bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced Glycation End Products (AGEs)-Role in Development and Progression of Kidney Disease in Type 1 Diabetes in DCCT/EDIC
Authors: BEISSWENGER PAUL J. , BEBU IONUT , HOWELL SCOTT , LACHIN JOHN
Published: June 2018

Introduction: Early diagnostic measures that predict development of complications in individuals with type 1 diabetes would be clinically relevant. Our goal was to determine if glycative and oxidative stress biomarker levels are independent risk factors in the development of advanced diabetic kidney disease (DKD) prior to detection of overt disease in the DCCT and follow-up EDIC.

Methods: Using a case-cohort design, we measured plasma and urine levels of 5 Advanced Glycation (AGEs) and 2 oxidation end-products by LC-MS/MS in 109 DKD cases (>40% eGFR decline from baseline confirmed on two consecutive visits) and 350 non-progressor controls. Sampling, done at study baseline and three other time points during DCCT and early EDIC prior to later GFR decline, was analyzed by Cox models adjusted for risk covariates (Age, HbA1c, BMI, HDL, LDL, Sex, SBP, and DBP) to assess the association between the AGEs and risk of DKD.

Results: Significant associations between GFR decline and plasma biomarkers occurred for three specific AGEs: Carboxymethyllysine (CML, p=0.003), 3-deoxyglucosone hydroimidazolone (3DG-H, p=0.0007), and carboxyethyllysine (CEL, p=0.021) using multi-variate adjusted analyses. Prediction by AGEs was independent of HbA1c at the same time points. Urinary AGEs were not predictive. Calculation of c-statistics also showed that plasma 3DG-H significantly increased predictive value for progression of DKD above traditional risk factors.

Conclusions: Two predictive AGEs, CML and CEL, previously shown to predict DKD

(Diabetes Care, 36, 3234-9, 2013) were found to independently identify progression in DCCT/EDIC. DKD prediction by 3DG-H also confirms prior data showing that

DKD is associated with increases in its precursor, 3-deoxyglucosone. Early identification of those at high risk of progression to DKD by measuring specific AGEs may provide predictive power above traditional risk factors and allow the institution of preventive therapies.

Disclosure

P.J. Beisswenger: Employee; Self; PreventAGE Health Care, LLC.. I. Bebu: None. S. Howell: None. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation.
Significant Association of TGF-Beta1 C-T Transition in Codon 10 of the Gene with Posttransplant Diabetes
Authors: JAHROMI MOHAMED M.J.
Published: June 2018

Post-transplant Diabetes (PTD) is a serious complication of transplantation. We hypothesize that transforming growth factor-beta (TGF-β1), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of PTD.

Our purpose was to examine the functional polymorphism within the TGF-β1 gene in codons 10 of promoter region of the gene association with Kuwaiti PTD post kidney transplantation.

Method: We conducted a large case-control study using cases with kidney transplantation who have developed diabetes post transplantation, 152. Controls were renal recipient patients who did not present diabetes a year post-kidney transplantation, 150. Neither cases nor controls had previous history of diabetes. Genotyping was by amplification refractory mutation system polymerase chain reaction. Fisher’s exact test was used to analyze the data. Our diagnosis criteria incorporated with the international consensus guidelines regarding the definition of PTD.

Results: There was a significant difference in the frequency of the TGF-β1 codon 10 genotype in the PTD cases compared with controls. There were neither gender nor age at onset specificity statistical differences among the PTD cohort compared to non-PTD cohort. Individual with the TT (TGF- β1 gene in codons 10) was strongly susceptible to PTD (p=0.001); whereas, the CC of the same gene showed protection against PTD progression. Although T allele was strongly associated with progression of PTD, p=1.4 * 10-5, it could not exert its impact during CT genotype, p=0.6.

Discussion: In our study the TGF-β1 codon 10 polymorphism is associated with PTD post-kidney transplantation. Variation in this gene may contribute to the genetic predisposition to this complication in kidney transplantation. Further subgroup analyses are underway to find out if there is any correlation between bone mass indexes, familial history of diabetes, hepatitis C infection among both cohorts.

Disclosure

M.M.J. Jahromi: None.
SAD-A Promotes Pancreatic ß-Cell Proliferation by Regulating ß-Cell Cycle as a Downstream Target of mTORC1 Signaling
Authors: NIE JIA , MUSI NICOLAS , SHI YUGUANG
Published: June 2018

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction, which leads to the depletion of β-cell mass. Understanding the molecular mechanisms driving islet β-cell dysfunction is paramount for developing therapies to increase β-cell function. The mammalian target of rapamycin complex 1 (mTORC1) plays a key role in regulating β-cell function by integrating growth factors and mitogens to direct cell cycle and survival; yet, mechanistically this process is not fully understood. Synapses of amphids defective protein kinase A (SAD-A) is a member of AMP-activated protein kinase (AMPK)-related family kinases, with high expression in the pancreas. My earlier work demonstrated that SAD-A is a β-cell specific mediator of insulin secretion and islet β-cell size. Furthermore, glucose dramatically stimulated SAD-A protein translation in islets that was potently inhibited by rapamycin, an inhibitor of mTORC1. My recent preliminary studies showed that 1) SAD-A overexpression increases β-cell proliferation in the MIN6 β-cell line and islets; 2) Ablation of SAD-A in pancreas of mice (pSADKO) promotes β-cell apoptosis and attenuates compensatory islet growth in obese mice; 3) SAD-A depletion in the pancreas increases mRNA expression of cyclin D2 in islets of pSADKO mice. Based on these observations, I hypothesize that SAD-A promotes pancreatic β-cell proliferation by regulating β-cell cycle as a downstream target of mTORC1 signaling.

Disclosure

J. Nie: None. N. Musi: None. Y. Shi: None.
Elevated Baseline Glomerular Filtration Rate Is Associated with a More Rapid Decline in Chinese Patients with Type 2 Diabetes with Normoalbuminuria
Authors: WAN JING , CHEN HAIBING
Published: June 2018

Aims: To investigate the association between estimated baseline glomerular filtration rate (GFR) and renal function decline in Chinese patients with type 2 diabetes with normoalbuminuria.

Main Methods: A longitudinal study was performed on 368 Chinese patients with type 2 diabetes whose estimated GFR (eGFR) was determined at baseline with a 3.12-year follow-up. The patients were divided into three groups according to baseline eGFR (mL/min/1.73 m2): G1 (eGFR ≥ 120), G2 (90 ≤ eGFR < 120), G3 (60 ≤ eGFR < 90). The association between baseline eGFR and the renal function decline rate was assessed using binary logistic regression. Decliners were defined as a negative change ≥ −3.3% per year.

Key Findings: Among G1 patients, the decliners were younger, had a higher baseline eGFR, shorter duration of diabetes, and lower diastolic blood pressure, compared with non-decliners. The G1 eGFR decline slope (% per year) was significantly higher than that in G2 and G3 patients. The percentage of decliners among G1 patients was significantly higher than that among G2 and G3 patients. Baseline eGFR group, HbA1c, hypertension history, and diastolic blood pressure were independent risk factors for progressive renal decline. Patients in the decliners group were more likely to progress to microalbuminuria and macroalbuminuria compared with those in the non-decliners group; however, the albuminruria progression percentage was not significantly different among G1, G2, and G3 decliners.

Significance: Patients with baseline eGFR ≥ 120 mL/min/1.73 m2 had a higher risk for more rapid eGFR decline among Chinese patients with type 2 diabetes with nomalbuminuria.

Disclosure

J. Wan: None. H. Chen: None.
Wider Peripheral Retinal Vessel Predicts Renal Dysfunction in Adolescents with Type 1 Diabetes
Authors: VELAYUTHAM VALLIMAYIL , CRAIG MARIA E. , LIEW GERALD , WONG TIEN Y. , JENKINS ALICIA , DONAGHUE KIM C.
Published: June 2018

Objective: The renal and retinal vasculature shares similar pathophysiologic features. Retinal vasculature changes, even without typical retinopathy, can predict microvascular disease in type 1 diabetes (T1D). We hypothesise that peripheral retinal vessels are wider and predict incident renal dysfunction in adolescents with T1D.

Research Design and Methods: In this longitudinal study of 441 retinopathy free and normoalbuminuric adolescents with T1D retinal photographs were measured by computer software (Singapore I Vessel Assessment) with vessel calibres summarized in the standard “central zone” [Central Retinal Arterial and venular equivalents (CRAE and CRVE respectively)] and “extended zone” [Mean width of arterioles and venules (MWa and MWv)]. Retinal vascular geometry including length diameter ratio (LDR) and simple tortuosity (ST) was quantified. Generalised estimating equation was used to explore associations between vessel calibres, LDR, ST and incident renal dysfunction. Incident renal dysfunction was defined as Albumin excretion rate (AER) > 7.5µg/min, with results expressed as odds ratio (OR) and 95% CI.

Results: Mean ± SD age was 14.1±1.5 year, median diabetes duration 4.8 year [IQR 3.3, 7.5], A1C 8.4 ±1.3% (IFCC 68 ±14.2mmol/mol). Incident renal dysfunction occurred in 186/441 (42%) over a median 4 year follow-up. Wider MWa and MWv (4th vs. 1st quartile), higher LDR (4th vs. 1st -3rd quartile) and lower ST (1st vs. 2nd-4th quartile) were associated with renal dysfunction: MWa OR 2.0 (1.2, 3.5); MWv 2.2 (1.3, 3.6), LDRa 1.5(1.07, 2.08), LDRv 1.4 (1.02, 1.9), STa 1.5(1.1, 2.2), STv 1.4 (1.1, 1.8) after adjusting for covariates (A1C, diabetes duration, gender, height and blood pressure). Central vessels were not related to renal dysfunction: CRAE: 0.9 (0.5, 1.5); CRVE: 1.3 (0.8, 2.1), all p<0.05.

Conclusions: We speculate that small vessel dilatation and tortuosity are modulators of diabetic renal disease.

Disclosure

V. Velayutham: None. M.E. Craig: None. G. Liew: None. T.Y. Wong: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. K.C. Donaghue: None.
Superior Glycaemic Control Effects with Dulaglutide (Dula), a Once-Weekly Glucagon-Like Peptide Receptor-Antagonist (GLP-1RA), to Liraglutide (Lira) in Diabetic Hemodialysis Patients Assessed by Continuous Glucose Monitoring (CGM)
Authors: FUNAKOSHI SATOSHI , HAYASHIDA MASATOSHI , SAWASE KENJI , HASHIGUCHI JYUNICHIRO , ETOH RICA , MORI YUTAKA , UTSUNOMIYA KAZUNORI , HARADA TAKASHI
Published: June 2018

Objective: Dulaglutide (Dula) is a novel, long-acting glucagon-like peptide receptor antagonist (GLP-1RA) used in the treatment of T2D patients with or without renal impairment. In this study we compared by using CGM once-daily Lira and once-weekly Dula, each combined with various doses of insulin degludec (IDeg).

Methods: Eighteen adult HD patients with T2D (men/women, 11/7) who had been treated with once-daily Lira (0.6-0.9 mg) combined with daily IDeg (5-26 units) (Lira + IDeg) were switched to once-weekly Dula 0.75 mg combined with daily IDeg (Dula + IDeg). The dose of IDeg stayed the same in each patoent, and all patients were monitored for PG control by CGM, and the mean amplitude of glycaemic excursions (MAGE) was calculated before and after switching.

Results: A significant reduction was observed in MAGE with Dula + IDeg 4 weeks after switching to Lira + IDeg both in on-HD days (122.3±38.3 mg/dL vs. 66.7±22.1 mg/dL, p<0.001) and off-HD days (88.8±24.1 mg/dL vs. 42.6±20.3 mg/dL, p<0.001). No episode of hypoglycemia, and 4 out of 18 patients reported mild gastrointestinal adverse events with Dula treatment, but were thought to be transient.

Conclusions: Thus, Dula appears to be potentially superior to Lira in reducing PG fluctuations in HD patients with T2D receiving IDeg.

Disclosure

S. Funakoshi: None. M. Hayashida: None. K. Sawase: None. J. Hashiguchi: None. R. Etoh: None. Y. Mori: None. K. Utsunomiya: None. T. Harada: None.
Large-Scale DNA Methylation Profiling of Human Diabetic Peripheral Neuropathy in Subjects with Type 2 Diabetes Mellitus
Authors: GUO KAI , ELZINGA SARAH , EID STEPHANIE , FIGUEROA-ROMERO CLAUDIA , MCGREGOR BRETT A. , DE ANDA-JÁUREGUI GUILLERMO , PACUT CRYSTAL , FELDMAN EVA L. , HUR JUNGUK
Published: June 2018

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Emerging evidence suggests that aberrant DNA methylation may play a critical role in the pathogenesis of diabetic complications. Yet, its involvement in DPN is not fully characterized. In this study, we performed a large-scale genome-wide methylation profiling of sural nerve samples obtained from subjects with type 2 diabetes mellitus (T2DM) using Reduced Representation Bisulfite Sequencing (RRBS). A total of 78 samples were sequenced and mapped to the human reference genome. Differential analysis was performed on two groups, identified by our previous transcriptomic analysis of the same samples, which showed significantly different HbA1c levels: Group 1 (=8.5%±1.6%) and Group 2 (<7.0%±1.4%). Using MethylKit R package, with an adjusted p-value < 0.01 and 15% methylation change as significance cutoffs, we identified 2,066 differentially methylated CpG sites and 440 regions, corresponding to 1,519 and 429 unique differentially methylated genes (DMGs). These genes were highly enriched in biological processes related to nervous system development, neuron fate specification and neuron differentiation. KEGG pathway enrichment analysis demonstrated that genes involved in cancer, ECM-receptor interaction and axon guidance pathways were significantly differentially methylated between the two groups, highlighting the importance of DNA methylation in DPN pathogenesis.

In summary, we demonstrate that type 2 diabetic patients with peripheral neuropathy and high HbA1c show distinct variations in sural nerve methylome, suggesting that DNA methylation and DPN are associated and that these associations are at least in part HbA1c-dependent. Our results provide new insights into the role of HbA1c in epigenetic variation, and identify candidate genes relevant to the pathogenesis of DPN in human sural nerves of subjects with T2DM.

Disclosure

K. Guo: None. S. Elzinga: None. S. Eid: None. C. Figueroa-Romero: None. B.A. McGregor: None. G. de Anda-Jáuregui: None. C. Pacut: None. E.L. Feldman: None. J. Hur: None.
The Effect and Molecular Mechanism of Pancreatic Kallikrein in Painful Diabetic Neuropathy Based on CX3CL1/CX3CR1 Pathway
Authors: XIANG XU , HUI JIN , LAN XU
Published: June 2018

Objective: This study evaluated the effect and molecular mechanism of pancreatic kallikrein (PKK) in improving mechanical allodynia in STZ-induced C57 mice, an animal model of type 1 diabetes, based on CX3CL1/CX3CR1 pathway.

Methods: Male C57 mice, weighing 20-23g, were fasted overnight for 12h (20:00-8:00 next day) and injected with STZ (100mg/kg) to induce type 1 diabetes model. 24 diabetic mice were divided into PKK-1 group (PKK 6u/kg/d, ip, n=8), PKK-2 group (PKK 60u/kg/d, ip, n=8) and DNS group (0.9% NaCl 0.15ml/d, ip, n=8). Eight normal C57 mice were injected with PKK (6u/kg/d, ip) as the NPK group. The mechanical allodynia of each group was evaluated from 1h to 5 weeks after PKK injection. The expression of CX3CL1/CX3CR1 at the lumbar spinal cord was also measured at the 5th week using Western Blot analysis.

Results: 1) More than 80% of C57 mice were tested FBG>11.1mmol/L at the 7th day after STZ injection and divided into the diabetic group. 2) Compared with the normal mice, we showed that the diabetic mice developed mechanical allodynia at the early stage of diabetes. Meanwhile, The intraperitoneal injection of PKK could decrease such mechanical allodynia in a dose-independent manner. 3) Compared with the DNS group, the intraperitoneal injection of PKK significantly attenuated the expression of CX3CL1/CX3CR1 at the dorsal horn.

Conclusion: Our previous study indicated that the CX3CL1/CX3CR1 pathway played an important role in the progress of painful diabetic neuropathy. These results showed that intraperitonea injection of PKK significantly decreased mechanical allodynia and attenuated the expression of CX3CL1/CX3CR1 at the dorsal horn. This study may contribute to a better understanding of the therapeutic effect and mechanism of PKK on painful diabetic neuropathy.

Disclosure

X. Xiang: None. J. Hui: None. X. Lan: None.
Effect of Diabetes on Peripheral Neuropathy in an Adult U.S. Population
Authors: OLAIYA MUIDEEN T. , HANSON ROBERT L. , KAVENA KAREN G. , SINHA MADHUMITA , NELSON ROBERT , KNOWLER WILLIAM C.
Published: June 2018

Background: Peripheral neuropathy (PN) is a diabetes complication but also occurs without diabetes. The effect of diabetes on PN is not well quantified.

Methods: Subjects ≥ 18 years old had a health exam, including an OGTT for diabetes. Distal sensory PN, assessed using 3 graded Semmes Weinstein monofilaments, was classified as none (felt all filaments), latent (insensate to 1 g filament), clinical [mild (insensate to 10 g) or severe (75 g)]. Associations with PN were assessed using ordinal logistic regression assuming equal coefficients across classes of PN.

Results: In 1564 subjects (median age 42 years, 50% women, 58% American Indians), PN was latent or worse in 68.9% (95% CI 66.7-71.2), clinical in 11.2% (CI 9.7-12.9), and associated with male sex, older age, and worse glucose regulation (Figure). Age-sex-race-adjusted prevalence was greater in people with than without diabetes (odds ratio; OR 2.2, CI 1.7-2.8), and in those with diabetes, with longer diabetes duration (OR 1.9 per decade, CI 1.5-2.4) or albuminuria, A/C ≥30 mg/g (OR 2.4, CI 1.6-3.6). In those without clinical PN, latent PN was associated with diabetes (OR 1.7, CI 1.2-2.2), longer diabetes duration (OR 2.2 per decade, CI 1.4-3.5) and albuminuria (OR 1.8, CI 1.0-3.2).

Conclusions: Although PN is common in people with no diabetes, diabetes greatly increases its risk. Use of 3 monofilaments rather than 1 adds precision and allows detection of latent PN.

Disclosure

M.T. Olaiya: None. R.L. Hanson: None. K.G. Kavena: None. M. Sinha: None. R. Nelson: None. W.C. Knowler: None.
Sensory Cutoff Value for Predicting Postural Instability in People with Peripheral Neuropathy Secondary to Diabetes
Authors: AUNG NAY LINN , MEARDON STACEY A. , LIN CHIA-CHENG , TANENBERG ROBERT J.
Published: June 2018

People with peripheral neuropathy (PN) secondary to diabetes have higher risks of falls due to loss of the somatosensation of the feet. The purpose of this study was to investigate the cutoff values of the vibration threshold and the monofilament test to predict postural instability. Ten healthy younger adults, ten healthy older adults and ten people with PN secondary to diabetes were recruited in this study. A handheld bio-thesiometer and a set of monofilaments were used to measure the vibration threshold (VT) and tactile sensitivity (TS), respectively. VT and TS were measured at six different sites on the plantar surface, including big toe, 1st metatarsus, little toe, 5th metatarsus, middle arch, and calcaneus (heel), plus the lateral and medial malleoli. Subjects also underwent a Sensory Organization Test (SOT) to identify postural instability, defined as equilibrium scores less than age matched norms. Linear regression was used to determine which site(s) was able to predict the balance test performance. Receiver operating characteristic curves were used to compute the VT and TS cutoff values associated with postural instability. A cutoff value of 10V for lateral malleolus VT was able to predict postural abnormality with 100% Sensitivity and 54.5% Specificity. A cutoff value of 3.61 for middle arch TS was able to predict postural abnormality with 100% Sensitivity and 86.4% Specificity. Postural instability appears earlier than the current recommended clinical cutoff values for peripheral neuropathy (25V for VT and 5.07 for TS). Although current cutoff values of the vibration threshold and the monofilament test are useful for detecting a propensity for neuropathic foot ulcer, they may not be adequate for detecting early postural instability. Fall prevention strategies may be needed early in the progression of PN.

Disclosure

N. Aung: None. S.A. Meardon: None. C. Lin: None. R.J. Tanenberg: None.
OPTIFAST® Medical Weight Loss Program—Outcomes in the Endocrinology Clinics at UPMC
Authors: DETOYA KARLA B. , HAN KATRINA , REGISTER BRENNAN R. , ROMETO DAVID A.
Published: June 2018

Background: The OPTIFAST® program at UPMC is a medically supervised program using very low calorie diet from Nestle products. It focuses on nutrition and lifestyle counseling, and transitioning to a low glycemic load diet to sustain glycemic benefits of weight loss. We evaluated the impact of our program on weight reduction in a 3-year period at UPMC clinics, and secondary parameters defining cardiovascular risk factors.

Methods: Patients were divided into Completer (C) and Non-Completer (NC) cohorts. For the C-group, HBA1C for diabetics, lipid profiles and systolic blood pressure (SBP) were compared at baseline and at >5 months. Adjusting for weight loss, effect of DM, BP and lipid-lowering drugs on HBA1C, SBP and lipid profile, respectively, was also evaluated.

Results: A total of 215 patients (mean age=49.63, 69% female) had mean baseline and end weights of 263.7 and 222.8 pounds respectively, with mean 14.04% weight loss (p<0.0001). 59% completed the program with mean 19.52% weight loss (p<0.0001). For the NC-group, weight difference from baseline was not significant.

Among diabetics, there was decrease in HBA1C (7.8% to 6%, p<0.0001), with a decrease in the no. of insulin units/day (71.4 to 34.6 units, p=0.015), but no significant decrease in the no. of noninsulin drugs from baseline to >5 months. There was a decrease in mean baseline to end SBP (139.3 to 122.5 mmHg, p=0.0325), and no. of BP meds (1.9 to 1.2, p<0.0001). There was a decrease in mean baseline to end values of: total cholesterol (TC) (192.4 to 140.7 mg/dl, p<0.0001), LDL (104.3 to 84.59 mg/dl, p=0.02) and triglycerides (TG) (209.2 to 111.9 mg/dl, p<0.0001). The increase in baseline to end HDL and difference in lipid lowering drugs were not significant. Adjusting for weight loss, medications had no significant association on trends of HBA1C, SBP and lipid profile.

Conclusions: Among completers, the medically supervised VLCD program at UPMC promotes significant weight loss, glycemic and SBP improvement, and lowering of TC, LDL and TG for over >5 months.

Disclosure

K.B. Detoya: None. K. Han: None. B.R. Register: None. D.A. Rometo: None.
Eyekon Is a Novel Diagnostic Tool for Diabetic Neuropathy
Authors: NASR MOUFIDA BEN , GIULIANI ELENA , D'ADDIO FRANCESCA , MAESTRONI ANNA , USUELLI VERA , MARZOLI STEFANIA BIANCHI , FIORINA PAOLO
Published: June 2018

Diabetic neuropathy (DN) is a major complication of diabetes, causing more than 50% of all hospital accesses related to type 1 diabetes (T1D). However, diagnostic criteria are not yet standardized, and diagnosis also of symptomatic DN is often underestimated. Given the medical need for an accurate non-invasive diagnostic tool, we developed a test based on tracking eye movement for early detection of DN called Eykon. SRLab -Tobii TX300 Eye tracker®, an eye-tracking device, is coupled with a series of screens on a computer to test the velocity and accuracy of gaze movement in healthy controls (CTRL, n=30), T1D patients without neuropathy (T1D, n=19) and T1D patients with neuropathy (T1D-N, n=14). The screens are divided in 5 classes: Resistance, Wideness, Pursuit, Velocity and OKN. They aim to evaluate both smooth and saccadic movement in different directions. We evaluated a total of 483 parameters and observed that 27 (5.6%) were altered in T1D patients without signs of advanced DN at the electromyography as compared to CTRL, while 29 (6%) were altered in T1D-N patients, for a total of 56 (11.6%) significantly altered parameters (T1D vs. CTRL). Our pilot study demonstrated the feasibility of this non-invasive exam and its ability to early detect DN, despite the limitations of a small number of subjects.

Disclosure

M. Ben Nasr: None. E. Giuliani: None. F. D'Addio: None. A. Maestroni: None. V. Usuelli: None. S. Bianchi Marzoli: None. P. Fiorina: None.
Exercise Training to Target Gait Unsteadiness in People with Diabetes
Authors: BROWN STEVEN J. , BOULTON ANDREW J. , BOWLING FRANK L. , ESQ.  , REEVES NEIL D.
Published: June 2018

Balance impairment and an associated high fall rate in people with diabetes is common, and a huge burden to quality of life and healthcare systems. Causes of impaired balance are commonly attributed to both sensory and motor deficits, which includes impaired muscle strength and function. This study investigated the effects of resistance exercise training on balance control during walking over level ground and on stairs. Ten DM people (age: 62 years, BMI: 29kg/m2, VPT: 9V) and 6 DM people with DPN (age: 59 years, BMI: 27kg/m2, VPT: 31V) performed a 16-week intervention of weekly resistance exercise training to increase ankle and knee extensor muscle strength. Six DM controls did not take part in the intervention (age: 50 years, BMI: 26kg/m2, VPT: 12V). Balance during gait was quantified before and after the intervention, by separation between the body centre-of-mass and centre-of-pressure under the feet during both level and stair walking. Knee and ankle extensor muscle strength was assessed using a dynamometer. The exercise intervention increased strength of ankle plantar flexors (22%) and knee extensors (30%). Despite the increases in lower limb muscle strength produced by the intervention, no improvements in balance were seen post training. However, gait speed did increase by 8%, which previous research has shown to be associated with quality of life. Controls showed no training effects in any variables. Although this exercise intervention had a positive effect on gait by increasing walking speed, there was no effect on the control of balance. Previous research has identified that medio-lateral (side-to-side) balance is impaired in people with DPN. The muscles exercised in the present study mainly control the major sagittal plane (forwards-backwards) movements that occur during gait. Interventions targeting the lateral stabilising muscles of the hip and trunk, may show greater potential efficacy in redressing the balance impairment of this population.

Disclosure

S.J. Brown: None. A.J. Boulton: None. F.L. Bowling: None. N.D. Reeves: None.
Mast Cell Precursors and Diabetic Neuropathy—Is Immunity the Connection?
Authors: SAMBATARO MARIA , SAMBADO LUISA , TREVISIOL ENRICA , PACCAGNELLA AGOSTINO
Published: June 2018

Introduction: Diabetic neuropathy and distal foot lesions are common complications of type two diabetic patients (T2DM), however the underlying pathophysiology remains uncertain. Mast cells (MCs) provide a possible link with immunity and neuroinflammation. These cells of innate immune system are found near sensory nerves or the endoneurial compartment, where they differentiate and participate in innate host defense reactions. MCs are involved in wound healing, but their role in diabetes is unknown.

Aim: To evaluate a possible connection between peripheral bone marrow derived blood MC precursors and diabetic neuropathy without and with ischemic skin lesions.

Methods: We enrolled 26 healthy controls (C), 15 T2DM with peripheral sensimotor neuropathy (N) and 14 T2DM with neuropathy, distal ischemia (allux oximetry <30 mm Hg) and foot lesions (N1). Peripheral blood was analysed by flow-cytometry (CD34, CD117, lineage cocktail 1 and FcεRI antibodies).

Results: We found a significant decrease of MC precursors (LIN-, CD34+, CD117+, FcεRI+ cells) in N and N1 (0.00and 0.00051% of mononuclear cells vs. 0.0018% in C, p<0.04). MC number directly correlated with total lymphocyte (p<0.005, R =0.474) T-lymphocyte (p<0.005, R =0.396) and CD4+ T-lymphocyte (p<0.0005, R =0.515) numbers. There was an inverse but not significant correlation with monocytes (p=0.073, R =0.197).

Conclusions: Our results show a possible involvement of MC precursors in human neuropathy and neuroischemic diabetic foot lesions. Conceivably, MCs could have a protective role in favoring wound healing by interaction with cells such as fibroblasts, endothelial, immune, nervous and epithelial cells and by release mediators and neurotransmitters. The correlation with T-lymphocytes might explain the impaired wound healing in N1, suggesting a direct contact between the two populations at the lesion site. Although not significant, the inverse relation with monocytes could be i up-regulated by the decrease in MC precursors.

Disclosure

M. Sambataro: None. L. Sambado: None. E. Trevisiol: None. A. Paccagnella: None.
Clinical Association between Diabetic Peripheral Neuropathy and Diabetic Retinopathy
Authors: JARRY ZYDEN , JOSHI VINAYAK , VAHTEL MARIA , BURGE MARK R. , SOLIZ PETER
Published: June 2018

Purpose: To quantify the association between diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR), as expressed in terms of thermal regulation of the plantar foot and vascular abnormalities in the retina.

Background: DPN accounts for around 73,000 lower-limb amputations in diabetics annually in the U.S., partially due to low compliance with periodic screening for DPN. Similarly, annual retinal screening for DR in diabetics is recommended by ADA and others. Identifying and referring individuals at risk for DPN by using biomarkers in retina could improve compliance for DPN screening.

Methods: Subjects (55-75 years) clinically diagnosed with DPN (N=20) and a set of age-matched controls (N=29) were selected. Thermal videos and retinal images were collected for all subjects. Subjects’ feet were imaged with an infrared (thermal) imager to obtain: 1) baseline temperature for 3 min, and 2) thermal recovery temperature for 10 min after a cold-patch provocation. Presence of DPN was determined by clinical examination. Retinal imaging was performed on each eye to obtain macula- and disc-centered images. A certified grader read the retinal images for severity level of DR and other retinal abnormalities. A logistic regression analysis was performed to compare retinal and thermal features, with the clinical diagnosis of DPN.

Results: A logistic regression determined a statistically significant difference (p < 0.05) in DR severity levels between DPN subjects and controls. The association between thermal features and DPN was demonstrated by statistically significant difference in recovery temperatures for both feet obtained in 1 min after cold provocation (p < 0.01), between DPN and controls.

Discussion: This study demonstrates the value of using characteristics of DR screening to identify individuals also at risk for DPN. A thermal imager located at the same screening site as a retinal camera could improve compliance with DPN screening and potentially prevent unnecessary foot complications.

Disclosure

Z. Jarry: None. V. Joshi: None. M. Vahtel: None. M.R. Burge: Research Support; Self; VisionQuest Biomedical LLC.. P. Soliz: None.
Neutrophil Elastase Contributes to the Early Molecular Abnormalities of the Retina in Diabetes
Authors: LIU HAITAO , KERN TIMOTHY
Published: June 2018

Introduction: Previous studies by our lab indicate that neutrophils are involved with capillary degeneration in diabetic retinopathy (DR). The elastase is a serine protease in neutrophils that plays an important role in a variety of inflammatory diseases, such as chronic obstructive pulmonary disease. We are investigating the potential role of NE in the development of DR.

Method: The activity of neutrophil elastase (NE) was selectively inhibited (by daily sivelestat) or deleted (Elane-/-) from diabetic mice, and the effects of NE loss were compared to the effects of inhibition of general protease activity (over-expression of protease inhibitor, alpha-1 antitrypsin). Molecular abnormalities associated with the development of DR, including retinal superoxide production, expression of proteins associated with inflammation, and leukocyte-mediated cytotoxicity of retinal endothelial cells were used to determine the effects of NE in diabetic mice.

Result: At two months of diabetes, selective inhibition of NE or deletion of the elastase both inhibited diabetes-induced superoxide production and inflammation in the retina. Both also inhibited leukostasis and/or leukocyte mediated damage to endothelial cells in cell cytotoxicity assays. In contrast, over-expression of alpha-1 antitrypsin resulted in increased retinal superoxide production and leukocyte activity in cytotoxicity assays in both diabetic and nondiabetic animals.

Conclusion: NE may play an important role in the development of DR.

Disclosure

H. Liu: None. T. Kern: None.
Angiotensin-(1-7) Attenuates Protein O-GlcNAcylation in the Retina of Mice Fed a High-Fat Diet
Authors: DIERSCHKE SADIE , ARNOLD AMY C. , BARBER ALISTAIR J. , DENNIS MICHAEL D.
Published: June 2018

Increased retinal protein O-GlcNAcylation occurs in response to hyperglycemia and contributes to diabetic retinopathy (DR). Alternatively, systemic pharmacological blockade of the Renin-Angiotensin System (RAS) lowers the incidence of DR. The classic RAS that systemically regulates blood pressure is defined by the ACE/AngII/AT1R axis; this is counter-regulated by actions of the ACE2/Angiotensin-(1-7) (Ang1-7)/Mas axis of the RAS. Increased endogenous production of Ang1-7 is responsible for many of the beneficial effects of cardioprotective RAS blockers such as ACE inhibitors; however the mechanism whereby DR outcomes are improved remains unresolved. The hypothesis here is that Ang1-7 acts to reduce retinal O-GlcNAcylation by activating Protein Kinase A (PKA) and thereby inhibiting the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine-fructose-6-phosphate amidotransferase (GFAT). Mice fed a 60% high fat diet (HFD) for 11 weeks and treated with the ACE inhibitor captopril (50 mg/L) for 3 weeks exhibited a Mas receptor-dependent attenuation of retinal protein O-GlcNAcylation as compared to vehicle treated controls. To determine the mechanism by which Ang1-7 regulates O-GlcNAcylation, R28 retinal neurons were treated with Ang1-7 and the adenylate cyclase activator forskolin. Both Ang1-7 and forskolin increased cAMP concentrations and attenuated levels of protein O-GlcNAcylation induced by treatment with the O-GlcNAcase inhibitor thiamet G. Classically, cAMP activates PKA, which phosphorylates and inhibits GFAT. Overall, these studies establish the first link between dysregulation of the well-studied physiological RAS and diabetes-induced retinal tissue damage as a consequence of excessive protein O-GlcNAcylation.

Disclosure

S. Dierschke: None. A.C. Arnold: None. A.J. Barber: None. M.D. Dennis: None.
Abnormal Electroretinography in Patients with Long-Duration Diabetes but No Retinopathy
Authors: BROOKS BELINDA , YUE DENNIS , LANDY ELLEN , SHI YI
Published: June 2018

Retinopathy increases with duration of diabetes but the presence of this microvascular complication in individual patients remains unpredictable. Retinal neurophysiological changes have been postulated to be important in modulating susceptibility. We performed electroretinography (ERG) on patients with long duration of diabetes (>15 years) but no retinopathy to determine whether this setting of “normal retinal morphology” is also characterised by normal electrophysiology of the eyes. ERG was performed with a handheld RETeval-DR™ device. Flickering lights at 30Hz was used to stimulate retinal electrical activity recorded by skin electrodes placed below the lower eye lids. Implicit time (electrical conduction time, msec), amplitude (uV) and pupil diameter (mm) were recorded. A composite score < 20 of these three parameters indicates a <1% risk of vision threatening retinopathy. Altogether 26 type 2 and 9 type 1 patients with no retinopathy and diabetes duration 22.5±4.5 and 32.8±9.4 years respectively were studied. Nondiabetic individuals (fasting BGL<6.0mM or HbA1c<6.0% n=25) acted as controls. Results in Table 1 showed the implicit time of individuals with diabetes but no retinopathy was only minimally increased but the amplitude was significantly reduced by ∼30% (p<0.01). We conclude that the eyes of these patients protected from diabetic retinopathy nevertheless showed retinal neural dysfunction.

Disclosure

B. Brooks: None. D. Yue: None. E. Landy: None. Y. Shi: None.
Identification of ProliferAtive Diabetic REtinopathy to Asymptomatic Coronary Heart Disease in Chinese T2D Individuals—The IPAD Reach Study
Authors: ZHOU JIANBO , YANG JINKUI
Published: June 2018

Aim: Substantial percentage of patients with T2D have asymptomatic Coronary Heart disease (CHD). To explore identification of PDR to asymptomatic CHD. We reported the baseline data from this IPAD reach group study, a China retrospective cohort study on clinical predictors of asymptomatic CHD in type 2 diabetes.

Method: T2D individuals (211non-DR (NDR) and 140 proliferative DR (PDR)) from a national diabetes center in China. The area under the receiver operating characteristic curve (AUC) were created. Discrimination and reclassification were used to assess the value of addition of PDR to the base model.

Results: Investigation included 211 NDR and 140 PDR. With the model estimating risk of asymptomatic CHD based on UKPDS engine, the AUC analysis improved from 0.583 (95% CI, 0.51-0.66) to 0.697 (95% CI, 0.641- 0.752) in the model without PDR and with PDR. The addition of PDR to a base model (8 traditional risk factors) to identify asymptomatic CHD increased the C statistic from 0.746 (95% CI, 0.681-0.811) to 0.762 (95% CI, 0.699-0.825; P=0.73). With the addition of PDR to the base model, there was a continuous net reclassification indexes (NRI) of 5.9% (95% CI, 1.4%-10.2%, p=0.017) for asymptomatic CHD. The absolute integrated discrimination index (IDI) was 0.004 (p= 0.02), with a relative IDI of 10.4%.

Conclusions: The improvement in identification of asymptomatic CHD, compared with traditional risk factors, demonstrates that PDR could identify cardiovascular risk stratification in Chinese diabetic individuals. Follow-up of this cohort will provide reliable information on asymptomatic CHD risk.

Disclosure

J. Zhou: None. J. Yang: None.
Macular Choroidal Thickness in Pregnant Women with Type 1, Type 2, and Gestational Diabetes Mellitus
Authors: BENFICA CAMILA Z. , ZANELLA TERESINHA , FARIAS LUCAS B. , OPPERMANN MARIA LUCIA R. , CANANI LUIS H.S. , LAVINSKY DANIEL
Published: June 2018

Pregnancy is an independent risk factor for the progression of diabetic retinopathy (DR). A possible relation with morphological changes of the choroid should be studied. The aim of this study was to analyze choroidal thickness measurements of nondiabetic pregnant women and of pregnant women with type 1, type 2 and gestational diabetes mellitus using spectral-domain optical coherence tomography (OCT). This cross-sectional study included 144 eyes of 72 pregnant women in the third trimester divided into four groups: Group 1 consisted of 27 nondiabetic pregnant women (control group); Group 2 consisted of 15 pregnant women with gestational diabetes mellitus (GDM); Group 3 consisted of 16 pregnant women with type 2 diabetes mellitus (T2DM); and Group 4 consisted of 14 pregnant women with type 1 diabetes mellitus (T1DM). Choroidal thickness was measured using EDI-OCT at ten different locations: at the fovea and every 500µm from the fovea up to 2500µm temporally and up to 2000µm nasally. Other variables such as gestational age, glycosylated hemoglobin values (HbA1c), time from DM diagnosis, hypertension and severity of DR were analyzed. The analysis of the 4 groups adjusted for the presence of hypertension showed a thinner choroid in patients with T1DM in all locations, with statistical significance in subfoveal and temporal measurements. In the comparison only between patients with DM, adjusted for HbA1c, time from diagnosis and presence of hypertension and DR, choroid of patients with T1DM remained thinner at all macular points.

In conclusion, our study showed no statistically difference in choroidal thickness between nondiabetic pregnant women, pregnant women with GDM and pregnant women with T2DM during the third trimester. On the other hand, pregnant women with T1DM had significantly thinner choroidal thickness measurements.

Disclosure

C.Z. Benfica: None. T. Zanella: None. L.B. Farias: None. M.R. Oppermann: None. L.H.S. Canani: None. D. Lavinsky: None.
Expression of ApoE Attenuates Differentiation of the White Adipose Tissue from ApoE-Knockout Diabetic Mice
Authors: RAN JIANMIN , PAN XIAMING , ZHANG RUYI , ZHU PING , TAN RONGSHAO , LIU YAN
Published: June 2018

Background: What and how the adipose-derived ApoE regulates biological features and lipid metabolism in the diabetic adipose tissue remain little known.

Methods: ApoE-/- and wild type mice were randomly divided into 4 groups: ApoE-/- group (EKO); streptozotocin (STZ)-induced diabetic apoE-/- group (EKODM); wild type group(WT); and STZ-induced diabetic wild type group (WTDM). Epididymal white adipose tissue isolated from part EKODM mice were transplanted into backs of WT mice and WTDM mice respectively, all recipient mice were fed with standard chow for 8 weeks. Vital signs, fasting plasma glucose, serum triglycerides(TG) and total cholesterol(TC) were measured every 4 weeks. After sacrifice, epididymal and transplanted white adipose tissue were harvested from all recipient mice. Histomorphologic alterations of adipose tissue were observed. Lipid ingredients of adipose tissue were extracted and measured. Genes expression of ApoE,lipoprotein lipase (LPL),hormone sensitive lipase(HSL),fatty acid synthase(FAS) in adipose tissue were detected by the RT-PCR.

Results: 1) After transplantation, the donor adipocytes size from EKODM→WT and EKODM→WTDM mice were both larger than that of EKODM itself. 2) Adipose TG contents of EKO and WTDM group were both lower than that of WT group, while EKODM→WT transplantation increased TG content but kept TC content unchanged compared with the EKODM→WTDM. 3) Adipose tissues of EKODM→WT and EKODM→WTDM group both significantly expressed ApoE. 4) Gene expressions of HSL, LPL, and FAS in donor adipose tissues from either EKODM→WT and EKODM→WTDM group were all significantly increased if compared with the EKODM group.

Conclusions: Adipose-derived ApoE may facilitate adipocyte differentiation in mice, even in a diabetic state.

Disclosure

J. Ran: None. X. Pan: None. R. Zhang: None. P. Zhu: None. R. Tan: None. Y. Liu: None.
Increased Angiopoietin Like Proteins 4 (ANGPTL4) Is Associated with Higher Concentration of LDL-Triglycerides in Type 2 Diabetes
Authors: NAGAIKE HIROE , HAYASHI TOSHIYUKI , NAKANISHI NORIKO , OHARA MAKOTO , YAMAMOTO TAKESHI , FUKUI TOMOYASU , HIRANO TSUTOMU
Published: June 2018

Background/Aims: Diabetic dyslipidemia is typically characterized by an increase in plasma triglycerides (TG), a concomitant increase in small dense (sd) low density lipoprotein (LDL) and atherogenic LDL-TG. Angiopoietin like protein 4 (ANGPTL4) is well established regulators of plasma TG level through regulating the activity of lipoprotein lipase. Plasma level and association between ANGPTL4 and sdLDL or LDL-TG is not well established in human subjects. We aimed to examine the level of ANGPTL4 and investigate the association between ANGPTL4 with sdLDL-C and LDL-TG in type 2 diabetes (T2D).

Methods: 250 (M176/F 74) Japanese diabetic patients and 9 of healthy controls (Controls) were enrolled in this study. SdLDL-C and LDL-TG were measured by homogeneous assays. ANGPTL3 and ANGPTL4 protein levels were measured by ELISA.

Results: As compared with Controls, plasma ANGPTL3, ANGPTL4, sdLDL-C and LDL-TG levels were increased in T2D. ANGPTL3 was not collated with sdLDL-C or LDL-TG. ANGPTL4 was positively correlated with HbA1c(r=0.15, p=0.019), TG(r=0.15, p=0.018)and LDL-TG(r=0.17,p=0.008), whereas ANGPTL4 was not collated with sdLDL-C. Furthermore, ANGPTL4 was also significantly associated with LDL-TG/LDL-C ratio (r=0.15, p=0.022) and LDL-TG/apoB ratio (r=0.18, p=0.009).

Conclusions: The ANGPTL4 level was increased in T2D and associated with atherogenic higher LDL-TG levels. ANGPTL4 may play a role in modulating lipid metabolism in LDL particles.

Disclosure

H. Nagaike: None. T. Hayashi: None. N. Nakanishi: None. M. Ohara: None. T. Yamamoto: None. T. Fukui: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.
Effects of Gly-LDL on LRP5/DKK1 Pathway in MC3T3-E1 Osteoblasts
Authors: LEI TAO , CHEN LIN , ZHANG BINGYU , TANG WENJUN
Published: June 2018

Background: The aim of this study was to investigate the effect of glycated low density lipoprotein (Gly-LDL) on the proliferation, differentiation and expression of low-density lipoprotein receptor-related protein-5 (LRP5), dickkopf-1(DKK1) in mouse MC3T3-E1 cells.

Methods: The MC3T3-E1 cells of mouse were cultured with native LDL(n-LDL) without chemical, and various levels of Gly-LDL was cultured respectively with 5mmol/L(A), 20mmol/L(B), 100mmol/L(C) of D+glucose for 4 weeks) for 48h. The proliferation of MC3T3-E1 cell was measured by CCK8, the osteocalcin level in the medium was determined by ELISA, the mRNA expression of LRP5,β-catenin and DKK1 was analysed by real-time PCR and proteins in Wnt signaling pathway by western blot.

Results: After cells incubation with group A of Gly-LDL, the inhibition of MC3T3-E1 cells was apparently promoted than that of n-LDL control group (P<0.01),The higher Gly-LDL level the more inhibited. The effects of Gly-LDL on the proliferation of MC3T3-E1 was dose-dependent under certain conditions. The levels of Osteocalcin in cells cultured with Gly-LDL were significantly inhibited compared with the control group. The mRNA expression of DKK1 was significantly up-regulated while the mRNA expression of β-catenin and LRP5 were down-regulated(P<0.01) in MC3T3-E1 cells, which cultured with group A Gly-LDL. According to the results of western blot, it also showed that, compared with n-LDL group,the effect of Gly-LDL on osteoblasts was down-regulated the LRP5 and β-catenin while up-reglulated the DKK1.

Conclusions: The Wnt signaling pathway being involved might be the possible mechanism of Gly-LDL effect on the proliferation and differentiation in MC3T3-E1 cells.

Disclosure

T. Lei: None. L. Chen: None. B. Zhang: None. W. Tang: None.