bluuebunny/crossref_metadata_2025_split huggingface dataset:
1852-P: Assessment of Hepatic Fibrosis with Noninvasive Parameters in Subjects with Alterations of Glucose Metabolism before and after Liver Transplantation
Authors: GRANCINI VALERIA , GAGLIO ALESSIA , RESI VERONICA , PALMIERI EVA , ORSI EMANUELA 
Published: June 2020

Hepatogenous diabetes is a known complication of cirrhosis and its prevalence increases with the severity of liver disease. Regarding to the post-transplant period, no data are currently available to correlate the persistence of alterations in glucose metabolism and the possible development of fibrosis in the transplanted organ. For this reason, we estimated the degree of liver fibrosis and its correlation with the presence of hepatogenous diabetes in 87 subjects affected by cirrhosis. The degree of fibrosis was estimated using the Fibrosis-4 Score (FIB-4) and the Aspartate to Platelet Ratio Index (APRI), which, in literature, best correlate with the degree of stiffness found with fibroscan. Among this population, 78 subjects underwent liver transplantation and were reevaluated 2 years later, in order to evaluate the possible influence of the persistence of post-transplant diabetes in developing new fibrosis in the transplanted organ. At pre-transplant evaluation, 39 of the 87 subjects were diabetic. Both FIB-4 and APRI indices were significantly higher in these patients than in nondiabetic patients (respectively: 12.21 ± 8.27 vs. 7.97 ± 6.89, P = 0.01 and 2.92 ± 2.62 vs. 1.75 ± 1.59, P = 0.01).2 years after transplantation, 35 of the 78 subjects were still diabetic and, again, showed a significantly higher FIB-4 if compared to nondiabetic patients (3.22 ± 2.80 vs. 2.13 ± 1.51, P = 0.03).
In conclusion, the increased fibrosis indexes found in diabetic subjects with cirrhosis reflect a more advanced stage of liver disease if compared to nondiabetic patients. Moreover, the persistence of diabetes after transplantation exposes subjects to an increased risk of developing fibrosis in the newly transplanted organ, with the possible consequent worsening of the long-term outcomes in this population.

Disclosure
V. Grancini: None. A. Gaglio: None. V. Resi: None. E. Palmieri: None. E. Orsi: None.
1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation
Authors: JOSEPH DEBORAH Y. , RIVERS SYDNEY L. , GIACCA ADRIA 
Published: June 2020

The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p&lt;0.05). IH+SB rats were protected from FFA-induced hepatic fat accumulation. To assess the role of p38 on FFA-induced insulin resistance, liver-specific p38 knockout mice and wild type mice were infused with ethyl-oleate and ethyl palmitate (EtOP) or ethanol (control) for 48 hrs. After 46 hours of the infusion, the mice underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. Results thus far suggest that genetic inhibition of p38 MAPK in the liver protects from FFA-induced insulin resistance in the periphery (p=0.06), consistent with tissue cross-talk also observed by our lab in liver-specific p38 knockout mice using a high fat diet model.
In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance.

Disclosure
D.Y. Joseph: None. S.L. Rivers: None. A. Giacca: None.

Funding
Canadian Institutes of Health Research (503010)
1859-P: Hepatic NIK Augments Hepatocyte Ferroptosis and Hepatic Inflammation in Liver Disease
Authors: ZHONG XIAO , RUI LIANGYOU 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity and diabetes. Hepatocyte injury and death pathologically mark a turning point from simple liver steatosis to nonalcoholic steatohepatitis (NASH). Chronic hepatocyte injury and hepatic inflammation drive liver fibrosis, leading to liver cirrhosis, end-stage liver failure, and/or hepatocellular carcinoma. We previously reported that NAFLD is associated with a marked elevation of NF-κB-inducing kinase (NIK) in the liver. NIK in turn augments the hepatic hyperglycemic response to counterregulatory hormone glucagon, contributing to hyperglycemia and diabetes progression. Here, we demonstrate that hepatic NIK also promotes hepatocyte injury and death, exacerbating liver disease. We found that hepatocyte-specific overexpression of NIK substantially increased hepatocyte death and liver inflammation in mice treated with acetaminophen (APAP), a hepatocyte-toxic drug. Conversely, hepatocyte-specific deletion of NIK significantly blunted APAP-induced liver injury and hepatitis. In line with these findings, in primary liver cell cultures, overexpression of NIK substantially enhanced APAP sensitivity to induce cell death. Notably, NIK overexpression dramatically increased liver reactive oxygen species (ROS) levels in APAP-treated mice, and ablation of hepatocyte NIK had the opposite effects. Treatment with antioxidant N-acetylcysteine abrogated the ability of NIK and APAP to induce hepatocyte death and liver inflammation. Given that ROS drives ferroptosis, we treated primary liver cells with ferroptosis inhibitors ferrostatin 1 and liproxtatin-1. Both ferrostatin 1 and liproxtatin-1 dose-dependently suppressed NIK/APAP-induced cell death. Collectively, our data suggest that aberrant activation of hepatic NIK augments hepatocyte ferroptosis, thereby promoting liver injury, liver inflammation, and liver disease progression.

Disclosure
X. Zhong: None. L. Rui: None.
186-LB: Diabetes Type 2 Is Associated with Higher Mortality in Patients Hospitalized with Diabetic Ketoacidosis: An Analysis of the Nationwide Inpatient Sample Database
Authors: SHAKA HAFEEZ , EDIGIN EHIZOGIE , YAP SARA ELIZABETH T. , XU JING , GOMEZ TRISHA MARIE A. , PADILLA SORTO MARIA ELENA 
Published: June 2020

Introduction: Diabetic ketoacidosis (DKA) is a known complication of patients with diabetes mellitus (DM) type 1, but less common in type 2. The aim of this study was to compare outcomes of patients admitted with DKA in DM types 1 and 2 patients.
Methods: This was a population-based, retrospective, observational study using data from the Nationwide Inpatient Sample (NIS) for 2016 and 2017. Hospitalizations of adults &gt;/=18 years old with a principal diagnosis of DKA were obtained using ICD 10 codes. Groups of patients with a secondary diagnosis of DM type 1 and 2 were identified. The primary outcome was inpatient mortality. Secondary outcomes were Length of stay and Total hospital charge.
Results: Between 2016-2017, about 245,170 adults had hospitalizations for a principal discharge diagnosis of DKA. Of these hospitalizations, 225495 (92.0%) had DM type 1 compared with 19675 who had DM type 2 (8.0%). Patients with DM type 2 were typically older (mean age 51.0 years vs. 34.4 years) and more likely males. A total of 650 inpatient mortality (0.27%) occurred in patients with DKA. The adjusted odds ratio (aOR) for mortality in patients with DM type 2 compared to DM type 1 was 4.1 (95% CI: 2.740- 6.180, p&lt;0.001) when adjusted for common confounders excluding age. After adjusting for age, the aOR for mortality dropped to 2.0 (95% CI: 1.317 - 3.175 , p&lt;0.001). DM type 2 patients were also found to have an adjusted increase in total hospital charge of $6035 (95% CI: 4420 - 7652, p&lt;0.001) and adjusted increase in length of hospitalization of 0.5 days ((95% CI: 0.3 - 0.6, p&lt;0.001).
Conclusions: After adjusting for sex, age, race, hospital location and illness severity, patients with DM type 2 has 2-fold higher odds of inpatient mortality compared to type 1, when admitted for DKA. The odds of mortality are likely higher per duration for which patients have had diabetes.

Disclosure
H. Shaka: None. E. Edigin: None. S.T. Yap: None. J. Xu: None. T.A. Gomez: None. M. Padilla Sorto: None.
187-LB: Risk Factors for Lower Hip-Bone Density in Older Adults with Type 1 Diabetes
Authors: SCHWARTZ ANN V. , BACKLUND JYE-YU C. , DEBOER IAN , RUBIN MISHAELA , BARNIE ANNETTE R. , FARRELL KALEIGH , TRAPANI VICTORIA R. , GREGORY NAINA S. , WALLIA AMISHA , LACHIN JOHN M. , BRAFFETT BARBARA H. , GUBITOSI-KLUG ROSE ,   DCCT/EDIC RESEARCH GROUP
Published: June 2020

Type 1 diabetes (T1D) is associated with lower bone mineral density (BMD) and elevated fracture risk. In this study, we examined risk factors for lower BMD in the DCCT/EDIC study, a well-characterized cohort of older adults with T1D. Dual x-ray absorptiometry (DXA) scans were obtained in 1,058 study participants who had been followed for &gt; 30 years. Cumulative glycemic control was defined as the time-weighted mean HbA1c from DCCT baseline (1983-1989) to the DXA visit. Levels of advanced glycation endproducts (AGE) were assessed by skin intrinsic fluorescence (SIF) in 2010-2011. Kidney disease (sustained eGFR&lt;60 mL/min/1.73 m2 or ESRD), retinopathy, peripheral neuropathy and cardiac autonomic neuropathy were assessed. Associations between risk factors and total hip and femoral neck BMD were analyzed using multiple linear regression models.
Mean age at DXA was 59±7 years; 48% of participants were female. Mean BMD for total hip and femoral neck was 0.921±0.149 and 0.757±0.129 g/cm2, respectively; 6% were osteoporotic, and 45% were osteopenic. Higher mean HbA1c, higher SIF, and kidney disease, but not retinopathy or neuropathy, were independently associated with lower BMD at the total hip in univariate and multivariable analyses, with similar results for femoral neck (Table).
In conclusion, poorer glycemic control, AGE accumulation, and kidney disease are independent risk factors for lower hip BMD in older adults with T1D.

Disclosure
A.V. Schwartz: None. J.C. Backlund: None. I. deBoer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals. M. Rubin: Research Support; Self; Amgen, Ascendis Pharma, Takeda Pharmaceutical Company Limited. A.R. Barnie: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. V.R. Trapani: None. N.S. Gregory: None. A. Wallia: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., UnitedHealth Group. J.M. Lachin: Board Member; Self; Tolerion, Inc. B.H. Braffett: None. R. Gubitosi-Klug: None.

Funding
National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Disease (5U01DK094157, RES514948)
1879-P: Targeted Disruption of Muscle-Specific ROCK2 Results in Insulin Resistance In Vivo
Authors: KIM HYUN JEONG , PEREIRA RODRIGO M. , UNER AYKUT G. , LEE HYON , KIM YOUNG-BUM 
Published: June 2020

Insulin signaling is essential for the maintenance of glucose homeostasis. ROCK2 has been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. However, the in vivo function of ROCK2 in muscle remains to be elucidated. To explore the physiological role of muscle ROCK2 in the regulation of whole-body glucose homeostasis and insulin sensitivity in vivo, mice lacking ROCK2 in skeletal muscle selectively (myogenic-Cre; ROCK2lox/lox) were studied. Here we show that muscle-specific ROCK1-deficient mice displayed insulin resistance, as revealed by the failure of blood glucose levels to decrease after insulin injection. However, glucose tolerance was normal in the absence of muscle-specific ROCK2. These effects were independent of changes in adiposity. To determine the mechanism(s) by which muscle-specific deletion of ROCK2 causes insulin resistance, we measured the ability of insulin to activate downstream distal pathways in skeletal muscle. Insulin-stimulated IRS-1 tyrosine phosphorylation in skeletal muscle was markedly reduced by ∼80% in myogenic-Cre; ROCK2lox/lox mice compared with control (ROCK2lox/lox) mice. Concurrently, impaired insulin-induced phosphorylation of Akt, AS160, GSK, and S6K was found when ROCK2 was specifically deleted in muscle. Of pathological significance, ROCK2 activity in skeletal muscle was markedly decreased in obese type 2 diabetic mice in response to insulin, along with an impairment of IRS-1 phosphorylation. These data suggest that ROCK2 deficiency results in systemic insulin resistance by impairing insulin signaling in skeletal muscle, at the level of IRS-1. Thus, our results identify ROCK2 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes.

Disclosure
H. Kim: None. R.M. Pereira: None. A.G. Uner: None. H. Lee: None. Y. Kim: None.
1880-P: Distinct Roles of UVRAG and EGFR Signaling in Skeletal Muscle Homeostasis
Authors: KIM MINJEONG , FEBBRARO DANIELLA , WOO MINNA 
Published: June 2020

Background: Autophagy is a physiological self-eating process that can promote cell survival or activate cell death in eukaryotic cells. In skeletal muscle, it is important in the maintenance of muscle mass and function that is critical to sustain mobility and regulate metabolism. UV radiation resistance-associated gene (UVRAG) regulates early stages of autophagy and autophagosome maturation, while also playing a key role in endosomal trafficking.
Methods: To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle specific UVRAG knock-out mice using the cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle.
Results: Myf6 Cre+ UVRAGfl/fl (KO) mice were compared to littermate Myf6 Cre+ UVRAG+/+ (WT) controls under basal (normal chow diet) and HFD (high-fat diet) conditions. KO mice developed accelerated sarcopenia and impaired muscle function compared to WT littermates with aging on chow diet or on HFD. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to up-regulated FGF-21, a marker of muscle dysfunction. KO mice showed mitochondrial dysfunction, altered muscle mitochondrial morphology with increased mitochondrial fission, as well as EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, mice were treated with an EGFR inhibitor, Gefitinib, which partially restored markers of muscle and mitochondrial dysfunction. Conversely, constitutively active EGFR transgenic expression in UVRAG deficient muscle led to further detrimental effects with non-overlapping distinct defects in muscle function, with EGFR activation affecting muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis.
Conclusions: UVRAG and EGFR signaling together are critical in the maintenance of muscle mass and function with distinct mechanisms in the differentiation pathway.

Disclosure
M. Kim: None. D. Febbraro: None. M. Woo: None.

Funding
Canadian Institutes of Health Research; Kangbuk Samsung Hospital; Banting & Best Diabetes Centre
1883-P: Metformin Increases Protein Phosphatase 2A Activity in Primary Skeletal Muscle Cells Derived from Lean Healthy Insulin-Sensitive Human Participants
Authors: MESTAREEHI AKTHAM H. , SEYOUM BERHANE , MSALLATY ZAHER , MALLISHO ABDULLAH P. , ZHANG XIANGMIN , KOWLURU ANJAN , YI ZHENGPING 
Published: June 2020

Skeletal muscle insulin resistance is one of the primary contributors of type 2 diabetes (T2D). Metformin is the first-line drug for the treatment of T2D. Main known effects of metformin include inhibition of glucose production in liver and attenuation of insulin resistance in skeletal muscle. However, molecular mechanism of metformin’s action in skeletal muscle is not well understood. Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase, plays a pivotal role in cellular processes (e.g., signal transduction, apoptosis), and acts through dephosphorylating key signaling molecules such as AKT, AMPK, etc. However, whether or not PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells remains to be elucidated. In the present study, hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in human subjects and skeletal muscle biopsy samples were obtained. Primary human skeletal muscle cells (shown to retain metabolic characteristics of donors) were cultured from these muscle biopsies from 8 lean insulin sensitive participants (4 Female and 4 male; age: 21.4±0.8 yrs; BMI: 22.1±0.7 kg/m2; 2-hour OGTT: 96.5± 6.3 mg/dl; HbA1c: 5.3±0.1 %; fasting plasma glucose: 87.5±1.4 mg/dl; M-value; 10.9±0.8 mg/kgBW/min). The cells were expanded, differentiated into myotubes, and treated with 50µM metformin (the physiologic concentration) for 24 hours before harvesting. PP2A activity was measured by a phosphatase activity assay (Millipore). The results indicated that metformin increased the activity of PP2A in the myotubes derived from all 8 participants, and the average fold increase is 1.59±0.13 (p&lt;0.05). These results provided the first evidence to suggest that metformin promotes activation of PP2A in human skeletal muscle cells derived from lean insulin sensitive participants, and may help to understand metformin’s action in skeletal muscle in humans.

Disclosure
A.H. Mestareehi: None. B. Seyoum: None. Z. Msallaty: None. A.P. Mallisho: None. X. Zhang: None. A. Kowluru: None. Z. Yi: None.

Funding
American Diabetes Association (1-13-TS-27 to Z.Y.); National Institutes of Health (R01DK107666, R01DK081750 to Z.Y.), (T32HL120822 to A.H.M.); DOTS Scholars (to A.H.M., Z.Y.)
1891-P: Palmitate-Enriched Lipid Ingestion Acutely Induces Insulin Resistance Associated with PKCγ Activation and Impaired Mitochondrial Function in Human Skeletal Muscle
Authors: SARABHAI THERESIA , KOLIAKI CHRYSI , KAHL SABINE , PESTA DOMINIK , MASTROTOTARO LUCIA , APOSTOLOPOULOU MARIA , MARKGRAF DANIEL F. , HERDER CHRISTIAN , RODEN MICHAEL 
Published: June 2020

Hypercaloric diets cause dyslipidemia, insulin resistance and contribute to the development of type 2 diabetes. Nevertheless, the degree of fatty acid (FA) saturation may differently affect metabolism and risk of cardiovascular diseases, with saturated FA (SAFA) considered to be harmful and polyunsaturated FA (PUFA) considered to be beneficial. Thus, we aimed at characterizing the acute effects of palm oil (POL, SAFA-rich) and safflower oil (SOL, PUFA-rich) on tissue-specific insulin sensitivity and skeletal muscle mitochondrial function in glucose-tolerant volunteers (10 m/6 f; age 24±2 years; BMI 23.1±0.9 kg/m2), who ingested 1.2 g/kg BW of POL, SOL or control (CON, water) on three occasions. Whole-body glucose disposal (Rd) was assessed with [2H2]glucose before and during hyperinsulinemic-euglycemic clamps. Skeletal muscle biopsies were performed to assess protein kinase C (PKC) ԑ and θ translocation and oxygen fluxes by high-resolution respirometry at 1 h before and 2, 4 and 7 h after the interventions. Before the clamp, POL but not SOL ingestion raised plasma palmitic acid levels by 102% (p&lt;0.01) compared to CON. Only POL decreased Rd by 28% and muscle mitochondrial oxidative capacity by 38% from succinate and by 39% from octanoyl-carnitine, but increased PKCɛ activity by 57% (all p&lt;0.05 vs. CON). During insulin stimulation, Rd decreased by 38% after POL and by 26% after SOL (all p&lt;0.05 to CON). Non-oxidative glucose disposal was lower after POL than after SOL (p&lt;0.05).
In conclusion, oral ingestion of palmitate-enriched lipids rapidly induces whole-body insulin resistance, which is likely mediated through skeletal muscle lipid-mediated PKCԑ activation and possibly accelerated by impaired mitochondrial function. Thus, the amount of dietary lipids determines acute insulin resistance, but its composition may differentially regulate skeletal muscle oxidative capacity.

Disclosure
T. Sarabhai: None. C. Koliaki: None. S. Kahl: None. D. Pesta: None. L. Mastrototaro: None. M. Apostolopoulou: None. D.F. Markgraf: None. C. Herder: Research Support; Self; Sanofi-Aventis. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.

Funding
German Federal Ministry of Health and Ministry of Culture and Science of the State North Rhine-Westphalia; German Federal Ministry of Education and Research by the European Regional Development Fund (KomIT, EFRE-0400191); German Research Foundation (DFG; SFB 1116/2)
1896-P: Adipocyte-Derived Fibroblast Growth Factor 21 (FGF21) Contributes to Circulating FGF21 Pools in Diet-Induced Obese Mice
Authors: WANG SHARI , GOODSPEED LEELA , OGIMOTO KAYOKO , HARTIGH LAURA DEN 
Published: June 2020

Fibroblast growth factor 21 (FGF-21) is a hormone derived from hepatocytes and adipocytes that plays a role in energy homeostasis, and promotes weight loss when given pharmacologically. Nutritional stress such as fasting increases liver-derived FGF-21 expression, whereas over-nutrition (i.e., obesity) promotes adipocyte-derived FGF-21 (Ad-FGF-21) production. Despite the current dogma that Ad-FGF-21 acts only in a paracrine manner, obesity is associated with elevated circulating FGF-21 levels which correlate with adiposity and adipose tissue FGF-21 mRNA expression. To date, a concise role for Ad-FGF-21 in obesity-associated energy balance has not been identified. To determine whether Ad-FGF-21 plays a pathological role in obesity, and whether it contributes to circulating FGF-21 levels, we generated mice with Ad-FGF-21 deficiency (Ad-FGF-21 KO) and placed them on an obesogenic high fat high sucrose diet for 18 weeks. Body composition, energy expenditure, glucose and insulin tolerance were assessed. Male and female Ad-FGF-21 KO mice were protected from obesity, gained less body fat, and exhibited improved glucose metabolism over wild type (WT) controls. Circulating FGF-21 levels were higher in obese WT mice than age-matched chow-fed WT or obese Ad-FGF-21 KO mice with no changes in hepatic FGF-21, suggesting that adipocytes are a source of FGF-21 in obesity. Moreover, adipose tissue explants from obese WT mice secreted higher levels of FGF-21 than explants from chow-fed mice, an effect that was blunted in Ad-FGF-21 KO mice. Finally, expression of fibroblast activation protein (FAP), an enzyme that cleaves FGF-21 to blunt its activity, was reduced from obese adipose tissue, providing a potential mechanism by which adipocyte-derived FGF-21 circulates in obesity.
In summary, adipocyte-derived FGF-21 may contribute to obesity-associated increases in circulating FGF-21, with the potential to influence the pathology of obesity.

Disclosure
S. Wang: None. L. Goodspeed: None. K. Ogimoto: None. L. den Hartigh: None.

Funding
National Institutes of Health (HL092969)