bluuebunny/crossref_metadata_2025_split huggingface dataset:
167-OR: Activation of Myocardial Mitochondria Akt1 Improved Diabetic Cardiomyopathy and Body Composition—The Heart as a Metabolic Organ
Authors: CHEN YU-HAN , TA ALBERT , LEE HSIAOCHEN , YOU-HSIEN LIN HUGO , CHEN YUMAY , WANG PING H. 
Published: June 2019

Insulin acutely stimulates Akt1 translocation into cardiac mitochondria, which is blunted in T2DM due to insulin resistance. To study the role of mitochondrial Akt (mito-Akt) in diabetic cardiomyopathy and its implication on whole body metabolism, we generated two transgenic mice lines with heart-specific Cre-lox, using inducible mitochondria-targeting dominant negative Akt (CAMDAKT) or constitutively active Akt (CAMCAKT). CAMDAKT mice developed cardiomyopathy and heart failure after Tamoxifen (T) induction when compared to corn oil (CO) injected CAMDAKT mice. To study whether activation of myocardial mito-Akt can reverse diabetic cardiomyopathy, two models of diabetic cardiomyopathy resembling different phases of T2DM were used in this study. First, after 5-months high fat/fructose diet (HFF), mice developed LV dysfunction, obesity, glucose intolerance, and hyperinsulinemia. In this model, T-CAMCAKT mice restored LV function and averted cardiomyopathy. A second metabolic model was induced with a 12-weeks HFF diet and low-dose streptozotocin injections, which led to overweight, hyperglycemia, and reduced insulin secretion. CO mice showed higher heart failure markers (ANF, BNP, MYH7) and increased expression of cardiac PDK4, CPT1, CPT2 and CD36. In the T-CAMCAKT mice, cardiomyopathy was reversed. Thus, activation of mito-Akt reversed diabetic cardiomyopathy. While T-CAMCAKT showed similar improvement of cardiomyopathy in these two metabolic models, body composition was different. In the first HFF model, mito-Akt activation did not alter body composition or glucose homeostasis, but fatty liver was improved. In the second metabolic model with reduced insulin secretion, T-CAMCAKT mice had better OGTT, lower fat mass (16.6% vs. 26.5%, p&lt;0.001) and higher lean mass (77.1% vs. 68.1%, p&lt;0.001).
Summary: myocardial mito-Akt locally modulated cardiac metabolism and LV function, and remotely modulated whole body metabolism.

Disclosure
Y. Chen: None. A. Ta: None. H. Lee: None. H.Y. Lin: None. Y. Chen: None. P.H. Wang: None.
1676-P: Racial and Ethnic Disparities in Type 1 (T1D) and Type 2 (T2D) Diabetes Incidence in Young Adults: The Diabetes in Young Adults (DiYA) Study
Authors: FERRARA ASSIAMIRA , ALEXANDER JANET G. , SRIDHAR SNEHA B. , RITCHIE JENNA , SLEZAK JEFF , TAKHAR HARPREET S. , VEGA-DAILY LETICIA I. , SAYDAH SHARON , IMPERATORE GIUSEPPINA , QUESENBERRY CHARLES , LAWRENCE JEAN M. 
Published: June 2019

Data on the incidence of T1D and T2D among racially and ethnically diverse young adults are sparse. To fill this gap, we conducted surveillance in a diverse population of 2.3 million members (15.3% Asian, 7.0% black, 34.6% Hispanic, 33.2% white, 9.9% other) of Kaiser Permanente California, in 2017, aged 20-45 years without recognized diabetes as of 12/31/2016. Incident cases were identified through electronic health records based on the following criteria: a) ≥2 ICD-10 diagnosis codes for diabetes, b) 1 ICD-10 diagnosis for diabetes plus ≥1 prescription for diabetes medication, or c) 1 ICD-10 diagnosis plus ≥2 glucose or HbA1c values diagnostic of diabetes according to the ADA criteria. T1D was defined based on &gt;50% of ICD-10 codes indicating T1D.
We identified 7,862 incident diabetes cases in 2017: 122 (1.6%) T1D and 7,713 (98.1%) T2D. Age- and sex-standardized T1D and T2D incidence rates per 100,000 person-years are reported in the Table. The incidence of T1D was highest in white and black, followed by Hispanic and Asian individuals. The incidence of T2D was highest among Hispanic followed by black, Asian and white individuals.
In young adults, there are large racial and ethnic disparities in the incidence of T1D and T2D. Targeted disease management strategies are needed. Further research into possible etiological factors may identify targeted prevention strategies.

Disclosure
A. Ferrara: None. J.G. Alexander: None. S.B. Sridhar: None. J. Ritchie: None. J. Slezak: None. H.S. Takhar: None. L.I. Vega-Daily: None. S. Saydah: None. G. Imperatore: None. C. Quesenberry: None. J.M. Lawrence: None.

Funding
Centers for Disease Control and Prevention (1U18DP006289)
1678-P: Comparisons of Combined C-Peptide and Glucose Intermediate Endpoints for Identifying Individuals at Very High Risk for Type 1 Diabetes
Authors: JACOBSEN LAURA M. , CLEMENTS MARK A. , REDONDO MARIA JOSE , NATHAN BRANDON M. , SCHATZ DESMOND , SOSENKO JAY M. 
Published: June 2019

Type 1 diabetes (T1D) prevention trials can be shortened if intermediate endpoints indicative of a very high risk of progression are reached before diagnosis. Since Index60, a composite C-peptide and glucose measure, has been shown to have potential use as such an endpoint, we evaluated additional combinations of C-peptide and glucose as endpoints. Diabetes Prevention Trial-type 1 participants (n=702) with baseline values below threshold (set arbitrarily at 95th percentile for each endpoint) were followed at 0.5-1.0 year intervals with 2-hour OGTTs for the first (incident) OGTT that thresholds were exceeded. Participants were then followed for T1D. All endpoints were reached, on average, over 1 year prior to the diagnosis of T1D. Risks for subsequent T1D after the incident OGTT were substantial, but variable (3-year risk=0.66-0.81). There was also appreciable variation in numbers reaching endpoints (n=55-117) and positive predictive values for T1D (PPV=62-77%). Ages were lowest for Glucose/C-peptide measures at incident OGTTs. Index60 performed best regarding key endpoint criteria: number reaching endpoint, 3-year risk, and PPV.
In conclusion, individuals highly likely to ultimately develop T1D can be identified over 1 year before diagnosis by combined C-peptide and glucose endpoints. It appears that such endpoints should be considered for T1D prevention trials.

Disclosure
L.M. Jacobsen: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. M.J. Redondo: None. B.M. Nathan: None. D. Schatz: None. J.M. Sosenko: None.

Funding
National Institutes of Health; JDRF
1727-P: A Novel Islet-Peripheral Blood Mononuclear Cell Coculture Model for Studying Type 1 Diabetes
Authors: YESILDAG BURCAK , PERDUE NIKOLE , MIR-COLL JOAN , BIERNATH ADELINN , NEELAKANDHAN APARNA , FORSCHLER FELIX , VON HERRATH MATTHIAS G. , WESLEY JOHNNA D. 
Published: June 2019

Type 1 diabetes is a heterogeneous group of disorders majorly characterized by autoimmune destruction of pancreatic β-cells, resulting in absolute insulin deficiency. Current research models lack many functions critical for understanding the onset and progression of this disease in humans. Although isolated primary islets are considered the standard tool for diabetes research, their experimental use is challenging due to inherent heterogeneity in size, cellular composition and purity, as well as rapid decline in their functionality and viability ex vivo. Here we investigate a novel co-culture platform of peripheral blood mononuclear cells (PBMCs) and a uniform 3D islet model. Human islet microtissues, produced by optimized dissociation and controlled reaggregation of primary islet cells, were cultured in a one-islet per well format in 96-well plates. They displayed uniform, long-term (&gt;28 days), and robust viability and function enabling high-throughput and longitudinal study of immune cell-endocrine cell interactions and β-cell function. PBMCs in their naïve form or following T-cell specific activation, were combined in various ratios with healthy or stressed islets - preconditioned with a mild cytokine cocktail. Co-culturing of naïve PBMCs and islet microtissues had only a minor impact on β-cell function. Whereas, combination of activated PBMCs and islet microtissues resulted in a PBMC-number dependent decline in islet health shown by increased basal insulin release and decreased glucose-stimulated insulin secretion, insulin content and PDX-1 positive nuclei within each microtissue. The observed destruction correlated with the amount of CD3+ cells infiltrating the microtissues and was significantly augmented by cytokine preconditioning. The established islet-PBMC co-culture platform represents a novel in vitro model to study the autoimmune component of T1D and to screen for compounds that could prevent immune-cell mediated destruction of pancreatic islets.

Disclosure
B. Yesildag: None. N. Perdue: None. J. Mir-Coll: Employee; Self; InSphero. Employee; Spouse/Partner; Roche Pharma. A. Biernath: None. A. Neelakandhan: None. F. Forschler: Employee; Self; InSphero. M.G. von Herrath: None. J.D. Wesley: Employee; Self; Novo Nordisk A/S.
1789-P: Ser/Thr Phosphatase-PP2C Negatively Regulates AS160 and GSK3β Activity in Neuronal Insulin Signal Transduction Pathway
Authors: YADAV YAMINI , DEY CHINMOY S. 
Published: June 2019

Serine/Threonine protein phosphatases regulate the activity of insulin signaling molecules involved in glucose homeostasis. Aberration in their functions have been reported in adipocytes, hepatocytes and skeletal muscle cells lead to abnormalities in signal transduction causing diabetes. Neuronal system is insulin responsive. Malfunctions have been reported to lead to development of metabolic disorders like diabetic neuropathy and Alzheimer disease. Our understanding of phosphatase mediated regulation in general is anyway very limited and role of PP2C in insulin signaling pathway in neuronal system is practically non-existent. Further exploration is required to understand the role of Ser/Thr phosphatases in neuronal system. Therefore, the aim of this work was to identify the role of PP2C in neuronal insulin signaling. To achieve this, PP2C in the differentiated Neuro-2a (N2A) cells was inhibited by treating with a potent and specific inhibitor of PP2C, Sanguinarine Chloride (SC), in presence (100nM) or absence of insulin and the effect was tested on the activity of AS160 and GSK3β. In insulin stimulated state inhibition of PP2C caused a significant 37% and 56% of decrease in the phosphorylation of AS160 at Ser588 and Thr642 residues, respectively. Similarly, a 37% decrease was observed in phosphorylation of GSK3β at Ser9. However, the expression of AS160 and GSK3β were found to be unaffected. Data shows for the first time that PP2C mediated dephosphorylation might be involved in regulating the activity of AS160 and GSK3β in neuronal system and hence suggest a possibility of its playing a major negative role in regulating neuronal insulin signal transduction pathway.

Disclosure
Y. Yadav: None. C.S. Dey: None.

Funding
Department of Science & Technology, Government of India, New Delhi; Department of Science & Technology, Government of India, New Delhi (SR/S2/JCB-24/2008(G))
1807-P: Central Leptin Administration Attenuates the Glucose Responsiveness to Epinephrine
Authors: QI YIJING , WHITE B. DOUGLAS 
Published: June 2019

Central leptin administration in streptozotocin-induced diabetic rats leads to normalization of blood glucose concentrations, independent of insulin. In previous studies, we observed that leptin-treated rats couldn’t maintain their blood glucose concentration during a short-term fast as well as control rats. We hypothesize that chronic central leptin administration inhibits the ability of counterregulatory hormones to increase hepatic glucose production and blood glucose concentrations by attenuating gluconeogenesis through the inhibition of the cAMP-CREB pathway in the liver.
To test this hypothesis, we determined the glucose responsiveness of leptin-treated nondiabetic and diabetic rats to epinephrine (EPI) injections during the fed and fasted states and whether alterations in blood glucose levels were associated with biochemical changes in the cAMP-CREB pathway in the liver. Baseline blood glucose levels were determined followed by an intraperitoneal injection of EPI or saline to each rat during both the fasting and fed states. Blood glucose levels were monitored for 3 hours post-injection. The area under the curve (AUC) was calculated for each EPI-treated animal and subtracted from the AUC during a saline injection in the same animal. Leptin normalized the daily blood glucose levels in diabetic rats.
Leptin attenuated the effect of EPI during fasting. In the fed state, leptin inhibited the glucose responsiveness to EPI in nondiabetic rats. (The responsiveness to EPI couldn’t be determined in fed diabetic rats due to the high blood glucose concentrations.) Diabetes increased hepatic phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase, and CREB. Leptin treatment of diabetic rats negated the increases in PEPCK and CREB. These results support the hypothesis that chronic central leptin treatment inhibits the cAMP-CREB pathway in diabetic rats and attenuates the effects of counterregulatory hormones to increase hepatic glucose production.

Disclosure
Y. Qi: None. B. White: None.

Funding
Alabama Agricultural Experiment Station (ALA043-1-13014)
183-OR: Placental Growth Factor and Fetal Growth in Women with Type 1 Diabetes Mellitus
Authors: BACON SIOBHAN , BURGER DYLAN , TAILOR MAYUR , TOMLINSON GEORGE A. , MURPHY HELEN R. , FEIG DENICE 
Published: June 2019

Background: Maternal hyperglycaemia alone does'nt explain the incidence of large for gestational age offspring (LGA) amongst women with T1DM. Placental vascular development is regulated by angiogenic factors. Placental growth factor (PIGF) is such a factor with a PlGF &gt;100 signifying a well-developed placenta. Co-measurement of PlGF and SFLT-1 (soluble receptor antagonist to VEGF), combined as a ratio, is predictive of maternal vascular perfusion. A low sFLT-1:PlGF (&lt;85) is a marker of good placental health. We assessed if markers of placental function and glycemic control can explain variations in birthweight in women with T1DM.
Methods: Amongst 157 women who participated in CONCEPTT; PlGF, sFLT-1:PlGF and a HbA1c&lt; or &gt;6.5% at randomisation and 34 weeks' gestation were assessed. Two separate linear regression models were used to test for a differential effect of placental function on mean birth weight in those with different levels of glycemic control, one using sFLT-1:PlGF and the other PlGF.
Results: No significant relationship was found between birthweight and markers of placental function and glycemic control at randomisation. At 34 weeks, the relationship of birth weight to sFLT-1: PlGF differed depending upon HbA1c (p=0.007). Where HbA1c&lt; 6.5%, birth weights were similar for a sFLT-1:PlGF &lt;85 (3592g) and &gt;85 (3699g). Where HbA1c &gt; 6.5%, birthweights were higher with a sFLT-1:PlGF &lt; 85 (3809g) vs. &gt; 85 (3355g). A similar pattern emerged for PlGF alone, with a differential effect of a healthy placenta on birthweight dependent upon glycemic control (p=0.013). Where HbA1c&lt;6.5%, birthweights were similar (3635±556g and 3604±602g) with low and high PlGF. Where HbA1c&gt;6.5%, an elevated PlGF (&gt;100) resulted in higher birth weight than in those with lower PlGF (3822g ±679 vs. 3344g ±556).
Conclusion: In women with T1DM, the combination of a healthy placenta with poor glycemic control resulted in the highest birthweights. Tighter glycemic control to avoid LGA is needed in women with healthy placental function.

Disclosure
S. Bacon: None. D. Burger: None. M. Tailor: None. G.A. Tomlinson: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic.
184-OR: In Utero Exposure to Gestational Diabetes Alters the Transcriptome and Methylome of Human Fetal Stem Cells Revealing an Enrichment of Interferon Related Pathways
Authors: PINNEY SARA E. , JOSHI APOORVA , YIN VICTORIA , MIN SO WON , CONDON DAVID E. , WANG ZHIPING 
Published: June 2019

Background: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu, induces marked abnormalities in fetal glucose and insulin secretion and is linked to obesity and diabetes in the offspring, but the mechanisms remain largely unknown.
Objective: To measure changes in gene expression and genome wide DNA methylation in human amniocytes, a fetal stem cell, exposed to GDM in utero.
Methods: EdgeR identified differentially expressed genes from RNASeq via fold change, p-values, and q-values calculated after Bonferoni correction (n=8; 4 per sex). RNA-Seq results were confirmed via QPCR. Ingenuity Pathway Analysis (IPA) identified enriched biological pathways. Differentially methylated regions (DMRs) were determined from Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) (n=16; 8 per sex) by identifying sequential CpGs with significant changes in DNA methylation &gt;5%, and with p&lt;0.05 over the entire DMR.
Results: We identified 20 differentially expressed genes (q&lt;0.10) analyzing data from male and female amniocytes together, but only 4 genes in male only and 2 in female only analyses. Using a significance threshold of p&lt;0.01, we identified 65 differentially expressed genes analyzing all samples together, 46 genes in the male only and 68 in the female only analyses. QPCR confirmed increases in IFI44, ULBP1 and SAMD9L. Differentially expressed genes were strongly enriched for interferon inducible proteins, a novel fetal programming pathway after in utero GDM exposure. IPA showed enrichment in molecular mechanisms of growth, oxidative stress metabolism and GCPR signaling pathways. Offspring sex-specific analysis greatly enhanced DMR identification. Nine DMRs were identified in all, 41 in male and 20 in female samples.
Conclusion: Exposure to GDM in utero leads changes in amniocyte gene expression and DNA methylation with enrichment in interferon inducible pathways.

Disclosure
S.E. Pinney: None. A. Joshi: None. V. Yin: None. S. Min: None. D.E. Condon: None. Z. Wang: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K08DK090302); National Institute of Environmental Health Sciences (P30ES013508); National Institutes of Health (UL1TR001878)
1879-P: The Liver Mitochondrial Oxidative Phosphorylation Increases in Diabetic Mice
Authors: ALIMUJIANG MIRIAYI , YU MUYU , YIN JUN 
Published: June 2019

Mitochondria play critical role in energy metabolism. However, the alteration of mitochondrial function in diabetes is still controversial. To address this issue, we measured the liver and muscle mitochondrial function in animal models characterizing different stages of type 1 and 2 diabetes. Streptozotocin-induced diabetic mice, db/db mice and high-fat diet-induced obese mice were used in this study. Both in early stage (3 weeks after STZ injection) and late stage (3 months after STZ injection) of type 1 diabetic mice, liver mitochondrial oxidative phosphorylation (OXPHOS) increased significantly, among which the complex IV-dependent oxygen consumption rate (OCR) was the most prominent, indicating that complex IV may play an important role in the pathophysiology of type 1 diabetes. The liver mitochondrial complex I and II-dependent OXPHOS increased greatly in prediabetes and early stage (12-week-old db/db mice) of type 2 diabetes. At the late stage (42-week-old db/db mice) of type 2 diabetes, the OXPHOS declined to almost normal, and alteration of complex I-dependent OCR was the most significant. In contrast, no change of mitochondrial OXPHOS was observed in the muscle of all disease models. Besides, no alteration of ATP, ADP and AMP contents in the tissues was observed. Our in vitro experiments showed that among specific chemical inhibitors to complex I, II, III or IV in mitochondrial respiratory chain, rotenone (complex I inhibitor) and myxothiazol (complex III inhibitor) enhanced glucose consumption and lactate release. But only rotenone decreased glucose output in primary hepatocytes in the absence of cytotoxicity.
In summary, the mitochondrial OXPHOS of liver rather than muscle increases in diabetes. And inhibition of complex I may ameliorate hyperglycemia by reducing hepatic glucose production and inducing glycolysis. Our results provide evidences for using complex I inhibitors (e.g., metformin and berberine) as oral antidiabetic agents.

Disclosure
M. Alimujiang: None. M. Yu: None. J. Yin: None.

Funding
National Natural Science Foundation of China (81670790, 31171128)
1899-P: Glucagon-Like Peptide-1 Receptor Signaling Is Required for an Osteocalcin-Mediated Improvement of Glucose Tolerance
Authors: MIZOKAMI AKIKO , HIRATA MASATO 
Published: June 2019

In the past decade, multiple studies have revealed that osteoblast-derived hormone osteocalcin, in its uncarboxylated form (GluOC), could reverse the diabetic conditions by affecting multiple aspects of systemic glucose and energy metabolism, male fertility, and brain function. Metabolic effects of GluOC are primarily achieved by its ability to stimulate insulin secretion and pancreatic β-cell proliferation either directly, or indirectly through stimulating the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells through its putative receptor GPRC6A. We have previously reported that oral administration of GluOC, the most common and safe route of drug administration, reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as the β-cell area in the pancreas in wild type mice. However, these effects were abolished by the prior subcutaneous administration of exendin (9-39), a GLP-1 receptor antagonistic peptide, suggestive of the requirement of GLP-1 receptor signaling for orally-administered GluOC effects. In this study, we examined the effect of GluOC using GLP-1 receptor-knockout mice to explore the involvement of GLP-1 receptor signaling in the GluOC-mediated improvement of glucose handling. We found that long-term oral administration of GluOC rather triggered glucose intolerance, enhanced gluconeogenesis, lipid accumulation in the liver, and adipocyte hypertrophy in GLP-1 receptor-knockout mice. Furthermore, we revealed that inactivation of GLP-1 receptor signaling in association with GluOC promotes FoxO1 action, leading to gluconeogenesis. These results indicate that the beneficial effect of GluOC on glucose and lipid metabolism is dependent on functional GLP-1 receptor signaling.

Disclosure
A. Mizokami: None. M. Hirata: None.

Funding
Japan Society for the Promotion of Science (16K20421, 17K19766)