bluuebunny/crossref_metadata_2025 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<0.dbT2 vs. C57 for NCVs, and p<0.db vs. dbT1 and p<0.01 db vs. dbT2 for tail flick). XO activity in SN was dose-dependently suppressed compared to db (p<0.vs. dbT1, p<0.01 vs. dbT2). To-treatment at a high dose also corrected reduced SNBF and IENFD in db (p<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<0.01). MI was significantly suppressed in dbT1 and dbT2 (p<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>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 > 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 (> 0.47 seconds in females, and > 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<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<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<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<0.01), regular drinkers (AHR=1.19; 95% CI, 1.06-1.35; p <0.01), and heavy drinkers (AHR=2.21, 95% CI, 1.56-3.13, p<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.
Impaired Baroreflex Sensitivity in Patients with Recent-Onset Type 2 Diabetes
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , BÓDIS KÁLMÁN , MÜSSIG KARSTEN , SZENDROEDI JULIA , RODEN MICHAEL , ZIEGLER DAN
Published: June 2018

Impaired baroreflex sensitivity (BRS) is a sign of diabetic cardiovascular autonomic neuropathy (CAN) which often remains undiscovered during the early course of diabetes. We aimed to determine whether BRS alterations can be detected in patients with recent-onset type 1 and type 2 diabetes. Continuous plethysmographic arterial pressure and R-R intervals were recorded using the Finometer (Finapres Medical Systems) from the left middle finger in 586 participants from the baseline German Diabetes Study (GDS) cohort with type 1 or type 2 diabetes and a known diabetes duration ≤1 year (T1D/T2D [mean±SD]: n=208/378; age: 34.7±11.1/51.6±10.3 years; male: 60/74%; BMI: 24.7±4.2/31.7±6.3 kg/m²; diabetes duration: 6.3±3.3/5.9±3.5 months; HbA1c: 6.5±1.1/6.5±0.9%) and corresponding controls (CON1/CON2: n=74/208; age: 36.4±10.1/49.4±14.8 years; male: 64/64%; BMI: 26.5±4.9/26.6±4.9 kg/m²; HbA1c: 5.2±0.3/5.3±0.3%). BRS parameters included the alpha index of spectral power (BRSα), transfer function cross spectrum (xBRS), and sequence analyses (BRSseq). After adjustment for sex, age, BMI, and smoking, all three BRS measures were reduced in T2D vs. CON2 (BRSα: 10.1±8.6 vs. 15.4±10.2 ms/mmHg; xBRS: 7.84±6.94 vs. 10.4±8.2 ms/mmHg; BRSseq: 9.85±9.07 vs. 13.3±9.6 ms/mmHg) (P≤0.01), while no such differences were observed in T1D vs. CON1. Multiple regression analyses revealed, that systolic blood pressure (SBP) was the strongest determinant of lower BRS in T2D (xBRS/BRSseq/BRSα: β=-0.32/-0.23/-0.22) followed by age (xBRS: β=-0.18) and lower HDL cholesterol (BRSseq: β=-0.23), while in T1D it was age (xBRS/BRSseq/BRSα: β=-0.37/-0.36/-0.34), SBP (xBRS/BRSα: β=-0.26), and BMI (BRSseq: β=-0.24) (all P≤0.01).

In conclusion, reduced baroreflex sensitivity indicates early CAN in recent-onset type 2 diabetes in relation to modifiable risk factors such as higher systolic blood pressure and lower HDL cholesterol.

Disclosure

G.J. Bönhof: None. A. Strom: None. K. Bódis: None. K. Müssig: None. J. Szendroedi: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. D. Ziegler: None.
Low Copy Number of the Salivary Amylase Gene (AMY1) Is Associated with Obesity, Dyslipidemia, and Chronic Low-Grade Inflammation but Not Insulin Sensitivity and Secretion
Authors: COURTEN BARBORA DE , MOUSA AYA , NADERPOOR NEGAR
Published: June 2018

Low salivary amylase gene (AMY1) copy number variations (CNVs) are associated with low serum amylase concentrations which have been shown to correlate with obesity, metabolic syndrome and predict type 2 diabetes. Recently, AMY1 CNV below 4 has been associated higher risk of obesity. Only one study has shown an association between AMY1 CNV and insulin resistance (HOMA). We assessed the relationship between AMY1 CNVs and adiposity (body mass index and dual X-ray absorptiometry), fasting and 2 hour glucose (75g OGTT), insulin sensitivity (hyperinsulinemic euglycemic clamp) and total, first and second phase insulin secretion (intravenous glucose tolerance test), inflammatory markers and adipokines (multiplex assays, Biolegend, CA) in 58 overweight and obese but otherwise healthy individuals (age 31±9 years, BMI 31±4 kg/m2). Participants were non-smokers and had modest alcohol consumption. The participants were divided into two groups according to a median of 4 AMY1 CNVs. Individuals with less than 4 AMY1 CNVs had higher BMI (33±4 vs. 30±3 kg/m2, p=0.04), fat mass (41±12 vs. 34±8kg, p=0.01), LDL cholesterol (3.3 ± 0.8 vs. 2.8±0.7mmol/l, p= 0.02), plasma interleukin 6 (53±56 vs. 24±22 pg/ml, p= 0.02) and leptin concentrations (0.83±0.56 vs. 0.50±0.46 ng/ml, p=0.02) compared to individuals with more than 4 AMY1 CNVs. There was no relationship between AMY1 CNVs and insulin sensitivity, insulin secretion, plasma fasting and 2 hour glucose, high sensitivity C-reactive protein, adiponectin, resistin and adipsin levels (all p>0.1). Our data indicated that AMY1 CNVs are associated with obesity, dyslipidemia and chronic low-grade inflammation but not glucose metabolism. Further larger studies are needed to confirm whether AMY1 CNVs could be a genetic biomarker for metabolic syndrome and type 2 diabetes.

Disclosure

B. de Courten: None. N. Naderpoor: None.
Alterations in Histone Acetylation in Diabetic Painful Neuropathy
Authors: CHATTOPADHYAY MUNMUN , THAKUR VIKRAM
Published: June 2018

Peripheral sensory neuropathy is one of the most common complications of diabetes. Accumulating evidence suggests that chronic low-grade inflammation is involved in the pathogenesis of the disease. We hypothesize that hyperglycemia causes changes in histone acetylation and release of inflammatory mediators in the peripheral nervous system of diabetic animals with painful neuropathy; therefore blocking this increase will prevent or delay the development of neuropathy. High mobility group box 1 (HMGB1), a nuclear protein released by injured and severely stressed cells, promotes cytokine release via histone acetylation and its interaction with the Toll-like receptor (TLR). In this study we investigated the changes in inflammatory mediators and histone modifications in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons as well as compared the changes in behavior with treatment. Type 2 diabetic (T2D) animals with pain were treated with HMGB1 inhibitor Glycyrrhizin (GLC) for 2 days a week for 3 weeks at 50 mg/kg I.P. injection 6 weeks after diabetes. T2D animals demonstrated significant changes in thermal hyperalgesia manifested by a decrease in withdrawal latency to heat, mechanical hyperalgesia as measured by the Randall Sellito method of paw pressure at 6 weeks after diabetes and also exhibited marked increases in HMGB1, IL1β, TLR4 and H3K9 acetylation as determined by the Western blot analysis and immunohistochemistry. We analyzed the T2D animals with treatment or without treatment at 3 weeks after treatment. Our results show that animals treated with GLC had significant decrease in thermal hyperalgesia along with changes in histone acetylation and expression of inflammatory mediators. This preliminary study suggests that HMGB1 and histone acetylation play an important role in the inflammatory aspect of the painful neuropathy in T1D animals and may provide a novel treatment approach for this difficult-to-treat complication of diabetes.

Disclosure

M. Chattopadhyay: None. V. Thakur: None.
Vestibular Deficits with Type 2 Diabetes Assayed by Motion Perception Thresholds
Authors: KING SUSAN , WEXLER DEBORAH J. , LEEDER TANIA , KARMALI FAISAL
Published: June 2018

Postural control depends on the coordinated action of many physiologic systems, and sensory feedback about body motion plays a critical role. Individuals with diabetes have increased postural sway and risk of falling. Many studies have implicated somatosensory neuropathy, but a vestibular role has also been suggested. To further explore vestibular deficits, we measured vestibular perceptual thresholds in subjects with type 2 diabetes. These thresholds quantify the smallest motion that an individual can reliably sense. We selected this approach because thresholds are sensitive to pathology, age and balance test performance. We tested four human subjects (ages 52-69, one female) who received a diagnosis of type 2 diabetes between 12 and 17 years before testing. Subjects were not screened for neuropathy or blood sugar control (HbA1c: 6.8, 9.1, 13 and 7.6). Thresholds were tested with the subject sitting in a chair on a moving platform with the head held firmly by a helmet. The platform repeatedly exposed subjects to small motions and subjects reported their perception (“press the button in your left hand if you thought you moved to the left and the button in your right hand if you thought you moved to the right.”) Motion amplitudes were adaptively adjusted to find the stimulus amplitude at which subjects were about 80% correct. Five motion conditions were tested. Subjects with diabetes had higher thresholds than published normative data (repeated-measures ANOVA, p=0.0059): +36% for yaw rotation, +15% for lateral translation, +220% for vertical translation, +13% for roll tilt (1 s motions), +3% for roll tilt (5 s motions). These results emphasize the need for further studies on the effects of diabetes on the vestibular system.

Disclosure

S. King: None. D.J. Wexler: None. T. Leeder: None. F. Karmali: Employee; Spouse/Partner; Biogen.
Effect of Sacubitril/Valsartan vs. Valsartan on Vascular and Neural Complications in Type 2 Diabetic Rats
Authors: YOREK MARK A.
Published: June 2018

Previously we had shown that a vasopeptidase inhibitor, combination drug containing angiotensin converting enzyme and neprilysin inhibitors, was an effective treatment for diabetes vascular and neural complications. However, once in clinical trials, side effects prevented further development of this class of drugs. This lead to development of sacubitril/valsartan, combination drug similar to vasopeptidase inhibitors containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be also an effective treatment for diabetic peripheral neuropathy. Using a rat model of type 2 diabetes, early and late intervention protocols, 4 and 12 weeks post hyperglycemia, respectively, rats were treated daily by gavage with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural endpoints. The results demonstrated that efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the late intervention protocol, treatment of the diabetic rats was initiated well after the appearance of vascular and neural complications. Sacubitril/valsartan treatment was found to not only slow progression of vascular and neural deficits but also stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities and sensitivity/regeneration of sensory nerves of the skin and cornea. These studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy and since it already has FDA approval for treatment of heart failure advancing this drug to clinical trials could proceed quickly.

Disclosure

M.A. Yorek: None.
Anemia as a Risk Factor for Diabetic Retinopathy (DR) with Special Reference to Nutritional Etiology
Authors: IDICULLA JYOTHI , NITHYANANDAM SUNEETHA , JOSEPH MARY , CHRISTEENA J.
Published: June 2018

Background: Anemia is increasingly recognized as a risk factor for DR. Nutritional anemia is a major cause of anemia in India. This study was undertaken to explore anemia as a risk factor for DR.

Methodology: Patients with type 2 diabetes admitted to the medical wards of a tertiary care hospital were enrolled into the study, in the absence of renal failure, pregnancy and ocular disorders unrelated to diabetes. Retinopathy was classified as per ETDRS classification. Anemia was defined and graded based on WHO guidelines. In patients with anemia, serum B12, serum iron, total iron binding capacity (TIBC) and percent saturation were assayed.

Results: A total of 170 patients were enrolled into the study (males 93, females 77). The mean age of the study group was 59 ± 12.30 (SD) years. Patients with DR (n=85) were classified as Group 1 and those without DR (n=85) as Group 2. The mean age of patients in Group 1 was 60.74 ± 13.00 (SD) years and that in Group 2 was 57.26 ± 11.39 (SD) years. The mean duration of diabetes was 12.40 ± 7.60 (SD) years for Group 1 and 6.64 ± 4.48 (SD) years for Group 2.

The mean Hb of patients in Group 1 was 10.40 ± 0.25 (SD) gm% and in Group 2 was 12.70 ± 0.18 (SD) gm% (p=0.001). Within these groupings, 67 patients had anemia (56 in Group 1, 11 in Group 2). There was a significant association between anemia and DR (p=0.001) and a trend towards association between increasing grades of anemia and severity of DR (p=0.06). In Group 1, among patients with anemia, 28 (50%) patients had nutritional anemia (iron: 24, B12: 3 and dual: 1). On logistic regression analysis, anemia and duration of diabetes emerged as predictors of DR.

Discussion: Anemia in patients with diabetes may be multifactorial in etiology. While metformin therapy, albuminuria and reduced renal function are implicated, vegetarian diet is a major contributor for nutritional anemia. Regular monitoring of Hb and treatment with supplements or dietary modifications may reduce occurrence and arrest progression of DR.

Disclosure

J. Idiculla: None. S. Nithyanandam: None. M. Joseph: None. C. J.: None.
Test Strip–Positive Proteinuria and Its Combination with Low eGFR Are Predictive of Treatment-Required Eye Diseases in Japanese Patients with Diabetes Mellitus
Authors: YAMAMOTO MASAHIKO , FUJIHARA KAZUYA , OSAWA TAEKO , HARADA MAYUKO , ISHIZAWA MASAHIRO , ISHIGURO HAJIME , SUZUKI HIROSHI , SEIDA HIROYASU , YAMANAKA NAUTA , MATSUBAYASHI YASUHIRO , SONE HIROHITO
Published: June 2018

Proteinuria or low eGFR was separately shown to be associated with the development of retinopathy in patients with diabetes. However, it remains unclear whether semi-quantitatively assessed proteinuria by test strips either combined or not combined with low eGFR is predictive of incident retinopathy, especially in its advanced stages.To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that included 6,100 participants (1,074 women, mean age 49.3 y, HbA1c 6.9%) classified as having diabetes mellitus or treatment-required diabetic eye diseases (TRDED) during an 8-y period. Urinary protein was assessed by test strip and a result of ≥1+ indicated proteinuria, which reportedly corresponds to a urine protein concentration of ≥30 mg/dL. Multivariate Cox regression model was used to identify predictors of TRDED. During the study period, 147 patients developed TRDED (4.5/1000 person-years). Cox analysis showed that proteinuria was a significant and independent predictor of TRDED but not the serum creatinine level. Hazard ratios (HRs) for proteinuria, low eGFR (defined as <45 mL/min/1.73m2) and HbA1c (per 1% increment) for incident TRDED were 2.37(95% CI, 1.59-3.53), 3.95(1.56-10.01), and 1.73(1.55-1.94), respectively. Compared with participants with neither proteinuria nor low eGFR, those with proteinuria but not low eGFR and those with both proteinuria and low eGFR had 2.21 (1.46-3.34) and 13.82(5.50-34.71), respectively, times higher risk for TRDED. These results implied that proteinuria worked synergistically with low eGFR but the interaction was not statistically significant. These findings demonstrated that semi-quantitatively assessed proteinuria using test strips is quick and useful for assessing the risk of development of advanced retinopathy especially in combination with reduced eGFR.

Disclosure

M. Yamamoto: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Ishizawa: None. H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. H. Suzuki: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: 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..
High-Fat Diet Induces Mitochondrial Dysfunction in Saphenous Nerve Axons—A Study by Confocal Microscopy In Vivo
Authors: SAJIC MARIJA , KANHAI ANISH , DENTONI GIACOMO , VARATHARAJAH SHARLINI , HINDER LUCY M. , RUMORA AMY , FELDMAN EVA L. , SMITH KENNETH
Published: June 2018

Diabetic peripheral neuropathy (DPN) is a common, progressive and irreversible complication of diabetes (DM). Glucose regulation has no effect on the development and/or progression of the disease in type 2 DM and so, as the prevalence of DM increases, there is a growing unmet need for a mechanism-based therapy.

We have examined the effect of high fat diet (HFD, 60% kcal fat) on axonal mitochondrial membrane potential and intra-axonal Ca2+ concentration [Ca2+]i in C56Bl/6 mice, in vivo, using confocal microscopy. The HFD resulted in obesity, hyperglycaemia and glucose intolerance. Mitochondria within saphenous nerve axons of mice fed a HFD for 16 or 36 weeks were significantly depolarised compared with those in mice fed a control diet. Furthermore, HFD mitochondria did not depolarise in response to high frequency electrical stimulation, in contrast to controls where depolarisation is associated with the increased energy demand of sustained impulse conduction. Confocal microscopy revealed that the number of mobile mitochondria was significantly greater in electrically active axons after 16 weeks of HFD, compared with controls, whereas after 36 weeks the number was significantly lower. Histologically, these changes were accompanied by significantly increased labelling for the mitochondrial biogenesis marker PGC1α in neuronal cell bodies at 16 weeks, but a reduction at 36 weeks, consistent with exhaustion of compensatory mechanisms activated early in the disease course. Interestingly, we found that [Ca2+]i was decreased in mice fed a HFD.

We conclude that a HFD impairs axonal mitochondrial function early in the course of type 2 MD. Impaired ATP production, especially during sustained impulse activity, may be a mechanism in the development of DPN.

Disclosure

M. Sajic: None. A. Kanhai: None. G. Dentoni: None. S. Varatharajah: None. L.M. Hinder: None. A. Rumora: None. E.L. Feldman: None. K. Smith: None.
Extreme Hyperglycemia Causes Vascular Hypoperfusion at Optic Nerve Head in Diabetic Patients (DM)
Authors: MITSUMATSU TAKAKO , YAGI FUMIHIKO , KONDO YUKO , ANRAKU AYAKO , OKAHATA SUMIE , SAKAMOTO KENTARO , TOMITA GOJI , SHIBA TERUO
Published: June 2018

Background: OCT angiography (OCTA) and laser speckle flowgraphy (LSFG) are novel and noninvasive imaging modalities which could evaluate fundus blood flow quantitatively. However, the role of OCTA and LSFG as diagnostic tools has not been widely investigated. Previous reports indicated that NO, reduced by hyperglycemia, exerts a key role for the autoregulation of retinal blood flow. We designed this study to evaluate the retinal blood flow by OCTA and LSFG in hyperglycemic DM.

Method: 10 patients with extreme hyperglycemia at our outpatient clinic (FPG>250mg/dL, or casual PG>350mg/dL, age 58±5, 7 males, HbA1c 11.1±0.5%) and 32 healthy volunteers (age 48±2, 17 males) were included. Vascular density was calculated using OCTA. LSFG measured relative blood velocity (mean blur rate: MBR) in the optic nerve head (ONH). MBR-A (the mean of all area), MBR-V (the vessel mean) and MBR-T (the tissue mean) were analyzed.

Result: OCTA revealed no difference between two groups in the vascular density at macula (47.37±1.14% for DM and 47.44±0.67% for NDM) and a tendency of decrease in the diabetic vascular density at ONH (40.14±3.56% for DM and 42.48±1.25% for NDM) without statistical significance. With LSFG, MBR-A and MBR-T did not exhibit significant differences, while MBR-V significantly decreased in DM compared to the healthy (42.85±2.05% for DM, 49.25±1.34% for NDM, p = 0.025).

Discussion: Our results demonstrated that vascular hypoperfusion at ONH was associated with extreme hyperglycemia in DM with tendency to decrease in vascular density. It is generally supposed that the retinal blood flow decreases in DM and acute hyperglycemia. In DM actually presented physiological changes in the retina. Besides, there is a report that autoregulation of blood flow in the ONH is disrupted in diabetic rabbits, as well as in healthy ones with uncoupled gap junctions. It is possible that the similar mechanisms are involved in ONH blood flow decrease observed in this study.

Disclosure

T. Mitsumatsu: None. F. Yagi: None. Y. Kondo: None. A. Anraku: None. S. Okahata: None. K. Sakamoto: None. G. Tomita: None. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.
Diabetic Retinopathy Grade as a Predictive Marker of Stroke and Mortality in Type 2 Diabetes Mellitus Patients with Amputations—Seven-Year Follow-Up
Authors: SHAH KIRAN , SUNDARAM NATARAJAN , RAUT ABHAY A. , RAO KARTHIK , WADHWA NAVNEET
Published: June 2018

We explored the association of grade of Diabetic Retinopathy (DR) with amputations in 2500, T2DM patients (males 1295, females 1205) who were screened for DR in year 2010, underwent Mini Mental State Examination (MMSE) for cognitive decline, and followed-up for 7 years, till 2017. Cohort was stratified into tertiles based on demographics, grade of DR and type of amputation. DR was observed in 56% patients [Non Proliferative DR (NPDR) n=962, 38%; Proliferative DR (PDR) n=438, 18%] demonstrating a strong association with all types of amputations (p<0.00001), with highest association for amputation of both limbs (n=640) (p<0.00001). Significant association was observed with comorbidities of hypertension, dyslipidemia and hyperhomocysteinemia (p<0.00001). The age tertile of 40-60 years with amputations reported highest number of NPDR and PDR, n=561 and n=263 respectively; highest tertile of HbA1c (>15%) and duration of diabetes (>15 years) corroborated with the high incidence of NPDR (n=421, 70%) and (n=449, 70%), respectively (p<0.00001). MMSE scores revealed a moderate to severe cognitive decline, NPDR (n=453) > PDR (n=231) (p<0.00001). Seven years follow-up revealed high incidence of new amputations (n=610; NPDR n= 372, PDR n=238) (p<0.00001). 637 patients with DR (NPDR, n= 515; PDR n=122) developed stroke (p<0.00001). Two or more fundus lesions increased the propensity of stroke and mortality. The mortality in patients with DR was 33.76% (n=844) of which 282 patients died due to stroke (p<0.00001). Overall, ischemic stroke was the leading cause of mortality in 83.82% patients, with lacunar stroke (n=340) as the commonest anatomical sub-type of stroke (p<0.00001). Patients with DR, especially with NPDR should be managed intensively to prevent fatal cerebrovascular events. Diagnosis of DR in patients who underwent amputations, can be used as a stratified model in association with comorbidities to predict stroke and the mortality.

Disclosure

K. Shah: None. N. Sundaram: None. A.A. Raut: None. K. Rao: None. N. Wadhwa: None.
Identification of Early Biochemical Changes in the Diabetic Retina Using an Unbiased Proteomics Approach
Authors: WEBER SARAH R. , ZHAO YUANJUN , BARBER ALISTAIR J. , HERNÁNDEZ CRISTINA , SIMÓ-SERVAT OLGA , GARDNER THOMAS W. , SIMÓ RAFAEL , SUNDSTROM JEFFREY M.
Published: June 2018

Diabetic retinopathy (DR) remains a leading cause of blindness in developed countries. Current treatments target late stages of DR when vision has already been affected. The current study used an unbiased proteomic approach to gain a better understanding of early DR pathogenesis prior to clinically detectable microvascular lesions. During these early DR stages, neurodegeneration occurs and is marked by glial activation throughout the neuroretina. As glial activation increases, glial fibrillary acidic protein (GFAP) is upregulated and can be visualized histologically. Postmortem retinas from diabetic donors were divided according to the presence of abundant (n=5) or minimal (n=5) GFAP immunoreactivity and were compared to retinas from nondiabetic donors with no known ocular pathologies (n=10). Retinal lysates from each group were pooled and run on an SDS-PAGE gel. Bands were analyzed sequentially by LC/MS using an Orbitrap Mass Spectrometer. A total of 2,190 proteins were identified across all groups. Pathway activation analysis was performed via Ingenuity Pathway Analysis. Pathways were subsequently grouped into broader functional categories based on the existing literature. Differential pathway analysis revealed significant differences between diabetic retinas with abundant vs. minimal GFAP immunoreactivity. Of particular interest are those pathways that function in both neuroprotective/neurodegenerative and angiogenic pathways, as they may represent a link between early and late diseases stages. Antioxidant/anti-inflammatory pathways, cell survival and apoptosis pathways, and autophagy also appear to play a role. Future studies will be required to confirm and extend these findings. Close analysis of these signaling changes may permit the development of preventive and interventional strategies for use in the early stages of DR, before overt microvascular damage or vision loss occurs.

Disclosure

S.R. Weber: None. Y. Zhao: None. A.J. Barber: None. C. Hern ndez: None. O. Simó-Servat: None. T.W. Gardner: Research Support; Self; Novo Nordisk A/S. R. Simó: None. J.M. Sundstrom: None.