bluuebunny/crossref_metadata_2025 huggingface dataset:
2084-P: Sustained Weight Loss in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Injectable Testosterone Undecanoate (TU): Ten-Year Data from a Urological Registry Study
Authors: HAIDER AHMAD , HAIDER KARIM S. , SAAD FARID
Published: June 2019

Background: Testosterone is inversely correlated with weight and waist circumference (WC).

Methods: Of 324 men with hypogonadism and T2DM in a registry, 257 (79.3%) were obese, 60 (18.5%) overweight and 7 (2.2%) had normal weight. 152 received TU 1000 mg/12 weeks (T-group), 172 opted against treatment (CTRL). Changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction, and adjusted for age, weight, WC, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups.

Results: Mean age: 62.7±5.1, follow-up: mean: 7.9, median: 9 years. T-group: weight decreased by 21.4±0.5 kg at 10 years. CTRL: weight increased by 4.8±0.4 kg. Estimated adjusted difference between groups: 26.2 kg (p<0.0001 for all). T-group: WC decreased by 12.8±0.4 cm at 10 years. CTRL: WC increased by 5.6±0.4 cm, difference between groups: 18.4 cm (p<0.0001 for all). T-group: BMI decreased by 6.9±0.2 kg/m² at 10 years. CTRL: BMI increased by 1.5±0.1 kg/m², difference between groups: 8.4 kg/m² (p<0.0001 for all). Weight loss was 18.8±0.4% in the T-group and weight gain 5.5±0.3% in CTRL, difference between groups: 24.3% (p<0.0001 for all). T-group: waist:height ratio decreased by 0.07±0.00 at 10 years. CTRL: waist:height ratio increased by 0.03±0.00, difference between groups: 0.10 (p<0.0001 for all). T-group: Visceral adiposity index (VAI) decreased by 2.5±0.2. CTRL: VAI increased by 2.5±0.2, difference between groups: 5.0 (p<0.0001 for all). Since injections were administered in the office and documented, there was a 100% adherence to testosterone therapy.

Conclusions: Long-term testosterone therapy with TU in men with hypogonadism and T2DM sustainably improved anthropometric measures which worsened in untreated controls.

Disclosure

A. Haider: Research Support; Self; Bayer AG. Speaker's Bureau; Self; Bayer AG. K.S. Haider: Speaker's Bureau; Self; Bayer AG. F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Amgen Inc., Bayer AG.

Funding

Bayer AG
2090-P: Role of Thromboxane-Prostanoid Receptor in Obesity Related Insulin Resistance
Authors: THANGAVELU THIYAGARAJAN , VISWANATHAN SARASWATHI , DESOUZA CYRUS
Published: June 2019

Background: Thromboxane-Prostanoid Receptor (TP-R) is implicated in several chronic inflammatory disorders. Our preclinical animal studies showed that TP-R plays a critical role in obesity linked Insulin Resistance (IR).

Aim: To determine the link between TP-R and obesity and/or obesity-associated inflammation/IR in human subjects.

Methods: We collected PBMCs from lean normal and obese IR subjects and analyzed the expression of various inflammatory genes including TP-R, Thromboxane A2 Synthase (TXA2S), TNFα, and MCP-1. We obtained subcutaneous adipose tissue biopsies from obese subjects and analyzed the TP-R mRNA expression and its correlation with inflammatory cytokines mediating IR.

Results: TP-R mRNA expression is significantly increased in PBMCs of obese IR subjects compared to lean normal subjects (P<0.04 by Wilcoxon rank-sum test). In addition, PBMC TP-R expression is positively correlated with the expression of TXA2S, a gene involved in thromboxane A2 synthesis (n=29, Spearman’s r=0.36, P=0.05). Moreover, TP-R expression is positively correlated with body weight, BMI and fat mass (Figure). In AT, TP-R expression is positively correlated with IL-8 expression (n=31, r=0.49, P<0.005).

Conclusion: Our data demonstrate that TP-R expression is positively correlated with markers of obesity and/or IR and support our hypothesis that TP-R can be used as a biomarker or a therapeutic target for obesity related IR.

Disclosure

T. Thangavelu: None. S. Viswanathan: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US.

Funding

National Institute of General Medical Sciences; Great Plains Institutional Developmental Award for Clinical and Translational Research
2092-P: Impact of Insulin Resistance on Response to a Meal by Salience, Executive Control, and Default Mode Resting State Networks in Humans
Authors: SEWAYBRICKER LETICIA ESPOSITO , MELHORN SUSAN J. , ASKREN MARY K. , WEBB MARY , TYAGI VIDHI , DE LEON MARY ROSALYNN , GRABOWSKI THOMAS J. , SCHUR ELLEN
Published: June 2019

Functional connectivity (fc) in the Salience Network (SN) is reduced by a meal. We hypothesized that disengagement of the SN may be mirrored by increased fc in Executive Control (ECN) or Default Mode (DMN) networks (representing a switch away from interoceptive neural processing after feeding) and that insulin resistance might impact shifts in postprandial neural processing. Subjects (N=111) oversampled for obesity had body composition, fasting glucose and insulin evaluated and underwent resting-state fMRI before and after a standardized meal. Masks for ECN (Seeley2007) and DMN (Grecius2003) were applied to obtain the fc pre-, post-meal and change (%). Subgroups with low (N=37) and high (N=36) HOMA-IR were created from tertiles. Among all subjects (28±9 y; BMI 30.5±6 kg/m2), ECN fc was reduced by a meal (z=-2.9, P=0.004), but DMN fc did not change (z=-0.02, P=0.98). The low and high HOMA-IR groups had mean BMIs of 26.8 and 34.7±5. Fc response to a meal, adjusted for age, sex and fat mass, did not differ between low and high HOMA groups for ECN (group*time chi2(1)=2.39, PInt=0.12) or SN (chi2(1)=2.52, PInt=0.11); both groups reduced fc. However, for DMN a group*time was found (chi2(1)=9.12, PInt=0.003, adjusted), such that the low HOMA group increased post-meal fc (Fisher z-score 0.36 vs. 0.41, P=0.04), but high HOMA group decreased fc (0.37 vs. 0.31, P=0.03). Change (%) in connectivity was positively correlated among all 3 networks (P<0.002). A significant interaction for DMN vs. ECN (P=0.02) by HOMA group was present. Participants with high HOMA had a blunted correlation between DMN and ECN (coef=0.12, P=0.28) compared to those with low HOMA (coef=0.61, P=0.001).

Fc was reduced by a meal in the ECN and not modified in the DMN on average. However, DMN fc increased with feeding in non-insulin resistant individuals as hypothesized, but decreased in those with insulin resistance, suggesting that insulin resistance impacts shifts in neural processing in response to a meal.

Disclosure

L.E. Sewaybricker: None. S.J. Melhorn: None. M.K. Askren: None. M. Webb: None. V. Tyagi: None. M. De Leon: None. T.J. Grabowski: None. E. Schur: None.

Funding

American Diabetes Association (1-17-ICTS-085 to E.S.); Sao Paulo Research Foundation (2017/00657-0); National Institutes of Health (DK089036, DK098466); University of Washington Nutrition Obesity Research Center (P30 DK035816); Diabetes Research Center (P30DK017047); Institute of Translational Health Sciences (UL1TR000423)
2099-P: Assessing the Link between Metabolic Phenotype and Skeletal Muscle Index (SMI) in Obese and Nonobese Adults
Authors: ONAL-TASTAN YESIM , DIZMAN NAZLI , ERTUR ESEN , CAKIR-GUNEY BASAK , SARGIN MEHMET , OGUZ AYTEKIN
Published: June 2019

Background: Sarcopenia is strongly linked to impaired metabolic health. However, sarcopenia might be omitted in patients (pts) with metabolic syndrome which is commonly predominated by obesity. We seek to identify associates of low muscle mass in regard metabolic health and obesity.

Methods: Consecutive pts who presented to internal medicine outpatient clinics of a tertiary hospital for regular follow-up were included in this study. Those with comorbidities that are known to cause secondary sarcopenia such as chronic liver and kidney disease, inflammatory diseases and cancers were excluded. SMI was measured by bioelectrical impedance analysis (TANITA MC780) Pts with at least two components of metabolic syndrome were considered metabolically unhealthy. SMI values of metabolic healthy (MH) and unhealthy (MUH) patient groups were compared across obese and non-obese adults. Multivariate regression analysis was performed to identify factors related to low muscle mass.

Results: Amongst 200 pts (M:F 97:103) included in this study, median age was 49,9 ± 8. Mean SMI was 8.9±0.6 (F:M 8.3:9.5) The MUH phenotype was more frequent in pts with low muscle mass compared to those with normal muscle mass (p=0.048) Obesity was not associated with low muscle mass regardless of MH (p=0.345) Mean SMI was lower in MUH pts regardless of presence of obesity. After controlling the mentioned variables, multivariate analysis didn’t demonstrate an independent effect of MUH phenotype on low SMI but a trend towards effect was observed (Odds ratio[OR]:1.09 Confidence Interval[CI] 95% 0.95-9.51 p=0.062). High waist to hip ratio was the factor independently associated with low SMI (OR: 8.328, CI 95% 8.23-20.43 p=0.009).

Conclusion: Our results identify an association between impaired metabolical health and low muscle mass regardless of the presence of obesity. Most interestingly we observed an interplay between central obesity and impaired muscle mass that warrants further exploration in larger samples.

Disclosure

Y. Onal-Tastan: None. N. Dizman: None. E. Ertur: None. B. Cakir-Guney: None. M. Sargin: None. A. Oguz: None.
210-LB: Evaluation of Two Commercially Available Glycated Hemoglobin Methods
Authors: GOMEZ PAZMIÑO BETTY J. , VERA LORENTI FANNY E. , GUADALUPE VARGAS MARIANA E. , ALVAREZ CONDO GRACIELA M. , VERON DOLORES , CERCADO ALICIA G. , RODAS NEIRA EDGAR I. , BAHAR BURAK , VERON DELMA
Published: June 2019

HbA1c level reflects chronic glycemic status if reliable tests are used. The HbA1c testing improved with the efforts of many national and international organizations; however, in some regions, high performing assays might not be readily available. Here we report a comparison study of two immunoassay methods with a high-performance liquid chromatography (HPLC) assay, all of them available in Ecuador. We studied 114 fresh whole-blood samples from adults with normal and pathological HbA1c levels. HbA1c was measured in all samples by DCA-Vantage point-of-care analyzer, I-Chroma portable fluorescent scanner immunoassay and BioRad Variant II Turbo HPLC. Blood samples with variants of hemoglobin were excluded. HbA1c values were expressed in National Glycohemoglobin Standardization Program percentages and mmol/mol, as mean ± standard deviation.

Results: HbA1c measurements by HPLC and DCA-Vantage were similar: 6.3±1.7% (45±18.6 mmol/mol) vs. 6.3±1.8% (45±19.7 mmol/mol), respectively, P=0.057, while HbA1c values by I-Chroma were lower than HPLC, 5.8±1.9% (40±20.8 mmol/mol), P<0.001. Interestingly, the coefficient of variation was below 2% for high and low HbA1c levels, in all methods studied, demonstrating high precision. HbA1c values by HPLC and DCA-Vantage were highly correlated, Kendall's Correlation Coefficient [KCC]: 0.817, whereas the correlation among HPLC and I-chroma was weak, KCC: 0.294. The mean bias between DCA-Vantage and HPLC was -0.02±0.29% (-0.2±3.2 mmol/mol), 95% Confidence Interval of the differences (CID) [0.55%, -0.60%] (6.0 mmol/mol, -6.6 mmol/mol) while for I-Chroma and HPLC the mean bias was -0.50±1.62% (-5.5±17.7 mmol/mol), 95% CID [2.74%, -3.74 %] (30 mmol/mol, -40.9 mmol/mol). Conclusion: HbA1c results by DCA-Vantage were comparable to HPLC, showing a good correlation, an appropriate precision and a low bias. While I-Chroma assay was precise but inaccurate. Our results suggest a significant need for improvement in HbA1c immunoassays currently in use in our country, Ecuador.

Disclosure

B.J. Pazmiño Gomez: None. F.E. Vera Lorenti: None. M.E. Guadalupe Vargas: None. G.M. Alvarez Condo: None. D. Veron: None. A.G. Cercado: None. E.I. Rodas Neira: None. B. Bahar: None. D. Veron: None.

Funding

Ministry of Higher Education, Science, Technology and Innovation, Ecuador/Prometeo Project/State University of Milagro, Ecuador (UNEMI-OCAS-SO-27092013-N?26 DV2013?2014, UNEMI-OCAS-SO-03072014-N8-DV2014-2015, UNEMI-OCAS-SO-30052016-N5-DV2015-2017)
2105-P: Waist Circumference and All-Cause Mortality Independent of Body Mass Index in Korean Population from the National Health Insurance Health Checkup, 2009-2015
Authors: KIM YANG-HYUN , YOO SOON JIB , LEE SEONG-SU
Published: June 2019

Background: Waist circumference (WC) is an index of abdominal obesity and associated with co-morbidities and mortality. Higher WC is positively associated with increased mortality; therefore, we examined the relationship between WC and mortality in Korean populations with the interaction of body mass index (BMI) and WC for mortality.

Methods: A total of 23,263,878 subjects (men = 11,813,850 and women = 11,450,028) who were older than 20 years and underwent the National Health Insurance Service health checkup were included. WC was divided into six categories by 5 cm increments and level 3 (85-90 cm in men and 80-85 cm in women) was referenced. Multivariable Cox proportional hazard models were used to obtain the hazard ratios (HRs) and 95% confidence intervals for all-cause mortality according to the six levels of WC.

Results: WC in 5 cm increments showed a positively increased all-cause mortality after adjusting for all covariates including BMI. Men showed higher HRs for mortality than women as WC increased, and the HRs were higher in the lower WC levels, but lower in the higher WC levels among the subjects aged 65-85 years than subjects aged 40-65 years. Even in subjects with normal weight and overweight, increased WC (levels 4, 5, and 6) showed increased HRs for mortality (HRs = 1.156, 1.412, and 1.614 in normal BMI and 1.145, 1.401, and 1.909 in overweight, respectively).

Conclusion: There was a linear association between WC and all-cause mortality across all BMI categories even in the subjects with normal or overweight BMI. Physicians should check WC routinely even in the subjects with normal weight or overweight.

Disclosure

Y. Kim: None. S. Yoo: None. S. Lee: None.
2108-P: Model-Based Assessments of Glucose Metabolism in Morbid Obese (MO) Subjects Before and After Bariatric Surgery (BS)
Authors: BRIX JOHANNA , KRZIZEK EVA-CHRISTINA , TURA ANDREA , PACINI GIOVANNI , LUDVIK BERNHARD
Published: June 2019

Improvement of insulin resistance (IR) as contributor of diabetes remission and prevention is a well known beneficial effect of BS. We investigated the changes in IR and sensitivity (IS) in MO patients with newly diagnosed type 2 diabetes (DM) before and 2 years after BS and compared the changes to patients with either impaired fasting glucose or impaired glucose tolerance (IGT/IFG). We included 27 patients with DM (mean age 44±12 years, mean±SD, BMI 49± 10kg/m²) and 104 patients with IGT/IFG (mean age 41±11 years, BMI 47± 7kg/m²). All patients had a 75g oGTT, glucose and insulin levels were repeatedly measured for calculation of IR and IS indices (Table). BMI (p= 0.742) and age (p= 0.194) were not different between both groups. Indices are shown in the Table. Before BS, IR was significantly higher in DM for all indices (p<0.001), except for AUC insulin (p=0.631). After BS, there were no significant differences in AUC glucose (p= 0.454), HOMA (p=0.905) OGIS (p=0.355), Matsuda (p= 0.469) and the oral disposition Index (0.171). IGT/IFG patients had a higher AUC insulin (p= 0.024) and a lower IGI (p= 0.024) compared to DM. Newly diagnosed DM patients are more insulin resistant compared to IGT/IGF. BS reduces IR to the same level in both groups. Post-glucose challenge AUC insulin remained higher in IGT/IFG, indicating better pancreatic insulin secretion reserve, which might translate to better diabetes prevention.

Disclosure

J. Brix: None. E. Krzizek: None. A. Tura: None. G. Pacini: None. B. Ludvik: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Takeda Development Centre Europe Ltd. Research Support; Self; Akebia Therapeutics, Eli Lilly and Company, Novartis AG, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.
2109-P: Symptomatic and Asymptomatic Hypoglycemia following Three Different Bariatric Procedures Is a Frequent and Severe Complication
Authors: KNOBLER HILLA , LAZAR LI OR , SAPOJNIKOV SHIMON , PINES GUY , MAVOR ELI , OSTROVSKY VIVIANA , SCHILLER TAL , ZORNITZKI TAIBA
Published: June 2019

Background: Post-bariatric surgery hypoglycemia has been previously reported. However, its prevalence remains uncertain due to variability of diagnostic criteria, types of bariatric procedures and possible lack of awareness.

Objective: To determine the frequency and severity of symptomatic and asymptomatic hypoglycemia in persons following 3 different surgical procedures ≥ 1 years before evaluation, and a group of non-operated obese persons.

Design and Setting: Observational cohort study conducted at an out-patient clinic. Fifty-one consecutive individuals were enrolled: post Roux-en-Y gastric bypass (RYGB) (n=16), post omega loop gastric bypass (OLGB) (n=12), post sleeve gastrectomy (SG) (n=15), obese persons prior to surgery (controls) (n=8). Hypoglycemic events (blood glucose ≤ 54 mg/dL) and severe hypoglycemia (blood glucose ≤ 40 mg/dL) were evaluated by: symptoms' questionnaire, mixed meal tolerance test (MMT) and continuous glucose monitoring (CGM).

Results: According to questionnaires, meal-related complaints were reported in 11 (26%) of the surgical group and 1/8 of controls. During MMT, 88%, 82% and 67% experienced hypoglycemia in the RYGB, OLGB and SG groups respectively, vs. none in the controls (P < 0.001). Severe hypoglycemia occurred in 38%, 45% and 7% of the RYGB, OLGB and SG groups respectively, (P= 0.025) but only 10 of the total operated group (24%) reported any symptoms. During CGM, fasting hypoglycemic events occurred more in the RYGB and OLGB vs. the SG group: 55%, 63% vs.17% respectively, (P= 0.036).

Conclusions: Post-bariatric surgery hypoglycemia is a very common phenomenon after 3 types of bariatric surgery and can be severe especially following bypass procedures. Intriguingly, our results show that hypoglycemia occurs not only in postprandial but also in fasting state, especially following bypass procedures. In many cases there were no specific complaints that may lead to underestimation of this serious complication.

Disclosure

H. Knobler: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. L. Lazar: None. S. Sapojnikov: None. G. Pines: None. E. Mavor: None. V. Ostrovsky: None. T. Schiller: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis. T. Zornitzki: None.
2115-P: Impact of Body Weight Change on Glycemic Control and Lipid Profiles in Obese Japanese Patients with Type 2 Diabetes
Authors: YOSHIMURA RAN , HASEGAWA YUKIKO , NAKAGAMI TOMOKO , BABAZONO TETSUYA
Published: June 2019

Objective: Body weight (BW) reduction is recommended for improvement of metabolic control in obese patients with type 2 diabetes (T2D). However, it is not fully understood to what extent of BW reduction is sufficient in Japanese. The aim of the study was to assess the impact of BW change on glycemic control and lipid profiles in obese Japanese patients with T2D.

Methods: The study subjects were 684 patients (65% men, mean age 59 years) with a body mass index (BMI) ≥25 kg/m2 among 8,179 patients with T2D who visited our diabetes clinic in both 2013 and 2015-2016. The changes in the levels for casual blood glucose (CBG), HbA1c, serum lipids, BW and proportions of patients taking medications (oral hypoglycemic agents and injection) between baseline and follow-up periods were determined. The liner regression analysis was performed to assess the relation of the changes in BW and changes in CPG, HbA1c, and serum lipid profiles. ANOVA and ANCOVA were used to compare these changes across five groups classified by the changes in BW as <-3% (n=195), -3 to -1% (n=138), -1 to 1% (n=126), 1 to 3% (n=78), and ≥3% (n=146).

Results: During the observational period, median values for BMI, CPG, HbA1c, triglyceride (TG), and LDL-cholesterol (LDL-C) were significantly decreased and HDL-C was significantly increased (all p<0.01). Changes in medications were observed in 72% of the patients. Multivariable liner regression analysis showed significant relations between the changes in BW and the changes in TG (beta=0.12, p<0.01) and LDL-C (beta =0.081, p=0.04). The adjusted mean change in TG in the five groups classified by the changes in BW were -7.8, 1.4, 6.8, 11.2, and 17.5%, and significant difference was found between the groups of BW <-3 and ≥3%. There was no difference in change in other parameters across the five groups.

Conclusion: In obese Japanese patients with T2D, change in BW was closely associated with change in TG and LDL-C, with statistically significant change in TG in those exhibiting -3% decrease in BW.

Disclosure

R. Yoshimura: None. Y. Hasegawa: None. T. Nakagami: None. T. Babazono: None.
2126-P: Physiological Concentrations of IL-1 Beta Promote Islet Amyloid Deposition by Increasing Beta-Cell Secretion of Human Islet Amyloid Polypeptide
Authors: TEMPLIN ANDREW T. , MELLATI MAHNAZ , ZEMAN-MEIER DANIEL , HOGAN MEGHAN F. , ESSER NATHALIE , ZRAIKA SAKENEH , HULL REBECCA L. , KAHN STEVEN E.
Published: June 2019

Aggregation of the β-cell secretory product human islet amyloid polypeptide (hIAPP) results in islet amyloid deposition as observed in type 2 diabetes (T2D). Formation of islet amyloid is associated with increased expression of proinflammatory cytokines and contributes to β-cell dysfunction and death. We previously showed that physiological levels of IL-1β increase inflammatory marker expression and islet amyloid deposition in isolated hIAPP transgenic mouse islets, a model of islet amyloidosis in T2D. To confirm these findings, we cotreated hIAPP transgenic islets with a physiological dose of IL-1β (4 pg/ml) and an IL-1β neutralizing antibody (1 μg/ml) for 48 h. Cotreatment reduced amyloid deposition by 55% compared to IL-1β alone (1.64±0.36 vs. 3.64±0.68% amyloid area per islet area, n=4, p=0.04), indicating this effect is dependent on IL-1β. Given that physiological levels of IL-1β have been shown to increase insulin secretion, we hypothesized they also stimulate IAPP secretion and thereby provide a mechanism for increased islet amyloid formation and inflammation. Islets treated with 4 pg/ml IL-1β secreted increased amounts of both insulin and IAPP over 48 h compared to vehicle treated islets (insulin: 87.5±8.9 vs. 48.3±17.3 nM/5 islets, n=4, p=0.04; IAPP: 409 ± 82 vs. 165 ± 51 pM/5 islets, n=4, p=0.02). Although IL-1β treated islets exhibited significant reductions in Ins2 (0.47 ± 0.03 vs. 1.01 ± 0.08, n=9, p<0.01) and Iapp (0.75 ± 0.06 vs. 1.01 ± 0.10, n=9, p=0.03) mRNA expression, content of insulin and IAPP was unchanged after 48 h (insulin: 167.9±14.2 vs. 144.3± 24.6 nM/5 islets, n=4, p=0.44; IAPP: 2272 ± 296 vs. 2340 ± 419 pM/5 islets, n=4, p=0.9).

In summary, physiological levels of IL-1β promote islet amyloid deposition, likely by increasing β-cell secretion of IAPP. Neutralization of this effect of IL-1β may therefore decrease the deleterious effects of amyloid formation on β-cell function and survival.

Disclosure

A.T. Templin: None. M. Mellati: None. D. Zeman-Meier: None. M.F. Hogan: None. N. Esser: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. 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

U.S. Department of Veterans Affairs (BX001060); National Institutes of Health (F32DK107022)
2129-P: DAP-Related Apoptosis-Inducing Kinase-2 Negatively Regulate Islet Beta-Cell Function by Autophagy Repression
Authors: LU YUTING , LI JINGYA , LI JIA
Published: June 2019

Islet apoptosis is a detrimental event causing or aggravating type 2 diabetes (T2D). The attenuation of islet β cells is always accompanied by the development of T2D. Current clinical antidiabetic drugs are shown to be effective, but they have not fundamentally solved the essence of islet cellular apoptosis and failure. Therefore, it is necessary to identify novel targets and potential therapeutics for hyperglycemic treatment with significant protection/delay islet function attenuation. DAP-related apoptosis-inducing kinase-2 (Drak2) is a member of death-associated protein kinase (DAPK) family. We found higher expression of Drak2 in pancreas of db/db mice compared with littermites. We demonstrated that Drak2 activity was negatively related with glucose-stimulated insulin secretion (GSIS) and the autophagic flux by knockdown or overexpression of Drak2 in primary islets. To further investigate the role of Drak2 in islet function, we generated β cell-specific Drak2 knockout mice (βKO) model. We found that the capacity of glucose tolerance was enhanced in βKO mice. And Drak2-deficient islets can resistant to palmitate-triggered apoptosis and GSIS impairment. On the other hand, Drak2 inhibitors were applied in the efficacy study, we demonstrated that these compounds effectively protected islets from apoptosis via autophagy promotion in vitro and ameliorated T2D in vivo in mouse models. Mechanistically, Drak2 may be involved in autophagy regulation through autophagy initiation complex, ULK1, to exerting its effects on the function and apoptosis of islet cells. Our preliminary work show that inhibition or deficiency of Drak2 protects β cell from apoptosis may due to autophagy promotion, and suggest that Drak2 might be a novel target for potential diabetic therapeutics development.

Disclosure

Y. lu: None. J. Li: None. J. Li: None.

Funding

Shanghai Municipal Science and Technology Commission (16430711700)
2138-P: Pancreatic Exocrine Changes in Longstanding Type 1 Diabetes
Authors: WRIGHT JORDAN J. , SAUNDERS DIANE C. , LINDNER JILL , BOGDANI MARIKA , BRISSOVA MARCELA , BOTTINO RITA , POWERS ALVIN C.
Published: June 2019

Individuals with longstanding type 1 diabetes (T1D) have smaller pancreata. Recent studies have found that pancreas volume is less at the time of T1D diagnosis and slightly decreased in auto-antibody positive, nondiabetic (ND) individuals. The reduced pancreas size in T1D cannot be due solely to β cell loss, since islets make up only ~2% of total pancreas mass. To better understand the T1D pancreas, we studied the pancreatic endocrine and exocrine compartments from T1D donors (N=23; age 18-62 years; duration 10-45 years) and age-matched, ND controls (N= 20; age 18-55 years). During islet isolation from T1D pancreata, standard approaches and enzymes were quite inadequate to free most islets or disperse the exocrine tissue. We also noted that T1D pancreata were more firm in physical consistency and had reduced relative pancreas weight (RPW, gm pancreas per kg body weight; 0.63 ± 0.04 in T1D vs. 1.1 ± 0.1 in ND, p<0.001) and volume (55.7 ± 7.2 vs. 99.9 ± 9.1 cc, p=0.001, n=21 and 11). The RPW did not correlate with T1D duration. Acinar cell density per tissue section was similar in T1D and ND (7400 ± 306 vs. 7502 ± 247 cells/mm2; n=11 per group; p=0.8), but T1D pancreata had fewer total cells as expressed per pancreatic mass (3.4 ± 1.7 vs. 5.8 ± 0.8 x 1010 cells, p=0.02, n=11 and 10). T1D acinar cells tended toward reduced size compared to ND acinar cells (86.1 ± 2.6 vs. 94.0 ± 3.8 μm2, p=0.055, n=8 and 10); acinar cell size did not correlate with pancreas weight, RPW, or proximity to islets. TUNEL and Ki67-positive exocrine cells were rare in both T1D and ND. Trichrome staining showed a qualitative increase in connective tissue in the exocrine compartment of T1D pancreata compared to ND, though specific staining for collagen IV and laminin appeared similar. Collectively these data illustrate exocrine-specific changes to pancreata in longstanding T1D, including an increase in connective tissue and a reduced pancreas size due to a reduction in total acinar cell number. How, when and why these changes occur in the T1D exocrine compartment remain to be determined.

Disclosure

J.J. Wright: None. D.C. Saunders: None. J. Lindner: None. M. Bogdani: None. M. Brissova: None. R. Bottino: Research Support; Self; Imagine Pharma. A.C. Powers: None.
214-OR: Effects of Fluid Rehydration Strategy on Correction of Acidosis and Electrolyte Abnormalities in Children with Diabetic Ketoacidosis
Authors: REWERS ARLETA , KUPPERMANN NATHAN DAVIS , STONER MICHAEL J. , GARRO ARIS , QUAYLE KIMBERLY , BENNETT JONATHAN E. , MYERS SAGE , MCMANEMY JULIE K. , NIGROVIC LISE E. , TRAINOR JENNIFER L. , TZIMENATOS LEAH , KWOK MARIA , OLSEN CODY S. , CASPER THERON C. , GHETTI SIMONA , GLASER NICOLE
Published: June 2019

Background: Fluid replacement to correct acidosis and electrolyte abnormalities is the cornerstone of treatment of diabetic ketoacidosis (DKA). We evaluated the rates of change in pH, pCO2, anion gap, Na, K, and Cl in children randomized to four DKA fluid treatment protocols.

Methods: From a large study conducted by The Pediatric Emergency Care Applied Research Network we used data from 714 children <18 y old with moderate or severe DKA. In a 2-by-2 factorial design, we evaluated the effects of intravenous rehydration with 0.9% vs. 0.45% NaCl and fast vs. slow rate of fluid administration, after an initial 0.9% NaCl bolus. The fast arm assumed 10% dehydration - half replaced in 12 h + maintenance fluids, the other half replaced over subsequent 24 h + maintenance fluids. The slow arm assumed 5% dehydration replaced evenly over 48 hours + maintenance fluids. We tested for differences in the rate of change of laboratory values between treatments using stratified Van Elteren and Cochran Mantel Haenszel tests.

Results: The median age, sex, and baseline laboratory characteristic of the patients did not differ by treatment arm. The rate of change of pH did not differ by the arm, however the rate of rise of pCO2 was more rapid in the fast vs. slow fluid arms during the initial 4 h. The rate of decrease in anion gap was more rapid in the fast vs. slow arms during the initial 4 h and 8 h (p<0.01 for all). Glucose-corrected Na remained steady for subjects assigned to 0.9% NaCl vs. those assigned to 0.45% NaCl whose glucose-corrected Na decreased at 4 and 8 h (p<0.01). K levels decreased and Cl increased more rapidly with 0.9% vs. 0.45% NaCl (p<0.01). Hyperchloremic acidosis developed in 46.1% of patients in the fast arms vs. 35.2% in the slow arms (p<0.01).

Conclusions: In children treated for DKA, faster fluid administration led to more rapid normalization of anion gap and pCO2 than slower fluid rates. However, more rapid fluid rates were associated with increased frequency of hyperchloremic acidosis.

Disclosure

A. Rewers: None. N.D. Kuppermann: Other Relationship; Self; InsuCalc. M.J. Stoner: None. A. Garro: None. K. Quayle: None. J.E. Bennett: None. S. Myers: None. J.K. McManemy: None. L.E. Nigrovic: None. J.L. Trainor: None. L. Tzimenatos: None. M. Kwok: None. C.S. Olsen: None. T.C. Casper: None. S. Ghetti: None. N. Glaser: Consultant; Self; Bristol-Myers Squibb Company. Other Relationship; Self; Insucalc.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development
2140-P: Pancreatic Islet and Exocrine Tissue Innervation Is Not Altered in Type 1 Diabetes
Authors: RICHARDSON TIFFANY M. , HALIYUR RACHANA , ARAMANDLA RADHIKA , BOTTINO RITA , POWERS ALVIN C. , BRISSOVA MARCELA
Published: June 2019

Impaired counterregulatory response of glucagon to hypoglycemia is a common complication of type 1 diabetes (T1D). One proposed contributor to abnormal glucagon secretion is decreased sympathetic innervation in T1D islets. To systematically assess the innervation of human pancreatic tissues, we examined samples from donors with recent-onset T1D (<10 years, age 13-45 years, n = 4), longstanding T1D (>10 years, age 27-63 years, n = 3), and nondiabetic controls (age 10-52 years, n = 4). Islet and exocrine tissue innervation was visualized by pan-neuronal marker tubulin β-3 and analyzed by a 2-D morphometry and 3-D rendering. By quantifying the nerve fiber length (1.9±0.4 nm/μm2) and density (646±94 fibers/mm2), we found that innervation in control human islets was nearly 20-fold less than previously reported in mouse islets. In contrast to mouse, human exocrine tissue was far more innervated than islets with fiber length of 6.8±0.4 nm/μm2(p<0.05), and density of 1336±50 fibers/mm2(p<0.05). The 3-D analysis showed that nerve fibers follow extracellular matrix (ECM) formed around acini and from there, they extend further into islets along the ECM made by islet vasculature. Although T1D islets were primarily composed of α cells, the islet area was similar to controls (control: 15.7±1.5 mm2, recent-onset T1D: 16.5±1.4 mm2, long-standing T1D: 15.3±1.5 mm2; p>0.05), and so was the 3-D arrangement of nerve fibers in exocrine tissue and islets. Regardless of T1D duration, the islet fiber length (recent-onset: 1.5±0.2 nm/μm2; long-standing: 1.0±0.2 nm/μm2) and density (recent-onset: 623±61 fibers/mm2; longstanding: 486±49 fibers/mm2), as well as exocrine fiber length (recent-onset: 5.2±.5 nm/μm2; longstanding: 5.8±0.4 nm/μm2) and density (recent-onset: 1119±77 fibers/mm2; longstanding: 1537±72 fibers/mm2) did not differ from controls (p>0.05). These data indicate that neuronal patterning of human pancreas is significantly different from that of mouse and islet innervation does not appear to be altered in T1D.

Disclosure

T.M. Richardson: None. R. Haliyur: None. R. Aramandla: None. R. Bottino: Research Support; Self; Imagine Pharma. A.C. Powers: None. M. Brissova: None.
2149-P: Mitochondrial Akt Modulated Human Embryonic Stem Cell Differentiation Lineages—Analysis with Single Cell RNA Sequencing
Authors: LEE HSIAOCHEN , CHEN YU-HAN , LIN HUGO YOU-HSIEN , TA ALBERT , WANG PING H. , CHEN YUMAY , ANDERSEN BOGI
Published: June 2019

How signaling pathways control embryonic stem cell (ESC) differentiation is poorly understood. Recent studies suggested mitochondria metabolism may play a role in the regulation of stem cell differentiation. In this study, we found a novel role for mitochondrial Akt1 (mito-Akt) that modulated human ESC (hESC) differentiation lineage. We observed that Akt was activated and translocated into mitochondria in hESC upon growth factor stimulation. To determine the effect of mito-Akt on hESC differentiation, hESC were transduced with His-tagged mitochondrial-targeting dominant negative Akt1/GFP (Ad-mdnAkt) or GFP adenoviral vector (Ad-GFP). The transgene was expressed in >90% cells, and mitochondria-targeting was verified. Ad-mdnAkt altered hESC respiration, as measured with Seahorse extracellular flux analyzer, and mitochondria proton leak was increased. After 21 days of differentiation in vitro, H&E stain showed Ad-mdnAkt transduced cells formed more organized cell clusters than control ones. Bulk RNA was extracted for qRT-PCR with primer array of representative marker genes, and the results suggested that marker genes for mesoderm and endoderm were up-regulated whereas marker genes for ectoderm were down-regulated when mito-Akt was inhibited by Ad-mdnAkt in hESCs. To further dissect how mito-Akt modulates cell lineage, single-cell RNA seq was analyzed with 10X Genomics platform. Among the 24 clusters identified by t-SNE plot, Ad-mdnAkt cells were over-represented in 5 clusters and under-represented in 4 clusters when compared to the controls. Interestingly, hESCs with Ad-mdnAkt favored lineages toward hematological system and lymphoid tissue development instead of pancreatic progenitor cells.

In summary, mito-Akt is a novel modulator of stem cell differentiation, altering mito-Akt signaling during the early phase of hESC differentiation may impact later embryonic development.

Disclosure

H. Lee: None. Y. Chen: None. H.Y. Lin: None. A. Ta: None. P.H. Wang: None. Y. Chen: None. B. Andersen: None.
2154-P: Mice Fed a Low Protein Diet In Utero Show Decreased Apelin Receptor Presence in Ins+Glut2Lo Cells during Pregnancy Associated with Lower ß-Cell Mass
Authors: AZIMI HOUSHANG , SZLAPINSKI SANDRA , HILL DAVID J.
Published: June 2019

The apelinergic system, consisting of the apelin receptor (APJ) and its cognate ligand apelin, is active in pancreas, skeletal muscle, adipose and other tissues. Apelin/APJ are implicated in energy metabolism as apelin is secreted by adipocytes and may bind APJ on β-cell membranes to reduce glucose-stimulated insulin secretion. Apelin-13 administration has been shown to increase islet cell mass and β-cell insulin content in mice with T1DM and can increase insulin sensitivity in obese, hyperinsulinaemic mice. The metabolic stress of pregnancy is normally accommodated by β-cell mass (BCM) expansion and increased glucose-stimulated insulin secretion. A failure to increase BCM can contribute to the risk of gestational diabetes. Exposure of mice to a low protein diet (LP) in utero can limit expansion of BCM during subsequent pregnancy. As previously shown, insulin-expressing but glucose-transporter-2-low (Ins+Glut2Lo) progenitor cells contribute to gestational BCM expansion. Thus, we investigated how APJ presence on Ins+Glut2Lo cells might differ in islets of pregnant C57Bl/6 mice previously exposed to LP vs. control (C) diet. F1 female offspring exposed to LP or C diet in utero and postnatal development were time mated and pancreata collected at gestational days (GD) 9 and 12. Insulin, Glut2, and APJ were visualized by immunohistochemistry with respect to β-cell localization in small endocrine clusters (1-5 β-cells) and in islets (≥ 6 β-cells). The percentage of Ins+Glut2LoAPJ+ cells relative to all Ins+ cells was significantly decreased in LP-exposed mice vs. C at GD12 (C 5.7±1.0%, LP 2.7±0.1%, p<0.05) when Ins+Glut2Lo cell expansion is maximal, but not at GD9 (C 4.9±1.6%, LP 3.4±0.9%). Significant differences were not found in % Ins+Glut2LoAPJ+ cells relative to extra-islet clusters or islets between LP vs. C at GD 9 and 12. Results suggest that APJ presence may contribute to BCM expansion during pregnancy mediated by Ins+Glut2Lo cells.

Disclosure

H. Azimi: None. S. Szlapinski: None. D.J. Hill: None.
2167-P: Gamma-Hydroxybutyrate Prevents Lipotoxicity-Induced ß-Cell Dysfunction
Authors: NGA YEUNG LUCY SHU , IVOVIC ALEKSANDAR , TAN YAO FANG , BATCHULUUN BATTSETSEG , MAMELAK MORTIMER , GIACCA ADRIA
Published: June 2019

Prolonged exposure to high levels of fatty acids impairs the insulin secretory capacity of pancreatic β-cells through mechanisms involving oxidative stress (lipotoxicity). Beta-cell lipotoxicity is thought to play an important role in the β-cell failure of type 2 diabetes. Antioxidants can protect β-cells from lipotoxicity by decreasing oxidative stress. Gammahydroxybutyrate (GHB), an endogenous neurotransmitter currently safely used as a treatment for narcolepsy, is also found in cells as an energy source and antioxidant. Previous studies have shown that GHB can protect mice from streptozotocin and alloxan induced diabetes; both compounds are generators of oxidative stress and yield models of type 1 diabetes. However, the effect of GHB in models of type 2 diabetes has not been investigated. We hypothesized that GHB can protect β-cells from lipotoxicity.

We first investigated the effectiveness of GHB in preventing β-cell dysfunction in high-fat treatment (palmitate) in an in vitro model with freshly isolated mouse islets. Beta-cell function was determined by glucose stimulated insulin secretion assays. Islets incubated with GHB were protected from β-cell lipotoxicity that resulted from the concurrent 48h exposure to palmitate. The antioxidant effects of GHB in lipotoxicity were further investigated by measuring reactive oxygen species (ROS) levels. GHB prevented the increase in ROS that was observed with the palmitate treatment while GHB by itself had no effects. While further studies need to be done to elucidate possible mechanisms of action of GHB beyond its antioxidant effect as well as GHB effectiveness in vivo, our findings suggest that GHB or potentially GHB derivatives may be of interest for their β-cell protective properties.

Disclosure

L. Yeung: None. A. Ivovic: None. Y. Tan: None. B. Batchuluun: None. M. Mamelak: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals.

Funding

Jazz Pharmaceuticals plc
217-LB: Associations between Multimorbidity and HbA1c in People with Type 2 Diabetes in Australian Family Practice
Authors: CHIANG JASON I. , FURLER JOHN , JANI BHAUTESH D. , MAIR FRANCES S. , THURAISINGAM SHARMALA , NICHOLL BARBARA I. , MANSKI-NANKERVIS JO-ANNE E.
Published: June 2019

Introduction: Multimorbidity (MM) is common in people with T2D (PwT2D) who in Australia, receive medical care predominantly in family practice (FP). We explored the association between MM condition count and HbA1c in PwT2D attending Australian FP, using electronic health record (EHR) data.

Methods: Cross-sectional study of 69,718 PwT2D who had a FP encounter between 2013-15 captured in the NPS MedicineInsight dataset (EHR data from >500 family practices and 3.5 million patients across Australia). MM condition count was based on coded and free text conditions in the reason for visit, prescription or medical history fields. Primary outcome: HbA1c. Multivariable mixed-effects linear regression examined associations between MM counts (total, concordant (T2D-related) and discordant (unrelated)) and HbA1c (%).

Results: We found statistically significant associations between HbA1c and total and discordant MM counts. Mean HbA1c (95% CI) was lower for those having 1, 2, 3 and 4+ total conditions compared to T2D only, -0.065 (-0.089, -0.041), -0.097 (-0.128, -0.066), -0.089 (-0.133, -0.046), and -0.097 (-0.146, -0.047) respectively, and for discordant conditions -0.085 (-0.108, -0.061), -0.100 (-0.134, -0.065), -0.141 (-0.195, -0.087), and -0.204 (-0.276, -0.133). There was no statistically significant association between HbA1c and increasing concordant count.

Conclusions: While EHR counts of MM and discordant conditions are associated with lower HbA1c, this is not likely to be clinically significant, suggesting the impact of MM on HbA1c remains unclear. The NPS dataset uses routine data entered by clinicians for the purpose of patient care, rather than epidemiological studies and may thus underestimate the number of conditions experienced by PwT2D. While clinicians need to consider the MM burden of PwT2D, the NPS MedicineInsight dataset needs further validation, eg through combining with other data sources, in the study of MM.

Disclosure

J.I. Chiang: None. J. Furler: Research Support; Self; Abbott, Sanofi. B.D. Jani: None. F.S. Mair: None. S. Thuraisingam: None. B.I. Nicholl: None. J.E. Manski-Nankervis: Research Support; Self; Australian National Health and Medical Research Council, Boehringer Ingelheim International GmbH, Diabetes Australia, Eli Lilly and Company. Speaker’s Bureau; Self; RACGP.

Funding

Royal Australian College of General Practitioners
2173-P: Effects of AMP-Activated Protein Kinase Activation on Insulin Secretion in Mice
Authors: NGUYEN-TU MARIE-SOPHIE , HARRIS JOSEPH P. , MARTINEZ-SANCHEZ AIDA , LECLERC ISABELLE , RUTTER GUY A.
Published: June 2019

AMP-activated protein kinase (AMPK) is an important cellular energy sensor in regulation of metabolic activity. AMPK activation improves glucose homeostasis by increasing muscle glucose uptake and reducing hepatic glucose production. Although the effects on glucose-stimulated insulin secretion in the pancreatic β cells are still controversial. Our aim was to investigate the regulation of insulin secretion in pancreatic β cells using specific pharmacological AMPK activators and in mouse models of constitutive activation. We used a chronic global AMPK (γ1D316A) and a pancreatic β cell specific (β-D316A) activation mouse model that express the AMPK γamma1 isoform with a D316A mutation under the control of β-actin and ins1 promoter respectively. We tested how chronic AMPK activation impacted insulin secretion on C57BL6 mouse isolated islets using direct activators PF-06409577 (β1 isoform-selective) and RA089 (binds both β1 and β2 isoforms). Global activation of AMPK reduced insulin secretion from islets isolated from γ1D316A mice on chow and high-fat diet (2.4-fold, p<0.05 and 1.9-fold p<0.01, respectively). Dual AMPK activation of β1 and β2 (RA089) on control mouse islets enhanced in a dose-response manner insulin secretion in response to high glucose (17mM) and KCl after 30 minutes of incubation (1.7-fold p<0.005 and 1.7-fold p<0.005, respectively). The same effects were observed by activating AMPK β1 isoform with PF-06409577, increasing insulin release in response to high glucose and KCl (2-fold, p<0.005 and 1.7-fold, p<0.05). These findings suggest that the effects of AMPK on insulin secretion depends on its mode of activation. Acute pharmacological activation targetting β1 and/or β2 subunit increased insulin secretion whereas chronic global activation in mice reduced insulin release. Investigating our second model of chronic activation β-D316A and further studies of our models will help us decipher the role of AMPK in the pancreas.

Disclosure

M. Nguyen-Tu: None. J.P. Harris: None. A. Martinez-Sanchez: None. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma.
2175-P: Isoform-Specific Roles of Prolyl Hydroxylase Domain Proteins in Regulating Beta-Cell Function
Authors: HOANG MONICA , JANSSEN SARAH M. , JOSEPH JAMIE W.
Published: June 2019

Pancreatic β-cells secrete insulin in a biphasic manner via KATP-channel dependent and independent pathways. The KATP-channel independent pathway produces a rise in the NADPH/NADP+ ratio and cytosolic α-ketoglutarate (α-KG). Prolyl hydroxylase domain proteins (PHDs) belong to the α-KG-dependent dioxygenase superfamily and regulates stability of hypoxia-inducible factor α (HIF-α). Prolyl hydroxylation of HIF-α for ubiquitin-mediated proteasomal degradation requires sufficient levels of oxygen, iron and α-KG. We have previously shown pharmacological inhibition of PHDs reduces glucose-stimulated insulin secretion (GSIS), glucose utilization, and mitochondrial function in clonal β-cells. Glucose-induced changes in cytosolic α-KG may regulate PHD and thus β-cell function. In mouse pancreatic β-cells, PHD isoforms express unique subcellular localization: PHD1 is expressed exclusively in the cytosol, PHD2 is expressed in the cytosol and nucleus, and PHD3 is mainly expressed in the nucleus. To further explore the isoform-specific roles of PHD, we employed a β-cell specific knockout (β-PHD KO) mouse model for each of the PHD isoforms. β-PHD1 KO, β-PHD2 KO and β-PHD3 KO. β-PHD KO mice show no significant in vivo defects associated with glucose tolerance and insulin resistance; however, β-PHD1 KO and β-PHD2 KO mice have significantly increased plasma insulin compared to wild type (WT) controls (p<0.05). Consistent with our cell culture model of PHD knockdown, PHD1 and PHD3 regulate insulin secretion as both β-PHD1 KO and β-PHD3 KO mice show impaired GSIS. Only β-PHD1 KO mice have reduced beta-cell mass (p<0.01).

In conclusion, there are significant and unique effects observed with isoform-specific suppression of PHD.

Disclosure

M. Hoang: None. S.M. Janssen: None. J.W. Joseph: None.

Funding

Natural Sciences and Engineering Research Council of Canada; Canadian Institutes of Health Research