bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Brown Adipose Tissue Attenuates Diabetic Nephropathy in Mice
Authors: GUAN MEIPING , CAI YINGYING , ZOU SHAOZHOU 
Published: June 2018

Brown adipose tissue (BAT) has been regarded as a potential target organ for the treatment of obesity and related metabolic disorders. However, the protective effect of BAT on type 2 diabetic nephropathy (DN) remains unclear. We aimed to test if BAT activation could prevent the development of DN in mice. Type 2 diabetic mice were induced by streptozotocin (STZ) combined with high-fat diet (HFD). CL 316,243, a β3-adrenergic receptor agonist to activate BAT, was administered intraperitoneally (1mg/kg/day) to diabetic mice for 4 weeks. There were no differences in body weight between the groups. Interestingly, the kidney weight and KW/BW ratio were significantly higher in the DM-Con mice compared with the Con and DM+CL mice (p &lt; 0.01). Treatment with CL 316,243 significantly reduced blood glucose and improved dyslipidemia. Simultaneously, activation of BAT led to marked decreases in urinary levels of albumin and 8-hydroxy-deoxyguanosine (8-OH-dG), suppressed fibrotic and inflammatory cytokine synthesis, and finally ameliorated renal morphological abnormalities. In addition to obviously enhancing BAT activity and white adipose tissue (WAT) catabolism, CL 316,243 significantly increased serum adiponectin and the renal sensitivity to FGF-21. Furthermore, the CL 316,243 treatment reactivated the AMPK-SIRT1-PGC1α signaling pathway in kidneys. These findings suggest that activation of BAT attenuates type 2 DN in mice through both the improvement of systemic metabolism and the renoprotective effect of adipokines.

Disclosure
M. Guan: None. Y. Cai: None. S. Zou: None.
On-Demand, App-Delivered Coaching to Enable Diabetes Self-Management in Adults with Type 2 Diabetes—A Feasibility Study
Authors: HERNANDEZ JOHN B. , LEE AMY ARMENTO , ROBERTSON SCOTT , SILVER CARA , MAJITHIA AMIT 
Published: June 2018

Introduction: Diabetes self-management training (DSMT) is clinically effective but places a heavy burden on patients. Personalized coaching delivered via scalable mobile app platforms has the potential to provide much needed patient support.
Objectives: This study assessed feasibility and participant experience of a new mobile app-based platform for delivering DSMT to people with type 2 diabetes (T2D). The primary objective was to evaluate participant enrollment (recruitment into the study and completing first sign-in). Engagement with app features and health coach for the study duration was also evaluated.
Methods: Adults with T2D were enrolled into a 4-week prospective, single arm, observational study of the T2D App-based program. The T2D App provided medication reminders, meal logging, blood glucose (BG) tracking, and secure text messaging with a health coach. Participant engagement, satisfaction, participation in self-management behaviors, and finger stick BG results were also measured.
Results: Of 67 participants recruited 99% (66) were able to sign-in to the app and 64 of 67 (96%) completed the 4-week program. The majority of program participants used the T2D App daily (median 100% of days, mean 95% of days). Engagement rates in coach messaging and BG logging exceeded 95% of subjects and were sustained across the study duration. Average blood glucose (AG) in the study participants decreased from week 1 to week 4 (mean -7.8 mg/dL, sd 20.3, P=0.008). The subgroup of individuals with starting AG greater than 154 mg/dL (n=13) experienced the largest declines in AG (mean -29.6 mg/dL, sd 17.9, P&lt;0.0001).
Conclusion: This initial feasibility study of a T2D App-based diabetes management program successfully enrolled participants and sustained their engagement. A decrease in AG was observed which, if sustained, would be clinically significant. Future studies with long term glycemic endpoints and an active control group are needed to validate this observation.

Disclosure
J.B. Hernandez: Employee; Self; Verily Life Sciences LLC.. A. Armento Lee: None. S. Robertson: Employee; Self; Verily Life Sciences LLC. C. Silver: Employee; Self; Verily Life Sciences LLC. A. Majithia: Employee; Self; Onduo.
NADPH Oxidase Nox5 Aggravates Renal Injury in Akita Mouse Model of Diabetic Nephropathy
Authors: JHA JAY C. , DAI AOZHI , COOPER MARK E. , TOUYZ RHIAN M. , KENNEDY CHRIS , JANDELEIT-DAHM KARIN 
Published: June 2018

Background: Renal reactive oxygen species (ROS) play an important role in mediating kidney injury in diabetes. Increasing evidence suggests that the pro-oxidant enzyme, Nox5 plays a significant role in human diabetic nephropathy (DN). Nox5 is present in humans and rabbits but not in mice or rats. Thus, there is a paucity of information about Nox5 in conventional animal models of DN. We examined the role of Nox5 in the insulin deficient diabetic Akita mice model using human inducible transgenic mice that express Nox5 selectively in endothelial cells (VEcad+Nox5+) or in mesangial cells (SM22+Nox5+). We also examined the endogenous expression of Nox5 in a high fat fed rabbit model of kidney disease.
Methods: At week 10 mice were culled and kidneys were removed for the assessment of structural damage as well as gene and protein expression of markers of inflammation, fibrosis and oxidative stress. Protein expression of Nox5 and its localization in glomerular cells (endothelial and mesangial cells) were examined in transgenic mice by immunostaining. We also examined expression of pro-fibrotic gene in high fat fed rabbits by next generation sequencing (NGS) and RT-PCR and renal injury by histochemistry.
Results: Expression of Nox5 was confirmed in glomerular endothelial and mesangial cells of transgenic mice. Diabetes induced increase in glomerulosclerosis, gene and protein expression of fibronectin and MCP-1 as well as nitrotyrosine were further increase in both diabetic Nox5 transgenic mice. Moreover, increased expression of Nox5 in high fat fed rabbits vs. normal diet fed rabbits was associated with increased expression of fibronectin, CTGF, collagen IV and VCAM-1 as well as increased mesangial expansion in the kidney.
Conclusions: These findings in both transgenic mice model (endothelial and mesangial cells) suggest that Nox5 plays a significant role in mediating renal injury in diabetes.

Disclosure
J.C. Jha: None. A. Dai: None. M.E. Cooper: Advisory Panel; Self; AbbVie Inc.. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novartis AG. R.M. Touyz: None. C. Kennedy: Research Support; Self; Prometic Life Sciences Inc.. K. Jandeleit-Dahm: None.
Early Growth Response 1 (Egr1) Is a Transcriptional Activator of RAAS in Diabetic Kidney Disease
Authors: XUE YAO-MING 
Published: June 2018

Background: Egr1 and renin-angiotensin system(RAAS)are invlovled in DKD, but the relationship between them is unclear.
Methods: Egr1 and RAAS were detected in HFD/STZ-induced mice and HK-2 cells treated with TGF-β1. Then, RAAS expression was detected in HK-2 cells and mice with overexpression and knock-down of Egr1. The direct relationship between Egr1 and RAAS was explored via ChIP assay.
Results: We found increased levels of Egr1 and RAAS in the kidney cortices of DKD mice and TGF-β1-treated HK-2 cells. Overexpression or silencing of Egr1 in HK-2 cells and DKD mice could upregulate or downregulate the expression of RAAS. ChIP assays revealed that TGF-β1 induced Egr1 to bind to the RAAS promoter.
Conclusions: Our study provides strong evidence that Egr1 is a transcriptional activator of RAAS in DKD.

Disclosure
Y. Xue: None.
Changes of Plasma and Urine hsa-miR-223-3p Was Correlated with the Severity in Different Stages of Diabetes Kidney Disease of Type 2 Diabetes Patients in China
Authors: HE JUNYI , LI RONG , LI LAN , WU YANAN , YANG QIUPING , ZHANG LIHUA 
Published: June 2018

We have previously shown that hsa-miR-223-3p can be as a candidate novel biomarker performing important roles in Diabetes Kidney Disease (DKD) disease process,resulted from co-expression analysis from miRNA (Agilent chips) and lncRNAs (Affymetrix HTA2.0 chips) in plasma.This study involved into 90 patients with type 2 diabetes mellitus (T2DM) and normal control (n=28). Then we divided these diabetes patients into Normoalbuminuric groups(DM) (n=30), Microoalbuminuric group (Micro-DKD) (n=30) and Macroalbuminuric group (Macro-DKD) (n=30), according to urinary albumin to creatinine ratio (ACR) levels (&lt;30mg/g; 30-300mg/g; &gt;300mg/g). The clinical data and biochemical indexes of all the subjects were collected. Real-time qPCR to detect miR-223-3p expression of plasma and urine were reported and compared by using the one-way ANOVA. Statistical analysis was performed using SPSS version 23 software. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to estimate the diagnostic value of the candidate miRs. Compared with controls, the expression of miR-223-3p in plasma were decreased significantly from DM,Micro-DKD to Macro-DKD groups (P &lt;0.001), and the decline was gradually accompanied with the progression of DKD (P &lt;0.001). Same decline pattern was observed in urine expression among four groups, however discrimination was not significant due to the limited patients enrollment in the study. The ROC curve showed that the level of miR-223-3p in plasma can be distinguished among Micro-DKD, Macro-DKD with controls [AUC = 0.750, 95% CI = 0.569-0.923, p = 0.009; AUC = 0.998, 95% CI =0.992-1.000, p = 0.000]. Therefore, plasma hsa-miR-223-3p is a novel biomarker for the severity in Different Stages of DKD in China.

Disclosure
J. He: None. R. Li: None. L. Li: None. Y. Wu: None. Q. Yang: None. L. Zhang: None.
Identifying a New Pathway to Regulate Autophagy in HK2 Cells
Authors: YAMADA EIJIRO , OKADA SHUICHI , YAMADA MASANOBU 
Published: June 2018

Diabetic nephropathy (DN) is one of the major diabetic complications, the leading cause of the end stage renal disease (ESRD). Recently autophagy, which is also implicated in diabetes and insulin resistance, was shown to regulate DN. Recently, we demonstrated that Fyn functions as a muscle mass regulator by suppressing macroautophagy through a STAT3-mediated inhibition of the Vps34/Beclin1/ATG14 complex 1 but it is still not known whether Fyn regulates autophagy in kidney and function as a pathogenesis of DN. To investigate this, siRNA mediating knockdown of Fyn in HK2 cells as an in vitro cell model of renal proximal tubular epithelial cells was performed and demonstrating not only decreased p62 expression but also increased LC3-1/2 ratio implicating increased autophagy. To further investigating autophagic flow we utilized ammonium chloride and leupeptin to inhibit the autophagic flow and consistently found that expression of LC3-2 was increased. Phospho-proteomic analysis were performed in vivo and revealed that Fyn phosphorylates Transglutaminase 2 (Tgm2), a known autophagic inhibitor through Beclin1, on Y369 and Y617. To demonstrate that Tgm2 is a direct Fyn substrate, we incubated human purified GST-Tgm2 protein with purified Fyn-CA. In the presence of ATP, Fyn was observed to robustly phosphorylate the Tgm2. Interestingly, Fyn-dependent phosphorylation of Tgm2 was abolished when Y369 and Y617 in Tgm2 was mutated (Tgm2-Y369/617F), suggesting that these sites were specific and unique for Fyn kinase. SiRNA mediating knockdown of Tgm2 in HK2 cells revealed decreased p62 expression and increased LC3-1/2 ratio while overexpressing Tgm2-WT decreased autophagic flow demonstrating Tgm2 could regulate autophagy in the renal tubulus. Taken together, these data suggest that Fyn phorphorylates Tgm2 on Y369 and Y617 and regulates autophagy in the renal tubulus implicating a pathogenesis of DN.

Disclosure
E. Yamada: None. S. Okada: None. M. Yamada: None.
Unbiased Stereological Quantification of Key Features of Diabetic Nephropathy
Authors: PEDERSEN TANJA X. , JOHANSEN THEA T. , FINK LISBETH N. , VRANG NIELS , SECHER THOMAS 
Published: June 2018

Diabetic nephropathy (DN) is a serious long-term complication of diabetes. There is no curative treatment of DN, and the lack of knowledge about mechanisms leading to DN hampers the development of efficient therapies. To facilitate drug development, the ability to quantify key histopathological changes in animal models of human DN is essential. In order to develop a more precise determination of translatable nephrotic changes, we used novel and refined image analyses and stereological quantification of key features of DN in a model approach combining genetic diabetes (db/db mice) with uninephrectomy (UNx). UNx or sham-operation was performed in db/db or db/+ male and female mice (n=8-16 mice per group) and the study was terminated 10 or 16 weeks after surgery. Diabetes development was similar in sham and UNx db/db mice. Compared to sham-operation, UNx increased average kidney weight in db/db females both after 10 (43%) and 16 weeks (48%). Blood urea nitrogen (BUN) was increased in UNx vs. sham-operated animals 4 weeks post-surgery, but not at termination. Notably, kidney fibrosis was increased in UNx and sham db/db vs. sham db/+ females (16 weeks; mg total collagen; 12.7 ± 1.3 and 10.7 ± 1.8, respectively, vs. 5.7 ± 0.8, p&lt;0.05). Urinary albumin was progressively increased in all db/db groups with significantly lower variance in UNx db/db females than sham (F-test, p=0.02), permitting smaller group sizes in pre-clinical studies. Unbiased stereological quantification is ongoing to establish volume of glomeruli and number of podocytes. Glomerular collagen is quantified by double-fluorescence imaging concomitantly detecting podocin and collagen.
In conclusion, renal hypertrophy and raised plasma BUN suggest increased pressure on the remaining kidney in UNx mice, leading to fibrosis and decreased kidney function. The thorough quantification of translatable features of DN in the db/db UNx model may provide refinement of this model enabling improved pharmacological testing of compounds targeting DN.

Disclosure
T.X. Pedersen: Employee; Self; Gubra. T.T. Johansen: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S.
Apolipoprotein C3 and Cardiovascular Disease in Patients with Type 1 Diabetes and Diabetic Nephropathy
Authors: STECHEMESSER LARS , FORSBLOM CAROL , WEITGASSER RAIMUND , GROOP PER-HENRIK 
Published: June 2018

Background and Aims: Apolipoprotein C3 (ApoC3) is a key regulator of triglyceride metabolism via its inhibitory effects on lipolysis and hepatic remnant uptake. Emerging evidence indicate that ApoC3 is an independent risk factor for cardiovascular events. The fact that glucose and insulin regulates ApoC3 expression raises the role of ApoC3 and cardiovascular risk in diabetes. We, therefore, investigated ApoC3 and its association with cardiovascular disease (CVD) in patients with and without diabetic nephropathy.
Methods: This cross-sectional and prospective analysis was part of the prospective, ongoing Finnish Diabetic Nephropathy (FinnDiane) Study. Between 1994 and 2015 data were obtained from 3926 type 1 diabetes (T1D) patients at more than 80 hospitals or health centers across Finland. ApoC3 levels were explored by groups of albuminuria, CKD stages, presence of CVD as well as prediction of CVD and death. Survival curves were calculated by Cox regression analysis.
Results: At baseline, normo-, micro- and macroalbuminuria were present in 71.7%, 13.8% and 14.5% of the population (n=3926, females 48%, age 37.8±12.2 years, diabetes duration 23.2±13 years, HbA1c 8.4±1.5%). CKD stage 3-5 was diagnosed in 14.3%. Coronary heart disease or stroke (CVD) were present in 5.5% at baseline, while 16.3% developed CVD during 15-year follow-up. Compared to normoalbuminuria ApoC3 was elevated in the presence of micro- (p=0.013) or macroalbumiuria (p&lt;0.001). Increasing ApoC3 levels were observed alongside progression of CKD stage (p&lt;0.001). Notably, higher baseline ApoC3 correlated with presence of CVD at baseline, development of CVD during follow-up and death. Differences in survival of those with the highest quartile of ApoC3 were independent of eGFR, triglycerides or HbA1c.
Conclusions: Baseline ApoC3 levels were elevated in T1D patients with micro- and macroalbuminuria, with impaired renal function, and with CVD. ApoC3 also predicted the development of CVD and death during follow-up.

Disclosure
L. Stechemesser: None. C. Forsblom: None. R. Weitgasser: None. P. Groop: Other Relationship; Self; AstraZeneca, AbbVie Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medscape, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi.
Recreational Running Training Favourably Affects Antioxidants Gene Expression in Type 2 Diabetes Patients
Authors: SOUSA MAYSA , SANTOS ARITANIA , SILVA MARIA ELIZABETH R. 
Published: June 2018

Increased levels of oxidative stress and inflammation have been linked to the progression of diabetes. To reduce oxidative stress and inflammation related to diabetes, diet and chronic exercise is often recommended. Data suggests high intensity interval training may be more beneficial than traditional aerobic exercise. However, appraisals of differing modes of exercise, along with explanations of mechanisms responsible for observed effects in humans, are lacking. This study assessed effects of twelve weeks of two models of high intensity intermittent training, recreational soccer (SO+D) or running (RU+D) training both combined with a caloric restricted diet vs. diet alone (D) in PBMC gene expression of type 2 diabetes patients. Training sessions were performed for 40 minutes, 3 times per week for 12 weeks. We examined PBMC mRNA expression of genes related to antioxidant enzyme activity (CASP9, SOD1, CAT, CASP3). Compared to the D group, only RU+D group resulted in increased mRNA expression of CASP9, SOD1 and CAT (p&lt;0.01) whereas SO+D group mRNA expression did not alter after 12 weeks intervention. Compared to SO+D group, RU+D resulted in increased mRNA expression of CAT, CASP9, SOD1 and CASP3 (p&lt;0.01) post-12 weeks treatment. The combined use of running training associated with dietary advice beneficially influenced expression of genes related to endogenous antioxidant enzyme activity and inflammation than soccer training and diet alone.
In conclusion, recreational running training was superior than soccer training and diet alone elicited lower oxidative stress and inflammation among type 2 diabetes patients.

Disclosure
M. Sousa: None. A. Santos: None. M.R. Silva: None.
Presence of Carotid Artery Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes and Normal Baseline Renal Function
Authors: SEO DA HEA , KIM SO HUN , AHN SEONG HEE , HONG SEONGBIN , NAM MOONSUK , WOO JEONG-TAEK , BAIK SEI HYUN , LEE KWANWOO , KIM YOUNG SEOL , PARK YONGSOO 
Published: June 2018

Background: Recent clinical evidences indicate that early rapid renal function decline is closely associated with the development of diabetic kidney disease. We have investigated the incidence and baseline clinical predictors of rapid renal function decline in patients with type 2 diabetes and normal baseline renal function.
Methods: A total of 967 type 2 diabetic patients from the Korean National Diabetes Program (KNDP), a prospective, multicenter, observational cohort study, with serial GFR measurement for 5 years and normal renal function were included for the analysis. Rapid renal function decline was defined as an eGFR decline &gt;3.3% per year. Carotid ultrasonography was used to assess carotid intima-media thickness (IMT) and the presence of plaque.
Results: The mean age was 53.7 years with body mass index of 25.4 kg/m2. Rapid renal function decline developed in 158 participants (16.3%) and average GFR decline was -5.2 ± 1.9% /year in rapid decliners and -0.4 ± 1.9% /year in non-decliners. There were no differences in the presence of albuminuria or retinopathy between the rapid decliners and non-decliners at baseline. Multivariable logistic regression analyses revealed that female sex (odds ratio (OR) 4.80 [95% CI 2.69-8.56], p&lt;0.0001), higher urine albumin/creatinine ratio (OR 1.26 [1.03-1.55], p=0.024), presence of carotid artery plaque (OR 2.58 [1.47-4.53], p=0.001), and previous history of hypertension (OR 1.93 [1.09-3.44], p=0.025) and CVD (OR 2.53 [1.24-5.15], p=0.011) were the independent clinical predictors for rapid renal function decline.
Conclusions: Our study suggests the need for close monitoring of renal function and early intensive management in patients with type 2 diabetes and carotid atherosclerosis.

Disclosure
D. Seo: None. S. Kim: None. S. Ahn: None. S. Hong: None. M. Nam: None. J. Woo: None. S. Baik: None. K. Lee: None. Y. Kim: None. Y. Park: None.
Serum Adipocyte Fatty Acid-Binding Protein Levels Are Linked to Rapid Renal Function Decline in Patients with Type 2 Diabetes and Normal Renal Function
Authors: SEO DA HEA , KIM SO HUN , AHN SEONG HEE , HONG SEONGBIN , NAM MOONSUK 
Published: June 2018

Background: Rapid renal function decline has been recognized as an important predictor for diabetic nephropathy (DN). Adipocyte fatty acid-binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and is closely associated with metabolic syndrome and type 2 diabetes. We aim to investigate the role of adipokines including A-FABP and inflammatory cytokines in the development of rapid renal function decline in type 2 diabetes and normal renal function.
Methods: A total of 456 subjects with type 2 diabetes with normal renal function were recruited from an outpatient clinic at the Diabetes Center of Inha University Hospital and were followed up for 6 years with serial glomerular filtration rate (GFR) measurements. The serum levels of tumor necrosis factor (TNF)-a, and interleukin (IL)-6, high molecular weight (HMW) adiponectin, endogenous secretory receptor for advanced glycation end products (esRAGE), A-FABP and pentraxin-related protein (PTX3) were measured at baseline. Rapid renal function decline was defined as an eGFR decline &gt;3.3% per year.
Results: During follow-up, 120 participants (26.3%) developed rapid renal function decline and mean annual eGFR decline was -5.4 ± 2.7% and -0.6 ± 2.4% in decliners and non-decliners, respectively. Median A-FABP levels were significantly higher in patients with rapid decliners than in non-decliners (19.1 vs. 16.8 ng/ml, p=0.011). No significant difference of three cytokines levels were observed between groups. Each log unit increase of A-FABP was independently associated with greater risk of rapid renal function decline (odds ratio [OR] = 3.60; 95% confidence interval [CI] 1.95-6.66; p &lt; 0.001) after adjustments for sex, BMI, A1C, GFR, hypertension, presence of carotid artery plaque and urine albumin creatinine ratio.
Conclusions: High plasma A-FABP was an independent risk factor for rapid renal function decline in type 2 diabetes and normal renal function.

Disclosure
D. Seo: None. S. Kim: None. S. Ahn: None. S. Hong: None. M. Nam: None.