bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&gt;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 &lt;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&gt;250mg/dL, or casual PG&gt;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&lt;0.00001), with highest association for amputation of both limbs (n=640) (p&lt;0.00001). Significant association was observed with comorbidities of hypertension, dyslipidemia and hyperhomocysteinemia (p&lt;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 (&gt;15%) and duration of diabetes (&gt;15 years) corroborated with the high incidence of NPDR (n=421, 70%) and (n=449, 70%), respectively (p&lt;0.00001). MMSE scores revealed a moderate to severe cognitive decline, NPDR (n=453) &gt; PDR (n=231) (p&lt;0.00001). Seven years follow-up revealed high incidence of new amputations (n=610; NPDR n= 372, PDR n=238) (p&lt;0.00001). 637 patients with DR (NPDR, n= 515; PDR n=122) developed stroke (p&lt;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&lt;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&lt;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.