bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lactogens Prevent ER Stress-Induced ß-Cell Death and Diabetes
Authors: LI ROSEMARY , HAMPTON ROLLIE F. , KONDEGOWDA NAGESHA GUTHALU , FENUTRIA RAFAEL , VASAVADA RUPANGI C. 
Published: June 2018

ER stress is highly relevant in the context of diabetes, as inducers of β cell death and dysfunction implicated in the disease - including proinflammatory cytokines and glucolipotoxicity - are known to impair ER function. Previous work has shown that prolactin (Prl) and placental lactogen (PL), which bind to the same receptor (Prl-R), are important for β cell function and proliferation, and enhance survival against cytokines and glucolipotoxicity. Here, we examine the effect of Prl/PL directly on ER stress and the associated unfolded protein response (UPR) in the β cell. ER stress was induced in vitro via tunicamycin in INS1, primary mouse, and primary human β cells, concurrent with Prl/veh treatment. Expression of ER stress and UPR associated genes was measured via qRT-PCR and preliminarily via WB, and insulin-TUNEL co-staining was used to assay for β cell death. As an in vivo model, heterozygous Akita mice - a well-established β cell ER stress model which becomes diabetic by 4 weeks of age - were bred to single-transgenic mice overexpressing PL in the β cell. Prl increases survival of INS1, primary mouse and human β cells against ER stress-mediated cell death in vitro (2.34±0.19% TM vs. 0.73±0.19% TM+Prl, human). Differences in mRNA expression point towards modulation of the PERK/IRE1 UPR arms. Non-Tg Akita mice quickly become and remain hyperglycemic/diabetic, while overexpression of PL in the β cells of these mice significantly improves glycemia in males (663±29mg/dL non-Tg vs. 327±37mg/dL Tg, 12 weeks) and results in normoglycemia in females. In vivo GSIS at 12 weeks shows a trend towards restoration of β cell function in Tg compared to non-Tg Akita mice. Males at this age exhibit improved β cell mass (0.28±0.12mg non-Tg vs. 2.29±0.44mg Tg), with similar trends in β cell proliferation. Taken together, these data demonstrate that Prl/PL can prevent and protect against ER stress in the β cell, in vitro and in vivo. As ER stress is highly relevant to diabetes, modulation of the lactogenic pathway could present a novel therapy for this disease.

Disclosure
R. Li: None. R.F. Hampton: None. N. Guthalu Kondegowda: None. R. Fenutria: None. R.C. Vasavada: None.
A Phase 3 Comparison of a Novel Liquid Glucagon Autoinjector to Glucagon Emergency Kit for the Symptomatic Relief of Severe Hypoglycemia
Authors: CHRISTIANSEN MARK P. , CUMMINS MARTIN J. , STEVEN J. PRESTRELSKI , STRANGE POUL 
Published: June 2018

Objective: A novel ready-to-use stable liquid glucagon autoinjector (GAI; Xeris Pharmaceuticals), was evaluated for relief of symptoms during rescue treatment of severe hypoglycemia.
Research Design and Methods: A randomized, controlled, double-blind, crossover clinical trial was conducted in 80 adults with T1D (mean age 43.6 years) to compare subcutaneous 1 mg doses of GAI vs. Glucagon Emergency Kit (GEK; Eli Lilly) for the treatment of insulin-induced severe hypoglycemia. Serial assessments of 4 autonomic and 4 neuroglycopenic symptoms and sensation of hypoglycemia were performed at each treatment visit.
Results: The mean time to symptom relief was comparable between GAI and GEK for both autonomic symptoms (15.4±12.1 min and 14.2±9.7 min, p=NS), and neuroglycopenic symptoms (16.3±10.9 min and 13.9±9.4 min, p=NS). Mean time to resolution of the global feeling of hypoglycemia was also similar between groups. The incidence of all AEs was low in both groups; the most commonly reported AE was nausea (GAI 20.5%, GEK 12.7%, p=NS).
Conclusions: The prompt relief of neurologic symptoms is critical in the rescue of severe hypoglycemic emergencies. GAI achieved both autonomic and neuroglycopenic symptom relief during induced severe hypoglycemia, and was safe and well tolerated. These results demonstrate that ready-to-use GAI is a viable alternative to GEK.

Disclosure
M.P. Christiansen: Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Abbott, Novo Nordisk Inc., Senseonics, REMD Biotherapeutics, Xeris Pharmaceuticals, Inc. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. P. Strange: Other Relationship; Self; AstraZeneca. Consultant; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
BioChaperone Glucagon (BCG), a Stable Ready-to-Use Liquid Glucagon Formulation, Is Well Tolerated and Quickly Restores Euglycemia after Insulin-Induced Hypoglycemia
Authors: GLEZER STANISLAV , HOVELMANN ULRIKE , TENG SOPHIE , LAMERS DANIELA , ODOUL MARION , CORREIA JOSÉ , ZIJLSTRA ERIC , GAUDIER MARTIN , SOULA OLIVIER , DURACHER DAVID 
Published: June 2018

BCG is a stable, ready-to-inject, aqueous formulation of human glucagon for hypoglycemia rescue therapy. In this randomized, double-blind, crossover trial we investigated the safety and efficacy of two BCG formulations vs. a commercially available glucagon (GlucaGen® HypoKit, GEN) in 27 patients with type 1 diabetes who received single subcutaneous doses of 1 mg of BCG1, BCG2 or GEN under insulin-induced hypoglycemic conditions (plasma glucose (PG)&lt;60 mg/dl). Both BCG formulations were safe and well tolerated with the most frequent adverse event being mild nausea with both BCGs and GEN. Both BCGs quickly restored PG of ≥ 70 mg/dl after hypoglycemia (BCG1 11.5±5.0 min; BCG2 10.0±3.5 min; GEN 7.3±1.8 min, p&lt;0.001 vs. BCG1 and BCG2). PG≥70 mg/dl was reached within 30 minutes by all but one patient with both BCGs and the mean PG increase at 15 minutes was 29±17 mg/dl with BCG1, 36±16 mg/dl with BCG2 and 47±11 mg/dl with GEN (p&lt;0.001 vs. BCG1 and BCG2).
In conclusion, the BioChaperone technology allows the formulation of stable ready-to-use liquid formulations of human glucagon suited for rescue therapy of severe hypoglycemia with only slightly slower effects than GEN.

Disclosure
S. Glezer: Stock/Shareholder; Self; Sanofi. Stock/Shareholder; Spouse/Partner; Sanofi. Employee; Self; ADOCIA, Novo Nordisk Inc.. Employee; Spouse/Partner; Pfizer Inc., Teva Pharmaceutical Industries Ltd.. Stock/Shareholder; Spouse/Partner; Teva Pharmaceutical Industries Ltd.. U. Hovelmann: None. S. Teng: Employee; Self; ADOCIA. D. Lamers: None. M. Odoul: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. J. Correia: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. D. Duracher: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA.
Mediators of the Racial Disparity in Diabetes Incidence—The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: CARSON APRIL P. , LONG D. LEANN , CHERRINGTON ANDREA , DUTTON GARETH R. , HOWARD VIRGINIA J. , BROWN TODD , MOY CLAUDIA , CUSHMAN MARY , SAFFORD MONIKA , HOWARD GEORGE 
Published: June 2018

Objective: To identify the contribution of individual and neighborhood factors to the racial disparity in diabetes incidence among older adults.
Methods: This study included 7,304 black and white adults, aged 45-91 years at baseline (2003-07), without prevalent diabetes. Incident diabetes was assessed at the 2nd in-home exam (2014-16) using plasma glucose or use of diabetes medications. Modified Poisson regression, stratified by sex, was used to obtain risk ratios. Mediation analyses using the change in beta coefficient method and bootstrapping were done to evaluate the contribution of socioeconomic, anthropometric, lifestyle, clinical and neighborhood factors, grouped separately and all factors combined.
Results: The risk of diabetes was 75% higher for black women compared with white women and 35% higher for black men compared with white men (Table). Among men, only lifestyle factors were significant mediators of the racial disparity. In contrast, among women, all grouped factors, except clinical, were significant mediators. When taking into account all factors combined, only 4.2% and 28.1% of the racial disparity was explained for men and women, respectively.
Conclusion: Although the factors underlying the racial disparity varied by sex, the excess diabetes risk for black vs. white adults remained after accounting for individual and neighborhood factors.

Disclosure
A.P. Carson: Research Support; Self; Amgen Inc.. D. Long: None. A. Cherrington: Advisory Panel; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. G.R. Dutton: None. V.J. Howard: None. T. Brown: Research Support; Self; Amgen Inc., AstraZeneca. C. Moy: None. M. Cushman: None. M. Safford: None. G. Howard: None.
Analysis of Transcriptome Data from 261 Individual Laser-Captured Islets from Nondiabetic, Autoantibody-Positive, and Type 1 Diabetic Organ Donors
Authors: CAMPBELL-THOMPSON MARTHA , BUTTERWORTH ELIZABETH A. , LENCHIK NATALIYA I. , ATKINSON MARK A. , MATHEWS CLAYTON E. , GERLING IVAN C. 
Published: June 2018

The purpose of this study was to obtain comprehensive gene expression datasets from a large number of individual islets, with defined pathological phenotypes, from organ donors with different clinical stages of type 1 diabetes. Here we will present results from an analysis that compared “normal” (Ins+CD3-) islets from the 3 clinical phenotypes: Autoantibody negative nondiabetic (C), Autoantibody positive nondiabetic (AB) and type 1 diabetic (T1D). We obtained pancreatic tissue from 43 male and female nPOD donors with the 3 clinical phenotypes (C=16, AB=11, T1D=16). Staining of islets for both insulin and CD3 resulted in the following histologic subtypes of the 261 islets collected and analyzed for gene expression: Ins+CD3- (n=147), Ins+CD3+ (n=78), Ins-CD3+ (n=12), and Ins-CD3- (n=23). The gene expression profiles of these 261 individual islets were obtained using Affymetrix HTA 2.0 arrays. We compared gene expression profiles of the 147 islets that were Ins+CD3- from each of the 3 organ donor types. The number of transcripts differentially expressed by &gt;1.5 fold and p&lt;0.001 (Student’s t-test with FDR&lt;0.05) were as follows: C vs. AB=448; C vs. T1D=240; AB vs. T1D=387. Those gene lists were subjected to a data mining workflow. The 448 transcripts differing between Ins+CD3- islets of C and AB organ donors were dominated by non-coding RNA (33%). Islets from AB donors had reduced transcripts associated with islet regeneration, cell replication, and immune responses. The 387 transcripts differing between Ins+CD3- islets of AB and T1D organ donors expressed increased levels of beta cell specific transcripts and markers of immune responses in T1D islets. A number of oxidative phosphorylation gene transcripts were lower in T1D islets. The 240 transcripts differing between Ins+CD3- islets of C and T1D organ donors demonstrated reduced levels of beta cell specific transcripts but increased HLA class II transcripts in T1D islets

Disclosure
M. Campbell-Thompson: None. E.A. Butterworth: None. N.I. Lenchik: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. C.E. Mathews: None. I.C. Gerling: None.
Food Insecurity in Older Adults with Diabetes
Authors: SCHROEDER EMILY B. , ZENG CHAN , STERRETT ANDREW , KIMPO TINA K. , PAOLINO ANDREA R. , STEINER JOHN 
Published: June 2018

Background: Food insecurity (FI) among individuals with diabetes has been associated with both hypoglycemia and worse glycemic control, but studies of elderly insured populations are lacking.
Methods: As part of its Medicare Annual Wellness Visit, Kaiser Permanente Colorado (KPCO) initiated a member survey in January 2012 that included a question about FI (“Do you always have enough money to buy the food you need?”). We combined this survey with electronic health record data and other data to conduct a nested case-control study of FI among KPCO members ≥ 65 years with diabetes. Of 32,666 members with diabetes, 10,052 (31%) completed a survey. Of those, the 742 (7.4%) who had FI were matched 1:3 based on date of the survey (± 7 days) to 2,226 individuals without FI.
Results: Individuals with FI were slightly younger (mean age ± SD of 73.2 ± 6.1 vs. 73.9 ± 6.8), and were more likely to be female (60.6% vs. 46.8%), non-white (36.8% vs. 21.8%), living without a partner (49.6% vs. 33.0%), have less than high school education (21.2% vs. 9.0%), and have Medicaid (16.4% vs. 3.2%). Individuals with FI reported higher frequency of fair or poor general health (29.2% vs. 16.7%) and quality of life (23.6% vs. 10.5%), and were more likely to eat ≤ 2 meals a day (19.0% vs. 8.9%). Rates of hypertension and chronic kidney disease were similar, but individuals with FI were more likely to have depression on PHQ2 screening (24.8% vs. 9.1%). Individuals with FI were more likely to be taking any diabetes medication (70.5% vs. 63.6%) or insulin (25.4% vs. 19.4%), have an emergency department (ED) visit (19.0% vs. 13.9%) or hospitalization in the prior year (8.6% vs. 7.0%), and have an A1c ≥ 9% (11.2% vs. 5.8%). Mean A1c for those with FI was 7.4 ± 1.4 and those without FI was 7.1 ± 1.1. ED visits or hospitalizations for hypoglycemia or hyperglycemia were infrequent (≤10) in both groups.
Conclusions: In this insured elderly population with diabetes, food insecurity was associated with higher health care utilization and A1c levels. Strategies to address FI in individuals with diabetes deserve further evaluation.

Disclosure
E.B. Schroeder: None. C. Zeng: None. A. Sterrett: None. T.K. Kimpo: None. A.R. Paolino: None. J. Steiner: None.
Selectively Agonizing Treg in Type 1 Diabetes with IL-2 Muteins
Authors: KHORYATI LILIANE , KUMARI SWARNIMA , NGUYET PHAM THI MINH , BOGDANI MARIKA , GAVIN MARC 
Published: June 2018

Regulatory T cells (Treg) play a pivotal role in maintaining self-tolerance. For their development and function, Treg rely on interleukin-2 (IL-2) and efficiently compete with other immune cells for IL-2 by expressing the highest levels of the IL-2 receptor alpha-chain (IL-2Ra or CD25). Treg deficiencies and alterations of the IL-2 pathway have been reported in several autoimmune diseases including type 1 diabetes (T1D) where the loss of self-tolerance leads to the destruction of insulin-producing beta cells in the pancreas. Low-dose IL-2 therapy has been shown to be successful in several autoimmune and inflammatory conditions; however, the potential for IL-2 to activate pro-inflammatory immune cells raises concerns regarding its widespread utility, particularly in type 1 diabetes (T1D) where pathogenic autoreactive T cells are activated by IL-2. Hence, there is a need to develop novel IL-2 based therapeutics with enhanced Treg-specificity. We have generated a series of Fc-fused murine IL-2 muteins (Fc.IL-2 mutein) to optimize Treg-selectivity, tissue distribution and PK. Twenty-eight Fc.IL-2 muteins were screened for their signaling potency and surface retention on Treg. Eight of the mutein candidates, showing a reduced signaling in Treg but prolonged association with CD25, were further characterized in vitro. Two of the weakest muteins were tested in vivo and showed a greater enrichment and Ki-67 induction in Treg compared to wild type (WT) IL-2, and less effect on CD4+ T effector cells, CD8+ cells and NK cells. Finally, in the non-obese diabetic mouse model of T1D, we observed a significantly improved protection in mice treated infrequently with Fc.IL-2 mutein compared to WT IL-2, and, unexpectedly, differences in efficacy between WT and mutein were more pronounced at a very high dose level. Altogether, our data suggest that Fc.IL-2 mutein treatment represent a safer and more efficient alternative for the WT IL-2 therapy, allowing a selective Treg enrichment and a targeted control of the autoimmune response.

Disclosure
L. Khoryati: None. S. Kumari: None. T. Pham: None. M. Bogdani: None. M. Gavin: None.
Potentiation of TRPM5 with Stevioside in the Beta Cells Stimulates Insulin Secretion
Authors: PHILIPPAERT KOENRAAD , VENNEKENS RUDI , LIGHT PETER E. 
Published: June 2018

The calcium-activated monovalent cation channel TRPM5 is expressed in human and murine beta cells. Members of the TRP ion channel family can be activated by a plethora of different stimuli as temperature, voltage, and ligands, including natural compounds. Studies have shown that TrpM5-knockout mice have increased blood glucose levels and an impaired insulin secretion. Mutations in TRPM5 are more prevalent in patients with diabetes or metabolic syndrome. Stevioside is a sweet tasting organic molecule isolated from the leaves of the scrub plant Stevia rebaudiana, it is widely used in consumer foods and beverages. Despite its wide use, the molecular interactions of stevioside in the body remained elusive. Here we show that stevioside potentiates TRPM5 channel activity. This leads to increased calcium dynamics in both human and mouse islets, which relates to increased insulin secretion. We show that the steviol core of stevioside is responsible for the TRPM5-potentiating effect. When mice on a high fat diet are given stevioside, we observe an attenuation of the development of hyperglycemia in a TRPM5-dependent manner. With this work, we elucidate the molecular mechanism of action of stevioside. Furthermore, we provide a deeper insight in the regulation of insulin secretion from the beta-cells and identify TRPM5 as an important part of a healthy secretion pathway. TRPM5 constitutes a novel possible drug target in the battle against type 2 diabetes.

Disclosure
K. Philippaert: None. R. Vennekens: None. P.E. Light: None.
Stem Cell-Derived Tissue-Associated Regulatory T Cells Suppress Autoimmune Diabetes
Authors: SONG JIANXUN J. 
Published: June 2018

Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy regulatory T cells (Tregs) to treat autoimmune diabetes as they have the ability to create nearly entire cell types in the body, including Tregs. However, the right conditions for the development of auto antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) has not been fully defined. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissues (e.g., islets) to suppress autoimmune responses after adoptive transfer, thus preventing possible overall immunosuppression from non-specific Tregs. In this study, a new approach was developed to generate functional auto Ag-specific Tregs from induced PSC (iPSCs), i.e., iPSC-Tregs, which have the ability to suppress autoimmunity in a murine model of autoimmune diabetes in auto Ag-associated fashion. Murine iPSCs were retrovirally transduced with a DsRed reporter construct containing genes of ovalbumin (OVA)-specific T cell receptor (TCR) and the transcriptional factor FoxP3. The DsRed+ iPSCs were in vitro differentiated into OVA-specific iPSC-Tregs with an OP9 stromal cell line in the presence of recombinant cytokines. A double transgenic (Tg) mouse model of autoimmune diabetes was established in F1 mice in which the first generation from RIP-OVA Tg mice that were crossed with OT-I T cell receptor (TCR) Tg mice was challenged with vaccinia viruses expressing OVA (VV-OVA). Adoptive transfer of OVA-specific iPSC-Tregs dramatically suppressed autoimmunity in the OVA-induced model of autoimmune diabetes, including the inflammation and prevents the insulin-secreting pancreatic beta cells from destruction. Of note, we demonstrated that the adoptive transfer significantly reduced the higher ratio of CD8+ to CD4+ T cells in diabetic mice. These results indicate that stem cells can be used to develop auto Ag-specific Tregs, which have a therapeutic potential for autoimmune diabetes.

Disclosure
J.J. Song: None.
Dapagliflozin Treatment Impacts ß, but Not a, Cell Function in Normal Human Islets
Authors: DAI CHUNHUA , SHOSTAK ALENA , BOUCHI YASIR H. , HART NATHANIEL , POFFENBERGER GREG , SAUNDERS DIANE C. , HALIYUR RACHANA , DEAN DANIELLE , ARAMANDLA RADHIKA , BRISSOVA MARCELA , SHIOTA MASAKAZU , GREINER DALE L. , SHULTZ LEONARD D. , BOTTINO RITA , POWERS ALVIN C. 
Published: June 2018

Dapagliflozin (DAPA), a selective Sodium Glucose Cotransporter-2 (SGLT2) inhibitor, is widely used for the treatment of type 2 diabetes (T2D). In T2D individuals, DAPA increases plasma glucagon, decreases insulin secretion, and improves muscle insulin sensitivity. DAPA has been reported to increase glucagon secretion in cultured normal human islets possibly because SGLT2 was more highly expressed in α cells. To investigate DAPA effect on human islets in vivo, we transplanted normal human islets (n=3 donors) into immunodeficient mice and treated them with DAPA (2mg/kg/day) or NaCl by oral gavage for 4 weeks. Basal blood glucose (NaCl vs. DAPA: 101±8 vs. 85±5 mg/dL, p=0.0858), glucagon (199.5±24.4 vs. 169.9±15.9 pg/mL, p=0.3107), and human insulin (1.15±0.17 vs. 0.99±0.14 ng/mL, p=0.4626) levels were similar in both groups. However, 15 minutes after glucose challenge, DAPA-treated mice had lower blood glucose (375±21 vs. 287±16 mg/dL, p=0.003), unchanged glucagon (86±14 vs. 75±8 pg/mL, p=0.4883), but lower human insulin levels (2.05±0.24 vs. 0.96±0.ng/mL, p&lt;0.0001). The ratio of human insulin/blood glucose was lower in the DAPA group (0.52±0.07 vs. 0.36±0.04, p=0.0322). Ultrastructure of transplanted human islets showed that the DAPA treatment decreased the % immature granules (52±2% vs. 43±2%, p=0.0109) but increased the % empty granules (5.7±0.6% vs. 13.7±0.7%, p&lt;0.0001) in β cells. To investigate if these changes were a consequence of improved insulin sensitivity or DAPA’s direct effect on β cells, we assessed insulin secretion by culturing human islets (n=3 donors) in 3.3 mM and 16.7 mM glucose with DAPA (0.5 μM) or NaCl for 1 hour. DAPA treatment had no effect on glucagon secretion at both glucose concentrations but reduced insulin secretion by 30% at 16.7 mM glucose (p=0.0259). By transcriptional profiling SGLT2 was expressed equally in α and β cells. These data suggest that DAPA does not directly affect glucagon secretion but has a direct impact on human β cell function.

Disclosure
C. Dai: None. A. Shostak: None. Y.H. Bouchi: None. N. Hart: None. G. Poffenberger: None. D.C. Saunders: None. R. Haliyur: None. D. Dean: None. R. Aramandla: None. M. Brissova: None. M. Shiota: None. D.L. Greiner: Consultant; Self; The Jackson Laboratory, Allakos, Inc. L.D. Shultz: None. R. Bottino: None. A.C. Powers: None.