bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucocorticoid Receptor Is Instrumental for the Mechanism of Beta-Cell Compensation for Insulin Resistance in Dietary Obesity
Authors: YAMAUCHI JUN , LEE SOJIN , DONG HENRY 
Published: June 2018

The glucocorticoid receptor (GR) is known as a receptor of steroids - potent anti-inflammatory ligands that are commonly used for the medication of allergy or asthma in children and adults. However, chronic use of steroids is associated with a significant risk of developing visceral adiposity and insulin resistance, a medical condition that is known as the Cushing syndrome. We hypothesized that excessive GR activation is deleterious to beta-cells such that genetic GR depletion would preserve beta-cell mass and function in response to metabolic stress. To address this hypothesis, we generated beta-cell specific GR knockout (KO) mice, using an inducible Pdx1-CreERT2-loxP system. We then fed beta-cell GR-KO and WT littermates both regular chow and high-fat diet for up to 30 weeks, followed by determination of beta-cell mass and function. We found that GR-deficient mice, as opposed to WT littermates, developed high blood glucose levels and glucose intolerance. This effect was not secondary to alterations in weight gain or insulin sensitivity. Instead, we detected a significant reduction in glucose-stimulated insulin secretion, correlating with abnormal glucose metabolism in GR-KO mice. We reproduced these findings in both male and female GR-KO mice. Anti-insulin immunohistochemistry revealed that GR-KO mice had significantly reduced beta-cell mass, and decreased beta-cell replication, as visualized by in vivo BrdU-labeling assay. GR deficiency appears to impair the ability of beta-cells to compensate for fat-elicited obesity and insulin resistance, resulting in prediabetes in GR-KO mice. These results unveiled an unexpected role of the glucocorticoid-GR signaling in safeguarding beta-cell mass and function in response to metabolic stress.

Disclosure
J. Yamauchi: None. S. Lee: None. H. Dong: None.
Foxo1-Expressing Cells in the Gut as a Source of Insulin for Diabetes Treatment
Authors: MCKIMPSON WENDY , KUO TAIYI , ACCILI DOMENICO 
Published: June 2018

The hallmark of type 1 diabetes is the irreversible destruction of insulin-secreting β-cells in the pancreas. Consequently, an attractive therapeutic approach is to trigger the regeneration of functional β-cells elsewhere within a diseased individual. We have previously demonstrated that removal of Foxo1 in Neurogenin3 (Ngn3)-expressing cells creates functional insulin-secreting cells within the intestine. The cells, however, only convert into insulin+ cells at a low frequency, limiting their therapeutic potential. Using a novel knock-in reporter mouse that encodes a Foxo1-Venus fusion protein (FoxV), we have identified a novel population of Foxo1-expressing cells in the glandular epithelium of the stomach. These cells are distinct from other gut FoxV+ cells in that, unlike Foxo1+ cells in the intestine, stomach FoxV+ cells rarely express serotonin. To identify the nature of Foxo1+ stomach cells, we next isolated single cells from stomach and, using flow cytometry and qPCR, analyzed the gene expression of FoxV+ cells. Although Foxo1-positive cells do not express markers of chief, pit, or neck cells, they have increased transcript levels of the parietal cell marker H+/K+ ATPase. We further validated these results by immunofluorescence and FACS. To determine if elimination of Foxo1 can convert stomach cells to insulin-producing cells, we next ablated Foxo1 in either Ngn3+ or parietal cells in mice using cre-mediated recombination. Strikingly, we detected cells positive for insulin and C-peptide in the stomach of mice harboring Foxo1 deletion. Similarly, when we inactivated Foxo1 in primary stomach cultures, we detected markedly increased “β-like” gene expression and insulin+, C-peptide+ cells. Taken together we have identified a new population of Foxo1-expressing cells in the stomach and demonstrated that Foxo1 ablation is sufficient to convert these cells to insulin-producing cells.

Disclosure
W. McKimpson: None. T. Kuo: None. D. Accili: None.
Molecular Mechanism of Androgen Receptor Stimulation of Insulin Secretion in Male ß Cells
Authors: XU WEIWEI , ASHFORD FIONA B. , HODSON DAVID , MAUVAIS-JARVIS FRANCK 
Published: June 2018

Androgen deprivation therapy increases the risk of type 2 diabetes mellitus (T2DM) in men. We previously showed that male pancreatic β-cell specific androgen receptor knockout (βARKOMIP) mice develop glucose intolerance because AR potentiates glucose-stimulated insulin secretion (GSIS) through increasing cyclic AMP (cAMP) production and amplifies the insulinotropic effect of glucagon-like peptide-1 (GLP-1). We show that male βARKOMIP mice exhibit impaired intraperitoneal (IP) glucose tolerance- because of impaired IP-GSIS- without alteration in oral glucose tolerance, suggesting that AR amplifies the islet-derived, but not the gut-derived GLP-1 to potentiate GSIS. Using male insulin-secreting β-cell line 832/3 transduced with exchange factor directly activated by a cAMP (EPAC)-based fluorescence resonance energy transfer (FRET) sensor, we observe that AR agonist dihydrotestosterone (DHT) allows GLP-1, glucagon and gastric inhibitory polypeptide (GIP) to increase cAMP production above level of the individual hormones and to a similar level to forskolin control. Accordingly, DHT increases the insulinotropic effect of forskolin, GLP-1, glucagon and GIP in mouse islets. The insulinotropic effect of DHT is abolished using EPAC and PKA inhibitors as well as rapamycin indicating that DHT amplifies the effect of GPCRs coupled to adenylate cyclase and stimulates GSIS via a cAMP/PKA/EPAC pathway and activation of mTOR.

Disclosure
W. Xu: None. F.B. Ashford: None. D. Hodson: None. F. Mauvais-Jarvis: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Beta-Cell Glucotoxicity in KATP-Induced Diabetes Is Alleviated by Genetic Reduction of Glucose Metabolism
Authors: FORTUNATO MANUELA , YAN ZIHAN , SHYR ZEENAT A. , CONWAY HANNAH E. , REMEDI MARIA S. 
Published: June 2018

Glucotoxicity, reduced β-cell function and mass are key events in the pathogenesis and progression of diabetes. We previously generated an insulin secretory-deficient mouse model of human KATP-induced diabetes. As predicted, KATP-GOF (gain-of-function) mice demonstrate severe diabetes due to low circulating insulin levels, reiterating the human disease. However, as diabetes progresses, KATP-GOF mice show reduction of insulin content and β-cell mass, consequences of glucotoxicity. Islets from diabetic mice also show increased glucose metabolism (NAD(P)H autofluorescence) and oxygen consumption rate (Seahorse analysis), and augmented mitochondrial membrane potential. Strikingly, they also demonstrate increased glucokinase (GK, first enzyme in glucose metabolism) and GLUT2 gene transcripts and proteins. We hypothesized that augmented glucose metabolism in diabetic mice will contribute to the glucotoxic reduction in in insulin content, β-cell function and mass; and that these consequences will be alleviated by reducing glucose metabolism. To test this in vivo, we crossed KATP-GOF mice with mildly glucose-intolerant heterozygous GK+/- knockout mice (with reduced glucose metabolism), to generate double-transgenic GK+/-/KATP-GOF mice. Progression of diabetes, assessed by blood glucose levels overtime, is slower in GK+/-/KATP-GOF mice, compared with KATP-GOF mice. Importantly also, glucose tolerance is enhanced in GK+/-/KATP-GOF mice 12 days after disease onset, with respect to KATP-GOF mice, without significant changes in insulin sensitivity. Insulin gene expression, insulin content and β-cell mass are partially preserved in GK+/-/KATP-GOF mice. Together, these results demonstrate that hyperglycemia induce accelerated metabolism in KATP-GOF mice damaging the islets, and that deceleration of metabolism by reducing GK activity delays/prevent hypermetabolism induced-glucotoxicity in KATP-GOF mice.

Disclosure
M. Fortunato: None. Z. Yan: None. Z.A. Shyr: None. H.E. Conway: None. M.S. Remedi: None.
Functional Roles of Proline/Arginine-Rich End Leucine-Rich Repeat Protein (PRELP) in Adipocytes
Authors: EGUCHI JUN , WADA JUN 
Published: June 2018

Adipose tissue fibrosis is recognized as a hallmark of adipose tissue dysfunction. We have previously identified PRELP as a novel regulator of adipogenesis by using lentiviral short hairpin RNA libraries targeting murine genomes. PRELP belongs to the family of leucine-rich repeat proteins, which are characterized by a series of adjacent leucine-rich motifs flanked by disulfide-bounded domains. Functionally, PRELP anchors basement membranes to connective tissues. However, roles of PRELP in adipocytes remain unclear. In the present study, we show that PRELP expression is up-regulated both in adipocytes of high-fat diet induced obesity mice and ob/ob mice. PRELP reduction in 3T3-L1 adipocytes leads to enhanced insulin signaling and insulin-stimulated glucose uptake. To determine functions of PRELP in the development of metabolic phenotypes, we generated adipocyte-specific PRELP transgenic mice. Adipose-specific overexpression of PRELP results in the development of significant adipose tissue fibrosis and insulin resistance on high fat diet without difference of body weight and adiposity. This phenotype is associated with increased expression of inflammation genes and decreased insulin signaling in adipose tissue of PRELP transgenic mice. Furthermore, we find that global Prelp deficient mice are protected from adipose tissue fibrosis and insulin resistance associated with high fat feeding. These data suggest that PRELP might play a key role in the development of adipose tissue remodeling in obesity.

Disclosure
J. Eguchi: None. J. Wada: None.
Deletion of 12/15-Lipoxygenase Preserves Retinal Neuronal Function in Diabetic Retinopathy
Authors: WAN MING , IBRAHIM AHMED , EL-SHAFEY MOHAMED , ELMASRY KHALED , ABDULMONEIM SAMER , SAUL ALAN , AL-SHABRAWEY MOHAMED 
Published: June 2018

Purpose: Diabetic retinopathy (DR) is a neurovascular complication of diabetes with critical limitations in current treatment due to a lack of neuroprotection. These limitations mandate the necessity for new therapy that considers the neuronal component of DR. The goal of this study is to explore the role of 12/15-lipoxygenase (LO) in diabetes-induced retinal neuronal dysfunction.
Methods: 12/15-LO deficient (12/15-LO−/−) mice were crossbred with Ins2Akita/+ Akita) mice, a classical model of DR, to generate a new mouse model with a double knockout (12/15-LO−/−/Akita). The generated mice were subjected to comprehensive electroretinogram (ERG) analyses after 6 months of diabetes.
Results: Profound effects of knocking 12/15-LO out on diabetes-induced reduction in visual system’s functionality were observed. First, Scotopic Threshold Response (pSTR) peak heights, which measure the functionality of ganglion cells (GCs), are consistently lower in Akita than in wild type (WT) mice. Knocking 12/15-LO out significantly improved the overall pSTR and significantly restored the loss of the GC marker (Brn3) as compared with Akita mice. Second, diabetes reduced the functionality of cone-bipolar cells by 32%, as assessed by photopic B-Wave (pBW) amplitudes, however, this reduction was significantly improved in 12/15-LO−/−/Akita mice compared with Akita mice (p&lt;0.05, n=9). Lastly, diabetes caused a significant reduction (22%) in cone photoreceptor functionality as indicated by a lower response to natural noise stimuli (NNS) in Akita compared to WT mice (p&lt;0.05, n=8) and this reduction was completely recovered in 12/15-LO−/−/Akita mice (p&lt;0.05, n=9).
Conclusion: To our knowledge, this is the first report that elimination of 12/15-LO protects against diabetes-induced visual system dysfunction. The findings may lead to new therapeutic approaches in prevention and treatment of DR.

Disclosure
M. Wan: None. A. Ibrahim: None. M. El-Shafey: None. K. Elmasry: None. S. Abdulmoneim: None. A. Saul: None. M. Al-Shabrawey: None.
Adipocyte mTORC1 Suppresses Treg Cell Development and Browning of White Adipose Tissue through CRTC2/COX-2/PGs Pathway
Authors: ZHANG XING , LUO YAN , DING XIAOFENG , WANG CHUNQING , YANG XUEXIAN , LIU MEILIAN 
Published: June 2018

Adipose tissue (AT) contains abundant CD4+Foxp3+ regulatory T (Treg) cells; however, the physiological signals that control AT Treg cell and the role of AT Treg cell in thermogenesis have not been defined. Here we show that obesity activated mTORC1 signaling while decreased frequency of Treg cells in white adipose tissue (WAT), and adipose-specific inhibition of mTORC1 by raptor deficiency promoted development of Treg cells and beige adipocytes and protected mice against diet-induced reduction of Treg cells and beige adipocytes in WAT and diet-induced obesity. Mechanistically, mTORC1 signaling phosphorylated CREB regulated transcription coactivator 2 (CRTC2) and subsequently suppressed expression of cyclooxygenase 2 (COX-2) and secretion of prostaglandins (PGs) including PGI2, PGD2 and PGE2 in vivo and in adipocytes. Treatment of PGE2 but not PGI2 and PGD2 promoted differentiation and activation of Treg cells in vitro and in vivo. Pharmacological inhibition of COX-2 or blocking Treg cell by neutralization of CD25 attenuated mTORC1 inhibition-induced browning of white fat. Further, deficiency of Treg cell suppressed the inducing effect of PGE2 administration on thermogenic gene expression and oxygen consumption in inguinal and epididymal WAT. Taken together, these results uncover that adipocyte mTORC1 is a key regulator of Treg cell and beige adipocyte development in adipose tissue via CRTC2/COX-2/PGs pathway-dependent mechanisms.

Disclosure
X. Zhang: None. Y. Luo: None. X. Ding: None. C. Wang: None. X. Yang: None. M. Liu: None.
Maternal Obesity, Diabetes during Pregnancy, Gestational Weight Gain, Breastfeeding, and Child’s BMI Growth Trajectory from Ages 2 to 6 Years
Authors: WANG XINHUI , MARTINEZ MAYRA P. , XIANG ANNY 
Published: June 2018

Limited studies have evaluated the interplay among maternal obesity, maternal diabetes including preexisting type 1 (T1D), type 2 (T2D) or gestational diabetes mellitus (GDM), excessive gestational weight gain (EGWG), and breast feeding (BF) in association with childhood growth trajectory. Here we assessed their associations with child’s BMI trajectory from ages 2 to 6 years. Data included 71,892 singleton children born at 28-44 gestational weeks in 2007-2011 at Kaiser Permanente Southern California hospitals who had at least 5 BMI measurements between ages 2 to 6. First, BMI trajectory patterns for these children were identified using group-based trajectory modeling method. Second, the relationships between maternal exposures and growth trajectory groups were evaluated using multinomial logistic regression adjusting for maternal age at delivery, race/ethnicity, education, and child’s sex. Three distinct BMI trajectory groups were identified: group 1 (59% of the cohort) had stable low BMI over time, group 2 (35% of the cohort) had stable median BMI over time, and group 3 (6% of the cohort) had high and increasing BMI over time. Relative to group 1, the adjusted odds ratio (OR[95% CI]) of being in group 3 associated with maternal exposures were 8.0 [7.3-8.8] for pre-pregnancy obesity, 2.8 [2.6-3.1] for pre-pregnancy overweight, 2.1 [1.2-3.8] for T1D, 1.7 [1.5-2.0] for T2D, 1.2 [1.1-1.4] for GDM, 1.5 [1.4-1.6] for EGWG, and 1.3 [1.2-1.4] for BF&lt;6 months after adjusting for each other. ORs of being in group 2 were much smaller and were insignificant for T1D and GDM. Further adjustment for birth weight and gestational age at delivery had a small effect on the OR estimates but did not change the conclusion. Thus, among the four exposures, high and increasing BMI trajectory in offspring from age 2 to 6 years was strongly associated with maternal obesity and overweight; modestly with maternal T1D, T2D, and EGWG; and slightly with BF&lt;6 months and GDM.

Disclosure
X. Wang: None. M.P. Martinez: None. A. Xiang: None.
The Adipose-Derived Insulin Sensitizer Adiponectin Can Activate Intracellular Signaling Independent of the Well Known AdipoR1 or AdipoR2 Receptors
Authors: GUNNET JOSEPH W. , LI WENYU , WANG YUANPING , CHAVEZ JOSE A. , HUSOVSKY MATT , MENG RONG , LANG WENSHENG , JEYASEELAN JEY R. , CALDWELL GARY W. , EDAVETTAL SUZANNE 
Published: June 2018

Adiponectin (ADN) is a crucial mediator of insulin sensitivity and vascular health. The discoveries of the adiponectin receptors AdipoR1 and AdipoR2 (R1 and R2) prompted efforts to identify ADN-mimetics. R1 and R2 are especially difficult drug targets due to the complex higher-order structures of ADN as well as challenges in creating receptor knock-out cell lines. We approached R1 and R2 as possible targets beginning with a rigorous validation of the ligand and receptors. ADN preparations from multiple internal and external sources were characterized in physicochemical, cell binding and in vitro assays (pAMPK/pACC and ceramidase). It is important to note that ADN from only one source passed this evaluation. This ADN triggered in vitro activities associated with this protein, including stimulation of phosphorylation of ACC (EC50 = 9.3 ug/ml), calcium influx (EC50 = 2.2 ug/ml), glucose uptake, fatty acid oxidation and ceramidase activity. With a biologically active ADN preparation identified, we strove to understand the interactions of ADN with R1 and R2. However, both R1 and R2 are ubiquitously expressed, complicating the in vitro confirmation of receptor-dependent functional activity. We selected HAP1 cells, an ADN-responsive haploid CML derived line well-suited for gene deletion via CRISPR-Cas9 technology, to generate R1, R2 and R1/R2 deficient cells. Surprisingly, the stimulatory activity of adiponectin in pACC and ceramidase assays in HAP1 cells deficient in R1, R2 or both R1 and R2 were indistinguishable from those in wild type HAP1 cells. In addition, transient overexpression of R1 in HAP1 cells or pretreatment with antibodies to block R1 did not alter their pACC responses to ADN. These data indicate R1 and R2 are not responsible for all the in vitro biological activity attributed to ADN and suggest that there must be other yet unidentified receptors for ADN.

Disclosure
J.W. Gunnet: Employee; Self; Janssen Research & Development. W. Li: None. Y. Wang: None. J.A. Chavez: None. M. Husovsky: None. R. Meng: None. W. Lang: None. J.R. Jeyaseelan: Employee; Self; Janssen Pharmaceuticals, Inc.. G.W. Caldwell: None. S. Edavettal: Employee; Self; Janssen Research & Development.
Fully Closed-Loop Glucose Control in Noncritical Care Settings—A Randomised, Controlled Two-Centre Study
Authors: BALLY LIA , THABIT HOOD , HARTNELL SARA , ANDEREGGEN EVELINE , RUAN YUE , WILINSKA MALGORZATA E. , EVANS MARK , WERTLI MARIA M. , COLL ANTHONY P. , STETTLER CHRISTOPH , HOVORKA ROMAN 
Published: June 2018

Automated fully closed-loop (CL) insulin delivery system without meal-bolusing was evaluated in medical and surgical non-critical care wards of two acute hospitals in Switzerland and United Kingdom. In a randomised controlled parallel design study, 136 adults with inpatient hyperglycaemia requiring subcutaneous (s/c) insulin were randomised to receive either CL-directed s/c insulin delivery (n=70) or conventional s/c insulin therapy as per local practice with masked continuous glucose monitoring (n=66) for up to 15-days. Participants consumed self-selected hospital meals and were matched for age (68±10 vs. 67±13 years; CL vs. control), HbA1c (7.8±2.5 vs. 8.0±1.9%) and BMI (32.7±8.2 vs. 32.3±8.1kg/m2). During CL, participant’s usual insulin and sulphonylurea therapy were withheld. In an intention to treat analysis, the proportion of time when sensor glucose was in target range from 5.6 to 10.0mmol/l was significantly higher during CL (p&lt;0.001, Table). CL reduced time spent above target (p&lt;0.001), and reduced mean and standard deviation of sensor glucose (p&lt;0.001). Time spent hypoglycaemic was low and comparable. Total daily insulin delivery was not different. No severe hypoglycaemia or serious adverse events occurred in either group.
In conclusion, fully closed-loop without meal-bolusing is safe, and may improve glucose control in a heterogeneous inpatient population.Closed-loop insulin delivery (n=70)Conventional insulin therapy (n=66)PTime spent at sensor glucose levels (%)5.6 to 10.0 mmol/l65.7±16.841.5±16.9&lt;0.001&gt;10.0 mmol/l23.7±16.649.5±22.8&lt;0.001&lt;5.6 mmol/l10.6±6.79.0±13.30.37&lt;3.0 mmol/l0.0 (0.0, 0.1)0.0 (0.0, 0.0)0.80Mean sensor glucose (mmol/l)8.5±1.610.5±2.4&lt;0.001SD of sensor glucose (mmol/l)2.6±1.03.2±1.1&lt;0.001Total daily insulin (U)44.0 (27.5, 73.3)40.2 (26.5, 65.6)0.36Data are mean ± SD or median (IQR).

Disclosure
L. Bally: None. H. Thabit: None. S. Hartnell: Speaker’s Bureau; Self; Medtronic, Roche Pharma. E. Andereggen: None. Y. Ruan: None. M.E. Wilinska: None. M. Evans: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, Cellnovo, Roche Pharma. Speaker’s Bureau; Self; Abbott, Novo Nordisk A/S. M.M. Wertli: None. A.P. Coll: None. C. Stettler: None. R. Hovorka: Speaker’s Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, AstraZeneca. Other Relationship; Self; B. Braun Medical Inc.. Research Support; Self; Medtronic. Other Relationship; Self; Medtronic. Research Support; Self; Abbott, JDRF, Diabetes UK, National Institute of Diabetes and Digestive and Kidney Diseases.
Human Regular U-500 Insulin via Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections in Adults with T2D—The VIVID Study—All Randomized Population
Authors: GRUNBERGER GEORGE , BHARGAVA ANUJ , LY TRANG T. , ZISSER HOWARD , ILAG LIZA , MALONE JAMES K. , ZHANG SHUYU , JOHNSON JENNAL 
Published: June 2018

VIVID is the first prospective randomized controlled trial evaluating CSII (using an investigational Omnipod U-500™ Insulin Management System) vs. MDI (TID) with U-500R (Humulin® R U-500). This was a 26-week, open-label, multicenter, parallel study in adults with T2D on high dose insulin (201-600 units/day) with or without other antihyperglycemic agents (NCT02561078). We present results for the all randomized population (N=420); results for the primary population (excluding participants on concomitant GLP-1 RAs or SGLT2 inhibitors) are reported separately. Baseline characteristics were similar between arms. Without adjusting for multiplicity, CSII demonstrated significantly greater reduction in A1C and FPG at a lower total daily dose vs. MDI at 26 weeks. Also, a higher percentage of participants on CSII reached A1C targets &lt;7.0%, &lt;7.5%, and &lt;8.0%. Severe hypoglycemia rates were low. Other hypoglycemia rates were similar (documented symptomatic) or higher (nocturnal) for CSII vs. MDI. Weight gain was similar (Table). In the all randomized population, U-500R via CSII demonstrated greater efficacy at a lower dose with a higher nocturnal hypoglycemia rate vs. MDI. CSII with U-500R may be a viable option for patients with T2D on high dose insulin. Individualized dose titration will be important for safely achieving glycemic targets.

Disclosure
G. Grunberger: Research Support; Self; Medtronic MiniMed, Inc., Novo Nordisk Inc.. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Janssen Pharmaceuticals, Inc.. A. Bhargava: None. T.T. Ly: Employee; Self; Insulet Corporation. H. Zisser: Employee; Self; Verily Life Sciences LLC.. Stock/Shareholder; Self; Verily Life Sciences LLC. L. Ilag: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J.K. Malone: Employee; Self; Eli Lilly and Company. S. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. J. Johnson: Employee; Self; Eli Lilly and Company.