bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment Patterns in Type 2 Diabetes Patients with Chronic Kidney Disease-A Cohort Study
Authors: BLANKENBURG MICHAEL , KOVESDY CSABA P. , EISENRING SELINE , FETT ANNE , SCHOKKER EMILE W. , KORN JONATHAN , GAY ALAIN 
Published: June 2018

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the U.S. and 40% of affected people develop chronic kidney disease (CKD). This study evaluated patients’ treatment patterns, disease burden and progression.
Methods: This retrospective study used the U.S. claims database PharMetrics Plus (January 2006-December 2015) and the Experian consumer data asset (January 2007-December 2015) to evaluate longitudinal treatment patterns in patients with T2DM and CKD using ICD codes. In addition, CKD progression, all-cause mortality rate, clinical events and health care costs were described.
Results: Of 250,742 patients identified, the median age was 61 years, 58% were male, 73% were Caucasian and 87% had hypertension. Proportions of patients using angiotensin II receptor blockers (ARB) or angiotensin-converting-enzyme inhibitors (ACEi) was lower in CKD stages 4 and 5 (54 and 52%, respectively) than in stages 1-3 (66-70%). The use of beta blockers (32-52%), calcium channel blockers (27-41%) and diuretics (37-54%) tended to increase from CKD stages 1 to 4 and decreased in stage 5. Antidiabetic drugs were prescribed to 65.7% of patients and their use decreased with increasing CKD stage. Of the 21% of patients who progressed within a year to a more severe CKD stage, the highest proportion advanced from stage 4 to 5 (42%). The most common clinical events were diabetic retinopathy, heart failure and acute kidney injury reported in 27%, 22% and 22% of patients, respectively. Overall, 4.6% died with a median time from index to death of 12.3 months. The annual health care costs of $46,028 per person included $9,103 and $36,925 for pharmacy and medical costs, respectively.
Conclusions: The treatment of T2DM patients with CKD was mostly in line with current guideline recommendations. However, only up to 70% of patients used ARB and ACEi, the first line treatments. In addition, 21% of patients progressed to a more severe CKD stage. These findings suggest a need for new treatment options in this population.

Disclosure
M. Blankenburg: None. C.P. Kovesdy: Consultant; Self; Abbott. Advisory Panel; Self; AbbVie Inc.. Consultant; Self; Bayer AG. Advisory Panel; Self; AstraZeneca. Consultant; Self; Sanofi Genzyme. Advisory Panel; Self; Amgen Inc.. Consultant; Self; Keryx. S. Eisenring: None. A. Fett: Consultant; Self; IQVIA. E.W. Schokker: None. J. Korn: None. A. Gay: Employee; Self; Bayer AG.
Genetically Reduced Chondroitin Sulfate Prevents the Progression of Diabetic Neuropathy
Authors: ISHIGURO HAJIME , USHIKI TAKASHI , KAWASAKI ASAMI , CHO KAORI , MASUKO MASAYOSHI , SANGO KAZUNORI , IGARASHI MICHIHIRO , SONE HIROHITO 
Published: June 2018

Background: The extracellular matrix is associated with the pathophysiology of diabetic complications; however, the role of chondroitin sulfate (CS) remains unclear. To clarify the effects of CS on diabetic neuropathy (DN), we assessed the effect of genetically reducing CS in mice through disruption of a gene encoding the rate-limiting CS-synthesizing enzyme, i.e., CS N-acetylgalactosaminyltransferase-1 (T1).
Methods: T1 knockout (T1KO) mice were generated from the C57BL/6N strain and C57BL/6N were prepared as wild type (WT). Diabetes was induced through streptozotocin injection in 6-week-old male mice. All data were obtained 3 weeks after streptozotocin injection.
Results: In the heat radiant test, while thermal nociception in nondiabetic WT and T1KO mice were normal and significantly disrupted in diabetic WT mice, that in diabetic T1KO mice was preserved. The number of plantar peripheral nerve fibers was also significantly decreased in diabetic WT mice; however, that in diabetic T1KO mice were relatively normal. Furthermore, immunohistochemistry revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, which contains a cluster of sensory neuron bodies. In contrast, those neurons were protected in diabetic T1KO mice. Hence, nociception and thermoception are preserved in diabetic T1KO mice. To investigate the mechanisms underlying these events, we analyzed gene expression in DRG through real-time polymerase chain reaction and confirmed the suppression of caspase-3 and caspase-9 in diabetic T1KO mice, compared to those in diabetic WT mice. However, levels of Bcl2, TNF-α, MMP9, and reactive oxygen species-related enzymes (HO-1, NOX) did not differ significantly between WT and T1KO diabetic mice.
Conclusions: Reduced CS production is suggested to have potentially beneficial effects on preventing DN by suppressing apoptotic signaling and could be a cutting-edge target of clinical application.

Disclosure
H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. T. Ushiki: None. A. Kawasaki: None. K. Cho: None. M. Masuko: None. K. Sango: None. M. Igarashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
Two-Way Orthogonal Partial Least Squares (O2PLS) Analysis of the Lipidome and Transcriptome in Prediabetic and Diabetic Neuropathy
Authors: GUO KAI , FELDMAN EVA L. , HUR JUNGUK 
Published: June 2018

Peripheral neuropathy (PN) is a common complication of prediabetes and type 2 diabetes (T2D) for which there are limited treatment options. Using mouse models of prediabetes and T2D we have demonstrated that dietary reversal (DR) corrects the PN phenotype. To identify the mechanisms that underlie PN development and reversal, we employed an omics-based approach. This was achieved by integrating transcriptomic and lipidomic datasets derived from mouse sciatic nerve using two-way Orthogonal Partial Least Squares (O2PLS) analysis, a platform that is useful in uncovering the large-scale organization of metabolic networks. Sciatic nerve was isolated from five groups of mice that consisted of controls, high-fat (HF) fed mice (prediabetic), HF mice injected with low dose STZ (T2D), HF mice subjected to 8 week dietary reversal (DR) and T2D-DR. Tissue was processed for gene expression by mRNA-seq or for lipid species profiling by untargeted shotgun lipidomics. A total of 6,024 genes and 578 lipid species were selected and the systematic joint covariation between gene and lipid species were modeled using O2PLS. A clear separation occurred between T2D/prediabetes and healthy/DR mice. Compared to a traditional ANOVA analysis, we selected genes with the top 1% values (52 genes) as highly inter-correlated genes with lipid species; we additionally identified 28 more genes (53.8%) which also highly correlated with lipid species. The top 50 lipid species, including 29 novel species, were identified based on these analyses and primarily consisted of triacylglycerols (TG) and diacylglycerols (DG). Moreover, a comprehensive lipid-gene interaction network was constructed based on these genes and lipid species. This study demonstrates that O2PLS can provide significant and biologically relevant coordination between gene expression and lipid levels and can offer new insights into our understanding of the metabolic networks underlying PN in T2D.

Disclosure
K. Guo: None. E.L. Feldman: None. J. Hur: None.
Beneficial Effects of Xanthine Oxidase Inhibitor, Topiloxostat, on Experimental Diabetic Neuropathy in Mice
Authors: MIZUKAMI HIROKI , KOYAMA REMINA , TAKAHASHI KAZUHISA , OSONOI SHO , OGASAWARA SAORI , YAGIHASHI SOROKU 
Published: June 2018

Xanthine oxidoreductase (XOR) catalyzes the final step of purine metabolism from xanthine to urate. XOR is then converted into xanthine oxidase (XO), incurring tissue damage when XO after XOR is activated such as in diabetes. The aim of this study is to evaluate the pathogenic role of XOR/XO in the development of diabetic polyneuropahty (DPN), and to clarify whether suppression of XO is beneficial for DPN. C57BL6 (C57) and db/db mice (db) 5-week of age were treated daily with a new potent XO-inhibitor, topiloxostat (To), 1mg/kg (dbT1) and 2mg/kg (dbT2) ad libitum with conventional laboratory chow for 8 weeks. During experimental period, glycemic levels, nerve conduction velocity (NCVs) and tail flick response were regularly monitored. At end, following the measurement of sciatic nerve blood flow (SNBF) by laser doppler, mice were killed for the evaluation of XO activity of the sciatic nerve (SN), intra-epidermal nerve fiber density (IENFD) and Iba-I positive macrophage infiltration (MI) intoSN. Glycemic levels were comparable among all diabetic groups. There was a significant delay of NCVs and elevated perception threshold of tail flick in db compared to C57. To-treatment improved these measures in a dose dependent manner (p&lt;0.dbT2 vs. C57 for NCVs, and p&lt;0.db vs. dbT1 and p&lt;0.01 db vs. dbT2 for tail flick). XO activity in SN was dose-dependently suppressed compared to db (p&lt;0.vs. dbT1, p&lt;0.01 vs. dbT2). To-treatment at a high dose also corrected reduced SNBF and IENFD in db (p&lt;0.01 dbT2 vs. db for both). There was a significant increase in Iba-I positive macrophages in SN of db compared to C57 after 4 week-treatment (p&lt;0.01). MI was significantly suppressed in dbT1 and dbT2 (p&lt;0.01). In contrast, there was no significant difference in MI at 8 week-treatment among all the groups. These results indicated the possible implication of XOR/XO metabolism in the pathophysiology of DPN and To may be a promising compound for the treatment of DPN.

Disclosure
H. Mizukami: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation. R. Koyama: None. K. Takahashi: None. S. Osonoi: None. S. Ogasawara: None. S. Yagihashi: None.
The Impact of Normoglycemia in Reducing Microvascular Complications in Patients with Type 2 Diabetes—A Follow-Up Study
Authors: TAVAKOLI MITRA , ISHIBASHI FUKASHI 
Published: June 2018

Aim: Hyperglycemia is associated with increased risk of microvascular complications in patients with type 2 diabetes (T2DM). The aim of the present study is to investigate whether reduction of the levels of HbA1c by tight glycemic control (GC) decreases the rate of microvascular complications and improves the neurological measures in T2DM.
Methods: Detailed clinical, neurological examinations including corneal confocal microscopy (CCM), were performed in 141 patients with poorly controlled type 2 diabetes (mean age 53, Duration diabetes: 9 years) at the baseline and 60 age-matched control subjects and followed-up with GC for 4 years. Nephropathy and Retinopathy also assessed. Patients were stratified according to mean HbA1c level during follow-up.
Results: At baseline CCM showed significant nerve fiber damage in all patients compared to controls. Despite strict GC and improvement in mean HbA1c by around 2.8%, overall the cumulative incidence of neuropathy increased from 17.7% at baseline to 21.3% and retinopathy increased from 21.3% to 35.5%, however the cumulative incidence of nephropathy reduced from 37.6% to 22%. Tight GC was effective in improving Neuropathy only in those with very poor Control at the Baseline. The interval changes in HbA1c levels were correlated with the interval changes in CNF measures and neurophysiological tests. The results showed one percent reduction in HbA1c levels per year significantly improved CNF measures and neurophysiological dysfunctions. Based on the results of this study, for improving neuropathy, only HbA1c close to 6.5% is effective for improvement in structure and function of the corneal nerves.
Conclusion: This study showed that the GC was just improved nephropathy among microvascular complications. Glucose control did only improve neurophysiological and corneal nerve measurements when near-normoglycemia was reached. Despite tight GC, the retinopathy progressed in patients with type 2 diabetes at this cohort.

Disclosure
M. Tavakoli: None. F. Ishibashi: None.
Vitamin D Supplementation and Microcirculation Parameters in Diabetic Patients with Neuropathy
Authors: STEPANOVA ANNA P. , KARONOVA TATYANA L. , JUDE EDWARD B. 
Published: June 2018

Type 2 diabetes mellitus (T2DM) is often combined with vitamin D (VD) deficiency. It is known that VD affects glycemic control as well as systemic inflammation and could play a role in diabetic neuropathy (DN) pathogenesis. High VD dose supplementation decreases impaired microcirculation in diabetic patients and reduces DN severity. NTSS-9, NDS scales were used, 25(OH)D, HbA1c were studied in 24 (12F) patients with T2DM and DN. Parameters of microcirculation (value of perfusion - M, standard deviation - σ, Kv - coefficient of microcirculation) by laser Doppler fluorometry (LAKK-M, Russia) baseline and after 24 weeks of VD supplementation. Inclusion criteria: T2DM duration more then 5 years, HbA1c ≤9.0%, NDS index 4 and more, signed IC. Patients were randomized in to two groups: 5000 IU (group I) and 40000 IU (group II) per week cholecalciferol treatment without hypoglycemic treatment changes. At baseline the two groups were comparable by sex, age, BMI, HbA1c level. We included in group I twelve pts (6F) aged 56,1±5,4 with mean HbA1c 8.2±0.4% and 25(OH)D level 21.4±3.4 nmol/l. In group II we included 12 pts (6F), mean age 51,3±5,9, HbA1c 8.4±0.6%, 25(OH)D 20.9±4,1 nmol/l. Baseline NDS index did not differ between the two groups 10.1±3.3 and 12.3± 4.7 accordingly, as well as the NTSS-9 index 15.8±5.2 and 17.1±6.8 (p&gt;0.05). Parameters of microcirculation were the same M=10.63±1.37 and 12.36±2.51 BPU, σ=5.32±0.79 and 4.44±1.05, Kv=11.36±1.59 and 10.64±2.93. After 24 weeks of VD treatment we did not find changes in group I - HbA1c 8.1±0.4%, 25(OH)D 24,7±2.5 (p=0,07), M=10.30±1.14 (p=0.08), σ=4.98±0.56 (p=0.05) and Kv=11.82±2.38 (p=0.87). HbA1c significantly decreased till 7.4±0.7% (p=0.023) in group II. 25(OH)D level increased to 60,9±3.1 (p=0,003). We found improvement of all microcirculation parameters M=19.69±2.52 (p=0.003), σ=6.05±0.93 (p=0.005), Kv=13.36±3.15 (p=0.017) compared to baseline. High dose of VD supplementation could improve microcirculation parameters in T2DM patients with DN.

Disclosure
A.P. Stepanova: None. T.L. Karonova: None. E.B. Jude: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Novo Nordisk A/S, Takeda Development Centre Europe Ltd., Bayer AG, Boehringer Ingelheim GmbH, Eli Lilly and Company.
Prevalence of Cardiovascular Autonomic Neuropathy and Gastroparesis Symptoms among Adults with Type 2 Diabetes Who Attend a Primary Health Care Center
Authors: ALOLAIWI LINA , ALHARBI TURKI , TOURKMANI AYLA 
Published: June 2018

Introduction: Cardiovascular autonomic neuropathy (CAN) and gastroparesis are two forms of diabetic autonomic neuropathy that could affect the quality of life of the patients and carry significant morbidity and mortality outcomes. This study aimed to estimate the prevalence and risk factors of both CAN and gastroparesis symptoms (GPS) among patients with type 2 diabetes (T2D).
Methods: A cross-sectional study was conducted among 347 adults (≥ 18 years) with T2D from April 1- December 15, 2017. CAN was defined by the presence of any of the followings: resting tachycardia (RT); resting heart rate &gt; 100 bpm, orthostatic hypotension OH (a fall in systolic blood pressure (SBP) by ≥ 20 mmHg or a fall in diastolic blood pressure by ≥ 10 mmHg within 3 minutes of standing) or prolonged corrected QT interval (QTc) in the electrocardiogram (&gt; 0.47 seconds in females, and &gt; 0.45 seconds in males). The GPS were assessed using a validated questionnaire: Gastroparesis Cardinal Symptom Index (GCSI). GCSI score ≥ 1.9 signified definite GPS.
Results: The mean age was 55.6 ± 10 years. The mean HbA1c and T2D duration was 8 ± 1.6% and 10.6 ± 6.9 years, respectively. CAN was present in 15.6%: 2.9% with OH, 5.8% with RT and 8.4% with prolonged QTc. Antihypertensive agents (anti-HTN), body mass index (BMI), SBP, triglycerides and HbA1c were significantly higher in patients with CAN, P&lt;0.05. Prolonged T2D duration (OR= 1.07, 95% CI 1-1.14; p= 0.04) and anti-HTN (OR= 5.2, 95% CI 1.2-23; p= 0.03) were independently associated with CAN. GPS were present in 3.2% and were significantly associated with higher BMI, P&lt;0.05. Metformin use emerged as the single significant independent predictor of the presence of at least one GPS (OR= 5.2, 95% CI 1.8- 14.7; p= 0.002).
Conclusion: The prevalence of CAN among T2D subjects was 15.5%. Prolonged T2D duration and anti-HTN emerged as significant predictors of CAN. The prevalence of GPS was 3.2% and was independently associated with metformin use.

Disclosure
L. AlOlaiwi: None. T. Alharbi: None. A. Tourkmani: None.
Alcohol Consumption and Risk of Type 2 Diabetes Mellitus—A Nationwide Cohort Study
Authors: LAI YUN-JU 
Published: June 2018

Background and Aims: Alcohol consumption correlates with type 2 diabetes through its effects on insulin resistance, changes in alcohol metabolite levels, and anti-inflammatory effects. We aim to clarify association between alcohol consumption and risk of diabetes in Taiwanese population.
Methods: The National Health Interview Survey (NHIS) in 2001, 2005, and 2009 selected a representative sample of Taiwan population using a multistage sampling design. Information was collected by standardized face to face interview. Study subjects were connected to the Taiwan National Health Insurance claims dataset and National Register of Deaths Dataset from 2000 to 2013. Kaplan-Meier curve with log rank test was employed to assess the influence of alcohol drinking on incidence of diabetes. Univariate and multivariate Cox proportional regression were used to recognize risk factors of diabetes.
Results: A total of 43,000 participants were included (49.65% male; mean age, 41.79±16.31 years). During the 9-year follow-up period, 3,650 incident diabetes cases were recognized. Kaplan-Meier curves comparing the four groups of alcohol consumption showed significant differences (p&lt;0.01). After adjustment for potentially confounding variables, compared to social drinkers, the risks of diabetes were significantly higher for non-drinkers (adjusted hazard ratio [AHR]=1.21; 95% confidence interval [CI], 1.09-1.34; p&lt;0.01), regular drinkers (AHR=1.19; 95% CI, 1.06-1.35; p &lt;0.01), and heavy drinkers (AHR=2.21, 95% CI, 1.56-3.13, p&lt;0.01).
Conclusions: Social drinkers have a significantly decreased risk of new-onset diabetes compared with non-, regular, and heavy drinkers.

Disclosure
Y. Lai: None.
PGC-1α Determines the Formation of Neuronal Respiratory Chain Supercomplexes That Regulate Mitochondrial Function
Authors: CHOI JOUNGIL , SALIMIAN MOHAMMAD , KONDURU SAI SRUTHI REDDY , RUSSELL JAMES 
Published: June 2018

Loss of PGC-1α signaling is important in the development of experimental diabetic neuropathy (DN) [Choi J et al. Neurobiology of Disease, 2014. 64; 118-130]. In PGC- α knockout (KO) mice there is exacerbation of DN with loss of large and small myelinated fibers, loss of mitochondria (Mt) and DNA content, and increased protein oxidation. We have shown potential important functions of 35-kDa PGC-1α, a novel PGC-1α isoform in regulating Mt integrity. The focus of the present work was to analyze the respiratory chain complex integrity in neurons of PGC-1 α KO mice. In the respiratory supercomplexes of 1,030, 980, and 840 kDa, the levels of complexes 1,030 and 980 kDa are significantly decreased, while the level of 840-kDa complex is significantly increased in PGC-1 α KO mice compared to wild type (WT) mice. Mass spectrometry analysis identifies; (1) subunits of complex I, III, and IV in the 1,030-kDa band, 2) subunits of complex I and III in the 980-kDa band, and (3) subunits of complex I in the 840-kDa band. Quantification results reveal that the activities of complexes I, III, and IV within the 1,030-kDa protein complex are significantly decreased in PGC-1α KO mice. In contrast, we observe little complex I, III, and IV activities either in the 980- or 840-kDa complex. We observed altered Mt morphology and impaired respiration in PGC-1 α KO mice. Co-immunoprecipitation and mass spectrometry analyses reveal that the 35-kDa PGC-1α is associated with NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2), a subunit of respiratory complex I in the Mt. Immunoblot analysis combined with two-dimensional-blue native gel show the presence of both 35-kD α PGC-1α and NDUFV2 proteins in the 1,030-kDa protein band. These results are consistent with a cooperative role of 35-kDa PGC-1α and NDUFV2 in the organization of Mt respiratory supercomplex assembly. The study provides evidence that 35-kDa PGC-1α is present in the Mt where it could directly regulate Mt function and affect response to diabetes.

Disclosure
J. Choi: None. M. Salimian: None. S. Konduru: None. J. Russell: None.
Cardiovascular Autonomic Neuropathy and Uric Acid in Subjects with Type 1 Diabetes—Preventing Early Renal Loss (PERL) in Type 1 Diabetes Trial
Authors: JAISWAL MAMTA , DORIA ALESSANDRO , MAUER MICHAEL , POP-BUSUI RODICA 
Published: June 2018

Elevated serum uric acid (SUA), an established risk factor for diabetic nephropathy (DN) may also be a risk factor for cardiovascular autonomic neuropathy (CAN). We evaluated the cross-sectional association between CAN and SUA levels in subjects with type 1 diabetes (T1D), mild to moderate chronic kidney disease (CKD) and a SUA ≥4.5 mg/dl enrolled in the ongoing PERL trial that is evaluating the effect of SUA lowering by allopurinol on kidney function decline, specifically iohexol plasma disappearance glomerular filtration rate (iGFR). Also measured are estimated GFR (eGFR) and albumin excretion rates (AER). Measures of baseline CAN included resting heart rate, standard deviation of normal RR interval (SDNN), and QTi (Bazzett formula) derived from resting ECG recordings (RR interval extracted from digital ECG images by ECGSCAN software). Four hundred ninety seven PERL participants had valid baseline CAN and renal function data (age 51 ± 11 years, 68% male, T1D duration 35 ± 12 years, HbA1c 8±1%). Subjects in the highest tertile of serum UA levels had worse measures of renal function (iGFR 60 ± 16 vs. 74 ± 60 ml/min/1.73 m2, eGFR 65.7 ± 18.1 vs. 82.7 ± 17.2 ml/min/1.73 m2, AER 370 ± 783 vs. 1181 ± 475 mcg/mg creatinine) compared to those in the lowest tertile. SDNN correlated negatively with SUA levels (r = -0.11, P = 0.0093). In a multiple linear regression model, lower SDNN was associated with higher SUA levels independent of age, gender, BMI, blood pressure, and HbA1c (β = -0.061, SE= 0.021, P = 0.0049), but this association was no longer significant when adjusted for iGFR (β = -0.0184, SE= 0.024, P = 0.46).
In summary, elevated SUA was significantly associated with CAN in subjects with T1D independent of some traditional cardiovascular risk factors. This relationship operated, at least in part, through the inverse association of SUA levels with renal function.

Disclosure
M. Jaiswal: None. A. Doria: Research Support; Self; Sanofi-Aventis. M. Mauer: None. R. Pop-Busui: Research Support; Self; AstraZeneca.