bluuebunny/crossref_metadata_2025 huggingface dataset:
Synchronized Microfluidic System to Dynamically Assess Pancreatic Islet Function beyond Glucose-Stimulated Insulin Secretion
Authors: NIEUWOUDT STEPHAN , MCDOWELL RUTH , ZHANG HUI , KIRWAN JOHN P.
Published: June 2018

The endocrine function of pancreatic islets goes beyond glucose stimulated insulin secretion (GSIS). Besides glucose, dynamic regulation through a variety of incretin hormones, drugs, and metabolites have been shown to modulate insulin secretion. The most commonly applied ex vivo and in vitro methodologies to study islet function are static in nature; carried out in standard well formats for extended incubation times. This approach ignores the dynamic nature of secretion and regulation thereof, and limits the complexity of scientific questions that may be posed. In the last decade several groups have begun using microfluidic devices to assess islet function in a dynamic environment, which aims to mimic a physiological bolus of glucose followed by imaging and secretory analysis. Thus far no commercial research device has been made available to the scientific community, requiring the in-house development of microfluidic islet analysis systems by groups aiming to take a more in-depth view of pancreatic islet function. We have developed a fabrication processes for poly-methyl methacrylate (PMMA) microfluidic chips, with micromilled channels and pockets into which islets will be hydrostatically trapped. These optically clear chips allow for direct fluorescent imaging of the trapped islets, with real-time calcium flux (Fura-2-AM) and mitochondrial potential (Rhodamine 123) assays. Using the I2C (Inter-Integrated Circuit, NXP Semiconductors) protocol, we are able to synchronize several microcontrolled syringe pumps (and a fraction collector) to produce precise concentrations of glucose, hormones, metabolites, and factors of interest in a time-dependent manner. This system has applications in our study of the effects of bariatric surgery (in rodents) on pancreatic islet function, as well as the mechanisms by which myokines may directly regulate pancreatic endocrine function.

Disclosure

S. Nieuwoudt: None. R. McDowell: None. H. Zhang: None. J.P. Kirwan: None.
The microRNA 199a Family Is Regulated by Glucose Levels in Pancreatic Beta Cells
Authors: DE CASTRO JOAO PEDRO WERNECK , BLANDINO-ROSANO MANOEL , BERNAL-MIZRACHI ERNESTO
Published: June 2018

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient availability and hormone/growth factors signaling to regulate cell metabolism; being essential to beta-cell mass and function. The microRNA 199a-3p negatively regulates translation of mTORC1 mRNA and impacts beta-cell function. We investigated how miR-199a expression is regulated in beta-cells by examining expression responses of miR-199a precursors genes (primiR-199-a1, a2 and b) and its mature forms (miR-199a-3p and -5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma (MIN6) cells treated with different stimuli. We found that islets from male and female mice equally express the mature miR-199a-3p and -5p. However, the primiR expression is different: while primiR-199a1 expression is 2-fold greater than primiR-199a2, primir-199b is barely detected in mouse islets. The same primiR expression profile was found in MIN6 cells except that only the mature miR-199a-3p is expressed. A 2-fold increase in primiR-199a1 and -a2 mRNA levels was observed by 24 h culture of mouse islets in high glucose compared to 5.5 mM. Similar responses to high and low glucose were observed in MIN6 cells as early as 6 h. Interestingly, 30 mM of KCl treatment was sufficient to prevent the low glucose-induced decline in primiR-199-a2 expression but not in 199-a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 also reveal that low glucose or 2-DG glucose-induced starvation decreases the primir-199a2 promoter activity and this decrease was rescued by KCl and Tolbutamide (Potassium channel blocker), confirming that calcium influx is playing a role. Indeed, blocking calcium channels with 20 uM Nifedipine reduced primiR-199-a2 promoter activity in MIN6 cells under 25 mM glucose.

In conclusion, we uncover that glucose regulates microRNA 199a family expression in beta cells and that glucose metabolism and calcium influx are involved.

Disclosure

J. Werneck de Castro: None. M. Blandino-Rosano: None. E. Bernal-Mizrachi: None.
The Association of Dispositional Mindfulness and Adverse Childhood Experiences with Glycemic Control among Young Adults with Type 1 Diabetes
Authors: NAGEL KATHRYN , DEARTH-WESLEY TRACY , HERMAN ALLISON N. , SMITH HANNAH G. , GANDICA RACHELLE , GOLDEN LAUREN , WEIL HENRY F. , WHITAKER ROBERT C.
Published: June 2018

To assess the potential of mindfulness practices to improve glycemic control in a diverse population of young adults with type 1 diabetes (T1D), we examined the cross-sectional association of hemoglobin (Hb)A1c levels with dispositional mindfulness and adverse childhood experiences (ACEs). In 2017 we conducted an online survey of all 19-31 year olds (y/o) with T1D receiving care at Columbia’s Naomi Berrie Diabetes Center. Responses were received from 423 of 752 (56%) patients and linked to medical record HbA1c. After adjusting for sociodemographic factors, HbA1c levels were compared between those with high and low mindfulness (median split) and those with (62%) and without ACEs (38%). The sample was 59% female and 69% non-Hispanic white, with a mean (SD) HbA1c of 8.0% (1.7). The relationship between HbA1c and mindfulness was moderated by age and ACEs. Among 27-31 y/o, those with high mindfulness had 0.7% lower HbA1c (95% CI:-1.2%, -0.2%) and this relationship was stronger in those with ACEs. The relationship between HbA1c and ACEs was also moderated by age. Among 23-26 y/o, those with ACEs had 0.4% higher HbA1c (-0.1%, 0.9%). Among 19-22 y/o, HbA1c levels were 0.5% higher in those with high mindfulness (-0.2%, 1.2%) and 0.8% lower in those with ACEs (-1.53%, -0.04%). The potential impacts of mindfulness practices for young adults with T1D may differ by age and history of ACEs.

Disclosure

K. Nagel: None. T. Dearth-Wesley: None. A.N. Herman: None. H.G. Smith: None. R. Gandica: None. L. Golden: None. H.F. Weil: None. R.C. Whitaker: None.
Sleep Disorders in Patients with Congenital Generalized Lipodystrophy
Authors: FERNANDES VIRGINIA O. , SILVA CARLA P. , MONTENEGRO ANA PAULA D.R. , PONTE CLARISSE M.M. , BATISTA LIVIA A.A. , PINTO THISCIANE F. , VASCONCELOS IZABELLA T. , KARBAGE LIA A.S. , FERNANDES PRISCILA M. , D'ALVA CATARINA B. , BRUIN PEDRO F.C. , MONTENEGRO RENAN M. ,   BRAZILIAN LIPODYSTROPHY STUDY GROUP (BRAZLIPO)
Published: June 2018

Background and Aims: Sleep disorders are often associated with the several metabolic complications. Congenital generalized lipodystrophy (CGL) is associated with severe insulin resistance, diabetes, dyslipidemia and hepatic steatosis in non-obese individuals, but there are no data evaluating the presence of sleep disorders in this condition.

The aim of this study was to describe the characteristics of sleep pattern in individuals with CGL and evaluate the presence of sleep disorders in these patients.

Materials and Methods: A cross-sectional study with 8 patients with CGL. It was performed a polysomnography following the guidelines of the American Academy of Sleep Medicine.

Results: There were 2 male and 6 female patients. The median age of these patients is 16,5 years old, ranging from 7 to 33 years old. All patients have hypertriglyceridemia and 6/8 had diabetes. Hepatic steatosis was observed in 4/8 cases (50%) and systemic arterial hypertension in 1/8 case (12,5%). Snore was observed in 7/8 (87,5%) of the sample. The diagnosis of obstructive sleep apnea syndrome was observed in 6/8 (75%) of the individuals, rapid eye movement sleep (REM) behavior disorder in 4/8 (50%), changes in sleep efficiency in 4/8 (50%), fragmented sleep in 8/8 (100%) and periodic leg movements in 7/8 (87,5%). There were no significant cardiovascular abnormalities in this study.

Conclusion: The patients with CGL evaluated showed a high frequency of sleep disorders. These findings in a young no-obese population, but with severe metabolic abnormalities, suggest its negative impact in sleep quality of these patients, increasing the cardiovascular risk in this population.

Disclosure

V.O. Fernandes: None. C.P. Silva: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. T.F. Pinto: None. I.T. Vasconcelos: None. L.A.S. Karbage: None. P.M. Fernandes: None. C.B. D'Alva: None. P.F.C. Bruin: None. R.M. Montenegro: None.
Morphological Changes of Platelets as a Marker of Early Progression of Diabetic Nephropathy
Authors: PERTSEVA NATALIIA , DARIA CHUB , IGOR TVERDOKHLEB
Published: June 2018

Aim: To study the main morphological changes of platelets in patients with type 1 diabetes mellitus (T1DM) depending on the level of estimated glomerular filtration rate (eGFR).

Materials and Methods: The study involved 37 patients with T1DM. Patients were divided to groups according to the level of eGFR (CKD-EPI, ml/min/1.73m²). Group 1 had eGFR ≥90; group 2 - eGFR 89-60; group 3 - eGFR 59-45. Control group consists of 10 healthy people. All patients were comparable for age and sex. The relative content of unactivated, aggregated, degranulated platelets and the density of packaging of α-granules in the platelet were determined using a transmission electron microscope120kV TEMs (JEOL USA).

Results: Changes were found in all three groups compared to the control. Decrease of unactivated platelets (%) 69.7 (62.4; 77), 64.6 (55.5, 73.7), 47.8 (39.6, 56.0), 75.5 (66.2; 84.8), respectively; increase of aggregated platelets (%) 7.4 (6.58; 8.22), 10.6 (9.4; 11.8), 15.4 (14.3; 16.5), 6.8 (5.98; 7.62), respectively; increase of degranulated platelets (%) 7.2 (6.22; 8.18), 10.4 (9.53; 11.27), 21.0 (18.88; 22.12), 6.3 (5.2; 7.4), respectively; decrease of the density of packaging of α-granules in the platelet (mkm³/mkm³) 0.0962 (0.0632; 0.0994); 0.093 (0.06; 0.126), 0.067 (0.038; 0.096), 0.1(0.077; 0.139), respectively. In the study group revealed a direct correlation between eGFR and: unactivated platelets (ρ=0.77; p<0.001), density packing of α-granules (ρ=0.55; p <0.001); the inverse correlation between eGFR and: aggregated platelets (ρ=-0.63; p<0.001), degranulated platelets (ρ=-0.72; p<0.001).

Conclusions: Morphological substrate of platelets damage is a complex of ultrastructural changes, which is an early predictor of the development of vascular complications. Morphological changes of platelets are detected with stored eGFR. Stronger changes correspond to low eGFR, that gives us to consider a complex of ultrastructural platelets changes, as an early sign of diabetic nephropathy.

Disclosure

N. Pertseva: None. C. Daria: None. T. Igor: None.
Retinal Thickness Is Not Associated with Renal Function in Diabetes
Authors: PATERSON EUAN N. , RAVINDRAN MEERA , GRIFFITHS KAYLEIGH , MCCARTER RACHEL V. , LE VELLY CLAIRE A. , MACGILLIVRAY THOMAS J. , HARBINSON MARK , MAXWELL ALEXANDER P. , HOGG RUTH E. , MCKAY GARETH J.
Published: June 2018

Introduction: Spectral domain optical coherence tomography (SD-OCT) has made possible in vivo investigation of the segmented neural retinal layers of the eye. Following previous reported associations between retinal segmentation and choroidal thickness with renal function in a healthy population, we assessed associations in a cohort with multiple co-morbidities related to diabetes, kidney and cardiovascular disease.

Methods: Cross-sectional data was collected from adults attending nuclear cardiology and renal medicine clinics. All participants were imaged with SD-OCT (Heidelberg Spectralis) using Enhanced Depth Imaging. Measurements included macular, retinal nerve fibre layer and choroidal thickness, and macular volume. Blood and urinary measurements were taken, including estimated glomerular filtration rate (eGFR), urinary protein and plasma C-reactive protein (CRP). Linear regression was used to assess associations with adjustment for age, mean arterial blood pressure (MABP), gender, CRP, BMI, LDL, and retinopathy status.

Results: Of 241 participants, 93 (39%) had diabetes mellitus, a mean age of 65 years (standard deviation [SD] 9), MABP of 99 mmHg (SD: 13) and mean eGFR of 67 ml/min/1.73m2 (SD: 25). Diabetes was associated with lower retinal thickness across the macula and reduced choroidal volume (B = -0.07, 95% confidence interval (CI) -0.14, -0.01, p = 0.04) although failed to remain significant in the fully adjusted model. In individuals with diabetes, a thinner retina was associated with lower eGFR although this also did not remain significant following adjustment for confounders.

Conclusion: In this cohort of high disease burden, diabetes was associated with lower retinal thickness and choroidal volume but did not remain significant following adjustment for confounders. Similarly, lower retinal thickness was associated with reduced eGFR in individuals with diabetes, but these associations also did not remain significant following adjustment for associated confounders.

Disclosure

E.N. Paterson: None. M. Ravindran: None. K. Griffiths: None. R.V. McCarter: None. C.A. Le Velly: None. T.J. MacGillivray: None. M. Harbinson: None. A.P. Maxwell: None. R.E. Hogg: None. G.J. McKay: None.
Does Improving Glycemic Control Accelerate Healing of Diabetic Foot Ulcers?
Authors: PATIL MADHURI D. , GUNASEKARAN UMA , FONTAINE JAVIER LA , MENEGHINI LUIGI
Published: June 2018

Diabetic foot ulcers (DFU) are common, complex and costly. Chronic hyperglycemia is associated with delayed wound healing and lower limb amputations. We performed a systematic review of literature looking for studies that assessed the impact of change in glycemic control on DFU healing.

Our search included key words such as ’glycemic control’, ’glycated hemoglobin (HbA1c)’, cross-linking them with text such as ’diabetic foot ulcer’, and ’wound healing’. We included published articles and studies in English with at least one component of observation or intervention that included effect of change in glycemic control and/or HbA1c on DFU healing; we excluded studies involving only DFU related amputations as outcome.

Six studies were identified- 1 randomized controlled trial (RCT), 2 observational studies, 1 pre-post study, 1 case report and 1 pooled analysis. All studies were heterogeneous in design, sample size, duration, patient characteristics, DFU characteristics, and end points or outcomes, including the manner in which glycemia was measured. While the RCT was inconclusive due to recruitment failure, the observational studies did show a relationship between wound healing and improvement in glycemic control. The pre-post study and case report described considerable improvement in healing rates of DFU that had been previously resistant to conventional care, after strictly controlling glycemia. The pooled analysis demonstrated that worsening glycemic control during DFU treatment significantly decreased the odds of wound healing.

Surprisingly, there exists a major gap of evidence with regards to whether prospectively lowering glycemic exposure improves DFU outcomes in patients with diabetes. The absence of a proper RCT, the heterogeneity of the existing studies, and the lack of consistency in their findings warrant a well designed prospective, randomized, controlled study to clearly establish whether aggressive glycemic control should be a standard in the management of diabetic foot ulcers.

Disclosure

M.D. Patil: None. U. Gunasekaran: None. J. La Fontaine: None. L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Sanofi US, Novo Nordisk Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; American Diabetes Association.
Analysis of Social Networks and Physical Activity Performed in the Management of Patients at Risk for Diabetic Foot—A Pilot Study
Authors: FRANCIA PIERGIORGIO , TEDESCHI ANNA , GULISANO MASSIMO , IANNONE GIULIA , VITTORI ALESSANDRO , SANTOSUOSSO UGO , PATERNOSTRO FERDINANDO , ANICHINI ROBERTO
Published: June 2018

Considering that the knowledge and control of the daily physical activity performed (PAP) is an important element in the management of patients with history of foot ulcers, peripheral neuropathy and/or peripheral vascular disease (at risk), the analysis of the social network map (SNM) perceived by themselves directly could also provide useful information to manage their diabetes. This study aimed to verify the possibility to evaluate the presence of a relationship between the characteristic of the SNM perceived and the PAP in addition to the metabolic control maintained in patients with longstanding diabetes mellitus at risk of foot ulcer. Interviews were conducted in 27 people: 10 patients: (males/females:6/4), mean age 56,2±16,7 years, duration of diabetes 18,3±10,3 years, mean HbA1c 8,0±1,1%, body mass index (BMI) 27,0±4,1 kg/m2, and in 17 age, sex and BMI matched nondiabetic controls. Participants were asked to fill in an egocentric SNM, which was divided into 5 areas: leisure and PAP, family, job, health care, and other. It was assigned a value ranging from 0 (none) to 5 (maximum) to define the importance and frequency of the relationships reported. The PAP was evaluated by the International Physical Activity Questionnaire-Short Form (IPAQ). In the patient group the duration of the disease was directly correlated with the health area (r = 0.83, p <0.1) while the level of physical activity reported (IPAQ) was inversely correlated with the family area (r = -0.74; p <0.01). The importance of friendly societies reported was lower in the patient group (1.0 ± 2 vs. 3.8 ± 1.5; p <0.01) while the area of leisure activities was inversely correlated with metabolic control (r = -0.65; p <0.05) and directly correlated with disease duration (r = 0.75; p <0.01). The results of this pilot study showed that the analysis of patients’ SNM could improve knowledge and therefore provide additional information useful for better management of these patients.

Disclosure

P. Francia: None. A. Tedeschi: None. M. Gulisano: None. G. Iannone: None. A. Vittori: None. U. Santosuosso: None. F. Paternostro: None. R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group.
Air Pollution Exposure during Pregnancy and Lactation Induces Obesity and Glucose Intolerance in the Offspring
Authors: ZORDÃO OLIVIA P. , CLARO LAÍS W. , SALDIVA PAULO , DONATO JOSE , VERAS MARIANA , PRADA PATRICIA O.
Published: June 2018

Air pollution has been a very significant environmental cause of diseases globally. Fine particulate matter (PM2.5) is one of the most toxic substances in air pollution and is associated with type 2 diabetes mellitus risk. However, there is a gap in knowledge regarding the effects of air pollution exposure on insulin resistance and obesity development. We aimed to investigate whether 3 months of PM2.5 exposure induces obesity, hypothalamic leptin resistance and inflammation in adult mice. Also, we aimed to determine whether PM2.5 exposure during pregnancy and lactation changes food intake (FI), energy expenditure, body composition and weight, glucose, and insulin metabolism in the offspring. Three months of PM2.5 exposure decreased O2 consumption measured by CLAMS, and increased body weight and fat mass in adult mice without FI changes. These mice presented hypothalamic leptin resistance with decreased STAT3 phosphorylation and enhanced IKK epsilon (IKKe) expression measured by immunofluorescence and Real-Time PCR. Knocking down IKKe, partially reversed this phenotype. PM2.5 exposure during pregnancy and lactation increased body weight and fat mass of male offspring, observed by a MicroPet CT analysis, accompanied by decreased FI and increased respiratory exchange ratio. Male offspring presented higher serum insulin levels and glucose intolerance measured by GTT despite normal insulin tolerance measured by ITT. Female offspring had no phenotype alterations, except by the light reduced food intake.

In conclusion, PM2.5 exposure during adulthood induced obesity, partially due to a marked reduction in energy expenditure caused by hypothalamic leptin resistance. Elevated inflammation may explain that with a significant role of IKKe in the hypothalamus. Air pollution exposure during pregnancy and lactation had a remarkable effect inducing obesity in the male offspring due to an energy unbalance, which may lead to increased insulin levels and glucose intolerance.

Disclosure

O.P. Zord o: None. L.W. Claro: None. P. Saldiva: None. J. Donato: None. M. Veras: None. P.O. Prada: None.
Immunomodulation of Dendritic Cells Using Tannic Acid-Based Capsules
Authors: FEDUSKA JOSEPH , TSE HUBERT M.
Published: June 2018

In type 1 diabetes (T1D), insulin-secreting β-cells are destroyed by autoreactive immune cells, for which tolerance to β-cell antigens is lost. Dendritic cells (DC) are potent antigen-presenting cells in the activation of autoreactive T cells during T1D progression. Activation of naïve CD4 T cells relies on three signals: 1.) binding of the T cell receptor with processed antigenic peptides presented by MHC-II complex, 2.) co-stimulatory molecule interactions, and 3.) synthesis of pro-inflammatory cytokines and reactive oxygen species. We previously demonstrated that dissipation of this third signal impairs autoreactive T cell activation. In this study, we tested the hypothesis that encapsulation of putative T1D autoantigens with an antioxidant-containing biomaterial would induce immune tolerance, following phagocytosis by activated DC. We generated bone marrow-derived DC and co-cultured these cells with LPS and microcapsules comprised of a neutral polymer and multilayers of tannic acid (TA), a known antioxidant. Induction of a tolerogenic DC phenotype was assessed by expression of pro-inflammatory cytokine mRNA by qPCR and secretion of cytokines by ELISA. Our data show that a subgroup of TA-based microcapsules can blunt DC responses, as shown by a significant decrease in mRNA accumulation of the pro-inflammatory cytokines Tnfa (p ≤ 0.01) and Il12b (p ≤ 0.01), as well as the chemokine Cxcl10 (p ≤ 0.01). We also observed a significant decrease in secreted IL-12p70 as measured by ELISA. Future studies will encapsulate autoantigens such as insulin and following phagocytosis, determine if a tolerogenic DC phenotype can abrogate autoreactive T cell responses.

Disclosure

J. Feduska: None. H.M. Tse: None.
Metagenomic and Functional Analysis of Athletes Identify an Exercise-Promoting Microbiome
Authors: KOSTIC ALEKSANDAR
Published: June 2018

To characterize the athlete microbiome, we have sequenced stool samples from marathon runners, ultramarathon runners, Olympic-caliber rowers, and sedentary controls (n=50) with each individual providing on average 7 samples (∼350 samples total). We have identified substantial alterations to the microbiome associated with athletic performance. In particular, we identified a bacteria genus, Veillonella, that increases in abundance after exercise. Veillonella’s primary source of energy is lactate - a metabolite that accumulates in the blood after exercise and is associated with fatigue. Through de novo assembly of ∼40 million contigs, we have developed a novel reference database from our athlete metagenomic/metatranscriptomic data sets - which consists of >2.5 million none redundant genes. Querying this database has yielded insights into potentially significant allelic variation, at the microbiome gene-level, involved in lactate related metabolic processes as well as multi’omic evidence of pathways that change between performance and recovery states. To validate this, we have isolated from our samples three species from this and introduced this cocktail of isolates to C57BL/6 mice prior to exhaustive exercise on a treadmill. Gavage of the Veillonella cocktail to mice four hours prior to exercise results in a significant decrease in serum lactate (lactate AUC of 40.31 mmol/L*hr relative to 66.07 mmol/L*hr in sham control mice; P < 0.05). Follow-up work currently being conducted involves assessing the role of Veillonella’s primary metabolic end product, the short chain fatty acid propionate, on limiting exercise-induced inflammation, and the effects of these components on recovery from exercise. Taken together, our study encompasses both high-resolution metagenomic analysis and experimental validation to understand the role that the microbiome naturally plays in the performance of elite athletes.

Disclosure

A. Kostic: None.
Accelerate the Self Understanding of Blood Glucose through the Summary Screen (ACCESS STUDY)
Authors: SUZUKI KATSUNORI , HASEGAWA KAZUKI
Published: June 2018

We previously assessed the effectiveness of a simple self-monitored blood glucose(SMBG) device with the function to display whether a blood glucose level is high or low in different colors (C device) (REFLECT STUDY, 2012 ADA), which reported that an interventional group using the C device and patient education materials showed a significant decrease in HbA1c compared to a group using a monochrome-display device. In our new ACCESS Study, we evaluated the effectiveness of a new SMBG device with an additional summary screen that shows past blood glucose patterns (device V) and a new educational material that advises on such blood glucose patterns. Outpaitients with diabetes mellitus (N=94, HbA1c 7.41 ± 0.85%) were randomly assigned to either an intervention group (N=50) where patients were switched from device C to device V with the new educational material, or to a non-intervention group (N=44) where patients were just switched from device C to device V and did not receive the new educational material. We evaluated the changes in HbA1c and patient satisfaction survey scores 8 weeks later. There was no significant difference in the change in HbA1c at 8 weeks between the intervention group (-0.06%; -0.165 to 0.045) and non-intervention group (-0.01%; -0.136 to 0.113). According to the results of the satisfaction survey, the intervention group showed a higher satisfaction in "Recognition of patterns/trends in blood glucose levels." There was a tendency in improvement of blood glucose pattern/trend recognition by patients by the intervention, there was no impact on HbA1c improvement. However, the outcomes of this study may have been affected by the short 8-week duration, as well as the fact that it was conducted during the period of seasonal change. Since device V and the new educational material improves blood glucose pattern/trend recognition, the results may have been different if a specific plan for blood glucose improvement tailored to each patient was further conveyed to each patient.

Disclosure

K. Suzuki: None. K. Hasegawa: None.
Development of a Glucose Sensor Using Palladium Electrode
Authors: HAN TAESUNG , NODA SAYAKA , HANEDA KEIGO , SHIGETOU NOBUYUKI
Published: June 2018

An amperometric glucose sensor was introduced where glucose oxidase was immobilized on palladium electrode. This sensor based on the glucose oxidase catalyzed oxidation of glucose and electrochemical oxidation of hydrogen peroxide which was produced by enzyme reaction. Basic concept of the glucose sensor is composed of inner and outer membrane systems, immobilized glucose oxidase layer, and palladium electrode. Inner membrane prevents the access of electrochemical interfering substrates. Outer membrane works as a diffusion barrier of glucose. The glucose sensor can achieve a wide dynamic range with this outer membrane. In this research, to verify this concept especially the role of outer membrane, the glucose sensor which was made with palladium electrode, glucose oxidase layer, and outer membrane was tested on different glucose concentrations. The sensor showed a good correlation between sensor responses and glucose concentrations. In addition, the dynamic range of this sensor was enough for glucose monitoring of diabetic patients. This sensor also demonstrated stable sensor responses during several days. These results show that this sensor has a strong potential for application to continuous glucose monitoring, or CGM.

Disclosure

T. Han: Employee; Self; Panasonic Healthcare Co., Ltd. S. Noda: Employee; Self; Panasonic Healthcare Co., Ltd. K. Haneda: Employee; Self; Panasonic Healthcare Co., Ltd. N. Shigetou: Employee; Self; Panasonic Healthcare Co., Ltd.
Maternal Obesity Is Associated with Reduced Hippocampal Volume in Children
Authors: PAGE KATHLEEN A. , LUO SHAN , WANG XINHUI , ALVES JASMIN , MARTINEZ MAYRA P. , XIANG ANNY
Published: June 2018

Offspring exposed to maternal obesity in utero are at increased risk for the development of metabolic disorders. Recent evidence also links exposure to maternal obesity with impaired cognition during childhood. While the underlying mechanisms are unclear, studies in animals have shown that fetal exposure to maternal obesity causes decreased neurogenesis in the dentate gyrus and impaired hippocampal learning. The hippocampus is important for memory, and its development is sensitive to the in utero metabolic environment. We tested the hypothesis that in utero exposure to maternal obesity would be associated with reduced hippocampal volume in children. Sixty-seven children (41 girls, 26 boys) ages 7 to 11 years participated in the study. Children were born at Kaiser Permanente Southern California. Maternal pre-pregnancy BMI was obtained from electronic medical records. Children’s height and weight were measured, and a high-resolution anatomical scan was performed using a 3 Tesla MRI. Total hippocampus volume and hippocampus subfield volumes were analyzed using FreeSurfer 6.0. Linear regression was used to investigate relationships between maternal pre-pregnancy BMI and child hippocampus volume. Maternal pre-pregnancy BMIs ranged from 19.0 to 50.4 kg/m2. Children’s BMI z-scores ranged from -1.8 to 2.6. Maternal pre-pregnancy BMI was negatively correlated with total hippocampus volume, adjusting for child age, sex, BMI-z score, intracranial volume (P=0.05). Results remained after further adjusting for maternal diabetes exposure (P=0.04). A 5-unit increase in maternal pre-pregnancy BMI was associated with 78 mm3 (95% CI:3.3-152.8 mm3) reductions in total hippocampus volume. The inverse correlation was also observed in CA3 (P=.04), CA4 (P=.03), dentate gyrus (P=.03) and subiculum (P=.01) subfields, adjusting for the same covariates. Our results suggest that exposure to maternal obesity adversely impacts hippocampus volume in children, and this impact is uniform across subfields.

Disclosure

K.A. Page: None. S. Luo: None. X. Wang: None. J. Alves: None. M.P. Martinez: None. A. Xiang: None.
Risk Factors for Hypoglycemia in Patients with Diabetes Mellitus
Authors: MIZOGUCHI ASAKO
Published: June 2018

Aims/Introduction: We utilized a continuous glucose monitoring device to analyze risk factors for hypoglycemia (defined as a blood glucose level <70 mg/dL) in outpatients with diabetes mellitus.

Materials and Methods: We utilized a continuous glucose monitoring device in 100 out patients (50 of whom were male, 19 of whom were type 1 diabetes, 73 of whom were type 2 diabetes)from April 2017 to October 2017. We use FreeStyle Libre for up to 14 days. We excluded CGM date within 24 hours because those data are not accurate.

Results: Hypoglycemia risk was higher in the patients whose body weight is lighter (72.3±18.0 vs. 57.0±11.3kg,P=0.001), and lower in patients who take more oral hypoglycemic agent (2.2±0.9 vs. 1.5±1.3 kind of medications,P=0.005) and higher in patients who use much insulin (0.27±0.20 vs. 0.41±0.22 units/kg/day,P=0.034) 70 patients have hypoglycemia and 30 of whom are unaware hypoglycemia. Patients with unaware hypoglycemia are significantly older (66.7±14.7vs73.6±11.2 years old P=0.035) and their body weight is significantly lighter (66.3±16.7 vs. 58.0±10.2kg,P=0.013) and their HbA1c is lower (7.5±1.2 vs. 7.0±0.7% P=0.048) and those with a lower average blood glucose level had a significantly higher risk (OR 1.09, 95% CI: 1.06-1.12, P < 0.0001). Patients who has nocturnal hypoglycemia are significantly shorter (161.5±10.4 vs. 157.0±8.0cm,P=0.026) and their body weight are significantly lighter (69.3±16.1 vs. 55.2±10.4kg P<0.001) and their standard deviation is bigger (45.4±18.3 vs. 56.9±20.0 mg/dl P=0.005)

Conclusions: In outpatients,77% patients have hypoglycemia (42% of whom are unaware). The hypoglycemia risk was higher in the patients whose body weight is lighter, and lower in patients who take more oral hypoglycemic agent and higher in patients who use more insulin. Therefore it is important to utilize a continuous glucose monitoring device in such patients and to ensure comprehensive blood glucose control in such patients to prevent hypoglycemia.

Disclosure

A. Mizoguchi: None.
Long-Term Use of Omnipod® Insulin Management System Associated with Lower A1c in Adults with Established Diabetes and A1c =8%
Authors: TINSLEY LIANE J. , LAFFEL LORI M. , GUO ZIJING , NAIK NISHA , LAYNE JENNIFER E. , LY TRANG T. , MEHTA SANJEEV N.
Published: June 2018

Tubeless patch pumps may offer unique benefits enhancing long-term glycemic benefits seen in adults with diabetes starting continuous subcutaneous insulin infusion (CSII) therapy. We retrospectively evaluated adults with diabetes >6 months to assess changes in A1c and weight 1 year after initiating the Omnipod® Insulin Management System (Insulet Corp., Billerica, MA). Changes were assessed by baseline A1c category (<7.0%, 7.0-7.9%, 8.0-8.9%, and ≥9.0%) and then stratified by prior insulin regimen (MDI 65%, CSII 35%). At Omnipod initiation, 195 patients (39% male, 97% T1D) had (mean±SD) age 42±14 years and diabetes duration 21±14 years. Baseline A1c and weight were 7.9±1.3% and 175±36 lbs with no significant differences according to prior regimen. After 1 year, patients had 0.2% A1c reduction (p<.05) and non-significant weight change (+0.8 lb). Significant A1c reductions were noted in adults with baseline A1c ≥8% (A1c 8.0-8.9%: -0.3% (p<.05) and A1c ≥9.0%: -1.1% (p<.005). Modest to no increase in A1c was found in patients with baseline A1c <8% (A1c <7.0%: +0.2% (p<.05) and A1c 7.0-7.9% (p=NS). Weight did not change across all A1c categories. The Table shows changes in A1c by insulin regimen before Omnipod initiation. In adults with diabetes and A1c ≥8%, Omnipod initiation was associated with significantly lower A1c, most notably in those transitioning from MDI.Change in A1c 1 Year after Omnipod Initiation by Baseline A1c and Insulin RegimenBaseline A1c (%)n (MDI/CSII)MDI, Baseline A1c (%)MDI, ∆A1c (%)CSII, Baseline A1c (%)CSII, ∆A1c (%)<7.023/146.4±0.40.4†6.3±0.6-0.047.0-7.949/307.5±0.30.17.4±0.30.3*8.0-8.929/108.4±0.3-0.3*8.6±0.3-0.2≥9.025/1510.0±1.3-1.5†9.6±0.6-0.4†p<.005, *p<.05

Disclosure

L.J. Tinsley: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC.. Z. Guo: None. N. Naik: None. J.E. Layne: Employee; Self; Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation. S.N. Mehta: None.
Increased Prevalence of Diabetes Mellitus after Lung Transplantation
Authors: LEUNG JOSEPH M. , ALMEHTHEL MOHAMMED , PARTOVI NILUFAR , YEE JOHN , LEVY ROBERT , PATY BREAY
Published: June 2018

Introduction: Cardiovascular (CV) disease is a significant cause of mortality after lung transplant. However, the prevalence of diabetes and CV risk factors has not been well-characterized in this setting.

Methods: Using an electronic database and chart review, we collected and analyzed retrospective data before and 12-months after lung transplant at our institution between 2010-2016 (n=172).

Results: Between pre-transplant and 12-months post-transplant, there were increases in diastolic BP (71.2 vs. 76.5 mmHg, p<0.0001); weight (71.5 vs. 78.8 kg, p <0.0001); BMI (24.5 vs. 27.0 kg/m2, p <0.0001); prevalence of diabetes (21.5% vs. 41.4%, p <0.0001); and prevalence of dyslipidemia (20.9% vs. 30.3%, p <0.0001). Also, more post-transplant patients used long-acting insulin (6.43% vs. 12.90%, p=0.047) and beta-blockers (8.77% vs. 18.71%, 0.0087), but fewer patients took ACE/ARB (23.39% vs. 11.61%, p=0.0055). There were no differences in A1C (6.4% vs. 6.1%, p=0.29), fasting plasma glucose (FPG) (5.96 mmol/L vs. 5.49 mmol/L, p=0.35), or proportion of patients taking metformin (5.85% vs. 2.58%, p=0.15), sulfonylurea (3.51% vs. 0.65%, p=0.075), short-acting insulin (5.85% vs. 9.03%, p=0.27), statin (18.71% vs. 13.55%, p=0.21), any anti-hyperglycemic (13.45% vs. 16.77%, p=0.40), or any anti-hypertensive (36.84% vs. 30.97%, p=0.26).

Conclusion: The prevalence of diabetes and CV risk factors observed 12-months after lung transplant was increased compared to pre-transplant. The reasons for this are unclear, but may be related to immunosuppressive medication. Although the prevalence of diabetes is higher after transplant, the lack of differences in A1C and FPG may reflect the greater use of long-acting insulin in post-transplant patients with diabetes. Further study is needed to determine whether these risk factors contribute to an increased risk of adverse clinical outcomes and whether more systematic surveillance and management of these risk factors might mitigate this risk.

Disclosure

J.M. Leung: None. M. Almehthel: None. N. Partovi: None. J. Yee: None. R. Levy: None. B. Paty: None.
A Phase 1b/2a Study of Glutazumab for the Treatment of Type 2 Diabetes and Obesity
Authors: JING SHUQIAN , ZHANG CHENG , FAN KESUO , GUO YONG
Published: June 2018

Glutazumab is a humanized anti-GLP-1 receptor monoclonal antibody carrying a GLP-1 fragment. Previous in vitro and in vivo studies showed that glutazumab possessed some biased activities toward different signaling pathways of GLP-1 receptor. As a result, glutazumab exhibited significantly better safety profiles than dulaglutide (Trulicity) in our preclinical cynomolgus and phase 1a clinical studies. Although the potencies or efficacies of glutazumab and dulaglutide appeared similar to each other in all studies, the maximum tolerable dose of glutazumab determined either in preclinical cynomolgus or in phase 1 clinical studies was 3 times higher than that of dulaglutide. A randomized, placebo-controlled, double-blind, semi-sequential dose escalation phase 1b/2a study was recently initiated to further evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of glutazumab in type 2 diabetes patients. Preliminary results further indicated the well-tolerated safety profile and the glucose lowering effects of glutazumab.

Disclosure

S. Jing: None. C. Zhang: None. K. Fan: None. Y. Guo: None.
Physical Inactivity and Sleep Inefficiency Accentuate the Genetic Risk of Obesity
Authors: WOOD ANDREW R. , JONES SAMUEL E. , RICHMOND REBECCA , AHMAD SHAFQAT , YAGHOOTKAR HANIEH , BEAUMONT ROBERT , RUTH KATHERINE S. , TUKE MARCUS , MURRAY ANNA , FREATHY RACHEL M. , SMITH GEORGE DAVEY , LEE I-MIN , TIMPSON NIC , CHASMAN DANIEL , KUTALIK ZOLTAN , WEEDON MICHAEL N. , TYRRELL JESSICA , FRAYLING TIMOTHY M.
Published: June 2018

Gene-lifestyle interactions of relevance to type 2 diabetes have been difficult to identify but may help stratify groups of people at especially high risk. In large genetic studies, measures of diabetes risk factors such as diet and activity are usually limited to self-reported data. We used genetic and accelerometer data from 97,8individuals to test for genetic interactions with physical activity and sleep lifestyles. We tested the hypothesis that lower levels of physical activity and abnormal sleep patterns accentuate genetic susceptibility to obesity. We used 82,322 individuals from the UK Biobank, 10,885 from the Women’s Genome Health Study (WGHS) and 4,599 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We derived measures for physical activity and sleep, including total physical activity, time spent undertaking sedentary, light, moderate and vigorous activity, and sleep duration and sleep efficiency. We used BMI as the outcome and tested for interactions between a BMI genetic risk score (GRS) and the accelerometer derived measures of activity and sleep. We also performed several negative control experiments to test for residual confounding. We found evidence of gene-activity interactions. For example, in the UK Biobank, when analysing non-sedentary physical activity, the 10% of individuals carrying the most BMI-raising alleles were 5.9kg heavier if they were inactive compared to active (for height 1.73m). In contrast, the 10% of individuals carrying the fewest BMI-raising alleles were 4.1kg heavier if they were inactive compared to active (Pinteraction=4×10-4). This observation was consistent in the WGHS and ALSPAC data although not all tests reached P<0.05. The results were robust to negative control tests, including the testing of interactions using random variables simulating the BMI-activity correlations. Our results are consistent with previous studies suggesting that low levels of physical activity accentuate the genetic risk of obesity.

Disclosure

A.R. Wood: None. S.E. Jones: None. R. Richmond: None. S. Ahmad: None. H. Yaghootkar: None. R. Beaumont: None. K.S. Ruth: None. M. Tuke: None. A. Murray: None. R.M. Freathy: None. G. Davey Smith: None. I. Lee: None. N. Timpson: None. D. Chasman: None. Z. Kutalik: None. M.N. Weedon: None. J. Tyrrell: None. T.M. Frayling: None.
The Effect of Efpeglenatide on Lipid Profiles and Overall Metabolism in Patients with Type 2 Diabetes and Obese Patients without Diabetes
Authors: PRATLEY RICHARD E. , KANG JAHOON , CHOI IN YOUNG , TRAUTMANN MICHAEL E. , HOMPESCH MARCUS , YOON KUN-HO , SORLI CHRISTOPHER H.
Published: June 2018

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for T2D. Efpeg reduced blood glucose and body weight (BW) in Phase 2 trials in patients with T2D (EXCEED 203) and patients with obesity without diabetes (BALANCE 205; Table). To assess whether these effects were associated with benefits on lipids, the effects of efpeg QW on total cholesterol [TC], high [HDL-C], low [LDL-C], and very low density lipoprotein cholesterol [VLDL-C] and triglycerides [TG] were assessed in patients from these Phase 2 trials (VLDL-C measured in BALANCE 2only). In the 12-week EXCEED 203 study in patients with T2D, efpeg QW led to significant (p<0.05) reductions vs. placebo in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and BW (3-mg and 4-mg doses), and significant reductions in LDL-C and TG (4 mg only; Table). In the 20-week BALANCE 2study in nondiabetic patients with obesity, efpeg QW led to significant reductions vs. placebo in BW, HbA1c, FPG, TC, VLDL-C, TG (4-mg and 6-mg doses) and LDL-C and HDL-C (6 mg only). The safety profile of efpeg in both trials was consistent with GLP-1 RAs. These findings suggest that BW loss and glycemic effects with efpeg are accompanied by significant benefits on lipid profiles, providing an overall improvement in the abnormal metabolic state associated with T2D.

Disclosure

R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc. J. Kang: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. K. Yoon: None. C.H. Sorli: Employee; Self; Sanofi.
Euglycemic Diabetic Ketoacidosis—Newer Class of Medication Can Lead to Rare Presentation of an Old Foe
Authors: BREAUX BRITTANI M. , DIPP SUSANA L.
Published: June 2018

Background: Diabetic ketoacidosis (DKA) is a complication of diabetes mellitus (DM) that has high morbidity and mortality. Most are aware of diagnostic criterion including uncontrolled hyperglycemia, metabolic acidosis, and ketonemia. However, with the development of newer pharmacologic therapies, specifically the sodium-glucose co-transporter (SGLT2) inhibitor, we should be aware of a rarer presentation of DKA that may have normal serum glucose levels. We present a case euglycemic DKA.

Clinical Case: We present a 31 year old male with a past medical history of hypertension and type 2 DM, initially treated with glucophage. While this lowered his HgA1C, he self-discontinued therapy due to gastrointestinal side effects. He later developed symptoms of “acid reflux” and vomiting. He was admitted to an outside facility for hyperglycemia and acute kidney injury. DKA was ruled out, and his home regimen was adjusted to glucophage, canagliflozin, and sitagliptin. After starting the medications, he self-discontinued glucophage due to reoccurrence of symptoms, but continued canagliflozin and sitagliptin. Four days later, he presented to our clinic with additional symptoms of blurry vision and light-headedness. Canagliflozin was discontinued and stat labs were drawn. They were significant for acidosis (pH 7.16), elevated anion gap, elevated beta hydroxybutyrate, and a glucose level of 131 mg/dL (normal range: 70-120 mg/dL). Despite the relatively normal serum glucose, these findings were consistent with DKA. If one had focused on the serum glucose and not the entire biochemical picture, the diagnosis would have been overlooked.

Conclusion: Diagnosing and appropriate management of DKA, regardless of serum glucose, is critical for diabetic patients. With increasing use of newer anti-hyperglycemic medications, one must have a basic knowledge of the SGLT2’s direct/indirect effects that lead to increased counter regulatory hormones, as this mechanism can lead to euglycemic DKA.

Disclosure

B.M. Breaux: None. S.L. Dipp: None.