bluuebunny/crossref_metadata_2025 huggingface dataset:
The Complement-1q-Like-3 Inhibits Insulin Secretion by an Adhesion G-Protein Coupled Receptor, BAI3 in Pancreatic ß Cells
Authors: GUPTA RAJESH , SCHAID MIKE , KIMPLE MICHELLE E. , KOLTES JAMES E. , BHATNAGAR SUSHANT
Published: June 2018

Secreted proteins are important metabolic regulators and our objective was to identify proteins that are important regulators of β-cell function. Microarray data from multiple tissues including liver, adipose, gastrocnemius, islets from lean and obese mice were analyzed to identify candidate regulators. For this, we developed a data filtering approach to identify candidate secreted protein regulators. Next, cross-tissue correlation network and gene enrichment based analyses were performed to determine cellular pathways affected by each candidate secreted protein in the target tissue. By using this methodology, complement-1q-like-3 (C1ql3) was identified to affect ’secretory processes’ in islets. Preliminary data showed that the expression of C1ql3 was increased by 32-fold in islets of obese mice. Incubating islets with C1ql3 containing culture media inhibited high glucose, GLP-1 receptor agonist (exendin-4), cAMP, and potassium-induced insulin secretion in mouse islets. Interestingly, C1ql3 did not affect insulin secretion in response to low and submaximal concentrations of glucose, fatty acids, amino acids, and mitochondrial metabolites. We further observed that the expression of BAI3, a receptor for C1ql3, is elevated in islets of obese compared to lean mice. Knockdown of BAI3 in β-cells increased glucose-stimulated insulin secretion by 2-fold and soluble C1ql3-binding fragment of BAI3 completely blocked the inhibitory effects of C1ql3 on cAMP-stimulated insulin secretion. These findings report the identification of a novel pathway in C1ql3/BAI3 that antagonizes GLP-1/cAMP signaling to inhibit insulin secretion from β-cells. We propose that the activation of C1ql3/BAI3 signaling contributes to type 2 diabetes and may offer therapeutic alternatives to treat type 2 diabetes.

Disclosure

R. Gupta: None. M. Schaid: None. M.E. Kimple: None. J.E. Koltes: None. S. Bhatnagar: None.
Hyperproinsulinemia in OGlcNAc Transferase Deficient Mice Is Associated with Loss of CPE and eIF4G1, but ß-Cell Deletion of eIF4G1 Induces Glucose Intolerance Independent of CPE Dysregulation
Authors: JO SEOKWON , LOCKRIDGE AMBER D. , ALEJANDRO EMILYN
Published: June 2018

β cell loss of OGlcNAc transferase (βOGTKO), the sole enzyme that adds OGlcNAc post-translational modification onto target proteins impacting their function and stability, leads to diabetes and islet failure in mice. βOGTKO mice present hyperproinsulinemia, typified by increased serum proinsulin/insulin ratio. Here, we show that βOGTKO islets have reduced carboxypeptidase E protein but not mRNA (CPE, an exopeptidase that converts proinsulin to insulin), independent of sex, age and glucose levels. We identified that CPE is neither the target nor a binding partner of OGT. Eukaryotic initiation factor 4 gamma 1 (eIF4G1), previously shown to regulate CPE in vitro, is reduced at the protein level, but not mRNA, in βOGTKO islets. We identified that eIF4G1 is OGlcNAc-modified in β cells and mutation of the putative OGlcNAc site at serine 61 to alanine led to decreased protein stability, but not on CPE translation. To assess the role of eIF4G1 on CPE regulation in vivo, we generated mice with β cell specific deletion of eIF4G1 (RIPCre; eIF4G1flox/flox (βeIF4G1KO)), in R1207H eIF4G1 (eIF4G1) background. At 6 weeks of age in normal chow diet, glucose intolerance was evident between βeIF4G1KO and littermate control eIF4G1 mice, without alteration in peripheral insulin sensitivity. Surprisingly, no apparent insulin processing deficit was observed between βeIF4G1KO and eIF4G1 mice, consistent with the observed normal level of CPE protein among islets of βeIF4G1 KO, eIF4G1 or wild type mice via immunofluorescence, and comparable serum proinsulin/insulin ratio in βeIF4G1 KO and eIF4G1 mice. Significant reduction in the average β cell size and increased number of α cells was evident in βeIF4G1KO vs. eIF4G1 mice, hinting at loss in β cell mass. Together, these data unveil the regulation of OGT on eIF4G1, and underscore the novel role of eIF4G1 on glucose homeostasis and modulation of β cell size.

Disclosure

S. Jo: None. A.D. Lockridge: None. E. Alejandro: None.
Towards Generating Spatiotemporal Multiscale Models of Human Pancreatic Beta Cells
Authors: WHITE KATE L. , MCCLARY KYLE , SINGLA JITIN , STEVENS RAYMOND C.
Published: June 2018

Diabetes is a worldwide problem affecting hundreds of millions of people with increasing patient numbers every year. Our goal is to assemble a spatiotemporal, multi-scale (atomic to cellular) model of a human pancreatic β-cell to gain a more holistic understanding of β-cell function in diabetes. This effort requires the convergence of structural biology, electron microscopy, X-ray tomography, -omics, live cell imaging, computational and integrative modeling, systems biology, and digital arts. To best integrate these approaches, we formed a consortium of leaders in each field to help collect the necessary data for assembling such a model. As a first step, we have characterized the cellular ultrastructure and generated a consensus of the components of a cell (proteins, nucleic acids, metabolites, lipids, etc.). Two important aspects of this project are developing new tools for data integration and improving communication between collaborators in distant fields. To achieve this goal, we are collaborating with the USC School of Cinematic Arts to generate a virtual reality experience of a β-cell that serves as a new type of tool that can toggle between experimental techniques and scales. This immersive model will allow researchers, students, and the public to explore the rich biochemical world of a β-cell. Together, these models will represent a sophisticated convergence of our understanding of cellular structure and function, revolutionize biological discovery, open new dimensions of research, and accelerate advancements in healthcare.

Disclosure

K.L. White: None. K. McClary: None. J. Singla: None. R.C. Stevens: None.
Does Continuous Glucose Monitoring (CGM) Restore Hypoglycemia Awareness in Patients with Type 1 Diabetes (T1D) Who Previously Had Impaired Awareness of Hypoglycemia (IAH)?
Authors: ZEKARIAS KIDMEALEM , MOHEET AMIR , KUMAR ANJALI , SEAQUIST ELIZABETH R.
Published: June 2018

IAH occurs in up to 1/3 of adults with T1D and it increases the risk of severe hypoglycemia (SH).Studies demonstrate that using CGM reduces the time spent in hypoglycemia (HG), but the effect of CGM on reversing IAH is not clear. We have enrolled many study subjects with T1D and IAH over the years and recently contacted them to determine how many continue to have IAH, how many have used CGM, and if there is a correlation between CGM use and restoration of HG awareness.

Thirty six with T1D and IAH according to the Clarke/Cox questionnaire (CC) administered 2009-2015 were contacted to complete an online survey that included the CC, the Gold questionnaire, and questions about their diabetes. 12 M, 11 F responded. One had an islet cell transplant and was excluded. Median duration was 36 ± 12 years, mean age was 50 ± 12 years and the median HgB A1C was 6.8 ± 1%.

Persistent IAH defined by both questionnaires was typical. Nineteen of 22 classified as IAH on the current survey reported severe HG over the last 6 mo. While there was a trend that showed consistent use of CGM was higher among people with no episodes of severe HG over the last 6 months this was not statistically significant.

These observations show that persistent IAH is common in T1D. While the consistent use of CGM among our participants was high it did not translate into restoration of HG awareness in this population.

Consistent use of CGM defined as more than 75% of the time over the last six monthsNo consistent use of CGMParticipants with persistent IAH (n = 18/22 using Gold)126Participants with persistent IAH (n = 19/22 using Cox)137Participants without persistent IAH (n= 4/22 using Gold)22Participants without persistent IAH (n= 3/22 using Cox)12Participants with severe HG in 6 months before survey (n = 19/22)118Participants without severe HG in 6 months before survey (n = 3/22)21

Disclosure

K. Zekarias: None. A. Moheet: None. A. Kumar: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..
Effects of Hypoglycemia Unawareness on Exercise Management
Authors: COSSEN KRISTINA , PATTERSON BRIANA , MUIR ANDREW
Published: June 2018

Objective: Recent guidelines for management of T1D with exercise prompted us to determine if exercise management differs in T1D patients <15 yo with high or low hypoglycemia (hypo) awareness.

Methods: 229 subjects or caretakers in a single academic practice completed a modified T1D Exchange questionnaire, describing hypo awareness and exercise management (changes of carbohydrate (carb) intake and insulin doses). Hypo awareness was self-scored on a 5-point scale. Hypo awareness was defined as high (always/often) or low (never/rarely) (n=167). Patients had to exercise at least 1 day/week (mean 4.9) (n=158). Changes to carb intake for exercise were scored on a Never-to-Always 5-point scale. Insulin changes for exercise were scored on a yes/no scale. Because of differences in hypo awareness (p=0.0002), patients were divided into ages <8 year olds (yo) (n=35) and 8-14 yo (n=123). Fisher exact or Student t-test was applied.

Results: Between high and low hypo awareness groups, no significant differences were seen within each age category for: age at diagnosis, duration of T1D, insulin administration method, daily insulin dose, HbA1C, glucose meter checks/day, glucose checks <70mg/dL, and mean blood glucose. Children <8 yo were more likely to wear continuous glucose monitors (CGM) than 8-14 yo (34% vs. 24%; p=0.0002). Across all ages, hypo awareness was not associated with differences with insulin management (p=0.43) or carb use (p=0.18) before or during exercise. Increased CGM use was observed in low hypo awareness (48%) compared to high hypo awareness children (21%) (p=0.005), particularly among children <8 yo (57% vs. 19%; p=0.03) vs. 8-14 yo (40% vs. 21%; p=0.2).

Discussion: Increased CGM use was observed among patients <8 yo with low hypo awareness. Nonetheless, hypo awareness did not relate to adjustments of carb intake or insulin dose for exercise. This presents an educational opportunity to improve exercise-induced blood glucose fluctuation.

Disclosure

K. Cossen: None. B. Patterson: None. A. Muir: None.
Blood Pressure Variability and Nocturnal Dipping in Diabetic Patients With and Without Chronic Kidney Disease
Authors: LIBIANTO RENATA , BAQAR SARA , VU THUY D. , MACISAAC RICHARD , EKINCI ELIF I.
Published: June 2018

Background: Both increased blood pressure variability (BPV) and lack of nocturnal blood pressure dipping (NBPD) are independently associated with excess mortality in patients with diabetes mellitus. We hypothesised that patients with diabetes and CKD have higher BPV and are more likely to demonstrate a lack of nocturnal blood pressure dipping, than their counterparts without CKD.

Methods: Clinical and biochemical data were collected from 124 patients attending diabetes clinics at Austin Health, Melbourne Australia. Stage 3 to 5 CKD (from here on referred to as “CKD”) was defined by a CKD-EPI eGFR of <60ml/min/1.73m2. Patients underwent 24h ambulatory blood pressure monitoring within one year either side of the eGFR measurement. BPV was calculated using standard deviation (SD) and coefficient of variation (SD/mean*100). Night-to-day systolic BP ratio of>90% suggested abnormal NBPD (“non dippers”).

Results: Thirty-four patients (27%) had CKD. The mean±SD 24h systolic blood pressure was higher in patients with CKD than those without (135±16mmHg vs. 129±13mmHg respectively, p=0.03), and there was a negative correlation between eGFR and 24h systolic BP (r = -0.21, p=0.02). No association was found between eGFR and BPV. A negative correlation was found between eGFR and night-to-day systolic BP ratio, whereby lower eGFR was associated with higher night-to-day systolic BP ratio (i.e., with lack of NBPD). This relationship remained significant after adjusting for age and sex.

Conclusion: Amongst patients with diabetes, reduced eGFR was associated with higher blood pressure and abnormal NBPD, but not with BPV. Further study is needed to characterise blood pressure fluctuations in diabetic patients with CKD, who constitute a high risk group.

Disclosure

R. Libianto: None. S. Baqar: None. T.D. Vu: None. R. MacIsaac: None. E.I. Ekinci: None.
Prevalence and Associated Factors to Peripheral Arterial Disease in Patients with Diabetes Type 2
Authors: MARMOL FERNANDO A. , BUENO LUIS E. , VASQUEZ DIEGO A.
Published: June 2018

Type 2 diabetes mellitus (T2DM) is the principal risk factor for developing Peripheral Arterial Disease (PAD), which is the most frequent non cardiac arteriopaty according to the American Heart Association (AHA). The Ankle-Brachial Index (ABI) is the main diagnostic test for PAD with a 90%-95% sensibility and 96%-100% specificity.

Objective: Establish the prevalence and associated factors for PAD in patients with T2DM according to their ABI, in primary care.

Material and Methods: Descriptive and cross-sectional study, in “Sur Valdivia” medical center between August 2015-March 2016, with T2DM patients older than 50 years to whom the ABI test was performed according to the AHA guidelines. A multiple logistic regression analysis was made between independent variables and the presence of an ABI≤0,90.

Results: ABI test was performed on 196 people, 14 were excluded because they weren’t evaluable for having an ABI> 1.40. The final sample was conformed of 182 patients, with an average age of 64.1 years old, consisting of 95 (52.20%) women and 87 (47.8%) men; from which 27 (14.84%) obtained an ABI≤0.90. The multivariate analysis showed a significant relationship with age ≥70 years (p = 0.0001, OR 1.14), having more than 10 years with T2DM (p = 0.036, OR 2.91), and the presence of intermittent claudication (p = 0.025; OR 2.67). An unilateral negative correlation was determined between age and ABI results (rs = -0.279, p = 0.001); In addition, an adjusted model of binary regression was performed in those with less than 10 years with T2DM and intermittent claudication, showing a statistically significant relationship with the presence of an ABI ≤0.90 (p = 0.01, OR 11.46).

Conclusions: The prevalence of an ABI ≤0.90 was higher than the world prevalence. The ABI test should be a common practice in primary care, especially on patients with several years with diabetes, advanced age and/or intermittent claudication.

Disclosure

F.A. Marmol: None. L.E. Bueno: None. D.A. Vasquez: None.
Serum Ferritin Independently Associated with Carotid Intima-Media Thickness in Male Patients with T2DM from Tibetan Plateau
Authors: CHENGHUI ZHANG , SUYUAN WANG , YUNHONG WU
Published: June 2018

Background: Although the association with serum ferritin (SF) and carotid intima-media thickness (IMT) has been demonstrated by various studies, SF levels in those studies were mostly in the normal reference range. High SF levels were usually found in the patients who suffered from hematological system diseases and hereditary hemochromatosis. Our data (unpublished) had shown SF levels in Tibetan population had increased, and this study focused on the male Tibetan patients with T2DM to explore the association between SF and IMT.

Methods: This cross-sectional study involved 718 male Tibetan patients with T2DM. BMI, SBP and duration were collected. SF, HbA1c and blood lipid profiles were measured in clinical laboratory in our hospital. IMT was performed by carotid artery ultrasonography examination. Patients were categorized into four groups based on the level of SF. Multivariate regression was used to examine the association of SF and IMT.

Results: Patients in the fourth quintile were more likely to present higher baseline of BMI, TC, HbA1c and IMT. After adjustment for age, duration and BMI, comparing with the first quintile, the β, 95% CI and p-value of the second, third as well as fourth quintile of serum ferritin were 0.029 (-0.001, 0.059) (p = 0.056), 0.046 (0.017, 0.076) (p = 0.002) and 0.053 (0.023, 0.083) (p <0.001), respectively. After further adjustment for HbA1c, TC and SBP, the β, 95% CI and p-value of the second, third as well as fourth quintile of SF were 0.025 (-0.005, 0.055) (p = 0.102), 0.040 (0.010, 0.071) (p = 0.008) and 0.045 (0.015, 0.076) (p = 0.004), respectively.

Conclusion: SF was independently associated with IMT in male patients with T2DM from Tibetan plateau, the cutoff of serum ferritin in this study would help us to find an appropriate value to intervene the hyperferritinemia.

Disclosure

Z. Chenghui: None. W. Suyuan: None. W. Yunhong: None.
Few Pediatric Diabetes Patients Access Outpatient Psychotherapy following Screening and Referral
Authors: TSIKIS JOANNA , VALENZUELA JESSICA M. , VASSILOPOULOS ARETI , WILCOCKS CHELSEA , REITBLAT LITAL , BLANCO ERNESTO J. , NICHOLLS SHELLEY , WOLF RISA
Published: June 2018

Introduction: Adolescents and young adults (AYAs) with diabetes are at risk for suboptimal psychological functioning. This study aims to describe the prevalence of elevated depression scores, outpatient psychotherapy referrals, and individuals receiving follow-up care in a clinic with an integrated psychologist. Further, we examine whether having an integrated psychologist leads to better access to mental health services for AYA.

Methods: Participants were seen in a multidisciplinary diabetes clinic from September 2016 to 2017. Assessment included a semi-structured interview and depression screener (PHQ). Families with concerns related to diabetes management were offered on-site outpatient psychotherapy, others given community referrals. Follow-up with referrals was assessed at next diabetes visit.

Results: Participants included 100 ethnically diverse AYAs, 11-21 years (M=16.06±2.42; 56% female), diagnosed with type 1 (79%), type 2 (19%), or MODY (2%), with a range of glycemic control (HbA1c 5.5 to >14%). PHQ scores were: no/minimal (58%), mild (26%), moderate (11%), moderately severe (3%), and severe (2%). 59% of patients were referred for outpatient psychotherapy. Referral reasons included depression, anxiety, behavioral difficulties, family conflict, and diabetes management challenges. At follow-up, only 9% were receiving services. Barriers included transportation, organization (e.g., losing referral), and stigma.

Conclusions: Pediatric psychologists within integrated diabetes teams offer effective mental health screening and referrals. Almost half (42%) of AYA in our cohort had ≥5 depressive symptoms, and while 59% were referred for outpatient therapy, only 9% received these services. Despite patient access to a pediatric psychologist in clinic, a large discrepancy between referral and follow-up rates remains. This disparity highlights the importance of identifying and reducing barriers to follow-up care for AYAs with diabetes.

Disclosure

J. Tsikis: None. J.M. Valenzuela: None. A. Vassilopoulos: None. C. Wilcocks: None. L. Reitblat: None. E.J. Blanco: None. S. Nicholls: None. R. Wolf: None.
Alogliptin and Pioglitazone, Alone or in Combination, Prevent Palmitate-Induced Apoptosis and Autophagy in Human Cardiac Progenitor Cells
Authors: INCALZA MARIA ANGELA , D'ORIA ROSSELLA , CACCIOPPOLI CRISTINA , LEONARDINI ANNA , SCHIPANI ROSSELLA , CIGNARELLI ANGELO , NATALICCHIO ANNALISA , PERRINI SEBASTIO , MARGARI VITO , PAPARELLA DOMENICO , LAVIOLA LUIGI , GIORGINO FRANCESCO
Published: June 2018

Physiological tissue turnover in the heart requires proper activation and viability of multipotent cardiac progenitor cells (CPCs). A defective CPC compartment, in terms of CPC number and maturation capacity, contributes to diabetes- and hyperglycemia-related heart failure in humans. GLP-1-based therapies, including the DPP-4 inhibitors, improve cardiac function in vivo and ameliorate myocardial and endothelial dysfunction in vitro. Pioglitazone has also demonstrated pleiotropic anti-oxidant and anti-atherogenic effects. The aim of this study was to evaluate the effects of alogliptin and pioglitazone, alone or in combination, on the viability of human CPCs exposed to 0.25 mM palmitate for 16 h. Human CPCs were obtained from patients undergoing cardiac surgery for coronary artery bypass grafting and/or valve surgery. Exposure of human CPCs to both alogliptin (10 µM) and pioglitazone (10 µM) for 16 h resulted in Akt, but not Erk, activation. Exposure to palmitate was associated with increased human CPC apoptosis and autophagy evaluated by ELISA assay and LC3-II immunoblotting, respectively (p<0.05). Pretreatment with alogliptin, alone or in combination with pioglitazone for 1 h before exposure to palmitate, reduced palmitate-induced apoptosis and autophagy (p<0.05).

In conclusion, palmitate induces apoptosis and autophagy in human CPCs, and alogliptin and pioglitazone, as well as their combination, prevent the effects of palmitate, likely through enhancement of pro-survival pathways. Hence, DPP-4 inhibitors and thiazolidinediones, alone or in combination, may limit the lipotoxic damage of the human heart by preserving the viability of myocardial progenitor cells.

Disclosure

M. Incalza: None. R. D'Oria: None. C. Caccioppoli: None. A. Leonardini: None. R. Schipani: None. A. Cignarelli: Advisory Panel; Self; Aegerion Pharmaceuticals. Consultant; Self; Roche Diagnostics Corporation, Eli Lilly and Company. A. Natalicchio: None. S. Perrini: None. V. Margari: None. D. Paparella: None. L. Laviola: Advisory Panel; Self; AstraZeneca, Animas Corporation. Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; Medtronic, Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk Inc., Roche Diabetes Care Health and Digital Solutions, Sanofi-Aventis, Takeda Development Centre Europe Ltd. F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd..
Metformin Ameliorates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits TGF-ß1-Induced Upregulation of Cadherin-6 in Renal Proximal Tubule Epithelial Cells
Authors: LIANG DIEFEI , LIU SHANYING , SONG ZIJIAO , LIANG WEIWEN , CHANG RUIMING , LI YAN
Published: June 2018

Background: Metformin has been reported of nephroprotective effects by suppressing TGF-β1-induced renal tubulointerstitial fibrosis. The mechanisms have not been fully clarified. Cadherin-6(CDH6) is a TGF-β1 target gene related to epithelial-to-mesenchymal transition(EMT). This study aimed to examine the effects of metformin on TGF-β1-induced expression of CDH6 and renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and HK-2 human renal proximal tubule epithelial cells.

Methods: Six-week-old male Kunming mice(n=18) were randomly divided into three groups: 1. Sham: sham-operated mice; 2. UUO: mice underwent UUO; 3. MET+UUO: UUO mice received metformin by gavage for 21 days after UUO. Kidneys were harvested for histopathologic examination and urine was collected for creatinine evaluation. HK-2 cells were stimulated with either TGF-β1 and/or metformin. RT-qPCR and Western Blot were used to evaluate mRNA and protein level respectively.

Results: Masson’s Trichrome staining showed significant tubulointerstitial accumulation of extracellular matrix in obstructed kidneys, which could be reduced by metformin. Meanwhile, urinary creatinine was increased with metformin treatment. Upregulation of CDH6, COL1A1, PAI-1 mRNA level was observed in obstructed kidneys, which was reduced in MET+UUO group. Immunohistochemistry showed increased expression of CDH6, α-SMA in obstructed kidneys, which was alleviated in metformin treated group. In HK-2 cells, TGF-β1 upregulated mRNA level of CDH6, vimentin, PAI-1 and protein level of CDH6. Pretreatment with metformin attenuated TGF-β1-induced upregulation of CDH6, vimentin, PAI-1 mRNA level.

Conclusion: Metformin prevents renal fibrosis partly through inhibition of TGF-β1-induced increase of CDH6 expression and EMT in renal proximal tubule epithelial cells.

Disclosure

D. Liang: None. S. Liu: None. Z. Song: None. W. Liang: None. R. Chang: None. Y. Li: None.
Number of Intact Teeth and Nutritional Status Are Correlated in Hemodialysis (HD) Patients with Type 2 Diabetes
Authors: FUNAKOSHI SATOSHI , OHATA YUKO , FUJIMORI KATSUTOSHI , ETOH RICA , SAWASE KENJI , HASHIGUCHI JYUNICHIRO , MORI YUTAKA , UTSUNOMIYA KAZUNORI , HARADA TAKASHI , HAYASHIDA MASATOSHI , KAWANO MAI
Published: June 2018

Objective: To investigate oral health status in patients receiving maintenance hemodialysis (HD) and to examine the characteristics of diabetic patients receiving HD.

Methods: A questionnaire survey was conducted in a total of 249 outpatients receiving HD using the Japanese Academy of Clinical Periodontology’s Self-administered Questionnaire on Periodontal Disease to compare oral/nutritional health status between diabetic and nondiabetic patients.

Results: Of the patients surveyed, diabetic and nondiabetic patients totaled 83 and 166 (mean age, 64.3 ± 21.7 years and 73.9 ± 33.3 years), respectively. While there was no significant difference in the prevalence of periodontal disease between the diabetic and nondiabetic patients (26.5% and 34.9%), the diabetic patients had a significantly fewer number of intact teeth than the nondiabetic patients (14.9 ± 11.5 vs. 21.7 ± 12.9) as well as a lower geriatric nutritional risk index than the nondiabetic patients (85.7 ± 20.9 vs. 93.9 ± 27.4).

Conclusions: While there was no difference in the prevalence of periodontal disease between the diabetic and nondiabetic patients among those receiving HD, the diabetic patients were associated with a fewer number of intact teeth as well as poorer nutritional status. Further study is required to investigate whether these may represent causes or consequences of diabetes and/or nutritional status.

Disclosure

S. Funakoshi: None. Y. Ohata: None. K. Fujimori: None. R. Etoh: None. K. Sawase: None. J. Hashiguchi: None. Y. Mori: None. K. Utsunomiya: None. T. Harada: None. M. Hayashida: None. M. Kawano: None.
Quality of Life in Type 2 Diabetic Patients With and Without Proliferative Retinopathy and Macular Edema
Authors: RADHAKRISHNAN CHANDNI , CK SHAHANAS , K. SREEJITH , S. BINDU
Published: June 2018

Diabetic retinopathy is the most common diabetic eye disease and a leading cause of blindness in adults. In India diabetes is an epidemic, so the prevalence of diabetic retinopathy is also increasing. The main objective of the study is to compare both health related and vision targeted quality of life of type 2 diabetic patients with and without proliferative diabetic retinopathy or diabetic macular edema. A prospective, observational study was conducted in a tertiary care referral hospital at Kerala, India, over a period of 7 months. Patients age between 33-76 years, suffering from type 2 diabetes mellitus either with or without proliferative diabetic retinopathy or diabetic macular edema were interviewed using EQ 5D 5L questionnaire and national eye institute visual function questionnaire to assess their quality of life. Out of 189 type 2 diabetic patients included in the study, 94 were with Proliferative diabetic retinopathy or diabetic macular edema and remaining 95 were without PDR or DME. Presence of PDR or DME does not affect health related quality of life (p>0.05). Severity of retinopathy significantly reduces health related QoL (p=0.004). Presence of PDR or DME reduces vision related QoL significantly (p=0.000). Vision related QoL is also affected by severity of retinopathy (p=0.000). There was statistically significant correlation between duration of diabetes and severity of retinopathy (p=0.018). Both HRQoL and vision related QoL were positively correlated (p=0.001).

Disclosure

C. Radhakrishnan: None. S. Ck: None. S. K.: None. B. S.: None.
Regulation of Immune Cell Proliferation by microRNAs
Authors: JOGLEKAR MUGDHA , MAYNARD CODY-LEE , HARDIKAR ANAND
Published: June 2018

Transplantation of cadaveric islets is currently the only clinically recognized cell therapy for treatment of type 1 diabetes. Long-term success of this therapy is severely limited by multiple factors, including the immune-mediated destruction of transplanted islets. Development of molecular immunosuppressive strategies could offer much efficient graft survival thereby improving graft function and quality of life. Here we demonstrate that one of the novel mechanisms of immune regulation involves inter-cellular transfer of microRNAs via exosomes.

We have established and extensively characterized human islet-derived progenitor cells (hIPCs), which are generated following epithelial-to-mesenchymal transition (EMT) and proliferation (expansion) of human cadaveric islet cells. Initial characterization of hIPCs indicates that they exhibit most of the characteristics of mesenchymal stem cells, including expression of CD73, CD90 and CD105. We observed that hIPCs can significantly inhibit (>90%) in vitro proliferation of different immune cell subsets (CD4+ T, CD8+ T, CD19+ B) of (PHA)-stimulated PBMCs in a co-culture system. RNA-sequencing and validation studies pointed to a potential role of microRNAs in inhibition of T cell proliferation. Recently, microRNAs have been demonstrated to shuttle between cells and are reported to be involved in inter-cellular gene regulation. When microRNAs were analysed in hIPCs alone and in hIPCs co-cultured with PBMCs, we found a small subset of significantly altered microRNAs. These microRNAs showed increase in abundance in PBMCs from co-culture setting and were higher in co-culture supernatant. When exosomal inhibitors were used to prevent the transfer of microRNAs from hIPCs in a co-culture setting, we found that T-cell proliferation was rescued back to normal.

We believe that this study could help in discovering novel immunoregulatory molecules that may have a potential role for improving graft survival in islet transplantation for type 1 diabetes.

Disclosure

M. Joglekar: None. C. Maynard: None. A. Hardikar: None.
Insulin Initiation and Intensification Strategies—Effect of Case-Based Online Education on Physician Competence and Confidence
Authors: GRIFFITH GILLIAN A. , PRATO STEFANO DEL , TRIER JOACHIM
Published: June 2018

Purpose: To determine if case-based online medical education for primary care physicians (PCPs) and diabetologists/endocrinologists (diabs/endos) can improve competence and confidence regarding the appropriate initiation of insulin therapy and intensification with novel basal insulins/GLP-1 receptor agonist (GLP-1 RA) fixed-ratio combinations (FRCs) in complex patients with T2DM.

Methods: This educational activity featured an interactive case study that challenged learners to develop and apply the skills needed for providing optimal treatment of T2DM. Educational effect was assessed with a repeated pairs pre- and post-assessment study with a 3-item, multiple-choice, competence, one-item confidence questionnaire in which participants act as their own controls. A χi-squared test assessed statistical significance at the P <.level. The activity launched April 25, 2017; data were collected until June 1, 2017.

Results: Participation in the activity significantly improved competence of PCPs (average from 52% to 75%; n=869) and diabs/endos (from 55% to 71%; n=209) regarding the role of basal insulin analogs in improving glycemic control, the expected effects of a basal insulin/GLP-1 RA FRC on a patient’s weight and risk of hypoglycaemia, and the appropriate recommended starting dose of such a novel insulin FRC in a given case scenario (p<.05). Confidence levels in selecting appropriate treatment regimens for patients sub-optimally controlled on basal insulin also improved (41% in PCPs, 28% in diabs/endos).

Conclusions: Participation in online interactive case-based education resulted in improvement of competence and confidence regarding the initiation and intensification of insulin therapy in a complex patient with T2DM. Further education is warranted on the utility of novel insulin formulations and intensification strategies, available novel FRCs, and their appropriate use in patients with poorly controlled T2DM.

Disclosure

G.A. Griffith: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott. J. Trier: None.
SH2B3 (lnk) Regulates Type 1 Diabetes Immune Phenotypes
Authors: CAMARGO ANA , PERRY DANIEL J. , BRUSKO TODD M. , WALLET MARK A.
Published: June 2018

Background: The type 1 diabetes (T1D)-associated risk gene SH2B Adaptor Protein 3 (SH2B3) encodes a phosphatase with specificity for Janus Kinase 2 (JAK2). We hypothesized that variations in SH2B3 would affect immune signaling pathways relevant to T1D autoimmunity. Here we report: 1) Occurrence of the SH2B3 risk variant among T1D patients, unaffected first-degree relatives and controls; 2) Prevalence of SH2B3 risk genotype in African Americans in the Southeastern U.S.; and 3) Alterations to immune composition associated with the SH2B3 risk variant.

Approach and Results: 1) The University of Florida Diabetes Institute (UFDI) cohort (n=1946) was analyzed for genetic risk of T1D using a Taqman single nucleotide polymorphism (SNP) genotyping array with coverage of 32 SNPs. Two SNPs (rs3184504 and rs653178) corresponding to SH2B3 were in perfect linkage disequilibrium and will be described here as minor (T1D risk) or common variant. Among Caucasian subjects, the odds ratio (OR) for the minor variant among T1D subjects was 1.30 (1.06-1.59, p=1.42x10-2), similar to previous reports. Among African American subjects, the minor variant OR was elevated (2.93, 1.22-7.03, p=1.30x10-2), representing the most highly-associated non-HLA gene. Complete blood count (CBC, n=954) and flow cytometric human immunophenotyping (HIP, n=252) were performed on a subset of subjects. Individuals carrying the risk variant of SH2B3 had significantly more blood monocytes and neutrophils but similar numbers of lymphocytes compared to non-carriers. HIP revealed a significantly higher frequency of type 1 (CXCR3+) CD8+ T cells in subjects with the risk variant of SH2B3.

Conclusions: The risk variant of SH2B3 is associated with both increased risk for T1D and seroconversion in Caucasian and African American subjects. Phenotypically, this element of T1D genetic risk presents as increased frequency of some myeloid cell populations and either expansion or polarization of CD8+ T cells bearing the canonical Th1 chemokine receptor CXCR3.

Disclosure

A. Camargo: None. D.J. Perry: None. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis. M.A. Wallet: None.
Do Statins Adversely Affect Skeletal Muscle Function?
Authors: CORTES TIFFANY M. , DASARI SURENDRA , ROBINSON MATTHEW M. , NAIR K. SREEKUMARAN
Published: June 2018

Objective: Statins are well known to cause myalgia and in very rare cases rhabdomyolysis. It remains to be determined whether statin treatment causes any adverse effects on muscle precluding benefits of exercise. We investigated the impact of statin therapy on exercise capacity, muscle strength, mitochondrial respiration, and gene expression in older adults before and after a 12 week exercise program consisting of either aerobic interval (HIIT), resistance (RT), or combined aerobic and resistance (CT) training.

Design: Participants aged 65 and older reported in a prior exercise study were analyzed to determine the impact of statin use. Anthropometric measurements, muscle strength, exercise tolerance and a muscle biopsy for determination of mitochondrial respiration and gene transcripts (RNA sequence) were obtained at baseline and then repeated after 12 weeks of exercise training.

Results: Among participants, 7 were in CT (2 on statins, 5 not on statins), 8 were in HIIT (4 on statins, 4 not on statins), and 8 were in RT (2 on statins, 6 not on statins) groups. Statin and non-statin users at baseline had no observed significant difference in BMI (p=0.936), VO2 (p=0.812), leg press strength (p=0.916), state 2 respiration (p=0.266), state 3 respiration complex I and II (p=0.345), stage 4 respiration (p=0.231) or gene transcripts of 15232 genes examined. Following 12 week exercise program, no significant differences were noted between statin and non-statin users in their BMI (9=0.149), VO2 (p=0.681), leg press strength (p=0.925), state 2 respiration (p=0.078), state 3 respiration complex 1 and II (p=0.142), or state 4 respiration (p=0.945). Significant differences were noted in gene transcripts in statin and non-statin users in CT+RT group (6 genes) and HIIT group (33 genes).

Conclusion: Although there is a slight difference in gene expression in statin and non-statin users, this difference does not have a significant effect on exercise tolerance, muscle strength or mitochondrial respiration after a 12 week exercise program.

Disclosure

T.M. Cortes: None. S. Dasari: None. M.M. Robinson: None. K. Nair: None.
Are Physical Activity Associations with Bone Mineral Density Modified by Metabolic Traits?
Authors: BUTTAN ANSHU , GUO XIUQING , IDA CHEN YII-DER , HSUEH WILLA , ROTTER JEROME I. , GOODARZI MARK O.
Published: June 2018

We assessed the relationship of physical activity with BMD at various sites (by DEXA), and examined potential modifying factors, including insulin sensitivity by euglycemic clamp in 765 healthy subjects. Responses from physical activity questionnaires were used to determine total physical activity (PA), moderate physical activity (mod-PA), and sedentary time. Neither activity nor sedentary time correlated with rib, L-spine, or T-spine BMD in univariate analysis (Table). Significant univariate variables were included in multivariate analyses. In multivariate analyses of arm BMD, only female sex (β=-0.74, P<0.0001) and adiponectin (β=-0.08, P=0.016) were significant. Multivariate analyses of pelvis BMD found independent associations with BMI (β=0.35, P<0.0001), female sex (β=-0.18, P=0.0003), PA (β=0.10, P=0.04), and mod-PA (β=0.12, P=0.024). Age (β=-0.11, P=0.003), female sex (β=-0.67, P<0.0001), BMI (β=0.25, P<0.0001), and mod-PA (β=0.11, P=0.005) were independently associated with leg BMD. These results suggest that BMD increases with the physical activity in the arms, legs, and pelvis and is inversely related to sedentary time in the pelvis and legs, and these associations may be modified by age, sex, BMI, and adiponectin, depending on the site, with physical activity being more important to pelvis and leg BMD than arm BMD. Sedentary time, CRP, PAI-1 and insulin sensitivity play a minor role in BMD.Table: Association of Activity and Metabolic Traits with Arm, Pelvis, and Leg BMDArm average BMDPelvis BMDLeg average BMDTotal physical activity (PA)r=0.20 (P<0.0001)r=0.11 (P=0.0033)r=0.20 (P<0.0001)Moderate PAr=0.36 (P<0.0001)r=0.11 (P=0.0036)r=0.33 (P<0.0001)Sedentary timeNot significantr=-0.09 (P=0.015)r=-0.09 (P=0.015)AgeNot significantNot significantr=-0.10 (P=0.0051)BMINot significantr=0.36 (P<0.0001)r=0.20 (P<0.0001)Sex (M-F mean difference)0.13 (P<0.0001)0.(P<0.0001)0.17 (P<0.0001)Adiponectinr=-0.22 (P<0.0001)r=-0.20 (P<0.0001)r=-0.18 (P=0.0002)C-reactive protein (CRP)r=-0.22 (P<0.0001)r=0.12 (P=0.012)r=-0.13 (P=0.0045)Plasminogen activator inhibitor-1 (PAI-1)Not significantr=0.13 (P=0.0045)r=0.12 (P=0.015)Insulin sensitivityr=0.13 (P=0.0005)r=-0.20 (P<0.0001)Not significant

Disclosure

A. Buttan: None. X. Guo: None. Y. Chen: None. W. Hsueh: Advisory Panel; Self; Merck & Co., Inc., AstraZeneca, Novo Nordisk Inc.. J.I. Rotter: None. M.O. Goodarzi: None.
Decreased Bioelectrical Impedance Phase Angle in Children and Adolescents with Newly Diagnosed Type 1 Diabetes—A Case-Control Study
Authors: WIECH PAWEł , BAZALINSKI DARIUSZ , BINKOWSKA-BURY MONIKA , KORCZOWSKI BARTOSZ , DąBROWSKI MARIUSZ
Published: June 2018

Bioelectrical impedance phase angle (PA) is considered to be the most sensitive indicator of the nutritional and functional status. The aim of this study was to assess the body composition and nutritional status of children and adolescents with newly diagnosed type 1 diabetes (T1DM) by using bioelectrical impedance analysis (BIA) with PA calculation. PA has not been evaluated in such population yet.Study group consisted of 63 children and adolescents (28 girls) aged 4 to 18 years, with newly diagnosed T1DM. The same number of healthy girls and boys, without diabetes or other chronic disease having impact on the nutritional status, strictly matched by gender and age in a 1:1 case-control manner consisted control group. In both groups a BIA was performed and PA was calculated to assess the body composition and nutritional status. In T1DM patients BIA was performed after acid-base and water-electrolyte balance were normalized.Results are summarized in the table. Mean HbA1c at the time of T1DM diagnosis was 11.37 ± 2.26%. No correlation between PA and HbA1c was found.

In conclusion, the lower PA score together with lower MM%, BCM% and BCMI in children and adolescents with T1DM indicate their worse nutritional and functional status compared to healthy subjects. To assess the predictive and prognostic value of these findings further prospective studies in this population are required.

Disclosure

P. Wiech: None. D. Bazalinski: None. M. Binkowska-Bury: None. B. Korczowski: None. M. Dąbrowski: Other Relationship; Self; Ascensia Diabetes Care, AstraZeneca, Berlin-Chemie AG, Eli Lilly and Company, MSD K.K., Sanofi-Aventis, Servier.
Changing Food Patterns in Indian Children
Authors: JHINGAN ASHOK KUMAR
Published: June 2018

Introduction: Change in food patterns has played an important role in making children overweight and obese as seen in the recent years. It has become a matter of concern since one in five children studying in schools of Delhi, have been reported obese or overweight. These overweight and obese children have 70% risk of becoming over-weight/obese adults.

Methods: We conducted a study to observe the effect of food habits on children in 8 schools in Delhi. In this study 1155 children studying in class 3rd, 4th and 5th were included and a regular follow-up was done. A questionnaire was prepared to know about food habits, choice and change in food habits.

Results: The analysis of data revealed some disturbing facts about eating patterns and preferences for fast foods. It was observed, 39% of children preferred fast foods like burgers, pizzas, french-fries as compared to 11% who liked eating fruits. 44% of the children drink 1 soft drink per day. Class 3rd children, only 11% preferred fast food Class 4th children -the percentage remarkable increased to 39% preference for fast food. Class 5th children, alarming observation was that in Class 5th the percentage rose to 66% in these children for preference to fast food.

Discussion: The present study indicated that a lot of preventable factors like family members, television and media ads plays and important in increasing this preference for fast food in children. Children started developing preference for fast food from class 3rd and by the time they reached class 5th majority of them had developed a preference for the fast food.

Conclusions: Recommendations since the above category children have the highest incidence to become overweight / obese and this can lead to diabetes and it’s complications in adult years Intervention should be initiated from class 3rd onwards by family, schools authorities and media to create an environment so that children get inclined towards healthy food habits.

Disclosure

A. Jhingan: None.
Effectiveness and Tolerability of Vildagliptin plus Metformin Dual Therapy Compared with Insulin Secretagogue plus Metformin Dual Therapy in Patients with Type 2 Diabetes—A Real-World Study (China PDS)
Authors: CHEN LIXIAN , HAN YING , HU DAQING , JIN HUI , YANG NAILONG , SHI XIAOYUN , LI QUANMIN , LIANG LINLANG , ZANG LI , LIU MINGMING , HE JAMES , MU YIMING
Published: June 2018

Background and Aim: The China PDS aims to investigate the effectiveness and safety of vildagliptin dual therapy in type 2 diabetes mellitus (T2DM) patients. Here, we compared the vildagliptin plus metformin (VM) and insulin secretagogue plus metformin (ISM).

Materials and Methods: China PDS was a prospective, 1-year, real-world study conducted in 52 sites in patients with T2DM and inadequately controlled on monotherapy. Eligible patients were assigned either vildagliptin dual therapy or other dual therapy according to local physician’s decision. The proportions of patients with HbA1c<7%, without tolerability events (hypoglycemia, weight gain, or discontinuation due to gastrointestinal event), and tolerability were compared in VM and ISM in this study.

Results: In total, 933 patients received vildagliptin dual therapy with 64.7% for VM, while 670 patients received other dual therapy with 48.7% for ISM (Table 1). Compared with ISM (31.6%), VM (50.8%) had higher proportion of patients reaching the primary outcome (P<0.001; adjusted OR, 2.14; 95% CI, 1.59-2.87). VM (5.8%) had less tolerability events than ISM (16.4%) (RR, 0.386; 95% CI, 0.26-0.58).

Conclusion: China PDS demonstrates that in a real-life setting, VM was effective in glycemic control and was well tolerated when compared with ISM.

Disclosure

L. Chen: None. Y. Han: None. D. Hu: None. H. Jin: None. N. Yang: None. X. Shi: None. Q. Li: None. L. Liang: None. L. Zang: None. M. Liu: None. J. He: None. Y. Mu: None.