bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole Genome Sequence Association Analysis and Diabetes-centric Functional Annotation of Type 2 Diabetes
Authors: WESSEL JENNIFER , BRODY JENNIFER A. , MANNING ALISA ,   TOPMED DIABETES WORKING GROUP
Published: June 2018

Our understanding of the genetic basis of T2D has been significantly advanced by identification of T2D loci through analysis of common variation; however, evidence suggests a role for rare regulatory variation influencing T2D. We leveraged the largest available whole genome sequence (WGS) data from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) initiative and diabetes-centric genomic function data to the interpretation of results. We performed single-variant pooled-ancestry association analyses with (>30x deep sequence) WGS in 13,200 individuals (2,601 T2D and 10,599 controls) from 6 studies. The association analyses were performed in the Analysis Commons hosted on DNANexus. We demonstrated the utility of the OASIS (Omics Analysis, Search and Information System) platform and integrating diabetes-specific functional annotation in a recently discovered locus (GIP-IGF2BP1) to fine-map to the likely causal variants. Our results identified common (minor allele frequency [MAF] > 0.05) variant associations (P < 5 × 10-8) at a known locus with T2D: TCF7L2 (rs7903146, P = 3.8 × 10-12). We also identified a potentially novel association on Chr15q21 with 27 rare variants (MAF = 0.2%, P =1.3 × 10-8, r2=1) spanning a 7.5 MB region. In the Old Order Amish study, 53 individuals carry the haplotype tagged by these 27 variants; 17% of carriers are diagnosed with T2D compared to 3% of the non-carriers. Interrogation of the GIP-IGF2BP1 locus, utilizing diabetes-specific annotation and association evidence of both common and rare non-coding variants, within the OASIS browser implicated nearby genes in the region as being the likely biologic candidates.

In conclusion, preliminary results suggest WGS analysis can discover novel loci for complex traits. Work is ongoing to refine annotation for rare variant association tests and perform functional fine-mapping across the genome. We soon will extend our analysis into the next release of WGS data from TOPMed (N∼69,000 individuals).

Disclosure

J. Wessel: Employee; Spouse/Partner; Eli Lilly and Company. J.A. Brody: None. A. Manning: None.
Neighbourhood Deprivation and Quality of Life among People with Diabetes in England
Authors: ABUBAKARI ABDUL-RAZAK
Published: June 2018

Background: Income levels and Socio-economic status at the individual level are known to be associated with adverse health outcomes including risk of diabetes and its complications. However it is unclear how neighbourhood deprivation levels influence perceived quality of life among people with diabetes. This study investigated the relationship between neighbourhood deprivation and quality of life among people with diabetes attending two hospital trusts in Liverpool, England.

Methods: eligible participants completed a set of study questionnaires including demographic characteristics and the Audit of Diabetes Dependent Quality of Life questionnaire. Postcode based neighbourhood deprivation data were obtained from the UK’s Department for Communities and Local Government website. Relevant statistical analyses were undertaken using SPSS version 22.

Results: a total of 123 people with type 1 and type 2 diabetes participated in the study. Majority of participants were type 2 diabetes patients (53%) and about half were men (51%). Overall 20% of participants reported poor quality of life. Compared to those with type 2 diabetes, a higher proportion of people with type 1 diabetes reported good quality of life (58% vs. 61%; p<0.05). Poor neighbourhood deprivation was associated with poor quality of life, both in univariate and multivariate analysis (p<0.05). However, there was no significant association between neighbourhood deprivation and patients’ perceptions of how diabetes affected their quality of life (p>0.05).

Conclusion: Neighbourhood deprivation levels are significantly associated with quality of life among people with diabetes and could potentially be used to guide interventions aimed at promoting their health and well-being.

Disclosure

A. Abubakari: None.
Relationship between NK Cell Activity and Glucose Regulation in Type 2 Diabetes Patients
Authors: KIM JUNG HYE , PARK KAHUI , LEE SANG BAE , KIM MIN KYUNG , NAM JI SUN , KANG SHINAE , PARK JONG SUK , AHN CHUL WOO , KIM YU SIK
Published: June 2018

Introduction: NK cells are cytotoxic lymphocytes critical to innate immunity. The purpose of this study is to find out the difference in NK cell activity between type 2 diabetes patients and controls, and to investigate the association between NK cell activity and glucose control.

Methods: 49 subjects were enrolled in this study, with 23 type 2 diabetes patients and 26 normal glucose tolerant controls. Anthropometric and biochemical parameters were assessed. Homeostatic model assessment (HOMA) was calculated for insulin resistance. NK cell activity was measured using a newly developed NK Vueⓡ Kit (ATgen, Seoul), which is a method of detecting and comparing interferon-gamma level from NK cells.

Results: NK cell activity was lower in type 2 diabetes patients compared to control subjects. There was a significant inverse linear relationship between NK cell activity and fasting plasma glucose after adjusting for age and gender (r = -0.346, P = 0.045). Postprandial glucose and HbA1c showed a similar tendency with NK cell activity (r = -0.313 and -0.241, and P = 0.072 and 0.17, respectively). Regression analysis showed HbA1c, fasting glucose and postprandial glucose to be independent predictors of NK cell activity (beta = -0.303, -0.360, -0.356, and P = 0.034, 0.011, 0.033). There was no relationship between NK cell activity and HOMA-IR.

Conclusions: NK cell activity was lower in type 2 diabetes compared to controls, and it was significantly related to degree of hyperglycemia. A further, larger population study is warranted to confirm the possible correlation.

Disclosure

J. Kim: None. K. Park: None. S. Lee: None. M. Kim: None. J. Nam: None. S. Kang: None. J. Park: None. C. Ahn: None. Y. Kim: None.
Innate Lymphoid Cells—A New Medium That Berberine Affect Glycolipid Metabolism
Authors: TONG XIAOLIN , GUO XIAOHUAN , ZHAO LINHUA , GAO ZEZHENG , FU LIUHUI , WANG XINMIAO , LI QINGWEI , ZHENG YUJIAO
Published: June 2018

Diabetes mellitus (DM) is one of the most familiar chronic diseases threatening human health. Studies showed the occurrence and development of type 2 diabetes mellitus (T2DM) are closely related to obesity. Obesity gives rise to higher level expression of inflammatory cytokines, which activate the inflammatory signaling pathway and suppress the insulin signaling transduction, thus lead to insulin resistance. Management of obesity is beneficial for improving T2DM, and the innate lymphoid cells (ILCs) play an important role in obesity as well as T2DM. Group 2 innate lymphoid cells (ILC2s) could regulate fat metabolism, while Group 3 innate lymphoid cells (ILC3s) and their secreted IL-22 are capable for suppressing inflammation and reducing insulin resistance. The Berberine (BBR), an extractive of coptis chinensis, has been verified that had certain hypoglycemic effect. In this study, We used high fat diet (HFD)-induced diabetes model, and observed an effective weight control, reduced blood glucose and lower insulin level after mice were fed with exogenous BBR. Further studies showed that the proportion of ILC3s was increased and the expression of IL-22 was up-regulated in the small intestine. Meanwhile, the proportion of ILC2s and expression of IL-4, IL-5 and IL-13 was also increased in the adipose tissue. In short, the BBR might affect glycolipid metabolism through regulating the differentiation and function of ILCs in the fat or intestinal mucosa.

Disclosure

X. Tong: None. X. Guo: None. L. Zhao: None. Z. Gao: None. L. Fu: None. X. Wang: None. Q. Li: None. Y. Zheng: None.
Caveolin-1 Was Required for Glargine to Improve Insulin Sensitivity and Activate PI3K/AKT Pathway in Visceral Adipose Tissue of Type 2 Diabetic Mice
Authors: PENG HANGYA , LI HAICHENG , LIN SHUO , ZENG WEN , LIN CHUWEN , LIN KEYI , ZENG LONGYI
Published: June 2018

Insulin treatment improves insulin sensitivity, but the underlying mechanism remains unknown. Caveolin-1(Cav-1) konckout mice present insulin resistance.Our aim is to investigate the effect of Cav-1 depletion on insulin sensitivity and PI3K/AKT activation in glargine treatment of type 2 diabetic mice. C57BL/6J mice were divided into five groups(n=5 for each group).We firstly used high-fat high-carbonhydrate diet with intraperitoneal injection of streptozotocin(40mg/kg for 3 days) to induce type 2 diabetic(T2DM group) mice. Next, glargine was started at a dose of 0.4u/day to T2DM mice for 3 weeks(Insulin group).Lastly, Cav-1 expression was silenced by lentiviral-vectored short hairpin RNA (shRNA) through tail vein injection in glargine treated T2DM mice(CAV1-shRNA group) with scramble virus injection as a negative control(Ctrl-shRNA group). As a result, improvement of insulin sensitivity and PI3K/AKT activation with upregulation of Cav-1 were observed in visceral adipose tissue of Insulin group compared with T2DM group (P<0.05). In CAV1-shRNA group,impairment of insulin tolerance and PI3K/AKT activation couldn’t be improved by glargine compared with Ctrl-shRNA group (P<0.05). Our findings suggest that Cav-1 is required for insulin to improve insulin sensitivity and PI3K/AKT activation. More studies are needed to elucidate the mechanism.

Disclosure

H. Peng: None. H. Li: None. S. Lin: None. W. Zeng: None. C. Lin: None. K. Lin: None. L. Zeng: None.
Dynamic Resting State Connectivity after a High-Sugar Meal—A Neural Signature of Feeding
Authors: SHEARRER GRACE E. , SADLER JENNIFER R. , BURGER KYLE
Published: June 2018

The brain must integrate both external and internal feeding signals in an effort to maintain homeostasis and respond to the external food environment. Examination of the brain’s intrinsic connectivity, through resting state functional MRI (rsMRI), provides insight into how the brain integrates such signals. While this method has been used to identify differential connectivity associated with metabolic diseases (type 2 diabetes, obesity), fewer studies have tested differences in rsMRI following short-term manipulations, such as intake of a meal. Here, we studied the effect of a high-sugar meal using a within-subject design to test blood glucose and rsfMRI following: 1) an overnight fast and 2) a high-sugar breakfast (720 total kcals, 86g sugar) in 27 individuals (mean BMI 26.8). Independent component analysis resulted in 10 validated brain networks that were used to test within-network functional connectivity differences as a function of food intake. Fed vs. fasted resulted in an increase in blood glucose (p<0.0001) and modulation of sensorimotor networks. Specifically, intake of a high sugar breakfast increased connectivity within the oral somatosensory (gustatory processing, i.e., mouth feel) and dorsolateral prefrontal (dlPFC; contextual stimuli control) cortices (voxels=13; coordinates (mm)=-50,8,24; FWEpcorrected =0.03). This result suggests that increased connectivity between state-based behavior control (dlPFC) and somatosensory areas may be a neural signature of a post-prandial state.

Disclosure

G.E. Shearrer: None. J.R. Sadler: None. K. Burger: None.
High-Fat Diet Induces Diabetogenic Alteration of Ventromedial Hypothalamus (VMH) Glucose Sensing Neurons That Is Reversed by Circadian-Timed Bromocriptine Treatment
Authors: STOELZEL CARL , DUVALLET EMILIE , ZHANG YAHONG , TSAI TSUNG-HUANG , EZROKHI MICHAEL , CINCOTTA ANTHONY
Published: June 2018

The VMH is a glucose sensing center that elicits the counterregulatory response to local glucopenia. However, VMH sensing of local post-meal hyperglycemia can potentiate post-meal peripheral insulin action. The insulin resistant (IR) state is coupled to postprandial hyperglycemia and may derive from a shift in glucose sensing status in VMH. To test this postulate in vivo electrophysiological multi-unit responses (MURs) to local glucose (1-5 mM) or 2-deoxyglucose (2-DG, 1-15 mM) infusion at VMH were obtained and compared from rats (age 12 weeks, on 14 hour daily photoperiods) maintained for 5 weeks on either regular lab chow (RC, 18% of calories from fat) or high fat diet (HFD, 60% of calories from fat) (to induce the IR state) (N= 8 RD, 10 HFD). The impact of circadian-timed bromocriptine (BC) (10 mg/kg), a dopamine D2 receptor agonist and postprandial insulin sensitizer vs. vehicle (N=5-7/group), upon MURs in HFD rats was also examined. Relative to VMH MURs of RC rats, in HFD rats VMH MURs to local hyperglycemia were reduced 53% (P<.05) and MURs to 2-DG-induced hypoglycemia were elevated 93% (P<.05). Neuronal receiver operator characteristic analyses suggest these changes in MUR rates (VMH output activity) can significantly alter the brain’s ability to detect and respond appropriately to such changes in VMH physiological glucose levels. BC treatment of HFD rats at circadian time (CT) of daily waking, but not outside this CT window reduced VMH MUR to 2-DG and increased VMH MUR to hyperglycemia to levels observed in rats on RC diet (P<.02-DG, p<.001 glucose) accompanied by reduced blood glucose (12%, P<.001) and hyperinsulinemia (66%, P<.05). These findings indicate that the VMH glucose sensing apparatus is altered by HFD to facilitate hyperglycemia and inhibit post-meal insulin action at physiological glucose levels and that this perturbation of the HFD can be abrogated by circadian-timed bromocriptine administration.

Disclosure

C. Stoelzel: Employee; Self; VeroScience, LLC. E. Duvallet: Employee; Self; VeroScience, LLC. Y. Zhang: Employee; Self; VeroScience, LLC. T. Tsai: Employee; Self; VeroScience, LLC. M. Ezrokhi: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..
Inhibition of Transcriptional Regulator Taz (Wwtr1) by Antisense Oligonucleotide (ASO) Treatment Improves Obesity and Hepatic Steatosis in a Mouse Model of NASH
Authors: PERALTA RAECHEL , LOW AUDREY K. , SCHMIDT JOANNA , FERNG ANNIE , MURRAY SUE , GUO SHULING
Published: June 2018

Nonalcoholic fatty liver disease (NAFLD) is a common disorder that affects millions of people around the world. People with fatty liver disease alone are usually asymptomatic until a second insult to the liver, such as oxidative stress, triggers more severe steatosis, inflammation and fibrosis resulting in nonalcoholic steatohepatitis (NASH). The additional stress and damage to the hepatocytes results in the release of signals, such as hedgehog (Hh), to induce the wound-healing response. Data from animal models and human NASH have demonstrated Hh pathway activation correlates with the severity of liver disease. (1). In addition, the transcriptional coactivator, Taz/Wwtr1, was shown to be increased in hepatocytes from human and mouse NASH livers. (2). Based on these findings we performed DGE and qRT-PCR analysis on mice fed a high fat, fructose, and cholesterol (AMLN) diet for 24 weeks and found elevated mRNA expression of Taz in the livers compared to the lean mice. We treated C57B/6 mice fed the AMLN diet for 24 weeks with ASOs targeting Taz RNA. After 12 weeks of Taz ASO treatment, we observed a 95% knockdown in Taz mRNA expression in the liver compared to the control ASO group. This was accompanied by a 38% loss in whole-body fat mass (EchoMRI) and a 69% decrease in epidydimal white adipose tissue weight. Plasma analysis demonstrated a significant decrease in glucose and cholesterol compared to the control ASO levels. In addition, we observed reductions in liver triglyceride content resulting in levels similar to a lean mouse. No improvements in liver fibrosis were observed with Taz ASO treatment. These positive effects on obesity, plasma cholesterol, and liver steatosis suggest that Taz is a potential therapeutic target for preventing the progression of NASH into a more dangerous and irreversible liver disease.

Disclosure

R. Peralta: None. A.K. Low: Employee; Self; Ionis Pharmaceuticals, Inc.. Other Relationship; Spouse/Partner; Abbott. J. Schmidt: Employee; Self; Ionis Pharmaceuticals, Inc.. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc.. A. Ferng: None. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. S. Guo: Employee; Self; Ionis Pharmaceuticals, Inc..
Longitudinal Association of Microaneurysm Wall Characteristics with Perfusion and Local Neuroretinal Pathology
Authors: SUN JENNIFER K. , ABU-QAMAR OMAR , SAMPANI KONSTANTINA , FICKWEILER WARD , AIELLO LLOYD P.
Published: June 2018

Although microaneurysms (MAs) are a hallmark lesion of diabetic retinopathy, it is unclear why some MAs result in local neural retinal pathology while others are benign. To address this issue, longitudinal follow-up of MAs with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SDOCT) was performed. AOSLO MA images were graded for wall hyperreflectivity (WH), wall deformability (WD), cross-sectional area and perfusion percentage. SDOCT images were graded within a 500μm zone centered on each MA for disorganization of the retinal inner layers (DRIL). Fluorescein angiography evaluated leakage in a subset. A total of 457 MAs of 102 eyes (57 subjects: mean±SD age 44±12 years, DM duration 23#x00B1;10 years, 61% male, 73% type 1 DM) were assessed over 843 visits (154 MAs with ≥1 visit and mean follow-up of 0.52#x00B1;0.35 years). At baseline, MAs with WH were larger (p≤0.0001), less perfused (p≤0.0001), and associated with DRIL (p=0.002). There was a borderline trend for such MAs to leak fluorescein (p=0.05). Over time, MAs with resolved WH had greater likelihood of DRIL improvement. Conversely, MAs that developed WH had more DRIL worsening (p=0.005). WH change vs. stability was associated with decreased perfusion over time (p≤0.0001). At baseline, WD was associated with smaller MAs (p≤0.0001) and increased perfusion (p≤0.0001), but was not related to fluorescein leakage or DRIL. WD resolution and development were associated with decreased and increased perfusion, respectively (p≤0.0001), but not with change in DRIL. These data suggest that whereas WH is a feature of more mature, larger and less perfused MAs associated with local neural pathology, WD may be present in earlier-stage MAs that are smaller and more fully perfused. Future studies will determine whether these parameters can be used to predict changes in MA size, perfusion, leakage or local neural retinal pathology over time.

Disclosure

J.K. Sun: Other Relationship; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Genentech, Inc., Optovue, Incorporated, Boston Micromachines Corporation, Adaptive Sensory Technology, Kalvista Pharmaceuticals, Inc.. Other Relationship; Self; Novo Nordisk Inc.. O. Abu-Qamar: None. K. Sampani: None. W. Fickweiler: None. L.P. Aiello: Consultant; Self; Novo Nordisk Inc., Sanofi Genzyme. Stock/Shareholder; Self; Kalvista Pharmaceuticals, Inc.. Consultant; Self; Kalvista Pharmaceuticals, Inc..
Intracellular Calcium Levels in Patients with Type 2 Diabetes, First-Degree Relatives of Patients with Type 2 Diabetes, and Age-Matched Controls
Authors: STERGIOU IOANNIS F. , DIDANGELOS TRIANTAFYLLOS , TZIOMALOS KONSTANTINOS , KONTONINAS ZISIS , RAIKOS NIKOLAOS , VYZANTIADIS TIMOLEON-ACHILLEAS , HATZITOLIOS APOSTOLOS I.
Published: June 2018

Purpose: Measurement of Intracellular Calcium (iCa) levels in red blood cells in patients with predisposition to type 2 diabetes (T2D), such as the first-degree relatives of patients with T2D, in comparison with healthy individuals and patients with T2D.

Materials and Methods: Our study comprised of three groups of 25 age-matched, 38-65 years-old persons (58% males): 1.) non-insulin treated T2D patient (body mass index (βμΙ) 28.3±3.4 kg/m2, HbA1c 7.5±1.6%) 2.) first-degree relatives of T2D patients (βμΙ 25.3±3.6 kg/m2, HbA1c 5.3±0.4%) 3.) healthy controls (βμΙ 24.3±3.4 kg/m2, HbA1c 4.9±0.5%). Measurement of iCa was conducted by the method of atomic resonance with the use of a spectrophotometer.

Results: Lower levels of iCa were observed in the relatives of patients with T2D vs. the control group (0.39±0.16 vs. 0.48±0.3 mg/L, p=0.049) and in patients with T2D vs. the control group (0.33±0.21 vs. 0.48±0.3 mg/L, p=0.041). In contrast, iCa levels did not differ between patients with T2D and the first-degree relatives of patients with T2D (p=0.38).

Conclusion: The comparison of iCa levels in the three groups shows a gradual decrease from control group to T2D patients. It is impressive that statistical analysis revealed significant differences between the first-degree relatives of patients with T2D and the control group, and between patients with T2D and the control group, but not between patients with T2D and the first-degree relatives of patients with T2D. It could be reasonably hypothesized that individuals with known predisposition for T2D have a defective genotype that negatively affects intracellular molecular signaling in which calcium is implicated.

Disclosure

I.F. Stergiou: None. T. Didangelos: None. K. Tziomalos: None. Z. Kontoninas: None. N. Raikos: None. T. Vyzantiadis: None. A.I. Hatzitolios: None.
Serum Uric Acid Reduction Is Associated with Gender Differences and Body Fat Distribution after Laparoscopic Sleeve Gastrectomy
Authors: ZHANG XUANE , MEI FANGYUN , GAO JINGYANG , CHENG XIAOYUN , BU LE , ZHU CUILING , QU SHEN
Published: June 2018

Background: Uric acid is believed be an important modulator in glucose and lipid metabolism. This study is aimed to estimate the efficacy of laparoscopic sleeve gastrectomy (LSG) on obese patients and find out the relationship of serum uric acid (SUA) to body fat distribution in both male and female of Chinese patients.

Methods: A total of 65 obese patients (32 females and 33 males) who underwent LSG were enrolled for this study. Their body composition was measured by dual-energy X-ray absorptiometry (DEXA). The data of anthropometric measurements, glucolipid metabolism and SUA was collected before and 6 months after LSG separately.

Results: More significant reduction of SUA was observed in the female group than the male group after LSG (female (17.98±12.72)% vs. male(3.22±15.66)%, p<0.001). Furthermore, changes in SUA showed significantly positive correlation with visceral adipose tissue (VAT) in female patients (r=0.542,p=0.011). And it was also positively correlated with changes of the area under the curve(AUC) for glucose during 75g oral glucose tolerance test(r=0.567,p=0.002), fasting insulin(r=0.505,p=0.006) and natural logarithm of HOMA-IR (r=0.427,p=0.023). Post-surgery high-density lipoprotein (HDL) levels significantly increased from 0.89±0.19 to 1.18±0.23 mmol/L (p<0.001) in males. The reduction of SUA in male patients were positively associated with changes in neck circumference(r=0.617,p=0.000)and hip circumference(r=0.381,p=0.042), and negatively correlated with changes in HDL levels (r = -0.422, P = 0.018). It was also positively correlated with changes of fat content in upper arm, legs and gynoid area (r=0.450, r=0.650, r=0.432, respectively; all p<0.05), while unrelated to visceral fat in the male group.

Conclusions: The efficacy of LSG on glycolipid metabolism may be associated with gender-related differences in body fat distribution. Uric acid may be a gendered modulator of glucose and lipid metabolism.

Disclosure

X. Zhang: None. F. Mei: None. J. Gao: None. X. Cheng: None. L. Bu: None. C. Zhu: None. S. Qu: None.
Presessions to the National Diabetes Prevention Program Are a Promising Strategy to Improve Attendance and Weight Loss Outcomes
Authors: RITCHIE NATALIE , KAUFMANN PETER G. , GRITZ MARK , HOLTROP JODI S.
Published: June 2018

Introduction: The National Diabetes Prevention Program (NDPP) is a widely-disseminated lifestyle intervention. Retention in the NDPP is problematic and leads to suboptimal weight loss, especially among racial/ethnic minority participants. We report results of implementing a novel “pre-session” protocol to support engagement among a diverse sample of NDPP participants.

Methods: The NDPP was delivered in a safety net healthcare system. As of September 2016, pre-sessions were offered prior to NDPP attendance and focused on (1) education on diabetes risks, (2) motivational interviewing to participate in the NDPP, and (3) problem-solving barriers to engagement. We compared NDPP attendance and weight loss outcomes between 75 pre-session participants and a historical control group of 42 individuals who were not offered a pre-session prior to their beginning the NDPP in July 2016. This comparator group was selected to reduce potentially confounding effects of other prior modifications to NDPP dissemination over time.

Results: The majority of participants in this analysis were female (78.3%), low-income (51.1%), and Hispanic (57.6%). Mean age was 46.6 (SD=12.7) with a mean baseline BMI of 35.9 (SD=5.7). There were no significant baseline differences in characteristics between NDPP participants who received a pre-session and historical controls. Pre-session participants attended 5.3 (SD=1.4) more NDPP sessions (p<.001) and stayed in the program 96.4 (SD=24.6) days longer (p<.001) than historical controls. Pre-session participants achieved 1.8% (SD=0.8) greater weight loss (p=.039) and were 2.4 times more likely to achieve ≥5% weight loss in the NDPP as historical controls; p=.044, 95% CI [1.0-5.8].

Conclusions: By improving engagement and weight loss, findings suggest pre-sessions may be a promising strategy to improve NDPP effectiveness and mitigate health disparities in program outcomes.

Disclosure

N. Ritchie: None. P.G. Kaufmann: None. M. Gritz: None. J.S. Holtrop: None.
Cornus Officinalis Increases Proliferation, Inhibits Cytokine-Induced Apoptosis, and Promotes the Oxidative Capacity of the Human 1.1B4 Pancreatic Cell Line
Authors: SHARP ARIELLE , BURKHARDT BRANT R.
Published: June 2018

Type 1 diabetes (T1D) affects 1.25 million Americans with about 40,000 individuals newly diagnosed each year. T1D is caused by an autoimmune-induced loss of pancreatic β cells and subsequent deterioration of insulin production. Although exogenous insulin is an efficient treatment, there is a strong need to develop therapies that can inhibit the loss of β cells and promote their function. For this purpose, we have been analyzing the antidiabetic capability of Cornus officinalis (CF), which has been utilized in traditional Chinese medicine for over 2,000 years primarily for treatment of T2D. We hypothesize that CF may inhibit β cell destruction and promote β cell function. Using the human 1.1B4 pancreatic β cell line, we have examined the proliferative effect of CF treatment on 1.1B4 cells in a time- and dose-dependent manner via cell viability assays. Within two hours, CF rapidly and significantly induced 1.1B4 proliferation by over 300% as compared to controls. Activation of Th1 cytokines plays a detrimental role in the pathogenesis of T1D. Therefore, we determined whether CF can inhibit cytokine induced β cell death and promote β cell proliferation following treatment with Th1 cytokines of IL-1β, TNF-α, and IFN-γ. CF induced a 200% increase in 1.1B4 proliferation following Th1 cytokine treatment compared to controls. In addition, a metabolic analysis of CF induced 1.1B4 cells was examined using the Agilent Seahorse XF analyzer. At a two-hour time point, there was a remarkable increase in maximal respiratory and glycolytic capacity following CF treatment. Therefore, CF is a strong inducer of metabolism. Ongoing experiments will provide greater detail into the mechanism and metabolic role in which CF is promoting proliferation and metabolism and inhibiting cytokine-induced β-cell death.

Disclosure

A. Sharp: None. B.R. Burkhardt: None.
Enabling Data-Driven Decision Making for Personalized Care in Type 2 Diabetes with Clinical and Lifestyle Journey Data Using a Digital Therapeutic
Authors: CHAWLA RAJEEV , SHAIKH MAAZ , SHAH ABHISHEK , SABOO BANSHI D. , MAKKAR BRIJ M. , KESAVADEV JOTHYDEV , JOSHI SHILPA , DESHPANDE NEETA , AGARWAL SANJAY , MAHESHWARI ANUJ , SOSALE ARAVIND R. , MADHU SV
Published: June 2018

Background: Lack of data on patient lifestyle between consultation visits is a major limitation in practice of data-driven clinical decision making in type 2 diabetes (T2DM). We showcase Wellthy Diabetes (WD), a digital therapeutic, as an effective tool for the amplification of patient's clinical and lifestyle journey data between visits to aid doctors in practice of data-driven decision-making.

Methods: Wellthy Diabetes (WD) smartphone app is a digital therapeutic that delivers an artificial intelligence (AI) augmented lifestyle modification program for people with T2DM, developed in scientific collaboration with the Research Society for Study of Diabetes India (RSSDI). The WD app uses an AI-based digital persuasion model to encourage users through personalized reminders and nudges to self-report data on blood glucose, weight, meals, and physical activity. The app also tracks the duration of physical activity through inbuilt sensors on the phone. This study presents data from a cohort (N=102) of completers of a 16-week program.

Results: During the study 121,675 diabetes-related clinical and lifestyle data points (including 112,960 mins of sensor-tracked physical activity) were reported by 102 participants over 17,052 person days. The mean duration of a participant on WD was 167 days during which, on average, 452 clinical and lifestyle data points were tracked per participant at a mean velocity of 5.6 data points per day. On average each participant reported 68.8, 11.4, 5.1, and 1107.7 instances of meals, blood sugar, weight, and activity respectively.

Conclusion: The results confirm WD amplifies self-reporting of clinically relevant lifestyle data by users during the journey between doctor consultations. First-hand data on clinical trends and lifestyle between consultations provide personalized insight into patient behavior enabling doctors to make data-driven decisions for personalizing evidence-based care for T2DM.

Disclosure

R. Chawla: None. M. Shaikh: Employee; Self; Wellthy Therapeutics Pvt Ltd. A. Shah: Stock/Shareholder; Self; Wellthy Therapeutics. B.D. Saboo: None. B.M. Makkar: None. J. Kesavadev: Advisory Panel; Self; Novo Nordisk India Private Limited. Speaker's Bureau; Self; Novo Nordisk India Private Limited. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; MSD. Speaker's Bureau; Self; MSD. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. S. Joshi: None. N. Deshpande: None. S. Agarwal: None. A. Maheshwari: None. A.R. Sosale: None. S. Madhu: None.
Newly Designed Alginate-Based Microcapsules (AgMc) for the Molecular Therapy of Type 1 Diabetes
Authors: CALAFIORE RICCARDO , MONTANUCCI PIA , BASTA GIUSEPPE P. , NOCENTINI GIUSEPPE , PESCARA TERESA , RICCARDI CARLO
Published: June 2018

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) plays a crucial role in either thymic t-Treg differentiation and expansion, or peripheral p-Treg expansion, thus representing a potential tool to contrast the autoimmune process. AgMc are usually intended to constitute an immunobarrier to prevent rejection of the embodied islet/insulin producing cell grafts in T1D. We aimed to reverse this principle, and engineered the AgMc membranes, in order to make them permeable to outflowing rat anti-mouse GITR IgM MAb, derived from microencapsulated rat G3C hybridoma cells. To this end, we changed our AgMc original formulation to obtain thicker and looser membranes. We observed intra-AgMc IgM retention and their progressive release into the culture medium in vitro. Prediabetic NOD mice were divided into two groups: (1) n=20, received graft (TX) of G3C containing microcapsules; (2) n=10 received TX of empty microcapsules. Both (1) and (2) were monitored for the onset of DM. BG in basal and after IPGTT, morphological, immuno-molecular, and cell immuno-phenotyping testing, as well as G3C plasma levels assay in (1) were performed. In (2): 5/10 animals developed DM within 70d; in (1) no animals developed DM at 180 of TX. In the spleen of G3C-AgMc-treated mice either CD4+FoxP3+GITRbright, or CD4+CD25-GITR(sp), or CD8+CD25+GITRlowFoxP3+, or CD8+CD25-GITRintFoxP3+ Tregs significantly increased from 4 week of TX as compared to controls. Pancreatic histology at 26 week of TX was associated with either completely destroyed islets (1) or intact islets with minor insulitis (2). Significant diabetes-free time of (1) vs. (2) may relate to increase of islet B-cell specific Tregs, expanded by G3C-released MAb, and antigenic stimulation, at early stage of the autoimmune disease process.

In conclusion, the newly engineered AgMc, by permitting GITR triggering by anti-GITR IgM, may represent a new approach to expand Tregs and inhibit Teff, and to avert the onset of autoimmune DM in NOD mice.

Disclosure

R. Calafiore: None. P. Montanucci: None. G.P. Basta: None. G. Nocentini: None. T. Pescara: None. C. Riccardi: None.
Impaired Beta-Cell Compensation and Glucose Effectiveness in Insulin Resistant, Nondiabetic South Asians
Authors: SEDMAK CAROLINE , GREWAL SHIVRAJ , SIKDER SHANAZ , GLICKSMAN MICHAEL , MSZAR REED G. , CHEN ETHAN A. , RABEL ANTOINETTE , MUNIYAPPA RANGANATH
Published: June 2018

South Asians (SA) are insulin-resistant (IR) and are at increased risk for developing type 2 diabetes mellitus (T2DM) when compared with Caucasians (CA). However, the changes in pancreatic β-cell responsivity, glucose effectiveness (Sg), and insulin clearance in SA are not well characterized. Healthy SA (n=30) and CA (n=30) matched for age, sex, and BMI and with no history of T2DM were evaluated in the Clinical Center. A frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mixed meal test (MMT) were used for minimal modeling (MM). Insulin sensitivity, beta-cell function, and glucose effectiveness were calculated. Tissue-specific surrogate indices of insulin sensitivity and post-prandial incretin levels were also measured. SA were less insulin-sensitive (SI: 3.30±2.72 vs. 7.31±4.89, minutes-1/µU/mL, p<0.001; Matsuda index: 4.34±3.69 vs. 13.26±7.17, p<0.05). Tissue specific IR surrogate indices (hepatic IR index and adipocyte IR index) were higher and muscle insulin sensitivity index was lower in SA. Sg derived from an FSIVGTT was lower in SA (0.025 ± 0.033 vs. 0.012 ± 0.006, minutes-1, p<0.001). Beta-cell responsivity indices estimated by the C-peptide MM [phi (dynamic), phi (static), and phi (total)] were not different between the groups, but the disposition indices were significantly lower in SA. Post-prandial GIP but not GLP-1 levels were higher in SA than in CA. Insulin clearance at baseline and following MMT was also significantly lower in SA. Thus, when compared with age-, sex-, and BMI-matched CA, SA exhibit reduced overall insulin sensitivity in the muscle, liver, and adipose tissue. Despite similar β-cell responsivity to glucose, the disposition indices in SA were lower, suggesting diminished beta-cell compensation. In addition to defects in insulin-mediated glucose disposal and impaired beta-cell compensation, normoglycemic SA have reduced glucose effectiveness. These results suggest different approaches to prevent and treat T2DM in SA.

Disclosure
Liver-Specific Deletion of the Mitochondrial Stress UBL-5 Gene Leads to Fatty Liver That Is Rescued by Pioglitazone Administration or ACE2 Overexpression
Authors: NTOUMA VIKTORIA , HARALAMBOUS CHRISTIAN
Published: June 2018

Fatty liver disease is associated with metabolic syndrome, increased risk of type 2 diabetes (T2D), and other metabolic complications. There has been little progress in treatments for fat-induced liver failure and further studies are required for clarification of mechanisms. Mitochondrial dysfunction has been implicated in insulin resistance and is associated with hepatic fat accumulation and T2D. Studies in C. Elegans have shown that UBL-5 is involved in the activation of the mitochondrial unfolded protein response (UPRmt). This pathway upregulates mitochondrial proteases and chaperone proteins to alleviate proteostatic stress. To further explore the role of UBL-5 in the mammalian UPRmt, we generated a tamoxifen-inducible, liver-specific UBL-5 knockout mouse. Liver-specific deletion of UBL-5 in adult mice caused increased plasma hepatic enzymes, gross steatosis and death within 12 days following tamoxifen-induction. Histological examination of the liver revealed severe and diffuse multifocal hepatocellular necrosis, vacuolation, inflammation, lipid accumulation, and apoptosis. Most UPRmt genes (CHOP, ClpP, ClpX, Lonp1, HSP10, HSP70, ATF-5) were downregulated while mtHSP70 was upregulated. PGC1a mitochondrial biogenesis gene was downregulated. Interestingly, angiotensin-converting enzyme 2 (ACE2) expression was also reduced in KO livers. Mice were then treated with pioglitazone, or an ACE2-containing virus to determine if such treatments provide benefit. ACE2 expression was increased with both ACE2 virus and pioglitazone treatment. Liver enzymes showed significant improvement after treatment with both pioglitazone and ACE2.

In conclusion, we have generated a model that develops severe fatty liver disease and have shown that both genetic and pharmacological therapies may diminish this disease process. This study provides the first evidence for a critical role for UBL-5 in hepatic function.

Disclosure

V. Ntouma: None. C. Haralambous: None.
SGLT2 Inhibitor Ipragliflozin Induces Breast Cancer Apoptosis via Membrane Hyperpolarization and Mitochondria Dysfunction
Authors: KOMATSU SHIHO , NOMIYAMA TAKASHI , NUMATA TOMOHIRO , KAWANAMI TAKAKO , HAMAGUCHI YURIKO , TANAKA TOMOKO , INOUE RYUJI , YANASE TOSHIHIKO
Published: June 2018

Currently, cancer is one of major cause of death in patients with type 2 diabetes. We have previously reported the anti-prostate and anti-breast cancer effect of GLP-1R agonist Exendin-4 (Diabetes 2014, Endocrinology 2017). In the present study, we examined the anti-cancer effect of SGLT2 inhibitor ipragliflozin (Ipra) using a breast cancer model. In human breast cancer cell line, MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. 1-50nM Ipra significantly and dose-dependently suppressed the growth curve of MCF-7 cells. BrdU assay revealed that Ipra attenuates the proliferation rate of MCF-7 in a dose dependent manner. Further, apoptosis was also induced by Ipra in Tunel assay. Because the anti-breast cancer effect of Ipra was completely canceled by knocking down of SGLT2, this effect could be induced by SGLT2 inhibition by Ipra. We next measured membrane potential and whole cell current using the patch clamp technique. When we treated MCF-7 cell with Ipra or glucose free medium, membrane hyperpolarization was observed. In addition, the replacement of sodium with NMDG and knock-down of SGLT2 by siRNA suppressed glucose induced whole cell current of MCF-7 cell, suggesting that Ipra inhibits sodium and glucose incorporation through SGLT2. Further, mitochondrial membrane protein Bcl-2 was decreased and Bax was increased in western blotting, and JC-1 fluorescence was significantly increased, suggesting the change of mitochondrial membrane potential. These data suggest that SGLT2 inhibitor Ipra induces apoptosis in the breast cancer cell via membrane hyperpolarization and mitochondria dysfunction.

Disclosure

S. Komatsu: None. T. Nomiyama: Research Support; Self; MSD K.K., Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.T. Numata: None.T. Kawanami: None.Y. Hamaguchi: None.T. Tanaka: None.R. Inoue: None. T. Yanase: Research Support; Self; MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.
Regulation of Systemic Energy Metabolism by a Human-Specific Long Noncoding RNA In Vivo
Authors: RUAN XIANGBO , LI PING , CAO HAIMING
Published: June 2018

Long non-coding RNAs (lncRNAs) are widely expressed in mammals and play critical roles in a broad array of physiological processes. We have recently demonstrated that lncRNAs sense and regulate lipid and glucose metabolism in mice. However, it remains to be determined whether human lncRNAs regulate metabolism in vivo and whether they play a role in the pathogenesis of human metabolic disorders. The lack of knowledge of lncRNA’s functions in human metabolism is partly caused by the extremely low sequence conservation between human and mouse lncRNAs, which makes it difficult to apply the functional information of mouse lncRNAs to human physiology. To overcome this limitation, we have produced liver-specific humanized mice in which over 80% of mouse hepatocytes in the liver can be replaced by human ones and have confirmed that human metabolic genes in these mice maintain proper responses to metabolic cues. Using the liver-specific humanized mice, we identify a Fasting induced, Human-specific, and Liver-enriched lncRNA (lncFHL). Knocking down of lncFHL in humanized mice results in decreased expression of genes in Peroxisome Proliferator Activated Receptor Alpha (PPARalpha) pathway, which leads to decreased fasting plasma glucose and ketone levels. We further find that lncFHL interacts with and affects the mRNA interactions of HuR, a RNA binding protein that suppresses hepatic PPARalpha pathway in human. Finally, by analyzing published genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data, we find the hepatic expressions of lncFHL are associated with human metabolic diseases including diabetes and coronary artery disease. These studies not only provide a proof of principle that the humanized mice could sever as a suitable model to study the metabolic function of human lncRNAs but also demonstrate that regulatory mechanism mediated by human-specific lncRNAs contributes significantly to physiological and pathophysiological metabolic homeostasis.

Disclosure

X. Ruan: None. P. Li: None. H. Cao: None.
Research into the Effect of Sodium-Glucose Linked Transporter 2 Inhibition on Left Ventricular Remodeling in Patients with Heart Failure and Diabetes Mellitus
Authors: SINGH JAGDEEP S.S. , MORDI IFY , MOHAN MOHAPRADEEP , GANDY STEPHEN J. , PEARSON EWAN , HOUSTON JOHN G. , STRUTHERS ALLAN D. , LANG CHIM C.
Published: June 2018

Introduction: DM and heart failure (HF) are lethal, with limited diabetic therapy options. Sodium-glucose linked transporter 2 (SGLT2) inhibitors have been reported to have CV benefits in at risk DM patients. We are the first to study the CV effects of SGLT2 inhibition in patients with DM and HF.

Methods: In this randomized double-blind placebo controlled trial, 56 patients (mean age: 67.1 years, males: 66%) with DM and echocardiographically confirmed HF with reduced ejection fraction (HFrEF) on regular diuretic therapy were assigned to dapagliflozin 10mg OD or placebo for one year. Primary endpoint was the difference in left ventricular (LV) volumes between both groups using cardiac MRI. Secondary endpoints include LV mass, LV ejection fraction (EF), weight, BP and diuretic use. Outcomes were analysed using linear regression controlling for baseline values, age, sex and renal function.

Results: There was no difference between dapagliflozin and placebo in the primary endpoints of LV end diastolic volume (LVEDV) or LV end systolic volume (LVESV); +4.71mls; 95% CI: -17.to 26.50 and +1.52mls; 95% CI: -15.68 to 18.72 respectively. However, when an interaction term for starting LVEF was added to the model, dapagliflozin significantly lowered LVEDV, LVESV and LV mass in those with starting LVEF ≥ 45%; -15.59mls; p=0.019, -15.20mls; p=0.016 and -4.87gm/m2; p=0.026. Patients on dapagliflozin had weight reduction; -1.90kg; 95% CI: -3.83 to +0.04; p=0.054, lower diastolic BP; -6.34mmHg; 95% CI: -11.35 to -1.32; p=0.014 and higher hemoglobin; +1.23 g/dl; 95% CI: 0.65 to 1.82; p<0.001. They were also more likely to stop or reduce loop diuretics; 50.0% vs. 8.7%; p=0.005.

Conclusions: Our data show dapagliflozin treatment resulted in weight and blood pressure reduction among patients with DM and HFrEF. There was evidence to suggest that dapagliflozin may cause LV reverse remodelling in DM patients with mild, but not with more severe HFrEF.

Disclosure

J.S.S. Singh: None.I. Mordi: None.M. Mohan: None.S.J. Gandy: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company.J.G. Houston: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca.C.C. Lang: None.
Dapagliflozin plus Saxagliptin Shows Noninferior A1C Reduction vs. Insulin Glargine in Patients with Type 2 Diabetes Inadequately Controlled by Metformin With or Without Sulfonylurea
Authors: VILSBØLL TINA , EKHOLM ELLA , JOHNSSON EVA K. , DRONAMRAJU NALINA , JABBOUR SERGE , LIND MARCUS
Published: June 2018

This international, multicenter, randomized, open-label phase 3b trial (NCT02551874) evaluated the efficacy and safety of dapagliflozin (DAPA) 10 mg/day plus saxagliptin (SAXA) 5 mg/day vs. titrated insulin glargine (INS) in patients with type 2 diabetes (T2D) poorly controlled by metformin (MET) ≥1500 mg/day ± sulfonylurea (SU) ≥50% maximum dose (A1C levels 8-12%). The primary end point was change in A1C from baseline to week 24; DAPA + SAXA was tested for non-inferiority vs. INS. Secondary end points were: change in body weight; proportions of patients a) with hypoglycemia, b) achieving A1C <7% without hypoglycemia, c) achieving A1C <7% at week 24; and change in 24-hour glucose at week 2 assessed by continuous glucose monitoring. Mean±SD baseline data were age 55.5±9.6 years; A1C 9.1±1.0%; BMI 32.2±5.3 kg/m2, and were similar in both arms. DAPA + SAXA resulted in non-inferior reductions in A1C without weight gain, reductions in mean 24-hour glucose, and was associated with a lower prevalence of hypoglycemia and a greater proportion of patients achieving A1C <7% without hypoglycemia vs. INS (Table); there were no additional safety concerns. DAPA + SAXA therapy resulted in similar glycemic control, prevented weight gain and reduced risk of hypoglycemia compared with titrated INS in patients with T2D poorly controlled by MET ± SU.

Disclosure

T. Vilsbøll: None. E. Ekholm: None. E.K. Johnsson: Employee; Self; AstraZeneca. N. Dronamraju: None. S. Jabbour: None. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic.