bluuebunny/crossref_metadata_2025 huggingface dataset:
2100-P: The Association between Blood Glucose and Different Anthropometrics and Body Composition Measures in the Chinese Population: Results from the Pinggu Metabolic Disease Study
Authors: ZHANG FANG , LI YUFENG , ZHAO YINGXI , ZHOU XIANGHAI , JI LINONG
Published: June 2019

Introduction: Empirical cohort have evidenced that central adiposity is the strongest modifiable risk factor for T2DM, however most studies neglect the absolute measures including visceral fat area (VFA) and subcutaneous fat (SFA). This study aims to analyze the strength of association between FPG, 2hPPG, HbA1c and nine anthropometrics measures, to explore the best indicator for hyperglycemic risks.

Methods: Analyses were based on the data from the Pinggu Metabolic Disease study in 2013-2014. Excluded participants with self-reported DM, dyslipidemia and hyperuricemia, 2940 were included. Anthropometrics, VFA and SFA were measured. Logistic regression was used to find the association between per standard increase and risk for high FPG (≥7.0 mmol/L), 2hPPG (≥11.1 mmol/L), HbA1c (≥6.5%).

Results: Higher VFA and SFA were associated with higher FPG, 2hPPG and HbA1c after adjusting for other covariates. The strongest association was waist to hip ratio (WHR) for FPG and 2hPPG, and waist circumference (WC) for HbA1c. The strength of association between SFA, VFA and FPG, 2hPPG and HbA1c was less than WHR and WC. VSR showed a comparably weak strength of association. See Figure for detail result.

Conclusion: WHR and WC remains the best indicators of high risk factor for hyperglycemia among healthy Chinese population.

Disclosure

F. Zhang: None. Y. Li: None. Y. Zhao: None. X. Zhou: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.
2103-P: Sex Differences in Human Adipose Tissue: Comprehensive Transcriptome Profiling
Authors: BOGU GIREESH , SNYDER MICHAEL , MCLAUGHLIN TRACEY
Published: June 2019

The sexual dimorphism of adipose tissue is incompletely understood. Differences in total and regional adiposity have been described, but the molecular basis for these differences is unclear. We have conducted the first comprehensive transcriptome analysis in adipose tissue from healthy age and BMI-matched women and men. Results demonstrate upregulation of lipid and carbohydrate metabolism in pre and postmenopausal women vs. men. In men few genes were upregulated: the majority of these were related to inflammation vs. upregulation of inflammatory genes in men. Measurement of regional and intrahepatic fat, adipose cell size, and systemic insulin resistance complement RNAseq (n=39) and rtPCR (n=54) results.

Disclosure

G. Bogu: None. M. Snyder: Advisory Panel; Self; Jungla. Consultant; Self; Merck & Co., Inc. Other Relationship; Self; 10x Genomics, Akna, Filtricine, Illumina, Inc., January, Personalis, Qbio, SensOmics. T. McLaughlin: Advisory Panel; Self; January. Stock/Shareholder; Self; Eiger BioPharmaceuticals.

Funding

American Diabetes Association (1-11-CT-35 to T.M.); National Institute of Diabetes and Digestive and Kidney Diseases
211-OR: Analysis of Longitudinal Autoantibody Profiles and the Progression Rates to Type 1 Diabetes
Authors: GHALWASH MOHAMED , ANAND VIBHA , LIU BIN , KOSKI EILEEN , NG KENNEY , DUNNE JESSICA L. , LUNDGREN MARKUS , REWERS MARIAN , VEIJOLA RIITTA ,   FOR T1DI STUDY GROUP
Published: June 2019

Clinical type 1 diabetes (T1D) is preceded by asymptomatic islet-autoimmunity (IA) with presence of islet autoantibodies (AAb). However, both AAb profiles (clusters) during IA phase and progression rate to T1D are heterogeneous. It is unclear if AAb profiles affect the progression to T1D similarly in different countries. We analyzed data from 3 prospective birth cohorts, DAISY (U.S.), DiPiS (Sweden), and DIPP (Finland), to address this question. We developed a similarity algorithm that considers subject-level temporal IA profiles (based on 4 AAbs - IAA, GADA, IA2A, and ZnT8A positivity or negativity), age at which AAb developed, and imbalance in AAb positivity by weighting positive AAb matches higher than negative ones. Using this subject-level similarity measure, we performed hierarchical clustering of AAb positive subjects having at least 3 visits. We used a log-rank test to identify the number of clusters in 1125 DIPP subjects (329 T1D cases), 309 DAISY subjects (70 cases), and 226 DiPiS subjects (33 cases). Each dataset was individually clustered. We identified three clusters in each dataset associated with different rate of progression from seroconversion to T1D - slow progressors (SP), moderate progressors (MP) and fast progressors (FP). These were distributed as follows: DIPP (654 SP with 3% 10-year T1D risk, 356 MP with 60% risk, 115 FP with 96% risk); DAISY (215 SP with 6% 10-year risk, 92 MP with 62% risk, 2 FP with 100% risk); and DiPiS (160 SP with 3% 10-year risk, 62 MP with 58% risk, 4 FP with 100% risk). Finally, we tested the generalizability of the clusters by 1) learning a clustering from one data set “learned clusters,” 2) classifying subjects from another (independent) data set with the “learned clusters,” and 3) measuring how often the subjects were assigned to the same cluster (SP, MP, FP) as the “internal” clustering. The average accuracy of cluster transfer was high (mean = 87.9%, sd = 1.1%) suggesting that the IA profile predicts progression rate to T1D independently of the population.

Disclosure

M. Ghalwash: None. V. Anand: None. B. Liu: None. E. Koski: None. K. Ng: None. J.L. Dunne: None. M. Lundgren: None. M. Rewers: None. R. Veijola: None.

Funding

JDRF
2114-P: Use of Visceral Fat Area Measurement for Evaluating Obesity in Elderly Patients with Type 2 Diabetes
Authors: MINAMIZUKA TAKUYA , MAEDA YUKARI , KOSHIZAKA MASAYA , ISHIKAWA TAKAHIRO , MAEZAWA YOSHIRO , YOKOTE KOUTARO
Published: June 2019

Objective: In Japan, obesity is defined as a body mass index (BMI) ≥25 kg/m2. Sarcopenic obesity (low BMI with visceral fat accumulation) has high mortality and is common in elderly people. We evaluated the value of visceral fat area (VFA) measurement in elderly type 2 diabetes (T2D) patients for determining sarcopenic obesity.

Methods: We analyzed 124 T2D patients who were hospitalized for glycemic control. They were divided into elderly people (aged ≥65 years) (n=74) and non-elderly people (aged <65 years) (n=50). They were further divided according to BMI (<25 kg/m2 and ≥25 kg/m2) and VFA (<100 cm2 and ≥100 cm2). We compared the number and percentages of significantly different metabolism related items by BMI or VFA grouping between the elderly and non-elderly groups. The correlation between BMI and VFA was also analyzed.

Results: We observed the following patient characteristics: the elderly group; 55 men (74.3%), average age 73.2 years, BMI 24.7 kg/m2, and VFA 137.7 cm2; and the non-elderly group; 25 men (50%), average age 49.8 years, BMI 31.8 kg/m2, and VFA 180.7 cm2. Only 6/43 (14.0%) metabolism related items differed significantly between patients with BMI ≥25 kg/m2 and those with BMI <25 kg/m2 in the elderly group, whereas 18/43 (41.9%) items differed significantly between patients with BMI ≥25 kg/m2 and those with BMI <25 kg/m2 in the non-elderly group. In the elderly group, 15/43 (34.9%) metabolism related items differed significantly between patients with VFA ≥100 cm2 and those with VFA <100 cm2, whereas in the non-elderly group, 18/43 (41.9%) items differed significantly between patients with VFA ≥100 cm2 and those with VFA <100 cm2. The correlation between BMI and VFA was stronger in the non-elderly group than in the elderly group.

Conclusion: Although BMI is a simple and useful index of obesity evaluation, sarcopenic obesity may be overlooked. In elderly patients who tend to have sarcopenic obesity, VFA measurement might be a more useful index of obesity.

Disclosure

T. Minamizuka: None. Y. Maeda: None. M. Koshizaka: Research Support; Self; Astellas Pharma Inc., Pfizer Health Research Foundation, Taisho Pharmaceutical Co., Ltd. T. Ishikawa: None. Y. Maezawa: None. K. Yokote: None.
2128-P: Exploring the Role of Autophagy in Pancreatic Alpha Cells
Authors: HIMURO MIWA , MIYATSUKA TAKESHI , SUZUKI LUKA , MIURA MASAKI , KATAHIRA TAKEHIRO , GOTO HIROMASA , NISHIDA YUYA , SASAKI SHUGO , FUJITANI YOSHIO , WATADA HIROTAKA
Published: June 2019

Autophagy is known to play a pivotal role in intracellular quality control through the degradation of subcellular damaged organelles and components. Whereas autophagy is essential for maintaining β-cell function in pancreatic islets, it remains unclear as to how the cellular autophagy affects the homeostasis and function of glucagon-secreting α cells. To analyze the role of autophagy in α cells, we generated a mutant mouse model lacking Atg7, a key molecule for autophagosome formation, specifically in α cells. Histological analysis demonstrated an increased number of glucagon-positive cells, with a multilayered structure, in the islets under Atg7 deficiency, although metabolic profiles, such as body weight, blood glucose and plasma glucagon levels, were comparable between Atg7-deficient mice and control littermates. Consistent with our previous findings that Atg7 deficiency suppressed β-cell proliferation, cellular proliferation was suppressed in Atg7-deficient α cells.

These findings suggest that α-cell autophagy plays a role in maintaining α-cell mass and normal islet architecture, but appears to be dispensable for metabolic homeostasis.

Disclosure

M. Himuro: None. T. Miyatsuka: None. L. Suzuki: None. M. Miura: None. T. Katahira: None. H. Goto: None. Y. Nishida: None. S. Sasaki: None. Y. Fujitani: Research Support; Self; Takeda Pharmaceutical Company Limited. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

Funding

Japan Society for the Promotion of Science
213-OR: Lowering HbA1c during the First 2 Years Predicts a Lower Long-Term HbA1c on a Clinic Level
Authors: HANAS RAGNAR , HANBERGER LENA , SAMUELSSON ULF , ÅKESSON KARIN
Published: June 2019

Background: Mean HbA1c in children and adolescents varies between countries, but there is a considerable variation also between clinics within the same country. It has been difficult to characterize factors that contribute to this difference. We aimed to compare early metabolic control with long-term mean HbA1c in clinics within Sweden.

Methods: The Swedish pediatric diabetes quality registry (SWEDIABKIDS) covers 98% of children and adolescents < 18 years in Sweden. We captured overall mean HbA1c for 36/42 clinics (6 had less than 20 patients with < 2 years’ duration) and compared with HbA1c over the first 2 years of diabetes. Values with < 3 months’ duration were not included as these are affected by glucose levels before diagnosis.

Results: Mean overall HbA1c for all 42 clinics was 54.6 (95% CI 53.3-55.9) mmol/mol (7.1%, 95% CI 7.0-7.3) and over the first 2 years for the 36 clinics 50.1 (95% CI 48.0-52.2) mmol/mol (6.7%, 95% CI 6.5-6.9). The correlation for the 36 clinics was r=0.677 (p<0.001). R2 was 0.458, i.e., 45.8% of the variation in overall HbA1c was explained by HbA1c during the first 2 years of diabetes.

Conclusions: An intensive education program at the onset of diabetes resulting in a low HbA1c early on is a good investment for the long-term metabolic control. Mean HbA1c during the first 2 years will be a good variable to measure the effectiveness and success on a clinic level of new implementations in diabetes treatments.

Disclosure

R. Hanas: Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; AstraZeneca. L. Hanberger: None. U. Samuelsson: None. K. Åkesson: Speaker's Bureau; Self; Novo Nordisk A/S.
2131-P: Dextran Sulfate and HGF Ameliorate Type 1 Diabetes
Authors: LU GEMING , ZHANG TUO , HOMANN DIRK , GARCIA-OCAÑA ADOLFO
Published: June 2019

Type 1 diabetes (T1D) results from loss of immune tolerance and β-cells. Currently, research on T1D treatments focus on regeneration and preservation of β-cells and restoration of immune tolerance. The sulfated synthetic polysaccharide dextran sulfate (DS), a mild anticoagulant and blood volume expander used in clinic, inhibits dendritic cell maturation and activation. DS administration increases circulating hepatocyte growth factor (HGF) in rodents and humans. In this study, we tested the effects of DS on: T1D development in NOD mice; β-cell survival, function and mitochondrial activity in cytokine-treated islets; and, the profile of immune activation and tolerance markers. DS treatment reduced spontaneous T1D onset in female NOD mice from 70% to 20%. T1D prevention in the wake of DS treatment was associated with preserved plasma insulin and β-cell mass, and reduced β-cell death. DS synergized with HGF in protecting mitochondrial function of cytokine-treated islets in vitro, maintaining maximal respiration, ATP production and glucose-stimulated insulin secretion. Pancreas histology showed decreased immune cell infiltration in islets of DS-treated mice. Splenocytes and pancreatic lymph nodes of DS-treated mice displayed decreased IFNγ+ CD8+ and CD4+, and increased IL4+ CD4+ and FoxP3+ CD4+ cells. In vitro, DS+HGF increased both the inhibitory phenotype of bone marrow derived macrophages (BMDM) downregulating IL1β, TNFα, and iNOS and increasing IL10, and the number of FoxP3+ CD4+ treated with αCD3 and αCD28 in the absence of TGF β. DS+HGF enhanced mitochondrial mass, potential, oxidative phosphorylation and expression of OXPHOS complexes, metabolic features of inhibitory BMDMs and regulatory T cells. Collectively, these results indicate that DS and HGF ameliorate T1D in NOD mice by alleviating the metabolic impairment induced by inflammation in islets and by boosting mitochondrial function to preserve β-cell function and upregulate M2 macrophages and regulatory T cells. DS and HGF can be of great value for treating T1D.

Disclosure

G. Lu: None. T. Zhang: None. D. Homann: None. A. Garcia-Ocaña: None.

Funding

National Institutes of Health (DK113079, DK020541, W81XWH-17-1-0363)
2142-P: Toll-Like Receptors 2 and 4 Act as Brakes to Regulate Adaptive ß-Cell Mass Expansion in Diet-Induced Obesity
Authors: JI YEWEI , SUN SHENGYI , QI LING
Published: June 2019

Restoration of β cell mass via β cell regeneration is a promising approach for treatment of diabetes. However, β cell proliferative capacity declines after adolescence and remains extremely low during entire adulthood, posing a significant roadblock in β cell regeneration therapy. The mechanism that inhibits β cell replication in adult and obesity remains enigma. Toll-Like Receptors (TLRs) are membrane-spanning proteins that recognize microbes-derived structurally conserved molecules and play a key role in innate immune response. Serendipitously, our study demonstrated that Toll-like receptor (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged β cell mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and cyclin-dependent kinase 4 (CDK4) in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel negative regulatory mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.

Disclosure

Y. Ji: None. S. Sun: None. L. Qi: None.

Funding

American Diabetes Association (1-12-CD-04, 1-19-IBS-235 to L.Q.); JDRF (47-2012-767, 1-SRA-2014-251-Q-R, 2-SRA-2018-539-A-B); American Heart Association (17SDG33670192); Michigan Nutrition Obesity Research Center (P30DK089503); Howard Hughes Medical Institute (59107338)
2144-P: Early Administration of Dapagliflozin Preserves Pancreatic Beta-Cell Mass through an Epigenetic Modification in a Mouse Model of Type 2 Diabetes
Authors: ASAHARA SHUN-ICHIRO , KANNO AYUMI , KIDO YOSHIAKI
Published: June 2019

Aims: The preservation of pancreatic β-cell mass is an essential factor in the onset and development of type 2 diabetes mellitus. Recently, sodium-glucose co-transporter 2 inhibitors have been launched as anti-hyperglycemic agents, and their organ protective effects are attracting attention. They are also reported to have favorable effects on the preservation of pancreatic β-cell mass, but the appropriate timing for the administration of sodium-glucose co-transporter 2 inhibitors is obscure.

Materials and Methods: In this study, we administered a sodium-glucose co-transporter 2 inhibitor, dapagliflozin, to an animal model of type 2 diabetes mellitus, db/db mice, and investigated the adequate timing and duration for its administration. We also conducted microarray analysis and methylated DNA immunoprecipitation (MeDIP) using pancreatic islets from db/db mice.

Results: We found that dapagliflozin preserved pancreatic β-cell mass depending on the duration of administration, and markedly improved blood glucose levels. If the duration was the same, the earlier administration of dapagliflozin was more effective in preserving pancreatic β-cell mass, increasing serum insulin levels, and improving blood glucose levels. From the analysis of microarray, we discovered that the expression of Agr2, Tff2, and Gkn3 was significantly upregulated following the early administration of dapagliflozin. This upregulated gene expression might provide a legacy effect for the preservation of pancreatic β-cell mass. In addition, MeDIP analysis revealed that early administration of dapagliflozin affected DNA methylation in pancreatic islets of db/db mice.

Conclusions: We expect that the early administration of dapagliflozin would provide a long-lasting effect in preserving pancreatic β-cell mass.

Disclosure

S. Asahara: Research Support; Spouse/Partner; AstraZeneca. A. Kanno: None. Y. Kido: Research Support; Self; AstraZeneca.

Funding

AstraZeneca K.K.; Ono Pharmaceutical Co., Ltd.
2145-P: Notch1 Has Important Role in Beta-Cell Mass Determination and Development of Diabetes
Authors: EOM YOUNG SIL , KIM KWANG-WON , KIM BYUNG JOON
Published: June 2019

Notch1 signaling is an important regulator of embryonic development and cell fate decision. Notch1 signaling is also expressed in adult pancreas but there is no study on the role of Notch1 in glucose homeostasis and islet mass in adult pancreas. Here, we investigated the role of Notch1 in glucose homeostasis and islet mass using Notch1 Antisense Transgenic (NAS) mice. We conducted an IPGTT and IPITT in 8-week-old male NAS mice and C57BL/6 mice (control mice). Insulin secretion capacity was measured by GSIS and perifusion. Morphology of pancreatic islet and β cell was conducted in two groups and transcription factors were evaluated. NAS mice showed higher glucose levels and lower insulin secretion in IPGTT. There was no significant difference in insulin resistance. Total islet and β cell masses were decreased in NAS mice. The number of large islets (≥ 250 μm) decreased while that of small islet (< 250 μm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Our study provides that Notch1 inhibition decreased insulin secretion without any alterations in insulin resistance and decreased islet and β cell mass in the adult pancreas in NAS model. It is thought that Notch1 inhibition early suppresses islet proliferation and induces differentiation of not fully proliferated small islets.

In conclusion, the Notch signaling pathway may play an important role in beta cell mass and development of diabetes.

Disclosure

Y. Eom: None. K. Kim: None. B. Kim: None.

Funding

Korea Health Technology R&D Project (A101711, HI14C2539); Korean Ministry of Health, Welfare, and Family Affairs
215-LB: Diabetes and Obesity Are the Main Drivers of Increasing Chronic Liver Disease in the United States (U.S.) in the Past Three Decades
Authors: YOUNOSSI ZOBAIR M. , STEPANOVA MARIA , YOUNOSSI YOUSSEF , GOLABI PEGAH , MISHRA ALITA , RAFIQ NILA
Published: June 2019

Background: Recently, the face of liver disease (LD) in the U.S. may be changing. The aim was to assess the prevalence of LDs in the U.S. over 3 decades.

Methods: Clinical data from NHANES were used to establish the diagnoses of chronic hepatitis C (CHC), B (CHB) alcoholic LD (ALD), and nonalcoholic fatty LD (NAFLD).

Results: 58,731 adults with LD were included. During the study, prevalence of CHB and ALD remained stable (0.3%-0.4% and 0.8%-1.0%, trend p>0.05); while the prevalence of CHC decreased nearly 2 fold [from 1.6% to 0.9% (p=0.03)]. In contrast, prevalence of NAFLD increased from 20.0% to 28.3% to 33.2% (p<0.0001). At the same time, increases were observed in the rates of obesity (22.2% to 31.0% to 38.9%) and type 2 diabetes (7.2% to 8.2% to 13.5% same years). Yearly trend analyses showed that the only liver disease with consistently increasing prevalence was NAFLD (Kendall tau=0.64, P=0.01). Multivariate regression analysis showed that after adjustment for age, gender, and ethnicity, obesity 10.4 (9.5-11.3), diabetes 3.7 (3.2-4.2), hypertension 2.3 (2.1-2.5) and hyperlipidemia 1.8 (1.6-2.1)) were the major independent predictors of NAFLD.

Conclusions: Over the past 30 years in the U.S., NAFLD is the only liver disease with increasing prevalence. The increasing prevalence of NAFLD is primarily driven by diabetes and obesity.

Disclosure

Z.M. Younossi: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S. Research Support; Self; Bristol-Myers Squibb Company. M. Stepanova: None. Y. Younossi: None. P. Golabi: None. A. Mishra: None. N. Rafiq: None.
2153-P: PDX1- and Nkx6.1-Immunonegative ß Cells in the Developing Human Pancreas
Authors: PROSHCHINA ALEXANDRA , KRIVOVA YULIYA , GUREVICH LARISA , OTLYGA DMITRY , SAVELIEV SERGEY
Published: June 2019

Pancreatic endocrine and exocrine cells are of endodermal origin and differentiate during prenatal development from the epithelial cells of the primitive ducts. A specific program of transcription factor genes expression is subsequently activated and defines the fate of pancreatic progenitors. In our studies we have analyzed the distribution of two transcription factors - PDX1 and Nkx6.1 in the developing human pancreas. The study was performed on pancreatic samples from 22 fetuses (gestational age 10-40 weeks) using double and triple immunohistochemistry with antibodies to Pdx1, Nkx6.1, insulin and glucagon. In the adult human pancreas, the maintenance of β-cell identity is associated with the presence of key transcription factors (in particular Pdx1 and Nkx6.1), and changes in their expression and/or localisation have been described in the islets of type 2 diabetic individuals. In agreement with the literature, we have shown that Pdx1 and Nkx6.1 are present in the fetal pancreas already at 10th g.w. In all investigated pancreatic samples, we have observed two types of β-cells: Pdx1-positive β-cells and population of β-cells with the Pdx1-immunonegative nuclei. The results of reactions with antibodies to Nkx6.1 were similar: β-cells with both Nkx6.1 -positive and negative nuclei were detected in the human fetal pancreas. It can be suggested, that Pdx1 and Nkx6.1 are transiently expressed in the differentiating β-cells, thereafter their expression decreases and further restores in the mature β-cells. On the other hand, differentiation of some β-cells may possibly occur without Pdx1 or Nkx6.1 expression. In addition, Pdx1-positive glucagon-containing cells were observed in the developing human pancreas. Moreover, in contrast to other researchers, we found rare glucagon-containing cells with Nkx6.1-positive nuclei. This activation of Pdx1 and Nkx6.1 possibly indicates a partial transformation of α-cells toward a β-cell phenotype (and vice-versa).

Disclosure

A. Proshchina: None. Y. Krivova: None. L. Gurevich: None. D. Otlyga: None. S. Saveliev: None.

Funding

Russian Foundation for Basic Research (18-015-00147)
2155-P: Peripheral Nervous System Innervation of the Developing Pancreas
Authors: LA O SEAN DE , BYRNES LAUREN , WONG DANIEL M. , KNOX SARAH , SNEDDON JULIE B.
Published: June 2019

Pancreatic organogenesis is a complex, multistep process whereby multiple cell types must migrate, proliferate, and differentiate in a strict spatiotemporal manner to ultimately form the complete organ. Although pancreatic epithelial organogenesis is well characterized, the peripheral nervous system (PNS) innervating the organ is poorly understood. Although the PNS has been shown to be critical in the formation of other budding exocrine organs, and therefore likely plays a role in the formation of the pancreas, there is a dearth of information on innervation of this developing organ. To this end, our lab has taken advantage of an explant culture system and single-cell RNA-sequencing (scRNAseq) to characterize the nerves supplying the developing pancreas. Imaging of whole pancreata reveals that peripheral nerves develop in parallel with the pancreas, with intrapancreatic ganglia being present from early stages. Using scRNAseq analysis we have begun to decipher the timing of pancreatic PNS progenitor cell differentiation, and the potential signaling pathways guiding axonal growth and morphogenesis. Continued investigation of the mechanisms guiding innervation of the pancreas, deciphering how nerve-epithelial interactions are established and defining signaling pathways activated by the nerves will allow us to discover the role of the PNS in pancreatic morphogenesis, as well as mis-regulation during disease.

Disclosure

S. de la O: None. L. Byrnes: None. D.M. Wong: None. S. Knox: None. J.B. Sneddon: Advisory Panel; Spouse/Partner; Akouos. Advisory Panel; Self; Encellin. Advisory Panel; Spouse/Partner; Encellin. Consultant; Self; Semma Therapeutics, Inc.
216-LB: Risk Factors of Pancreatic Cancer in Persons with Advancing Diabetes
Authors: JEON CHRISTIE Y. , GOODARZI MARK O. , LIN YU-CHEN , KIM SUNGJIN , MOIN TANNAZ , PISEGNA JOSEPH R.
Published: June 2019

Background: People with new-onset diabetes face higher risk of pancreatic cancer (PC). However, data on PC risk in people with more advanced stages of diabetes are lacking. We aimed to identify factors associated with PC among people with progressing diabetes.

Methods: We conducted a retrospective cohort study on veterans aged ≥50, who were treated with either combination oral hypoglycemic therapy (n=578,543) or insulin (n=609,687) at the VA in 2000-2016. Incident PC was determined through the electronic health records and cancer registries. We examined the association of multiple risk factors with PC using Cox regression analyses.

Results: In both people initiating combination therapy and in those initiating insulin, increasing age, male sex, non-Hispanic ancestry, current smoking, acute and chronic pancreatitis, abdominal pain, alcoholism, increase in A1c, and decrease in weight were associated with increased risk of PC (Table). Based on the multivariable model, we can identify sub-populations with ≥5% risk of PC, such as ≥75 year-old non-Hispanic white males initiating insulin who have a history of alcoholism, and who show ≥2% increase in A1c and ≥15% decrease in weight prior to insulin initiation.

Conclusion: We identified risk factors associated with PC among people initiating combination oral hypoglycemics or insulin, which may be useful for stratifying people who may benefit from screening for PC.

Disclosure

C.Y. Jeon: None. M.O. Goodarzi: None. Y. Lin: None. S. Kim: None. T. Moin: None. J.R. Pisegna: None.

Funding

National Cancer Institute (R21CA220073)
2160-P: Islet Aggregation around Early Duct Lesions in Human Donor Pancreas
Authors: CHIEN HUNG JEN , CHIANG TSAI-CHEN , PENG SHIH-JUNG , CHUNG MEI-HSIN , LEE CHIH-YUAN , TIEN YU-WEN , TANG SHIUE-CHENG
Published: June 2019

Background: The link of pancreatic cancer to diabetes (type 3c) suggests that islets are influenced by the cancer lesion progression. However, at an early stage, i.e., when the pancreas appears to be normal, how the endocrine pancreas is affected by the initial duct lesion formation remains unclear. Aims. To apply panoramic 3-D histology to detect early duct lesions in human cadaveric donor pancreases and examine the peri-lesional islet environment.

Methods: Tissue clearing was applied to the freshly perfused donor pancreases (target) and cancer surgical biopsies (malignant control) for 3-D microscopy.

Results: Large-scale tissue scanning detects early duct lesions (PanIN 1A/B) in three donor pancreases (3/5; nondiabetic; age (yr)/BMI: 40/24, 53/28, and 51/20). High-definition 3-D fluorescence and 2-D transmitted-light and H&E images reveal: 1) peri-lesional islet aggregation, 2) epithelium-islet complex (e.g., intra-islet duct), 3) adipocyte association, 4) inflammation, 5) stromal activation, and 6) Ki-67+ ductal and stromal cells but not the β- or α-cells.

Conclusions: We systematically developed a 3-D/2-D integrative imaging approach to detect and characterize the islet microenvironment around early duct lesions. Our data indicate a proliferative setting, but the islet aggregation appears not to arise from β- or α-cell division; instead, it may be due to lobular atrophy and/or evolve from duct-to-islet differentiation.

Disclosure

H. Chien: None. T. Chiang: None. S. Peng: None. M. Chung: None. C. Lee: None. Y. Tien: None. S. Tang: None.
2161-P: Overexpression of UCP2 in Pancreatic Beta Cells Caused Impaired Insulin Secretion through Mitochondrial Dysfunction and Aldolase B Expression
Authors: INOUE RYOTA , SHIRAKAWA JUN , TOGASHI YU , TERAUCHI YASUO
Published: June 2019

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of the increase in UCP2 expression remained unclear. In this study, we investigated the regulatory mechanisms of UCP2 expression and its effects on β-cell functions. The mRNA expression of UCP2 in mouse islets was upregulated by the treatment with glucose, glucokinase activator, or insulin (p<0.05), while metformin downregulated it (p<0.01). Islets from db/db mice and insulin receptor substrate-2 knockout (IRS-2KO) mice showed the increment in the UCP2 expression. Transgenic mouse with specific UCP2 overexpression in β-cells (βUCP2Tg) demonstrated impaired glucose tolerance due to reduced insulin secretion. Adenoviral expression of UCP2 in MIN6-M9 β-cell line also attenuated glucose-induced insulin secretion. The ATP production in response to glucose and mitochondrial Complex I protein level were reduced (p<0.01) in βUCP2Tg islets. Dilatation (1.8-fold, p<0.05) and morphological alteration of mitochondria were observed in βUCP2Tg β-cells. Gene expression microarray analysis revealed 18 upregulated genes (1.5-fold, p<0.05) and 2 downregulated genes (<67%, p<0.05) in βUCP2Tg islets. The most upregulated mRNA by UCP2 expression encoded the aldolase B (Aldob) (77-fold), whose expression was reported to be negatively associated with insulin secretion in human islets (J Clin Endocrinol Metab. 103(12):4373-4383, 2018). We validated increased Aldob expression in islets from βUCP2Tg mice, db/db mice, and IRS-2KO mice. Taken together, UCP2 expression seemed to be increased under T2DM conditions including hyperglycemia or hyperinsulinemia. Our data also suggested that the increase in UCP2 expression in T2DM β-cells cell-autonomously attenuated glucose-induced insulin secretion, possibly via mitochondrial abnormality and Aldob expression.

Disclosure

R. Inoue: None. J. Shirakawa: None. Y. Togashi: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
2163-P: Characterizing Peptide Hormone and Metabolite Variability in Individual Islets and Individual Cells of the Human Islets via Mass Spectrometry
Authors: SWEEDLER JONATHAN V.
Published: June 2019

Chemical profiles and heterogeneity of islets may contribute to diabetes, but this chemical heterogeneity has been difficult to study. While significant progress has been achieved in uncovering of transcriptional diversity of cells composing pancreatic islets, the direct measurement of the hormones and metabolites has been difficult. We have created new approaches using direct matrix assisted laser desorption/ionization mass spectrometry (MALDI MS) to investigate the metabolite, and peptide contents of human pancreatic islets and of populations of individual islet cells. As illustrated in Figure 1, we observe multiple molecular features in the m/z 20-7000 mass range, including expected peptide hormones, lipids and transmitters. The specific peptide profiles vary cell to cell. Besides the expected peptide hormones, we also observe rarer peptides such as apelin and spexin. We also characterize unusual peptide profiles from rare cells that remain to be characterized. We observe five major cell types including a group of cells that appear only to contain thymosin beta four. We are extending our measurements to important molecules such as dopamine and d-serine. We are in the process of determining how the peptide hormones and metabolites co-localize, and are exploring how the molecular portraits change during disease progression.

Disclosure

J.V. Sweedler: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-19)
2169-P: A Gene Expression Network Analysis of the Pancreatic Islets from Lean and Obese Mice Identifies Complement 1q-Like-3 Secreted Protein as a Regulator of Beta-Cell Function
Authors: KOLTES JAMES , ARORA ITIKA , GUPTA RAJESH , NGUYEN DAN C. , BHATNAGAR SUSHANT
Published: June 2019

Secreted proteins are important metabolic regulators that function in healthy and disease states. Our objective was to identify those secreted proteins that are important regulators of pancreatic islet function in obesity. To facilitate this, we used Weighted Gene Co-Expression Network Analysis-based approach on the expression data that was obtained from the pancreatic islets of lean and obese mice to identify gene modules that enriched with obesity. Subsequently, filtering the data for transcripts expressing secreted protein based on the intramodular connectivity, module membership, and differential expression identified complement-1q-like-3 (C1ql3) secreted protein as a top candidate to affect islet function. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified C1ql3 to affect ‘secretory processes’ in islets. Biological validation showed that C1ql3 is expressed in human and mouse islets, and inhibits insulin secretion from pancreatic β-cells. Its expression in islets is increased by >32-fold with obesity. Moreover, C1ql3 in the islet β-cells specifically reduced the expression of genes that are critical for regulating insulin secretion. These findings demonstrate a streamlined approach to screen for the putative novel secreted protein regulators that function in an autocrine/paracrine manner to affect islet function in obesity. Herein, we have identified a critical role of C1ql3 in β-cells and propose that the increased secretion of C1ql3 from islets during obesity contributes to the reduced β-cell function in a paracrine/autocrine-dependent pathway to increase the susceptibility to type 2 diabetes.

Disclosure

J. Koltes: None. I. Arora: None. R. Gupta: None. D.C. Nguyen: None. S. Bhatnagar: None.

Funding

American Diabetes Association (1-18-PDF-103 to R.G.)
2174-P: FBW7 Regulates Beta-Cell Dedifferentiation
Authors: XU JING , LI XIAOMU
Published: June 2019

Tumor suppressor F-box and WD repeat domain-containing 7 (FBW7), an E3 ubiquitin-ligase, also plays important roles in the regulation of metabolism. However, the contribution of FBW7 on β-cells remains largely unknown. Our study indicated that the expression of FBW7 in pancreatic β-cells was significantly higher than that in exocrine cells. The expression of FBW7 in β- cells from high-fat diet (HFD) fed mice significantly decreased than chow diet fed mice. Similarly, the expression of FBW7 in β-cells from db/db mice were also decreased. The reduced expression of FBW7 in β-cells from these animal models accompanied with the elevated expression of dedifferentiation marker ALDH1A3. In vitro study suggested that overexpression of FBW7 suppressed expression of ALDH1A3 protein levels, but not mRNA levels, in MIN6 β-cells. We also found that FBW7 regulated ALDH1A3 stability by promoting its ubiquitination and degradation. Bioinformatic analysis revealed the conserved sequence in ALDH1A3 protein as the potential FBW7 substrates. Together, our study suggested that FBW7 may play important role in the regulation of β-cell dedifferentiation via its novel substrate ALDH1A3.

Disclosure

J. Xu: None. X. Li: None.
2178-P: Beta-Cell Gene Expression Pattern in Food Restricted db/db Mice and Moderate Dedifferentiation Status in ob/ob Islets
Authors: LEI XIAO , ISHIDA EMI , YAMADA EIJIRO , OKADA SHUICHI , YAMADA MASANOBU
Published: June 2019

In clinical, the 'fatigue' of beta cells is a famous phenomenon from way back. Nowadays, researchers describe how glucolipotoxicity, endoplasmic reticulum (ER) stress and oxidative stress impair beta cell function. In 2012, Talchai et al. revealed the novel machinery of beta cell dysfunction in diabetes - dedifferentiation. It's a gradual process along with the progressive feature of diabetes, and in several reports, it's proven to be preventable by existing diabetic treatment. Previously, we showed that each diabetic treatment had a different effect on beta cell dedifferentiation. For instance, food restriction had more manifold good effects to restore beta cell gene expression than SGLT inhibitor. In the current study, we aimed to unveil the molecular mechanism of beta cell dedifferentiation. First, we investigated the microarray analysis of islet RNAs in food-restricted db/db mice. Compared to the control db/db, the islets of food-restricted group had higher expressions of genes related to matured beta cell markers and ER maintenance. On the other hand, Gene expressions related to cell stress, cell growth and cell division were lowered by calorie restriction. To understand more about the relationship between beta cell dedifferentiation and ER stress, we utilized the other obese mice model, ob/ob, which is known to have more moderate hyperglycemia than db/db. The other study group demonstrated that ER and oxidative stress markers were maintained in ob/ob islets than that in db/db (Chan, Diabetes 2013). We found that beta cell dedifferentiation markers, such as Aldh1a3 and Sox9, were also lowered in ob/ob. But it's still unknown, whether the dedifferentiated beta cells are feeble against the ER and oxidative stress, or, these stress triggers the beta cell dedifferentiation.

Disclosure

X. Lei: None. E. Ishida: None. E. Yamada: None. S. Okada: None. M. Yamada: None.
2194-P: Il-6/Stat3 Pathway Contribute to the Islet Failure in High-Fat Diet-Induced Mouse Model of Obesity
Authors: JIANG ZONGZHE , TENG FANGYUAN , XU YONG
Published: June 2019

Objective: This study was aimed at revealing a new mechanism mediated by IL-6/Stat3 signaling pathway on islet failure in high fat diet-induced obesity through activation of inflammation.

Methods: We produced mice with non-obesity, moderate obesity and severe obesity respectively by feeding with normal diet (control), three months’ high fat diet (HFD-3M) and six months’ high fat diet (HFD-6M). Then 200 islets were isolated from the three groups and lysed for RNA extraction, following RNA-Seq analysis with MAPS (Multiplex Analysis of PolyA-linked Sequences) approach. Normal islets were cultured in vitro for IL-6 stimulation and mice with stat3 specific deletion in islet were used to prevent HFD-resulted islet failure.

Results: Mice with HFD for three months and six months show significantly higher fast glucose and severe glucose intolerance than control and the morphology of islets from HFD group was obviously abnormal. Additionally, these diabetic symptoms were aggravated in pace with HFD feeding. Further analysis of RNA-seq shows that the expressions of hormones secreted by different endocrine cells were all down-regulated, including INS1, GCG, SST and PPY. On the other hand, expression of IL-6/Stat3 pathway related genes were significantly elevated, including IL-6, CCL2, CCL5, CCL11, CCL28, Tnfrsf11 and NF-kB. Stat3 in islets from HFD-3M and HFD-6M group was also activated by phosphorylation of Y705. Cultured islets with IL-6 treatment show impaired insulin secretion and increased inflammation level. Notably, mice with stat3 specific deletion in islet were able to attenuate the HFD-induced increase of inflammation and secretory deficiency of islet.

Conclusions: HFD-induced obesity resulted in islet failure and the high level of serum IL-6 participate in the obesity induced islet failure through IL-6/Stat3 pathway mediated inflammation.

Disclosure

Z. Jiang: None. F. Teng: None. Y. Xu: None.

Funding

National Natural Science Foundation of China (81600597)
22-OR: Nasal Glucagon: A Viable Alternative to Treat Insulin-Induced Hypoglycemia in Japanese Patients with Type 1 and Type 2 Diabetes
Authors: MATSUHISA MUNEHIDE , TAKITA YASUSHI , NASU RISA , OHWAKI KENJI , NAGASHIMA HIROTAKA
Published: June 2019

Background/Objective: Currently available glucagon products for rescue treatment of severe hypoglycemia require cumbersome multistep reconstitution and injection procedures in an emergency situation. Nasal glucagon (NG) is a nasally administered, single-use, drug-device combination containing 3 mg glucagon dry powder. We aimed to evaluate noninferiority of NG to intramuscular glucagon (IMG) for treatment of insulin-induced hypoglycemia in patients with type 1 and type 2 diabetes (T1D/T2D) (NCT03421379).

Methods: This was a randomized, two-period, crossover trial with NG and IMG. Hypoglycemia was induced by an intravenous insulin infusion; insulin was stopped once plasma glucose (PG) reached <60 mg/dL. Approximately 5 minutes (min) after stopping insulin either 3 mg NG or 1 mg IMG was administered followed by PG measurements up to 4 hours. Treatment success was defined as an increase in PG to ≥70 mg/dL or an increase of ≥20 mg/dL from the PG nadir within 30 min after receiving glucagon. Spontaneously reported adverse events (AEs) and a Nasal and Non-Nasal Symptom Questionnaire (NNSQ) assessed local tolerability of NG.

Results: Of the 68 evaluable patients (T1D 32, T2D 36) who received both NG and IMG, all patients achieved treatment success with a mean time of 12.0 min (NG) and 11.0 min (IMG). Noninferiority of NG to IMG was demonstrated. PG responses were similar between T1D and T2D. During the treatment period 26 treatment-emergent AEs (TEAEs) occurred with NG and 13 with IMG. Most TEAEs were mild in severity and none was severe. TEAEs with an incidence ≥5% were rhinalgia (NG 8.5%, IMG 0%), nausea (NG 5.6%, IMG 11.4%), and blood pressure increase (NG 5.6%, IMG 0%). With NG, very common (≥10%) symptoms from NNSQ were watery eyes and nasal congestion.

Conclusion: NG was noninferior compared to IMG for the treatment of insulin-induced hypoglycemia in Japanese patients with T1D/T2D supporting the use of NG as a rescue treatment for severe hypoglycemia.

Disclosure

M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Y. Takita: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Nasu: None. K. Ohwaki: Employee; Self; Eli Lilly and Company. H. Nagashima: None.