetic organ donors (age: 74±6 years; gender: 3M/2F; BMI: 27.9±3.6 kg/m2) and then cultured for 48h in the presence of 50 U/ml interleukin (IL)-1β + 1000 U/ml interferon (IFN)-γ. Then, 40 or 250 μg protein extracts were used respectively for SG or 2DE (to assess lysine-acetylation) analysis, with the SG mass spectrometry data acquired by nano-liquid chromatography tandem mass spectrometry. SG identified around 3000 proteins, of which 286 were differentially expressed after CYT exposure. Of these, 176 were upregulated and 110 downregulated. Among the former, we found mediators of inflammation, proteins of the ER and the immunoproteasome system and oxidative stress modulators (e.g., CXCL2, CXCL10, PSMB8, PSMB9, PSMB10, SOD2). Among the downregulated proteins, there were cathepsins, antioxidant molecules and enzymes of glycolysis and Krebs’ cycle (e.g., CTSH (a candidate gene for T1D), PRDX2, MDH). Ingenuity Pathway Analysis indicated that several upstream regulators were predicted to be differentially affected. Of them, 118 were presumably activated, including STAT1 and STAT2, NF-κB, JAK1, IRF1, HMGB1 and 36 inhibited, such as ACKR2, TRIM24, MAPK1, SUMO3. Bi-dimensional gel electrophoresis showed 151 spots that were lysine-acetylated, of which 2 were upregulated (PRDX3 and SOD1) and 4 downregulated (GDH, CTSD, ACAD9 and EIF4A1) by CYT. The present study shows novel proteomic changes, including specific PTM, induced in human islets by cytokine treatment that could play a role in beta cell dysfunction and demise and be the target for specific treatments.

Disclosure

F. Grano: None. F. Ciregia: None. M. Ronci: None. M. Mazzoni: None. L. Overbergh: None. C. De Luca: None. M. Suleiman: None. L. Marselli: None. P. De Simone: None. U. Boggi: None. C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. D.L. Eizirik: None. A. Lucacchini: None. L. Giusti: None. P. Marchetti: None. M. Bugliani: None.

Funding

INNODIA
2141-P: Nrf2 Mediates Glucose-Stimulated Beta-Cell Proliferation
Authors: BAUMEL-ALTERZON SHARON , KATZ LIORA S. , BRILL GABRIEL , GARCIA-OCAÑA ADOLFO , SCOTT DONALD
Published: June 2019

Glucose catabolism drives adaptive beta cell mass expansion by promoting proliferation under conditions of increased insulin demand. Previously, we showed that induction of the antioxidant regulator, Nrf2, is required for glucose-stimulated β-cell proliferation, and that overexpression of Nrf2 stimulates human beta cell proliferation. Here we manipulate the Nrf2 pathway using pharmacological and genetic approaches to explore the link between glucose metabolism, Nrf2 activation and beta cell proliferation. Treatment of isolated mouse islets with either a Nrf2 inhibitor (brusatol) or Cre-recombinase deleted Nrf2, resulted in complete inhibition of glucose-stimulated proliferation (both n=3, p < 0.01). Conversely, stimulation of Nrf2 by CDDO-me or genetic gain of function (Cre-mediated depletion of Nrf2 inhibitor, Keap1) increased beta cell proliferation of beta cells from isolated mouse islets cultured in 5 mM glucose (4.9 ± 0.2 fold and 6.9 ± 1.4 fold, respectively; n=3, p < 0.05). Inhibition or depletion of Nrf2 was associated with a remarkable decrease in insulin content, suggesting that beta cell identity requires basal levels of Nrf2 expression. Importantly, isolated human beta cells displayed similar responses to Nrf2 loss and gain of function. Activation and nuclear translocation of Nrf2 requires dissociation from its inhibitor, Keap1, and phosphorylation of Ser-40 on Nrf2. Five minutes of 20 mM glucose treatment profoundly increased Ser-40 phosphorylation and translocation of Nrf2, while the same effect by CDDO-Me treatment took 50 minutes in INS1 cells. The glucose-mediated activation and translocation of Nrf2 was blocked by the antioxidant N-acetylcysteine (NAC), which also attenuated glucose-stimulated proliferation of isolated mouse beta cells. In addition, the activation and phosphorylation of Nrf2 was prevented by the pan-PKC inhibitor, calphostin C. We conclude that manipulation of the Nrf2 pathway is an exciting novel target for regulation of beta cell proliferation.

Disclosure

S. Baumel-Alterzon: None. L.S. Katz: None. G. Brill: None. A. Garcia-Ocaña: None. D. Scott: None.

Funding

American Diabetes Association (1-17-IBS-116 to D.S.); National Institutes of Health
2148-P: Islet Endocrine Cells Shows a Unique Pattern on Development and Growth of Each Cell Type in Human Subjects
Authors: OSONOI SHO , MIZUKAMI HIROKI , TAKAHASHI KAZUHISA , KUDO KAZUHIRO , YAGIHASHI SOROKU
Published: June 2019

Development and growth of islet endocrine cell volume are assumed to mainly depend on cell proliferation. In addition, the partial contribution of islet neogenesis and chromogranin A positive hormone negative cell (CPHN cell) is recently clarified. Detailed evaluation for the islet cell development and growth, however, is not well explored linking to the change of cell replication, neognesis and CPHN cell for each type of endocrine cells in human specimens. For this purpose, we recruited human autopsied pancreata, aged from 24 weeks old to 19 years old (n=32). Formalin-fixed paraffin embedded sections from pancreatic body were used for immunohistochemistry (IHC) and immunofluorescence (IF) analysis. The subjects were divided into 4 groups, Fetus (F: 24-31 weeks), Infant (I : 0-1 years), Child (C : 2-12 years) and Adolescence (A : 13-19 years). Quintuple-IHC with antibodies for glucagon, insulin, somatostatin, pp and Ki-67 was performed for the measurement of islet cell volume density (V) and replication status. Vαand Vβwere increased with age. Vβin A was more abundant than in F (p<0.01). On the other hand, Vδnegatively correlated with age (r=-0.701, p<0.01) and was more in F than in C and A (p<0.01). Ki-67 positive index for αand δ cells showed the highest in F (p<0.01), whereas that of β cells was the highest in I (p<0.01). Neogenic islet density, evaluated in IHC with an antibody for chromogranin A, showed negative correlation with age (r=-0.608, p<0.01). Double-IF with a cocktail of four kinds of antibodies for islet hormones and for chromogranin A was performed to evaluate VCPHN. CPHN cell was identified in both islets and neogenic islets. VCPHNwas more abundant in neogenic islets of F and I than those of C and A. Our results suggest that each kind of islet cell owns a unique pattern of the cell development and growth. In particular, neogenic islet and CPHN cell may play a role as the source of βcells in the later life.

Disclosure

S. Osonoi: None. H. Mizukami: None. K. Takahashi: None. K. Kudo: None. S. Yagihashi: None.
216-OR: Cardiovascular (CV) Impact of BMI in Youth with Type 1 Diabetes (T1D)
Authors: TOMMERDAHL KALIE L. , BAUMGARTNER KARL V. , BJORNSTAD PETTER , BAUMGARTNER AMY , PYLE LAURA , REGENSTEINER JUDITH G. , REUSCH JANE E.B. , NADEAU KRISTEN J.
Published: June 2019

Insulin resistance (IR) and obesity are independently associated with T1D and are known risk factors for CV disease, the leading cause of mortality in T1D. We evaluated the impact of BMI on CV outcomes in T1D youth and compared obese T1D (OT1D) youth to youth with type 2 diabetes (T2D). Pubertal youth aged 12-21 years with T1D and T2D were recruited from the RESistance to InSulin in type 1 and type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with type 1 Diabetes (EMERALD) cohorts. Participants were stratified as lean (LT1D), overweight, or obese T1D or T2D (Table). CV outcomes included resting heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), leptin, hsCRP, and adiponectin. T1D participants performed bicycle ergometry for peak oxygen consumption (VO2peak), brachial artery (BA) distensibility by Dynapulse, and aortic MRI. HR, SBP, DBP, mean arterial pressure, and prevalence of hypertension were higher and BA distensibility, descending aorta oscillatory shear index, VO2peak, leptin, and hsCRP were worsened in OT1D vs. LT1D. Beyond hypertension prevalence in OT1D vs. T2D, which was worse in OT1D, T2D did not differ significantly from OT1D. Higher BMI, which is increasingly prevalent in T1D, is associated with a worsened CV profile in T1D youth, nearly approximating the CV phenotype of T2D youth. Closer attention to lifestyle management in T1D youth is needed to help reduce CV risk.

Disclosure

K.L. Tommerdahl: None. K.V. Baumgartner: None. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. A. Baumgartner: None. L. Pyle: None. J.G. Regensteiner: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. K.J. Nadeau: None.

Funding

American Diabetes Association (7-11-CD-08 to K.J.N.); JDRF (11-2010-343); National Institutes of Health (1R56DK088971-01)
2164-P: Paired Box 6 Modulates Pancreatic Beta-Cell Insulin Secretion through Regulation of Munc18-1/2 Expression: Involvement of CREB Signaling
Authors: SO WING YAN , HAN WEIPING
Published: June 2019

The Paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in human. Previous studies demonstrated that PAX6 plays critical roles in insulin biosynthesis, glucose-sensing and glucose-induced ATP synthesis (the proximal signaling of insulin secretion). Yet the molecular mechanism of PAX6 in controlling beta-cell insulin secretion, especially the involvement of distal signaling, remains ambiguous. This study investigated the regulatory role of PAX6 in exocytotic proteins, the core components of distal signaling of insulin secretion, by using human pancreatic beta-cell line EndoC-bH1. The correlation between PAX6 and type 2 diabetes mellitus (T2DM)-associated beta-cell dysfunction was also assessed. Loss-of-function and gain-of-function studies showed that PAX6 positively regulated the expression of exocytotic proteins Munc18-1 and Munc18-2 in beta-cells by modulating the activity of cAMP response element-binding protein (CREB). The PAX6/CREB/Munc18-1/2 axis in turn controlled glucose-stimulated insulin secretion. On the other hand, EndoC-bH1 cells under diabetic condition displayed diminished PAX6 expression, blunted CREB phosphorylation and Munc18-1/2 down-regulation which were rescued by PAX6 overexpression. We conclude that PAX6 regulates distal signaling of insulin secretion through CREB/Munc18-1/2 axis; while maintenance of normal PAX6 expression or activity in human beta-cells may serve as a promising strategy in preserving beta-cell function and delaying the onset of T2DM.

Disclosure

W. So: None. W. Han: None.

Funding

National Medical Research Council of Australia