bluuebunny/crossref_metadata_2025 huggingface dataset:
A Smartphone App–Based Lifestyle Intervention Promotes Weight Loss—Results of a Prospective, Randomized, Controlled Clinical Trial (RCT)
Authors: VAZ CHERIE LISA , SUTHAR AKASHKUMAR G. , POUSTI BOBAK T. , AYE SU M. , WILLIAMS KEVIN JON , ZHAO HUAQING
Published: June 2018

Despite widespread use of smartphones and wearables, we have limited evidence that they aid weight loss or lifestyle. Here, we report results of a 6-month RCT of our smartphone app-based lifestyle intervention vs. standard of care (in-person weight management visits at 0, 3, and 6 months) in a cohort of overweight or obese subjects.

The app downloads objective data of daily weights from smartscales and physical activity from 3-axis accelerometers. The technology allows peer social networking and remote professional coaching employing behavior modification techniques delivered via group and private messaging, emoticons, shared activity and weight data, shared photographs of meals, and a virtual reward system for behavior modification. Intervention group: n=13, 85% F, age 39.5 ± 3.71 y, initial weight 94.3 ± 3.42 kg, BMI 34.5 ± 1.3 kg/m2. Control group: n=15, 86% F, age 45.1 ± 3.31 y, initial weight 92.3 ± 4.37 kg, BMI 33.8 ± 1.kg/m2 (means ± SE).

We found a clinically and statistically significant weight difference of -4.2 ± 2.0 kg (95% CI -8.3 to -0.02 p=0.0488) after 6 months of our smartphone app-based lifestyle intervention (prespecified primary outcome, intervention vs. control). In the intervention group, weight change was -7.2 ± 1.8 kg (95% CI -11.1 to -3.3, p = 0.0017); % weight change was -7.9% ± 2.2% (95% CI -12.6 to -3.2, p=0.0031). Weight change significantly associated with median step counts (Pearson’s correlation coefficient r=-0.61, p=0.027), numbers of text messages from each subject (r=-0.83, p=0.0005), and numbers of diet photos shared (r =-0.83 p=0.0005).

Our app-based lifestyle intervention met the prespecified primary outcome of clinically meaningful and statistically significant weight loss at 6 months over control. The strongest correlations with weight loss in the intervention group were physical activity (step counts) and subjects’ engagement in behavior modification coaching (messages and diet photos).

Disclosure

C. Vaz: None. A.G. Suthar: None. B.T. Pousti: None. S.M. Aye: None. K. Williams: Stock/Shareholder; Self; Hygieia, Gemphire, Inc.. Advisory Panel; Self; Gemphire, Inc.. H. Zhao: None.
Human Brown Adipose Tissue Density Assessed by Near-Infrared Time-Resolved Spectroscopy Inversely Correlates with the Body Mass Index in Patients with Type 2 Diabetes
Authors: WAKI HIRONORI , WATANABE NAOKO , FUSE SAYURI , KUROSAWA YUKO , YAMAUCHI TOSHIMASA , KIME RYOTARO , HAMAOKA TAKAFUMI , KADOWAKI TAKASHI
Published: June 2018

Background: Near-infrared time-resolved spectroscopy is a non-invasive method that facilitates analysis of human brown adipose tissue (BAT) density. We measured BAT density in middle-aged patients who had type 2 diabetes by this method and examined the relationship using clinical parameters.

Methods: We studied 33 Japanese middle-aged diabetic patients (30 male and 3 female, age 53.8±10.1 years, BMI 25.4±4.5, and HbA1c 7.2±1.1%). Tissue hemoglobin concentration (tHb) of the supraclavicular region was measured using near-infrared time-resolved spectroscopy, and normalized by subcutaneous fat thickness at the measurement sites.

Results: The average tHb concentration was 51.1±17.7 μM and lower than 77.8 μM—the value equivalent to the detection threshold of BAT by standard FDG-PET in young adults. Univariate regression analysis showed that the tHb of the supraclavicular region was inversely correlated with BMI (r = −0.55, p=0.0009), but the tHb of the deltoid region was not (r = 0.04, p = 0.31). Other parameters showing significant correlations with BAT mass included systolic blood pressure (r = −0.47, p = 0.01) and insulin treatment (r=0.45, p=0.01). Multivariate regression analysis suggested that BMI (β=−0.42, p=0.005), systolic blood pressure (β=−0.29, p=0.042), and insulin treatment (β=0.34, p=0.015) independently account for BAT density.

Conclusion: Our findings suggest that BAT density in middle-aged diabetic patients may relate to obesity more closely than previously thought.

Disclosure

H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. N. Watanabe: None. S. Fuse: None. Y. Kurosawa: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. R. Kime: None. T. Hamaoka: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
The Association between Body Mass Index and All-Cause Mortality in Type 2 Diabetic Inpatients With and Without Diabetic Microangiopathy—A Retrospective Cohort
Authors: HSUAN LI Y. , LEE I-TE
Published: June 2018

Background: The U-shaped association between body mass index (BMI) and mortality has been extensively reported in patients with type 2 diabetes. It has been shown that overweight patients had a lower mortality risk compared to normal-weight individuals, referred as “obesity paradox.” However, limited data reported the relation between on admission BMI and all-cause mortality in diabetic inpatients, and if obesity paradox exist in diabetic inpatients with microangiopathy.

Research Design and Methods: A total of 2885 patients had admitted due to a primary diagnosis of type 2 diabetic with poor glucose control were enrolled. BMI was measured when admission. Cox proportional hazards model hazard ratios for all-cause mortality were calculated after adjusting for confounders.

Results: During a mean follow-up period of 6.6 years, 1483 deaths occurred. A U-shaped association was observed between admission BMI and all-cause mortality, with BMI between 24 and 27 kg/m2 showing the lowest mortality risk across all BMI category. (BMI category including <18, 18-21.9, 22-23.9, 24-26.9, 27-29.9, ≥30 kg/m2, HR of 1, 0.68 [95% CI: 0.55 to 0.84], 0.54[95% CI: 0.43 to 0.67], 0.50[95% CI: 0.41 to 0.62], 0.52[95% CI: 0.41 to 0.65], 0.52[95% CI: 0.40 to 0.67, respectively]. However, among inpatients with macroalbuminuria, the protective effect of overweight was attenuated (P=0.52) and U-shaped association was not observed. The result was similar in patients with diabetes retinopathy (P=0.053).

Conclusions: A U-shaped association existed between admission BMI and all-cause mortality in diabetic inpatients. However, the obesity paradox was not observed in type 2 diabetic inpatients with existing diabetic microangiopathy.

Disclosure

L.Y. Hsuan: None. I. Lee: None.
U.K. First National Health Service (NHS) Endobarrier (EB) Service—Outcomes in First 38 Patients to Reach Six Months after Device Explant
Authors: RYDER ROBERT E.J. , YADAGIRI MAHENDER , IRWIN SUSAN P. , BURBRIDGE WYN , WYRES MELANIE C. , GANDHI HARDEEP , CULL MELISSA L. , ALLDEN RACHAEL , BLEASDALE JOHN , FOGDEN EDWARD , ANDERSON MARK , GUPTA PIYA SEN
Published: June 2018

EB, a 60cm endoscopically implanted proximal intestinal liner, reduces weight and HbA1c over 1 year. In the 1st NHS EB service, we provided EB for patients with sub optimally controlled diabesity and monitored outcomes in a registry. The 1st 38 patients have completed 6 months post EB removal and of these 31/38 (82%) (age 51.4 ± 6.8 years, 51.6% male, diabetes duration 12 (6-21) years) attended follow-up. During EB implant, mean ± SD HbA1c fell by 2.5 ± 2.0%, from 10.0 ± 2.0 to 7.5 ± 1.2% (p<0.001), weight by 15.8 ± 9.0 kg from 120.6 ± 27.6 to 104.9 ± 28.9 kg (<0.001), systolic BP from 138.3 ± 15.6 to 123.0 ± 14.6 mmHg (<0.001), serum alanine-aminotransferase (ALT-marker of liver fat) from 29.7 ± 17.6 to 19.6 ± 11.5 U/L (p<0.001). Median (IQR) total daily insulin dose reduced from 102 (48-129) to 25 (0-59) units (p<0.001), n=20. 6 months post EB explant 21/31 (68%) had maintained the improvement and this was reflected in the figures for the group as a whole (Table). 7/20 (35%) insulin treated patients discontinued insulin. Of the 10 whose weight and/or HbA1c deteriorated, 7/10(75%) had depression. 4/38 (10.5%) patients had early Endobarrier-removal: 3 GI bleed, 1 liver abscess (Table). All 4 had full recovery after removal. All other patients achieved a full year of EB treatment. Our data demonstrates EB as highly effective in patients with refractory diabesity, with maintenance of improvement after removal in 68%.

Disclosure

R.E.J. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. M. Yadagiri: None. S.P. Irwin: None. W. Burbridge: Other Relationship; Self; Menarini Group. M.C. Wyres: None. H. Gandhi: None. M.L. Cull: None. R. Allden: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None. P. Sen Gupta: None.
The A Body Shape Index and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events in Patients with Peripheral Artery Disease
Authors: VONBANK ALEXANDER , SAELY CHRISTOPH H. , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2018

The A Body Shape index (ABSI) is calculated based on waist circumference, height and BMI and is a validated measure of visceral adiposity. In the general population, the ABSI has been shown to be an independent risk factor for premature mortality. Its power to predict cardiovascular events in patients with peripheral artery disease (PAD) is not known and is addressed in the present study. We prospectively recorded cardiovascular events in 319 patients with sonographically verified PAD over a mean follow-up time of 7.2±2.1 years. At baseline, the ABSI was significantly higher in patients with type 2 diabetes (T2DM) than in those who did not have diabetes (19.5±1.9 vs. 14.0±1.1; p<0.001). Prospectively, the ABSI significantly predicted the incidence of cardiovascular events (n=57) both univariately (standardized HR 1.36 [1.20-1.52]; p<0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR 1.17 [1.08-1.29]; p=0.010); also T2DM significantly predicted cardiovascular events in this fully adjusted model (adjusted HR 1.48 [1.25-1.74]; p<0.001). We conclude that the ABSI and T2DM are mutually independent of cardiovascular events in patients with PAD.

Disclosure

A. Vonbank: None. C.H. Saely: None. C. Heinzle: None. D. Zanolin: None. B. Larcher: None. A. Mader: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
Metabolic Surgery Counseling, Diabetes Remission, and A1C Control in Patients with Diabetes and Obesity
Authors: CHANG LEE-SHING , MALMASI SHERVIN , HOSOMURA NAOSHI , ZHANG HUABING , BROWN CHRISTOPHER J. , LEI VICTOR J. , RUBIN ALEXA , TING CLARA , TONG KIMHOUY , TURCHIN ALEXANDER
Published: June 2018

Metabolic surgery (MS) can lower A1c and achieve DM remission. Counseling by a healthcare provider is an important initial step in considering MS. We hypothesized that MS counseling results in a significant increase in DM remission and A1c improvement. We retrospectively studied 3,676 adults aged 18-65 with T2DM, BMI ≥35 kg/m2, and A1c ≥6.5% followed at two academic medical centers between 2000-2015, using a software tool to identify MS counseling in EMR notes. Counseling and outcomes were assessed over one and three years after study entry, respectively. Study patients’ mean age was 50.8 years and mean baseline A1c was 8.2%. Over one year after study entry, 20.2% of patients had MS counseling. In univariate analyses, patients who received MS counseling had a higher rate of DM remission (A1c<6.5% and no DM medications besides metformin) and were more likely to have achieved A1c control (<7.0%) vs. those who did not (Figure). In multivariable analyses adjusted for patient demographics and comorbidities, MS counseling was associated with an OR of 1.43 (95% CI 1.11-1.84; p=.0051) for achieving DM remission and an OR of 1.44 (95% CI 1.15-1.81; p=.0015) for achieving A1c control. In this large study of patients with T2DM and obesity, MS counseling was associated with significantly greater rates of DM remission and A1c control. These findings suggest MS counseling is an important step in the treatment of DM and obesity.

Disclosure

L. Chang: None. S. Malmasi: None. N. Hosomura: None. H. Zhang: None. C.J. Brown: None. V.J. Lei: None. A. Rubin: None. C. Ting: None. K. Tong: None. A. Turchin: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Merck Sharp & Dohme Corp., Monarch Medical Technologies. Stock/Shareholder; Self; Brio Systems. Research Support; Self; Eli Lilly and Company.
Detection of Pancreatic Beta-Cell DNA in the Circulation Using the Dual Amplification Refractory Mutation System PCR
Authors: KURODA AKIO , YAMADA MISUZU Y. , TOMINAGA YUKARI , SUZUKI REIKO , TAMAKI MOTOYUKI , AKEHI YUKO , TAKASHI YUICHI , KOGA DAISUKE , SHIMOKITA EISUKE , TANIHARA FUMINORI , KURAHASHI KIYOE , YOSHIDA SUMIKO , ENDO ITSURO , AIHARA KEN-ICHI , ABE MASAHIRO , FERRERI KEVIN , MATSUHISA MUNEHIDE
Published: June 2018

Background: CpG cytosine in the human insulin gene (INS) is uniquely unmethylated in pancreatic β-cells. It has been reported that a few unmethylated CpG specific PCR in circulating cell-free DNA could detect injury of pancreatic β-cells. However, the same CpG methylation pattern with these CpG sites are also existing in non-β-cells, thus the false positive results might be involved in these reports.

Aim: To develop a precise method for detecting pancreatic β-cell DNA in the circulation.

Methods: We have developed the dual Amplification Refractory Mutation System (ARMS) PCR, which amplifies only if 4 CpG sites were all unmethylated. The first ARMS PCR amplifies if 2 CpG sites (+331, 404bp of transcription start sites (TSS) of INS) are unmethylated simultaneously, and followed by the second ARMS PCR, which amplifies if 2 CpG sites (+367, 374bp of TSS of INS) are unmethylated simultaneously. This method was applied to 52 patients with type 1 diabetes (T1D) (duration 12.6 +/- 10.1 years). We confirmed the positive samples using DNA sequence analysis.

Results: Pancreatic β-cell DNA were detected in 3 T1D (11.8, 2.5, 912.7 copies in 0.1mL of serum) who are diagnosed as slowly progressive T1D, and 4 among 16 healthy control subjects (1.2, 2.2, 1.9, 3.7 copies in 0.1mL of serum).

Conclusion: We have developed the dual ARMS PCR which is a precise method to detect circulating pancreatic β-cell DNA. Almost no β-cell DNA was circulating in the long standing T1D, however, β-cell DNA was detectable in slowly progressive T1D. Also, there were not so many, but a few β-cell DNA in the circulation of healthy control subjects. Therefore, this method is useful to evaluate pathogenesis of type 1 diabetes.

Disclosure

A. Kuroda: None. M.Y. Yamada: None. Y. Tominaga: None. R. Suzuki: None. M. Tamaki: None. Y. Akehi: None. Y. Takashi: None. D. Koga: Employee; Self; Otsuka Pharmaceutical Co.,Ltd.. E. Shimokita: None. F. Tanihara: None. K. Kurahashi: None. S. Yoshida: None. I. Endo: None. K. Aihara: None. M. Abe: None. K. Ferreri: None. M. Matsuhisa: None.
Metabolic Insufficiency Caused By Cellular Stresses Is Implicated in Beta-Cell Dedifferentiation in the Mouse Model of Wolfram Syndrome
Authors: AMO-SHIINOKI KIKUKO , TANABE KATSUYA , HATANAKA MASAYUKI , TANIZAWA YUKIO
Published: June 2018

Pancreatic beta cell loss is associated with augmented ER and oxidative stresses in Wolfram syndrome caused by mutations in the WFS1. In the Wfs1-/- mice, beta cells become dedifferentiated and revert to endocrine progenitor-like cells, and a subset of them takes alpha cell fate. Such beta cell plasticity appears after nursing, independently of hyperglycemia, and becomes more apparent along with diabetes progression accompanied with no significant increase in apoptosis. We have found that genetic inhibition of Txnip, which is a stress response molecule involving in various cellular processes, preserved beta cell mass and maintained glucose homeostasis in the Wfs1-/- mice. This suggests its roles in the regulation of beta cell plasticity in the setting of Wfs1 deficiency. One clue to the mechanisms underlying beta cell dedifferentiation was the paradoxical reduction of acetyl-CoA, citrate and ATP content in the Wfs1-/- islets in spite of the enhanced glycolysis with an increase in pyruvate. This metabolic dissociation was correlated with an increase in phosphorylated pyruvate dehydrogenase (PDH). Importantly, Txnip directly interacts with both PDH kinase and PDH, indicating its involvement in the regulation of PDH activity. Indeed, islets of Wfs1-/- mice lacking Txnip demonstrated a robust reduction of phosphorylated PDH and a restoration of capabilities of ATP production in response to glucose. Thus, these finding illustrate impaired energy metabolism in beta cells under the chronic stress conditions and suggest that beta cells may possibly become dedifferentiated to adapt to metabolic insufficiency caused by unresolvable stresses. This provides new insights into molecular mechanisms underlying beta cell loss in diabetes related to cellular stresses, such as Wolfram syndrome.

Disclosure

K. Amo-Shiinoki: None. K. Tanabe: None. M. Hatanaka: None. Y. Tanizawa: None.
MODY Signal Pathway in the Endoplasmic Reticulum Stress and the Role of Nkx6.1 in the Glucolipotoxicity of INS-1-3 Cells
Authors: DONG YANAN , LI YUKUN , XIAO JIANZHONG
Published: June 2018

Metabolic disturbances induce endoplasmic reticulum stress (ERS) in pancreatic beta cells. This study aims to investigate whether a common pathway exists in the ERS induced by various chemicals, including high levels of glucose and palmitate. ERS in INS-1-3 cells was induced by exposure cells to thapsigargin (TG), tunicamycin (TM) or palmitic acid (PA) +high glucose (HG). Digital gene expression (DGE) profiling technique was used to detect differentially expressed genes. The profile of gene expression was detected by gene oncology (GO) function and pathway enrichment analysis. On the basis of DGE results, Nkx6.1 over-expression was established in INS-1-3 cell lines by lentivirus infection to explore the importance of the findings. Real time reverse transcription polymerase chain reaction (RT-PCR) was used to verify the expression changes of key genes. Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. And the apoptosis was detected by flow cytometry. Glucose stimulates insulin secretion (GSIS) was used to measure the INS-1-3 cell function. DGE demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+PA groups, respectively. Genes that were differentially expressed were enriched to endoplasmic reticulum stress, antigen processing and presentation, and protein export pathways, and surprisingly, the maturity onset diabetes of the young (MODY) pathway. Nkx6.1 is a common abnormal-expressed gene in MODY signaling pathway among TM, TG and HG+PA groups. Apoptosis was ameliorated by 45.4% and proliferation was increased by 40.9% in the Nkx6.1 over-expression cells exposed to high level of glucose and palmitate. At the same time, both basal and glucose stimulated insulin secretion increased by 2.09 and 1.82 folds, respectively. ERS changed the expression of MODY pathway genes. Over-expression of Nkx6.1 protected the INS-1-3 cells from glucolipotoxicity.

Disclosure

Y. Dong: None. Y. Li: None. J. Xiao: None.
Deletion of SLC4A4 in Pancreatic ß Cells Protects from High-Fat Diet–Induced Glucose Intolerance and ß-Cell Dysfunction
Authors: BROWN MATTHEW , HOLMES HEATHER L. , RAKSHIT KUNTOL , ROMERO MICHAEL F. , MATVEYENKO ALEKSEY
Published: June 2018

Islet failure in type 2 diabetes (T2DM) is characterised by loss of glucose-stimulated insulin secretion (GSIS) attributed in part to β-cell dedifferentiation (e.g., mis-expression of alpha cell-specific genes). Recent single cell transcriptomics studies identified SLC4A4 (a gene encoding an electrogenic Na+-nHCO3- cotransporter, NBCe1) as one of the mis-expressed genes in β-cells of patients with T2DM. Thus, we set out to test the hypothesis that mis-expression of SLC4A4 in β-cells contributes to loss of GSIS and impaired glucose homeostasis in T2DM. To address this hypothesis, we first confirmed induction of robust SLC4A4 protein expression in β-cells of patients with T2DM utilizing immunofluorescence staining of autopsy-derived human pancreas specimens. We next generated β-cell-specific slc4a4 knockout (β-slc4a4-/-) and corresponding control (β-slc4a4+/+) mice through crossing of slc4a4 loxP/loxP and Ins2-Cre mouse models. Adult (3 month old) β-slc4a4-/- mice displayed normal body weight, glycaemia, glucose tolerance and insulin sensitivity under standard chow fed conditions (p>0.vs. β-slc4a4+/+). In contrast, β-slc4a4-/- mice exhibited enhanced glucose tolerance and in vivo glucose-stimulated insulin response under conditions of metabolic stress induced by ad libitum intake of 60% high fat diet (HFD) for 8 weeks (p<0.vs. β-slc4a4+/+ HFD). Interestingly, improved glucose tolerance in β-slc4a4-/-mice was also associated with a tendency for expansion of β-cells mass (82%, p=0.09 vs. β-slc4a4+/+ HFD) and increased β-cells proliferation (26%, p=0.11 vs. β-slc4a4+/+ HFD). These results suggest that β-cell mis-expression of the Na+-nHCO3- cotransporter encoded by SLC4A4 contributes to induction of β-cell failure under conditions of metabolic stress and T2DM.

Disclosure

M. Brown: None. H.L. Holmes: None. K. Rakshit: None. M.F. Romero: None. A. Matveyenko: None.
Investigation on the Protective Effect of Canagliflozin on Pancreatic Beta-Cell Mass Using SPECT/CT Imaging with 111In-Labeled Exendin-4
Authors: HAMAMATSU KEITA , FUJIMOTO HIROYUKI , FUJITA NAOTAKA , MURAKAMI TAKAAKI , SHIOTANI MASAHARU , SAJI HIDEO , INAGAKI NOBUYA
Published: June 2018

Background: Defects in insulin secretory function can be divided into two elements, the dysfunction of individual beta cells and a decrease of beta cell mass (BCM). Non-invasive methods to quantify BCM have not yet been established, and thus it is not possible to observe longitudinal changes in BCM. We developed [Lys12(111In-BnDTPA-Ahx)]exendin-4 ([111In]Ex4) as a radioactive probe targeting to the glucagon-like peptide-1 receptor with the aim of quantifying BCM by the measurement of probe accumulation in the pancreas. In this study, we investigated the protective effect of sodium-glucose co-transporter-2 (SGLT2) inhibitor on BCM using in-vivo SPECT/CT imaging with this probe.

Aim: We tried to investigate longitudinal change in BCM of diabetic model mice administered with SGLT2 inhibitor using in-vivo SPECT/CT imaging with [111In]Ex4.

Method: Male db/db mice were assigned into two groups: canagliflozin-administered group (group A) and non-administration group (group B). In-vivo SPECT/CT scans were performed before and after the intervention. The pancreatic uptake of [111In]Ex4 was evaluated using ROI with > 40% of the volume of the whole pancreas with the exception of the perirenal space.

Result: The pancreatic uptake was significantly decreased in group B, on the other hand, no significant change was observed in group A. After the intervention, the pancreatic uptake was significantly higher in group A than group B.

Discussion: SPECT/CT imaging analysis indicated that BCM was significantly larger in group A than group B after the intervention. It is considered that this difference was made by the protective effect of canagliflozin on BCM.

Conclusion: It is considered that the protective effect of canagliflozin on BCM could be investigated using in-vivo SPECT/CT imaging with [111In]Ex4.

Disclosure

K. Hamamatsu: None. H. Fujimoto: None. N. Fujita: None. T. Murakami: None. M. Shiotani: Employee; Self; Mitsubishi Tanabe Pharma Corporation. H. Saji: Research Support; Self; Nihon Medi-Physics Co.,Ltd. N. Inagaki: Research Support; Self; Daiichi Sankyo Company, Limited, AstraZeneca, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Japan Tobacco Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, Sanwa Chemical Industrial Co., Ltd., Teijin Pharma Limited.
A Low-Frequency Amerindian Specific Variant in PALD1, a Negative Regulator of Insulin Signaling, Associates with Type 2 Diabetes
Authors: NAIR ANUP K. , SUTHERLAND JEFF R. , ELSON GREGORY R. , PIAGGI PAOLO , KOBES SAYUKO , HANSON ROBERT L. , BOGARDUS CLIFTON , BAIER LESLIE
Published: June 2018

We recently completed a genome wide association study for type 2 diabetes (T2D) in 7659 American Indians who are predominantly of Pima Indian heritage using a custom designed Axiom array. A novel intronic variant (hg19 chr10:72276664 G>C) in PALD1 was identified that associated with T2D (risk allele frequency (RAF)=0.01, OR=2.19[1.49-3.22] per risk allele [C], P=6.6×10-5 adjusted for age, sex, birthyear, PCs 1-5 and accounting for genetic relatedness). Further analysis in a dataset of Urban American Indians (N=3029) representing several tribal groups living in the Phoenix area, identified a directionally consistent association (OR=2.32, P=0.12), but this variant was rare among the entire Urban American Indian sample (RAF=0.003). A meta-analysis of both datasets resulted in a summary OR of 2.15[1.49-3.13], P=4.9×10-5. In Pima Indians, this variant is highly concordant (r2=0.92) with a novel missense variant (hg19 chr10:72298980 C>T, p.[P568S]) in PALD1. The missense variant also had a significant association with T2D in Pima Indians (RAF=0.02, OR=1.80[1.25-2.60], P=0.002) and in Urban American Indians (RAF=0.008, OR=2.29[1.03-5.12], P=0.04). However, after conditional analysis, only the intronic variant remains significant in the Pima Indian dataset. PALD1 is a predicted phosphatase and acts as a negative regulator of insulin signaling. Overexpression of PALD1 leads to lower insulin stimulated AKT phosphorylation and insulin receptor abundance. For preliminary functional studies, a short fragment (100bp) containing each allele of the PALD1 intronic variant (C or G) was cloned upstream of a SV40 promoter luciferase vector and transfected into C2C12 myoblasts. The T2D risk allele (C) fragment had significantly (P=0.004) higher SV40 promoter mediated luciferase activity as compared to the non-risk (G) allele. This result is consistent with the possible role of PALD1 in T2D pathogenesis. Further mechanistic studies are currently ongoing.

Disclosure

A.K. Nair: None. J.R. Sutherland: None. G.R. Elson: None. P. Piaggi: None. S. Kobes: None. R.L. Hanson: None. C. Bogardus: None. L. Baier: None.
Synergistic Effects of Long-Term Combination Therapy of DPP-4 Inhibitor and SGLT2 Inhibitor on the Preservation of Beta-Cell Volume in Rats with Type 2 Diabetes
Authors: MIZUKAMI HIROKI , GUO DANYANG , TAKAHASHI KAZUHISA , OSONOI SHO , OGASAWARA SAORI , INABA WATARU , YAGIHASHI SOROKU
Published: June 2018

One of the main pathogenetic features of type 2 diabetes (T2D) is reduction of β cell volume (Vβ). Several antidiabetic oral agents were shown to improve Vβ in experimental studies. While DPP-4 inhibitor (DPi) ameliorated Vβ possibly via the action of GLP-1, recent studies reported that SGLT2 inhibitor (SGi) may facilitate GLP-1 secretion from L cells. These findings raised a hypothesis that the combination therapy (CT) of DPi and SGi may potentiate the effects of DPi on Vβ. To explore this possibility, we recruited non-obese spontaneous T2D Goto-Kakizaki (GK) rats and control Wistar rats (W) at 5 weeks of age. GK was divided into DPi treated group (GTe) (10mg/kg teneligliptine), SGi-treated group (GCa) (10mg/kg canagliflozin) and CT group (GTeCa). During experimental period, diabetic state was evaluated by glycated Hb (gHb), 2g/kg oral glucose tolerance test (OGTT), glucose-stimulated insulin secretion test (GSIS) and serum active GLP-1. At end, pancreata were underwent for the pathological evaluation of each endocrine cell volume by tetra-immnohistochemistry. Over 24 weeks of treatment, GK showed higher gHb and deteriorated OGTT (p<0.01 vs. W). Although DPi and SGi in each significantly improved gHb and OGTT compared to GK, the effect was the most marked in GTeCa. Of note, active GLP-1 was the highest in GCaTe among all groups (p<0.vs. GTe), while the level in GTe was higher than in W, GK, and GCa (p<0.01). GK showed attenuated GSIS (p<0.01 vs. W). It was significantly improved in GTe and GCaTe compared to GK (p<0.vs. GTe, p<0.01 vs. GCaTe), although it was comparable between GK and GCa. Pathological evaluation disclosed a significant decrease in Vβ in GK (p<0.01 vs. W). Vβ was the most well-preserved in GCaTe (p<0.vs. GTe), followed by GTe (p<0.vs. GK), while it was comparable between GK and GCa. Our findings suggest that CT of DPi and SGi is more effective for β cell function and pathology in T2D than the monotherapy of DPi or SGi.

Disclosure

H. Mizukami: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation. D. Guo: None. K. Takahashi: None. S. Osonoi: None. S. Ogasawara: None. W. Inaba: None. S. Yagihashi: None.
No Compensatory Increase in Non-ß Hormone Expressing Cells in the Pancreatic Duct Glands in Type 1 Diabetes
Authors: KULKARNI SHWETA S. , ATKINSON MARK A. , BUTLER ALEXANDRA
Published: June 2018

Longstanding type 1 diabetes (T1D) entails a near total loss of β cells secondary to autoimmunity, fibrosis and decreased total organ mass, but accumulating evidence suggests there may be an endogenous attempt to regenerate β cells. Pancreatic duct glands (PDGs) represent a distinct anatomical compartment of the pancreas, forming blind ending outpouchings from the main pancreatic duct and its branches. The PDG is purported to be a potential stem/progenitor cell niche. PDGs respond to inflammation in T1D by becoming activated, evidenced by a high frequency of epithelial cell replication and an increase in progenitor-like cells. Hence, we addressed the hypothesis that in T1D, perturbation of hormone-expressing endocrine cells in the interlobular ducts (ILD) and PDGs exist. Pancreatic sections from 10 T1D (disease duration 8-58 year) and 11 similarly aged control (ND) donors were evaluated for replication and expression of known pancreatic endocrine hormones in ducts and PDG. We confirmed increased duct and PDG replication in T1D (T1D vs. ND— ILD: 4.5 ± 1.8 vs. 0.8 ± 0.2%, p<0.05; PDG: 3.4 ± 1.3 vs. 0.4 ± 0.2%, p<0.05) and reduced frequency of insulin expressing cells (T1D vs. ND— ILD: 0.0 ± 0.0 vs. 0.4 ± 0.1%, p<0.001; PDGs: 0.± 0.07 vs. 2.4 ± 0.8%, p<0.05). No differences were found in the frequency of other known endocrine cell types (T1D vs. ND— ILD: Glucagon: 1.5 ± 0.7 vs. 2.1 ± 0.6%, Somatostatin: 1.2 ± 0.4 vs. 1.6 ± 0.3%, Pancreatic Polypeptide: 0.4 ± 0.2 vs. 1.3 ± 0.3%; PDGs: Glucagon: 0.9 ± 0.9 vs. 1.6 ± 1.0%, Somatostatin: 1.96 ± 0.8 vs. 3.7 ± 1.9%, Pancreatic Polypeptide: 1.7 ± 1.1 vs. 2.1 ± 0.8%; p=ns, all). These data suggest that increased cell replication and the deficiency of insulin expressing cells in the PDG compartment of subjects with T1D are not associated with a corresponding increase in non-insulin hormone-expressing endocrine cells. Furthermore, the consistent observation of increased cell replication in the ducts and PDGs in T1D may implicate regenerative mechanisms towards an exocrine cell fate.

Disclosure

S.S. Kulkarni: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. A. Butler: None.
Identification of Candidate Targets in Transcriptome of Islets from Offspring Exposed to High Glucose In Utero
Authors: CASASNOVAS JOSE , RAO XI , KUA KOK LIM
Published: June 2018

Offspring of diabetic mothers have higher risk to develop type 2 diabetes. Though exposure to hyperglycemia in-utero is an inciting event, the mechanism by which it impacts islet function and leads to increased risk of diabetes is unknown. We hypothesize that high glucose at late gestation alters pancreatic islet transcriptome during early life and impairs offspring islet function in adulthood. To test this, gestation day (GD) 20 fetal rats in left uterine horn were exposed to 48 hours of hyperglycemia (HG) by infusing 4mg/min glucose directly into maternal left uterine artery. Right uterine pups remained euglycemic as internal controls (Con). On GD22, HG and Con pups were either euthanized or cross-fostered to healthy dams. Glucose tolerance testing was performed on weaning and at 2month old (2mo) offspring. Islets of GD22 and weanling pups were isolated for RNAseq. While pregnant dams and Con fetal pups remained euglycemic during infusion, HG pups had higher blood glucose (88±9 mg/dL vs. 51±5mg/dL, p<0.05, n=20/20) and serum insulin levels (4.24±0.8 ng/mL vs. 3.04 ±0.6 ng/mL, p<0.05, 6/6 pups). HG pups also had higher beta cell area (31±12% increase, p<0.05, n=5/5 pups) but lower neonatal blood glucose level (72±9 mg/dL vs. 129±20 mg/dL, p<0.05, n=9/12 pups). Subsequently, weaning and 2mo HG offspring had impaired glucose tolerance (55±23% higher iAUC, n = 8/10 pups, p<0.05). 2mo pups also had lower insulin release during GTT. RNAseq identified 131 differentially expressed genes (DEG) in GD22 islets (fdr<0.1, n=3/3,) and 77 DEG in weanling islets (fdr<0.1, n=4/4,); with 10 common DEG. IPA analysis on these DEGs identified "cell signaling", "cellular movement", and "cell to cell signaling and interaction" as relevant biological processes. Weanling and young adult offspring exposed to late gestation hyperglycemia had impaired islet function with change expression in genes regulating critical biological processes. These genes will serve as target for future mechanistic studies.

Disclosure

J. Casasnovas: None. X. Rao: None. K. Kua: None.
Impact of Mig6 on ß-Cell Regeneration and Repair
Authors: BAUER BRANDON M. , EL KIMBERLEY , FUEGER PATRICK T.
Published: June 2018

Following autoimmune-mediated destruction of insulin secreting β-cells in type 1 diabetes (T1D), regenerative and repair pathways aim to restore β-cell mass and maintain euglycemia. However, these pathways are often unable to compensate for the loss of β-cell mass, resulting in insufficient insulin secretion and chronic hyperglycemia. Our lab previously demonstrated that this inability to compensate for the loss of β-cell mass may be at least in part due to mitogen inducible gene 6 (Mig6), an anti-proliferative negative feedback inhibitor of epithelial growth factor receptor signaling, which is induced by proinflammatory cytokines central to macrophage-mediated β-cell destruction in T1D. Both Mig6 haploinsufficient mice (Mig6+/-) and mice with pancreas-specific Mig6 knockout (PKO) have increased β-cell mass and improved glucose tolerance when compared to littermate controls in a β-cell ablation model. We sought to determine the extent to which β-cell specific loss of Mig6 confers resistance to depletion of β-cell mass by streptozotocin (STZ, 35 mg/kg). We hypothesized that mice with β-cell specific loss of Mig6 (βKO) would have increased β-cell mass and improved glucose tolerance following STZ treatment when compared to control mice. We treated βKO and littermate controls with multiple low doses of STZ and measured both glucose tolerance and β-cell mass for up to 20 days following STZ treatment. At baseline, Mig6 expression was reduced by 63 ± 3% in βKO mice, and βKO mice had normal glucose homeostasis, insulin sensitivity, and islet architecture compared to littermate control. Unlike Mig6+/- and PKO mice, βKO mice had no improvements in β-cell mass or glucose tolerance compared to STZ-treated control littermates. Therefore, whereas both Mig6+/- and Mig6 PKO mice are able to preserve or restore β-cells with STZ treatment, loss of Mig6 in β-cells alone does not confer the same level of protection, suggesting a potential role for Mig6 in beta β-cell transdifferentiation or neogenesis.

Disclosure

B.M. Bauer: None. K. El: None. P.T. Fueger: None.
Impaired Glucagon and Insulin Responses in Mice Lacking the Cl-Loader Nkcc2a
Authors: KELLY LISA E. , DIFULVIO MAURICIO
Published: June 2018

In pancreatic β-cells, glucose metabolism and plasma membrane depolarization are accountable for the early secretory response, a mechanism regulated primarily, though not exclusively, by ATP-sensitive K+ channels. In most cells, including β-cells, the net functional balance between Cl- loaders e.g., Nkcc1 and Nkcc2a and extruders like Kcc2 keeps the intracellular Cl- concentration above equilibrium creating an outwardly directed anionic gradient, which is electrogenically dissipated by Cl- channel opening. This makes possible the additional driving force for depolarization, which in β-cells prolongs the action potentials necessary for sustained insulin secretion.β-cells express low levels of the ’kidney-specific’ Na+K+2Cl- transporter Nkcc2a. This protein and Nkcc1 are targeted by bumetanide, which by blocking Cl- loading into β-cells, impairs insulin secretion provoking intermittent hyperglycemia, as seen in patients treated with this diuretic. Since the chronic functional implications of Nkcc2a in fuel homeostasis in vivo remain unexplored, we subjected Nkcc2aKO mice to dynamic tests of glucose homeostasis and determined their secretory responses in vivo and in vitro using islets. We found that Nkcc2aKO mice exhibit: i) increased steady-state blood glucose, plasma insulin, glucagon and de novo hepatic glucose production, ii) absent glucagon responses to physiological (6h) or prolonged (16h) fasting, iii) glucose intolerance and delayed in vivo insulin responses to glucose, iv) hyperplastic and hypertrophic α- and β-cells, v) conserved islet insulin responses to glucose, and vi) normal and reduced expression levels of Nkcc1 and Kcc2, the main Cl- loader and extruder in β-cells, respectively. Together, our results suggest for the first time that mice lacking Nkcc2a exhibit a complex metabolic phenotype related to unrestrained plasma glucagon, impaired insulin and glucagon responses in vivo in spite of compensatory mechanisms related to the regulation of Cl- transport in the islet.

Disclosure

L.E. Kelly: None. M. DiFulvio: None.
Glucose Oxidation Depletes Cytosolic Citrate and Glutamate in the Amplifying Pathways of Insulin Secretion
Authors: LEWANDOWSKI SOPHIE L. , MERRINS MATTHEW J.
Published: June 2018

In pancreatic β-cells, glucose metabolism generates signals that trigger and amplify insulin secretion. We generated β-cell specific FRET biosensors for the real-time measurement of cytosolic citrate and glutamate, two putative metabolic coupling factors with an undefined causal relationship to the signaling process. In islet β-cells, glucose elevation from 2.5 to 10 mM was accompanied by a sharp decrease in cytosolic citrate and glutamate. Steady-state oscillations in these intermediates induced by 10 mM glucose reveal that cytosolic citrate and glutamate levels decrease as calcium levels increase, precisely when the TCA cycle is most active. Subsequent membrane depolarization with 30 mM KCl resulted in a further decrease in citrate and glutamate, suggesting that mitochondria respond to work in the form of ATP hydrolysis by importing citrate and glutamate into the TCA cycle. Indeed, parallel measurements with Perceval-HR biosensors show that cytosolic ADP/ATP rises with calcium, and corresponds to a burst of mitochondrial NADH fluorescence. These data are inconsistent with existing models of the amplifying pathway in which mitochondrial glucose oxidation results in the export of TCA intermediates to the cytosol to generate NADPH and GSH/GSSG. The observed increase in cytosolic GSH/GSSG in response to glucose, shown with a FRET reporter targeted to β-cells, implies that GSH is generated from other sources such as the pentose phosphate pathway. Our results support the strong prediction that glucose oxidation in the mitochondria is inversely proportional to insulin secretion via the NADPH-generating citrate and glutamate cycles in the cytosol, since these pathways can never occur simultaneously.

Disclosure

S.L. Lewandowski: None. M.J. Merrins: None.
Insulin and Glucagon Interaction Studied by Separate and Combined Receptor Antagonism
Authors: GALSGAARD KATRINE D. , HOLST JENS J. , WINTHER-SOERENSEN MARIE , WEWER ALBRECHTSEN NICOLAI J. , PEDERSEN JENS
Published: June 2018

Insulin and glucagon are mutually influencing not only the actions of each other but also the secretion, which makes it very complicated to unravel their roles in integrated metabolism. Having studied in detail the actions of glucagon receptor antagonism in mice, we decided also to study the effects of insulin receptor antagonism and their combination. Female C57BL/6J mice (n=72) were administered an insulin receptor antagonist (IRA) (S961, 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648, 100 mg/kg), or both IRA and GRA (IRA+GRA) three hours before intravenous administration of saline, glucose (0.5g/kg) or amino acids (1 µmol/g) (both antagonists were generous gifts from Novo Nordisk A/S). As expected, IRA caused hyperglycemia (15.6±1.0 mM vs. 8.4±0.3mM, P<0.0001) and hyperinsulinemia (51.07±3.44ng/mL vs. 0.72±1.19ng/mL, P<0.0001) at fasting, but reduced glucose-induced inhibition of glucagon secretion (dAUC0-20 min; -114.0±24.0min × pM vs. dAUC0-20 min; -211.8±10.4 min × pM, P<0.0001). GRA treatment resulted in mild hypoglycemia (P=0.03), hyperglucagonemia (P=0.04), and did not influence insulin secretion (P=0.9) at fasting. However, after administration of both IRA and GRA, insulin secretion was significantly reduced (31.36±3.0 ng/mL vs. 51.07±3.44 ng/mL, P<0.0001). Finally, GRA+IRA administration resulted in blood glucose concentrations equal to those of vehicle treated mice upon a glucose challenge (tAUC0-20 min; 342.7±29.3 mmol × min vs. 353.1±39.1 mmol × min, P=0.6).

In conclusion, using both glucagon and insulin receptor antagonists, it can be demonstrated in mice that both hormones are essential for the maintenance of fasting glucose metabolism and that the secretion of both is regulated by powerful negative feedback mechanisms. Insulin contributes to glucose-induced inhibition of glucagon secretion, while glucagon has a positive effect on insulin secretion.

Disclosure

K.D. Galsgaard: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. M. Winther-Soerensen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J. Pedersen: None.
Mechanisms Underlying the Progressive Loss of Beta-Cell Function and Mass in Neonatal Diabetes Are Reverted by Dapagliflozin Therapy
Authors: SHYR ZEENAT A. , YAN ZIHAN , USTIONE ALESSANDRO , REMEDI MARIA S.
Published: June 2018

Progressive loss of β-cell function and mass are classic findings in diabetes, and are frequently attributed to membrane hyperexcitability, insulin hypersecretion and β-cell death. However, we demonstrated that in an insulin secretory-deficient mouse model of human neonatal diabetes (KATP-GOF), loss of β-cell mass still occurs in the absence of these factors. To study the underlying mechanisms of it, we performed experiments on day 7, 15, 22 and 30 post-disease induction. While KATP-GOF mice are hyperglycemic by day 7, insulin content is maintained at control levels. Surprisingly however, there is a dramatic decrease in insulin content at day 15, accompanied by augmented proinsulin/insulin ratio, altered calcium dynamics and increased oxidative and ER stress. We hypothesized that this is induced by hyperglycemia, and not by lack of insulin; and that lowering blood glucose alone will be sufficient to prevent loss of β-cell mass and improve function. KATP-GOF mice were treated with dapagliflozin, a sodium-glucose transporter-2 (SGLT2) inhibitor clinically used to reduce blood glucose by preventing renal glucose reabsorption. Dapagliflozin significantly reduced blood glucose by increasing urinary glucose excretion without changing circulating insulin levels. Dapagliflozin therapy (10 days) markedly improved insulin content, reduced proinsulin/insulin ratio and enhanced β-cell function by alleviating oxidative and ER stress. Together, we demonstrate that β-cell failure and loss of β-cell mass is induced by increased oxidative and ER stress in a reversible manner, and that normalization of blood glucose alone is sufficient to prevent/revert the progressive β-cell dysfunction and failure, opening the exciting possibility of prevention of diabetes progression.

Disclosure

Z.A. Shyr: None. Z. Yan: None. A. Ustione: None. M.S. Remedi: None.
Diminished Ca2+ Signaling, CaV1 Channel Expression, and Activity in Pancreatic Beta Cells Expressing Mutated DISC1 (Disrupted in Schizophrenia 1)
Authors: LU PING , SHARMA ROHIT B. , ALONSO LAURA C. , ZHUGE RONGHUA , RITTENHOUSE ANN R. , JURCZYK AGATA
Published: June 2018

In addition to cognitive impairment, schizophrenics often suffer from non-obese T2D. Here, we examined whether similar cellular changes occur in pancreatic beta-cells as found in neurons from a genetic model of schizophrenia. Specifically we tested whether beta-cells exhibit disrupted excitation-secretion coupling when a truncated human DISC1 (thDISC1) gene, originally discovered in a Scottish family having high penetrance for schizophrenia, is expressed selectively in mouse beta-cells upon ingesting doxycycline (+DOX). Expression of thDISC1 significantly decreases blood insulin levels and GSIS from isolated mouse islets, revealing an independent role for DISC1 in beta-cells. In central neurons, DISC1 regulates Ca2+ CaV2 channel expression, Ca2+ influx and transmitter release. To determine whether DISC1 similarly regulates Ca2+ physiology in beta-cells, we tested thDISC1 DOX+ vs. DOX- beta-cells for changes in: i) intracellular Ca2+signaling using Fluo 3-AM; ii) CaV1 channel expression, the dominant channel class controlling GSIS; iii) and CaV1 channel activity using whole-cell recording methods. We found increases in [Ca2+]i following 20 mM glucose were delayed >2 min and diminished ∼50% in dissociated beta-cells expressing thDISC1. When sections of pancreas were stained with an anti-CaV1.2/1.3 antibody, thDISC1 DOX+ vs. DOX- insulin-positive cells exhibited decreased staining. Lastly, both peak inward Ba2+ current and FPL 64176 induced long-lasting L-type tail current decreased significantly in thDISC1 DOX+ vs. DOX- beta-cells. No obvious change in activation kinetics was observed. These changes in excitation-secretion coupling parallel those in neurons expressing truncated DISC1. Thus at the cellular level, truncated DISC1 precipitates disorders of secretion such as schizophrenia and T2D.

Disclosure

P. Lu: None. R.B. Sharma: None. L.C. Alonso: None. R. Zhuge: None. A.R. Rittenhouse: None. A. Jurczyk: None.