bluuebunny/crossref_metadata_2025_split huggingface dataset:
248-LB: Deficiency of APPL1 in Macrophages Triggers Adipose Tissue Inflammation and Insulin Resistance by Potentiating NLRP3 Inflammasome Activation
Authors: WU KELVIN K.L. , XU AIMIN , CHENG KENNETH K. 
Published: June 2019

Adipose tissue inflammation participates in the pathogenesis of type 2 diabetes in obesity. While the activation of the multiprotein complex known as NLRP3 inflammasome and subsequent release of IL-1β contribute to the development of adipose tissue inflammation and insulin resistance, the mechanisms of its regulation remain unclear. Here we revealed that APPL1, an adaptor protein essential for adiponectin and insulin signaling, is upregulated in the stromal vascular fraction of visceral fat of db/db diabetic mice. Also, lack of APPL1 in bone marrow-derived macrophages specifically enhanced inflammatory response mediated by NLRP3 inflammasome. Mice with hematopoietic cells-specific APPL1 deficiency (APPL1-BMT-KO) were then generated using bone marrow transplantation approach and subjected to high-fat diet (HFD) feeding. After 36 weeks of HFD feeding, APPL1-BMT-KO mice exhibited increased insulin resistance and glucose intolerance, accompanied with elevated IL-1β in serum, liver and epididymal adipose tissue and impaired Akt phosphorylation in the subcutaneous adipose tissue and liver. In vitro experiments suggest that ablation of APPL1 in bone marrow-derived macrophages promotes IL-1β secretion by enhancing ROS generation, which is an important intracellular signal for NLRP3 inflammasome activation. Pharmacological inhibition of intracellular and mitochondrial ROS successfully abrogated the upregulation of IL-1β secretion in APPL1 deficient macrophages. In this study, we demonstrated the novel role of APPL1 in alleviating macrophage-mediated adipose tissue inflammation and insulin resistance. Lack of APPL1 in macrophages promotes ROS generation and NLRP3 inflammasome activation, which causes enhanced IL-1β secretion in adipose tissue and the development of insulin resistance.

Disclosure
K.K.L. Wu: None. A. Xu: None. K.K. Cheng: None.

Funding
Research Grants Council of Hong Kong (171018/15M)
2483-PUB: Glycemic Control with Pramlintide and Insulin Coformulations: Preclinical Evaluation of a Novel Single Injection, Room Temperature Stable Formulation
Authors: THOHAN SANJEEV , HU WENDY T. , DONOVAN MARTIN J. , PRESTRELSKI STEVEN J. , CHOI MONICA S. , HESTER DENNIS M. 
Published: June 2019

Mealtime pramlintide (PRAM) and insulin (INS) reduce postprandial glucose excursions, mimics natural pancreas physiology and improves glycemic control. Due to differences in physico-chemical characteristics of PRAM and INS, mixing these two products can cause precipitation. Xeris has developed novel room temperature stable co-formulations to overcome precipitation, simplify dose administration and reduce injection burden.
Streptozotocin (65 mg/kg) treated SD rats were given co-formulations of PRAM and Regular Insulin (RI) or Lispro Insulin (LISPRO) as a single injection and compared with dual injection of commercial Symlin, Humulin, or Humalog. Blood samples were evaluated for plasma glucose and PK.
A sparse sampling PK scheme resulted in ∼30% CV for glucose values. Mean glucose profiles with reductions in glucose AUC by treatment (efficacy).
PRAM-INS single injection co-formulations showed comparable efficacy and PK profiles to two injection commercial products. Consistent with PRAM's known pharmacological action, there was no glucose lowering with PRAM alone. These results support clinical development of room temperature stable PRAM-INS co-formulations.

Disclosure
S. Thohan: None. W.T. Hu: None. M.J. Donovan: None. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. M.S. Choi: None. D.M. Hester: None.
2484-PUB: Association of Gastrin Levels and Parameters of Glucoregulation in Type 2 Diabetes Patients
Authors: BERKOVIC MAJA CIGROVSKI , MAHECIC DAVORKA HERMAN , BILIC-CURCIC INES 
Published: June 2019

Background and Aims: Recent data suggest that co-administration of gastrin and GLP-1 improves glucose homeostasis and increase β-cell mass in a rodent model of diabetes, we hypothesized that higher baseline levels of endogenous gastrin prior treatment could be a predictor of beta cell function and glucoregulation in newly diagnosed DMT2 patients.
Patients and Methods: In this cross-sectional study 317 patients (116 males and 201 females) with new onset DMT2 were included. Patients treated with IPPs were excluded. Fasting plasma glucose (FPG), postprandial PG (PPG), HbA1c, fasting insulin, pancreatic B cell function (HOMA-B), insulin resistance index (HOMA-IR), c-peptide, CgA and gastrin levels were measured at the time of diagnosis, and after 6 months of follow-up.
Results: Baseline Hba1c was 7,49±2,09%, average age of patients was 62.53 ±11.33 years. 65.7% of patients were overweight and obese. Parameters of glucoregulation were not significantly correlated with gastrin (all p&gt; 0.05), while there was moderate negative correlation with HOMA-B (HbA1c r=-.58, p&lt;0.01, FPG r=-.62, p&lt;0.01 and PPG r=-.33, p&lt;0.01) and positive correlation with HOMA-IR (HbA1c r=.22, p&lt;0.01, FPG r=.42, p&lt;0.01 and PPG r=.25, p&lt;0.01). After 6 months follow-up there was a significant reduction of HbA1c, FPG and PPG (all p&lt;0.01), a significant decrease in fasting insulin level (p=0.006), while CgA and gastrin level increased (p=0.003 and p&lt;0.001 respectively). In the stepwise regression analysis, only two independent predictors of gastrin and CgA levels emerged PPG (p=0.009) and BMI (p=0.016).
Conclusion: At the time of DMT2 onset there was no association between baseline gastrin levels and parameters of glucoregulation however after 6 months of follow-up increase in gastrin and CgA levels was observed along with the improvement of glycemic control indicating a possible relationship of gastrin levels and amelioration of beta cell function followed by metformin initiation as well as life style changes.

Disclosure
M. Cigrovski Berkovic: None. D. Herman Mahecic: None. I. Bilic-Curcic: None.
2496-PUB: Effect of Body Mass Index on HbA1c, Blood Pressure, and Cholesterol (ABC) Control in Patients with Type 2 Diabetes from Tibet in China
Authors: CHENGHUI ZHANG , MINGXIA LI , SUYUAN WANG , YUNHONG WU 
Published: June 2019

Aim: To investigate the effect of body mass index (BMI) on the current control of HbA1c (A), blood pressure (B) and cholesterol(C) in patients with type 2 diabetes (T2D) from Tibet based on electronic medical records.
Methods: Patients aged 18-79 years with T2D documented from 2014 to 2018 were enrolled in this study. Control criteria were defined base on the 2017 Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes: HbA1c &lt; 7.0%, blood pressure &lt; 130/80mmHg and low-density lipoprotein-Cholesterol (LDL-C) &lt; 1.8 mmol/L with coronary heart disease (CHD) and 2.6 mmol/L without CHD. Patients were divided into three groups according to BMI. One-way ANOVA and Chi-square tests were used to compare differences among groups.
Results: A total of 1999 patients were included in the study. The mean (SD) age was 55.2 (10.5) years. The median diabetic duration was 7.0 (range: 0.1-32) years and 879 (43.9%) patients were female. Among the three groups, patients with obesity had the worst metabolic profile with the highest systolic blood pressure, diastolic blood pressure and LDL-C. The achievement of ABC control has worsened in parallel with increasing BMI (Table).
Conclusions: Higher BMI was associated with lower ABC control of diabetes. More intensive weight management is warranted in this population.

Disclosure
Z. Chenghui: None. L. Mingxia: None. W. Suyuan: None. W. Yunhong: None.
25-LB: SGLT2 Inhibitors Are Renoprotective via Mitigation of Tubular Hypoxia and Protein O-GlcNAcylation
Authors: BALOGH DORA B. , HODREA JUDIT , LENART LILLA , HOSSZU ADAM , MEZEI CSENGE , WAGNER LASZLO , SZABO ATTILA J. , FEKETE ANDREA 
Published: June 2019

Tubular hypoxia has a major pathogenic role in diabetic kidney disease (DKD). Hypoxia is in strong association with elevated glucose reabsorption and increased protein O-GlcNAcylation which could contribute to renal fibrosis. We recently showed that SGLT2 inhibitors (SGLT2i) are renoprotective in experimental type 1 diabetes. Considering emerging evidence of proximal tubular involvement in DKD and the major role of SGLT2 in glucose metabolism, here we investigated the direct effects of SGLT2i on hypoxia and O-GlcNAcylation.
Diabetes (D) was induced by streptozotocin in adult, male Wistar rats. Rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day). Renal function and fibrosis were evaluated. The effect of hyperglycaemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions. HG cells were treated with 10 µM DAPA. O-GlcNAc, O GlcNAc transferase (OGT) and O GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber for 2 hours. HIF1-α, EPO, VEGFA and PAI-1 were measured. Immunocytochemistry (ICC) of HIF1-α was performed.
DAPA improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p&lt;0.01) and decreased fibrosis. DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation and OGT, while OGA was elevated in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Abolishment of HIF-1α upregulation by DAPA was confirmed by ICC staining. EPO, VEGFA and PAI-1 levels were also increased in hypoxia and DAPA prevented EPO and PAI-1 elevation.
Here we identified a novel mechanism of SGLT2i by which the direct reduction of tubular hypoxia and inhibition of OGT by DAPA results in decreased O-GlcNAcylation in proximal tubular cells. These processes contribute to improved renal function and alleviated kidney fibrosis.

Disclosure
D.B. Balogh: None. J. Hodrea: None. L. Lenart: None. A. Hosszu: None. C. Mezei: None. L. Wagner: None. A.J. Szabo: None. A. Fekete: None.

Funding
Hungarian Academy of Sciences (LP008/2017, OTKA-K112629-FK124491-NN-114607, VKE-2017-00006); Semmelweis University; New National Excellence Program of the Hungarian Ministry of Human Capacities (?NKP-18-3)
253-OR: Microvascular Complications in Latent Autoimmune Diabetes of Adults: Results from the UKPDS
Authors: MADDALONI ERNESTO , COLEMAN RUTH L. , HOLMAN RURY R. 
Published: June 2019

Background: Latent Autoimmune Diabetes of Adults (LADA) is a mild form of autoimmune diabetes which can be identified in 3-12% of adults who have a clinical diagnosis of T2D. LADA differs in genetic and clinical features with T2D, but whether this translates into a different risk for complications remains controversial.
Aim: We examined the long-term risk of microvascular complications in the large population with a clinical diagnosis of new-onset T2D enrolled into the United Kingdom Prospective Diabetes Study (UKPDS), according to their LADA status.
Methods: Islet-cell cytoplasm, glutamic acid decarboxylase and islet antigen-2 autoantibodies (AAb) were measured in 5028 UKPDS participants at, or soon after, T2D diagnosis. Those with ≥1 detectable AAb were defined as LADA and their incidence of a composite microvascular outcome (first occurrence of renal failure, renal death or diabetic retinopathy [blindness, vitreous haemorrhage or photocoagulation]), was compared with T2D participants.
Results: There were 564 (11.2%) of participants with LADA. Compared with T2D, they were younger, with higher mean HbA1c and HDL-cholesterol, but lower body mass index (BMI), total cholesterol and systolic blood pressure (SBP) (all p&lt;0.01). The microvascular outcome occurred in 1041 (51.3%) of UKPDS participants during median 17.3 (range: 0.1-29.9) years follow-up. A time-varying cox-model showed a lower risk of microvascular events in LADA participants during the first nine years of follow-up (HR 0.52, 95% CI 0.35-0.78, p&lt;0.01), but a higher risk beyond nine years (HR 1.47, 95% CI 1.20-1.81, p&lt;0.01). These HRs were unchanged after adjustment for age, HbA1c, lipids, SBP, BMI, estimated glomerular filtration rate, smoking and UKPDS treatment arm.
Conclusions: The risk of microvascular complications in LADA patients differs over time, being lower in the earlier years after diagnosis but higher in later years compared with T2D, potentially impacting on their diabetic management.

Disclosure
E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc., Pikdare. R.L. Coleman: None. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.

Funding
European Foundation for the Study of Diabetes
254-LB: Induced Pluripotent Stem Cells for Type 1 Diabetes In Vitro Modeling and Immunoprotection of Beta Cells
Authors: LEITE NAYARA 
Published: June 2019

Our understanding of the causes and possible treatments for type 1 diabetes (T1D) has been profoundly limited by a lack of in vitro models that recapitulate human T1D disease progression. As the foundation for such a model, we have successfully differentiated human induced pluripotent stem cells into functional β cells (hiPSC-β cells) that can reverse diabetes in mice. Herein, we propose that an in vitro platform can model human T1D using hiPSC-β cells and hypothesize that the complex immune features of human T1D can be reproduced in vitro using the hiPSC-β cells and donor-matched immune cells. In our experiments, a cell-type specific, donor-matched response against the hiPSC-β cells but not the hiPSC-α cells was achieved in vitro. Specifically, co-culturing donor-matched hiPSC-β cells and PBMCs resulted in activation of the effector cells, as assayed through cytokine secretion, induction of activation surface markers in T cells and specific killing of the hiPSC-β cells. Most importantly, we sought to determine whether the β cell killing was mediated by specific T cell receptor (TCR) engagement. We performed two experiments to test the requirement for direct TCR recognition of hiPSC-β cells in stimulating T cell activation. First, we incubated the targets β cells with an HLA-class I blocking antibody to prevent binding of T cells with the target cells and second, we used a transwell co-culture system that eliminated direct contact between the immune cells and hiPSC-β cells. Both experiments approach prevented T cell activation, thereby confirming the TCR engagement hypothesis.The developed T1D in vitro platform to measure immune responses will be used in future experiments aimed to test the ability to protect hiPSC-β cells from autoimmune attack. Collectively these data suggest that we developed a novel tool for patient-specific testing of immunoprotection strategies of the hiPSC-βcells in vitro before autologous transplantation.

Disclosure
N. Leite: None.

Funding
American Diabetes Association (1-19-PMF-024)
254-OR: Novel Biomarkers Predicting Renal Dysfunction in People with Dysglycemia in the ORIGIN Trial
Authors: GERSTEIN HERTZEL , PARE GUILLAUME , MCQUEEN MATTHEW J. , LEE SHUN FU , KANNT AIMO , HESS SIBYLLE 
Published: June 2019

Diabetes is the most common cause of renal failure accounting for more than 50% of cases. Whereas HbA1c, age and albuminuria are independent risk factors for renal decline, adding novel serum biomarkers to routine clinical risk factors may help identify patients at high risk for renal decline. One ml of stored serum from 7,482 ORIGIN participants with a recorded eGFR at baseline and either the 2 year and/or final visit was assayed for 237 biomarkers using Myriad RBM’s customized human discovery multi-analyte profile 250+ panel, and hs troponin and anti-GAD biomarkers were measured locally. During a median follow-up of 6.2 years, 1,646 (22%) developed the renal outcome comprising renal failure, albuminuria regression or doubling of some creatinine. A linear mixed model using a forward selection approach was used to identify the subset of biomarkers that independently predicted a decline in eGFR after accounting for 9 clinical risk factors for renal decline including age, sex, smoking, body mass index, mean arterial pressure, log (albumin:creatinine), cholesterol, baseline eGFR and HbA1c. A Bonferroni-corrected P value for inclusion in the model of less than 0.00021 (i.e., 0.05/239) identified 13 significant and independent biomarkers that included: alpha 1 microglobulin (beta = -0.157); NT-pro BNP (beta = -0.081); IGF binding protein 4 (beta = -0.110); growth differentiation factor 15 (beta = -0.091); RAGE (beta = -0.052); myoglobin (beta = -0.073); growth regulated alpha protein (beta = 0.058); fibulin-1C (beta = -0.048); apolipoprotein A-4 (beta = -0.057); apolipoprotein A-2 (beta = 0.065); fas ligand (beta = -0.099); eotaxin E (beta = -0.052); and beta amyloid 1-40 (beta = -0.057). The addition of these selected biomarkers to the clinical variables improved the variance of the eGFR from 0.053 to 0.155 (difference in log likelihood = 849, P &lt; 0.001). These novel biomarkers are potential therapeutic targets. They can also help identify dysglycemic people at risk for renal decline. (NCT00069784)

Disclosure
H. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. G. Pare: Consultant; Self; Amgen Inc., Bristol-Myers Squibb Company, Lexicomp, Sanofi. Research Support; Self; Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Biosystems, Sanofi. M.J. McQueen: None. S. Lee: None. A. Kannt: Employee; Self; Sanofi. S. Hess: None.

Funding
Sanofi; Innovative Medicines Initiative (115974); European Union; European Federation of Pharmaceutical Industries; JDRF
255-OR: Temporal Trend in the Prevalence and Incidence of Depression and Antidepressant Usages in Incident Type 2 Diabetes from U.S. and UK
Authors: DIBATO JOHN , KOYE DIGSU , POLONSKY WILLIAM , MONTVIDA OLGA , PAUL SANJOY KETAN 
Published: June 2019

Aim: Temporal trend in the prevalence and incidence of depression (DP), any mental illness (AMI) and use of anti-depressants (ADM) in incident T2DM pts is not well known. We evaluate these trends and the risk of developing DP in young pts in real world settings from U.S. and UK.
Method: Adults with diagnosis (Dx) of T2DM from 2000 from Centricity Electronic Medical Records of U.S. and The Health Improvement Network (THIN) database of UK were examined.
Results: In U.S. (n= 1,395,572)/UK (n= 343,714) cohorts, the age at T2DM Dx was 59/58 years, 2/8% had Dx of DP but were not on ADM, 16/10% were on ADM without DP or AMI Dx, 9/15% were using ADM with Dx of DP. The prevalence of DP, AMI and ADM use increased exponentially in UK since 2000 (Figure B), while an increasing prevalence in AMI and ADM use was seen in U.S. (Figure A). Between 2000-2016, the use of ADM without Dx of DP or AMI increased from 16-26%/5-41% in U.S./UK cohort. Incidence rates of DP and ADM use were significantly higher in the U.S. cohort compared to UK (Figures C and D).
Among pts without a co-morbid condition at T2DM Dx, younger U.S./UK pts (≤ 50 years) had 28%/18% significantly higher risks of developing DP compared to older pts (≥ 60 years); among pts with existing co-morbidity, the risks were higher by 46%/33%.
Conclusion: In incident T2DM pts in UK and U.S., a striking rise in the prevalence of DP and the ADP use without Dx of AMI is seen, with younger pts having higher risk of developing DP.

Disclosure
J. Dibato: None. D. Koye: None. W. Polonsky: Consultant; Self; Abbott, Bigfoot Biomedical, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Johnson & Johnson Diabetes Institute, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. O. Montvida: None. S.K. Paul: Consultant; Self; AstraZeneca, Roche Pharma. Research Support; Self; Roche Pharma.
26-LB: Systemic Inhibition of MicroRNA-451 Impairs Renal Autophagy Process in a Mouse Model of Insulin Resistance and Early Diabetic Nephropathy
Authors: FLUITT MAURICE B. , SHIVAPURKAR NARAYAN , LI LIJUN , ECELBARGER CAROLYN M. 
Published: June 2019

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and a common cause of end stage renal disease (ESRD). Novel effective therapies are needed to combat disease progression. Several studies suggest a renal protective role of microRNA-451 (miR-451) in ameliorating progression of DN. However, the role of miR-451 in DN is not understood. Defects in the autophagy process has been associated with DN. The current study aimed to elucidate the role of miR-451 in the development of DN in a mouse model of insulin resistance. Male TALLYHO/Jng mice were placed on a high-fat diet (60% kCal) and divided into two treatment groups. Mice were injected (intraperitoneal) once a week for 8-weeks with locked nucleic acid (LNA) miR-451 inhibitor or LNA-scramble (2mg/kg/bw; n=8/treatment). Mice were humanely euthanized after 12 weeks and kidneys harvested. LNA-miR-451 inhibitor significantly reduced renal expression of miR-451 by 6-fold. Collagen deposition was higher in inhibitor treated mice, as revealed by Masson’s Trichrome. Period Acid Schiff did not reveal significant glomerular damage between the two groups. Kidney weight (normalized to body weight) was significantly higher in the inhibitor treated mice. Western blotting analyses of cortex homogenates revealed increased expression of markers of renal injury, KIM1 and NGAL (p&lt;0.05), in inhibitor treated mice. The expression of fibrotic signaling molecules mTOR, AMPKα, and TGF-β was significantly higher in the inhibitor treated group. The expression of autophagy markers SQSTM1/p62 and Beclin-1 was higher and lower, respectively, in inhibitor treated mice (p&lt;0.05). The findings of this study suggest that reduced expression of miR-451 in DN impairs autophagy response in the kidney possibly via hyperactivation of the mTOR-signaling pathway. miR-451 may confer protection against DN by targeting key components of the autophagy process in the diabetic kidney.

Disclosure
M.B. Fluitt: None. N. Shivapurkar: None. L. Li: None. C.M. Ecelbarger: None.

Funding
American Diabetes Association (1-18-PMF-002 to M.B.F.); National Institutes of Health (TL1TR001431)