bluuebunny/crossref_metadata_2025 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<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 >/=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<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<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<0.001) and adjusted increase in length of hospitalization of 0.5 days ((95% CI: 0.3 - 0.6, p<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 > 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<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<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<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<0.05 vs. CON). During insulin stimulation, Rd decreased by 38% after POL and by 26% after SOL (all p<0.05 to CON). Non-oxidative glucose disposal was lower after POL than after SOL (p<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)
1897-P: BECN1, a Key Autophagy Protein, Regulates Adiponectin Secretion in Adipocytes by Interacting with the Exocyst Components
Authors: KURAMOTO KENTA , HE CONGCONG
Published: June 2020

Autophagy is a lysosomal degradation pathway that plays pivotal roles in maintaining cellular homeostasis. Beclin1/BECN1 is a key autophagy protein that regulates the stability and kinase activity of the class III phosphatidylinositol 3-kinase complex. Dysregulation of autophagy results in the pathogenesis of a variety of diseases, including type 2 diabetes. However, the molecular mechanism of the autophagy machinery in metabolic regulation is poorly understood. To elucidate how autophagy and BECN1 are involved in energy homeostasis and insulin sensitivity, we generated a unique knock-in mouse model showing hyperactive autophagy. This mouse model carries a single amino acid substitution (F121A) in the BECN1 protein (BECN1F121A), which disrupts an inhibitory binding between BECN1 and BCL2, leading to constitutive activation of autophagy. Using this moue model, we discovered that in addition to a role in autophagic regulation, BECN1 also executes a non-degradative function. We found that in response to high-fat diet feeding, BECN1F121A mice show improved systemic insulin sensitivity, elevated adiponectin levels in the circulation, and enhanced adiponectin signaling in metabolic tissues, compared to wild type (WT) mice, despite that body weight and white adipose tissue weight are similar between the two genotypes. Using adipocyte-differentiated stromal vascular fraction cells, we further found that compared to WT BECN1, the BECN1F121A mutant interacts more strongly with components of the exocyst, a complex required for secretory vesicle docking at the plasma membrane. Finally, we demonstrated that the BECN1-exocyst interaction is mechanistically mediated through the coiled-coil domain of BECN1. Altogether, our findings suggest that BECN1 regulates adiponectin secretion through interacting with the exocyst in white adipose tissues, and highlight that autophagy proteins may play important non-degradative roles in energy metabolism.

Disclosure

K. Kuramoto: None. C. He: None.
190-LB: Exploring the Relationships between HbA1c Levels and Diabetes Care through NHANES Data, 2007–2016
Authors: YOUNG CLIPPER F. , VELASCO HECTOR E.
Published: June 2020

Objective: To examine the relationships between diabetes care measures and HbA1c levels through analyzing the National Health and Nutrition Examination Survey (NHANES) data between 2007 and 2016.

Methods: This cross-sectional study involved subjective and objective data obtained from the CDC NHANES website. Data was then analyzed by STATA14 with ordered logistic regression models, controlling for age, race, gender, health insurance coverage. Subjective data included participants’ answers to the general and diabetes-related questionnaires, and the objective data was their HbA1c levels at the time of the interview/standardized clinical examination.

Results: Three of the eight regression analysis models showed statistically significant associations between HbA1c levels and identified diabetes care questions.

Conclusion: The levels of HbA1c in people with diabetes were associated with how long ago the participant checked-in with a diabetes specialist, whether having a doctor for diabetes care or not, and how often the participant saw a doctor within a year before the NHANES interview/examination. These findings suggest that connecting with healthcare professionals (Questions 1 - 3) showed significant relationships with HbA1c levels, but the same relationships were not observed between receiving or performing the actual diabetes care measures (Questions 4 - 8) and HbA1c levels.

Disclosure

C.F. Young: None. H.E. Velasco: None.
1903-P: Low Level of and Decrease in Serum Amylase (AMY) Increases the Risk of Type 2 Diabetes Mellitus (T2DM)
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , RISA IGARASHI , YAMADA MAYUKO H. , NEDACHI RINA , HATTA MARIKO , KODAMA SATORU , MORI YASUMICHI , MATSUBAYASHI YASUHIRO , ARASE YASUJI , SONE HIROHITO , YAMAMOTO-HONDA RITSUKO
Published: June 2020

Low serum AMY values were previously reported to be associated with incident T2DM. We further investigated that association in detail by showing the combined effects of chronological changes in AMY and baseline AMY as well as results of stratified analyses of baseline age and HbA1c.

Analyzed were 5306 individuals who had health examinations yearly for 7 y. We monitored changes in AMY values between baseline1 (first visit) and baseline2 (2 y later). Multivariate Cox analysis was conducted to evaluate the impacts of baseline2 AMY and change in AMY on incident T2DM in consideration of age and HbA1c. During the 5-y follow-up, T2DM occurred in 716 patients. Both low baseline2 AMY and decrease in AMY were independently associated with the development of T2DM. Compared with those whose baseline2 AMY ≥57 (Quintiles (Q) 2-5) and changes in AMY ≥90.4 (Q 2-5), those whose baseline2 AMY ≤56 (Q1) and changes in AMY ≤90.3 (Q1) had a significantly increased risk for T2DM (HR 1.60 [1.22-2.09]). Stratified analyses by age and baseline HbA1c levels showed that the increased risk for T2DM due to low baseline2 AMY or its change occurred only among those <50 y old or with HbA1c levels <5.6%.

These findings imply the clinical relevance of using AMY values and their chronological changes over time for evaluation of T2DM risk among individuals who are relatively young or have low HbA1c.

Disclosure

I. Ikeda: None. K. Fujihara: None. I. Risa: None. M.H. Yamada: None. R. Nedachi: None. M. Hatta: None. S. Kodama: None. Y. Mori: None. Y. Matsubayashi: None. Y. Arase: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. R. Yamamoto-Honda: None.
1915-P: High-but-Normal Serum Thyrotropin Levels Increased the Risk of Nonalcoholic Fatty Liver Disease in Euthyroid Subjects with Type 2 Diabetes
Authors: TANG XIXIANG , TAN YING , LI MEI , NIE YUANPENG , CHEN YANMING
Published: June 2020

Aims: High-but-normal thyrotropin (TSH) is associated with visceral obesity, hyperlipidemia, insulin resistance in patients with type 2 diabetes (T2DM), which may lead to the occurrence of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the association between TSH levels and the incidence of NAFLD in euthyroid T2DM patients.

Methods: A total of 2289 T2DM patients with euthyroid function were included in this cross-sectional study conducted at the Third Affiliated Hospital of Sun Yat-sen University from January 2016 to December 2018. NAFLD was diagnosed by ultrasound. Thyroid function parameters, including the levels of TSH, free triiodothyronine (FT3) and free thyroxine (FT4) were analyzed. Multivariate logistic regression analyses were performed to evaluate the effect of TSH levels on the risk of NAFLD in T2DM patients.

Results: NAFLD was diagnosed in 940 subjects with T2DM (41.1%). The subjects were divided according to the inter-quartile of thyroid function parameters. The NAFLD prevalence rates show a positive correlation with the increasing TSH quartiles(Q1 to Q4: 34.8%, 37.5%, 44.9% and 47.0%, P<0.01), but not with the FT3 or FT4 quartiles. In the multivariate logistic regression analysis, the highest TSH quartile (OR=1.610, 95% CI=1.131-2.289, P=0.008) was independently associated with the risk of NAFLD in patients with T2DM, after adjusting for multiple confounding factors. After additionally stratified by HbA1c levels, the highest TSH quartile level was still independently associated with the risk of NAFLD in euthyroid T2DM patients.

Conclusion: High-but-normal serum TSH is a significant independent risk factor for increased incidence of NAFLD in T2DM patients with euthyroid function, thus providing a novel insight for treating NAFLD.

Disclosure

X. Tang: None. Y. Tan: None. M. Li: None. Y. Nie: None. Y. Chen: None.

Funding

Research and Development Plans in Key Areas of Guangdong Province (2019B020227003); National Natural Science Foundation of China (81770826); National Key Research and Development Program of China (2017YFA0105803)
1917-P: Alpha-Cell Function in Patients with Type 1 Diabetes Is Compromised with Different Levels of Residual C-Peptide
Authors: ZHANG LINGYU , SHI YUWEN , HUANG YITING , HU QIZHEN , QIN YAO , ZHANG MEI
Published: June 2020

Objective: It is poorly understood α-cell function changes to respond to the different detectable C-peptide levels in patients with type 1 diabetes (T1D). This study aims to investigate the relationship between glucagon secretion and declining β-cell function in patients with T1D.

Methods: Eighty-seven subjects [68, autoimmune type 1 diabetes (T1AD); 4, fulminant type 1 diabetes (FT1D); 15 healthy controls] were enrolled. All participants underwent a 100g steamed bread meal tests (SBMT). T1AD patients were divided into C-peptide negative (CPN), C-peptide middle (CPM) and C-peptide high (CPH) group based on peak C-peptide levels. Both fasting and postprandial of glucose, C-peptide and glucagon were measured. Glucagon among groups were compared by a linear mixed-effects model. The relationship between C-peptide, glucose and glucagon responses was evaluated by regression analysis.

Results: At baseline, fasting glucagon concentrations were comparable between CPN, CPM and CPH group (F=0.099, P=0.906). After SBMT, 180min-glucagon in CPN group were higher than in CPM (P=0.004) and in CPH group (P<0.001). The iAUC30-180 of glucagon was lower in CPH than in CPN (P=0.001) and in CPM group (P=0.034), whereas the iAUC0-30 glucagon did not differ among CPN, CPM and CPH group (F=1.246, P=0.295). The same results were observed in iAUC of glucagon/glucose. After adjustment for age, BMI and diabetes duration, the iAUC30-180 glucagon in T1AD was inversely related to peak C-peptide and positively related to peak glucose levels (Radj2=0.315, P<0.001); however, the iAUC0-30 glucagon in T1AD was only positively related to 30min-glucose (Radj2=0.466, P<0.001).

Conclusions: This study demonstrates α-cell function in patients with T1D are compromised with different levels of residual C-peptide. Glucose is also a contributor factor for postprandial hyperglucagonemia.

Disclosure

L. Zhang: None. Y. Shi: None. Y. Huang: None. Q. Hu: None. Y. Qin: None. M. Zhang: None.

Funding

National Natural Science Foundation of China (81670756, 81974103), Provincial Key Research and Development Foundation of Jiangsu (BE2018748)
192-LB: The Interaction between Health-Related Social Needs, Diabetes, and Health Outcomes
Authors: FRANKLIN STEPHANIE , HAGAN ANGELA , HANSEN PETER , HAUGH GIL , LONG CHARRON
Published: June 2020

Health-related social needs (HRSN), such as housing instability, food insecurity, and poor transportation or social support, adversely affect health. In diabetes, where evidence links health behaviors, which are influenced by social/environmental factors, to disease onset and progression, a deeper understanding of the degree to which specific HRSN, or multiple needs, affect health may be crucial to achieving one’s best health. HRSN for adults with Medicare Advantage coverage (n=33,690) who responded to an abridged version of the Accountable Health Communities screener developed by the Centers for Medicare and Medicaid Services were evaluated. Overall, 56% (n=18,925) of people with diabetes reported one or more HRSN. A higher percentage of people with diabetes screened positive for financial strain (47%), food insecurity (31%), and poor housing quality/safety (24%) compared to those without diabetes (38%, 24%, and 19%, respectively). As the HSRN burden increased, healthcare utilization and cost also increased while compliance with certain quality indicators decreased. Our findings highlight the interplay between clinical and social needs and indicate that an increased awareness and incorporation of patients’ HRSN into clinical care may be essential for achieving optimal health in patients with diabetes. As more practices move to value-based arrangements, data on HRSN, combined with proven interventions, will help drive better health outcomes.

Disclosure

S. Franklin: Employee; Self; Humana. A. Hagan: None. P. Hansen: Employee; Self; Humana. G. Haugh: Employee; Self; Humana. C. Long: Employee; Self; Humana.
1920-P: First Oral MC4R Agonist for the Treatment of Rare Genetic Obesity
Authors: PARK HEE DONG , YEO SUJIN , PARK HYUNSEO , PARK JIN-SOOK , HONG PETER S.
Published: June 2020

Melanocyte-stimulating hormones, neuropeptides induced by Pro-opiomelanocortin (POMC) in the hypothalamus, act as the endogenous ligands of Melanocortin 4 receptor (MC4R). They decrease appetite by MC4R activation, leading to weight loss. Dysfunction of genes in MC4R pathway is known to cause rare genetic obesity such as POMC deficiency, leptin receptor deficiency, Bardet-Biedl syndrome and Alström syndrome. Therefore, MC4R agonists have the potential to be therapeutic agents for such genetic obesities. Compound LB(LB) is an orally available, small molecule MC4R agonist under clinical development. In vitro activity of LB toward MC4R and selectivity over MC1R, MC3R and MC5R were measured by radio-ligand binding, luciferase, cAMP and β-arrestin assays. LB showed a high potency and selectivity toward MC4R. In vivo efficacy of LB was tested in high fat diet-induced obese mice, rats and KK-Ay mice. Following repeat-dose to obese rodents, LB led to appetite suppression and weight loss comparable to or higher than setmelanotide. To evaluate in vivo pharmacokinetic properties, a single dose of LB was administered to mice, rats, dogs and monkeys. The GLP toxicology program of LB was comprised of general toxicity studies in rats and monkeys up to 4 weeks, genotoxicity and safety pharmacology studies. The IND-enabling toxicology studies demonstrated good safety profiles in the rats and monkeys. LB showed no significant safety issue in the genotoxicity and safety pharmacology studies. Comprehensive in vitro and in vivo studies demonstrated that LB is potent and selective MC4R agonist. LB is safe and well-tolerated compound, as demonstrated in GLP toxicity studies. In addition, the observed efficacy and safety profiles of LB are well described by the preclinical pharmacokinetic properties of LB such as a great penetration to brain tissue.

In conclusion, these nonclinical studies suggested that LB can be a safe and effective drug for the patients with genetic obesity.

Disclosure

H. Park: None. S. Yeo: None. H. Park: Employee; Self; LG Chem. J. Park: None. P.S. Hong: None.
1923-P: Ablating Mitochondrial Creatine Kinase Does Not Affect Energy Expenditure, White Adipose Tissue, Mitochondrial Respiration, or the Susceptibility to High-Fat Diet-Induced Obesity
Authors: POLITIS-BARBER VALERIE , PETRICK HEATHER L. , HOLLOWAY GRAHAM
Published: June 2020

Introduction: Recently, creatine (Cr) mediated ’recycling’ of ADP was proposed to promote energy expenditure (EE) within white adipose tissue (WAT). We determined the influence of ablating mitochondrial creatine kinase (Mi-CK), an enzyme necessary to the proposed Cr cycling, to ascertain the biological importance of Cr-mediated EE in the development of high-fat diet (HFD)-induced obesity.

Methods: Female Mi-CK wild type (WT) and knock-out mice (n=6-8/group) were randomized to receive control (10% fat) or HFD (60% fat) for 8 weeks. Whole-body indirect calorimetry (EE, RER) and glucose tolerance were determined. Inguinal WAT (iWAT) and gonadal WAT (gWAT) were used to determine mitochondrial oxidative phosphorylation (OXPHOS) proteins and submaximal (100 μM ADP) and maximal (5 mM ADP) respiration in the presence and absence of Cr (0.01mM).

Results: In WT animals, HFD consumption increased body mass and whole-body fat oxidation, while decreasing rates of carbohydrate oxidation and glucose tolerance. HFD reduced mass-specific iWAT and gWAT submaximal and maximal ADP-supported respiration ∼50%. HFD also reduced WAT OXPHOS protein content ∼25%, however normalizing respiration to OXPHOS protein did not mitigate the observed HFD-induced reduction in respiration, suggesting an attenuation in mitochondrial-specific respiration. The presence of Cr did not drive respiration in any experiment, challenging the notion that Cr stimulates mitochondrial respiration. In further support of this finding, ablating Mi-CK did not influence HFD-induced weight gain, whole body EE, the development of glucose intolerance or respiratory function in either iWAT or gWAT depots.

Conclusion: Ablating Mi-CK does not affect HFD-induced phenotypic changes, suggesting Cr-mediated EE is not a primary determinant in the development of obesity-induced glucose intolerance.

Disclosure

V. Politis-Barber: None. H.L. Petrick: None. G. Holloway: None.

Funding

Natural Sciences and Engineering Research Council of Canada (400360)
1931-P: New Insights Into Lipoprotein Lipase Maturation in the ER
Authors: WU SHUANGCHENG , TORRES MAURICIO , QI LING
Published: June 2020

Lipoprotein lipase (LPL) is a key enzyme responsible for the hydrolysis of triglycerides packed in lipoproteins, and defects in this process have been linked to the development of obesity-associated pathological conditions such as hyperlipidemia, atherosclerosis and stroke. However, our understanding of early events leading the maturation of nascent LPL protein remains limited. Here, we report a previously unappreciated crosstalk between ER-associated degradation (ERAD) and autophagy in controlling LPL maturation in the ER. Sel1L, an essential cofactor involved in ERAD, is required for the export of active LPL from the ER and prevents the formation of high molecular weight LPL aggregates. In the absence of Sel1L, autophagy is activated in adipocytes to limit the size of LPL aggregates in the ER. Deletion of autophagy in Sel1L-deficient adipocytes leads to the formation of large LPL foci in the ER. Thus, we conclude that Sel1L-Hrd1 ERAD and autophagy, most likely in the form of ER-phagy, synergistically control the biogenesis and aggregation of nascent LPL proteins. Ongoing studies aim to decipher how ERAD controls the activation of ER-phagy and how ER-phagy recognizes and degrades LPL aggregates.

Disclosure

S. Wu: None. M. Torres: None. L. Qi: None.
1934-P: Branched-Chain Amino Acids Are Poor Markers of Insulin Resistance in Women: The Federal Women’s Study
Authors: MATTA SAMANTHA , CRAVALHO CELESTE K. , VILLALOBOS-PEREZ ALFREDO , MEYERS ABBY , MABUNDO LILIAN , COURVILLE AMBER B. , SAMPSON MAUREEN L. , SUMNER ANNE E. , CHUNG STEPHANIE T.
Published: June 2020

The data relating branched chain amino acids (BCAAs) with obesity and type 2 diabetes is conflicting but may be further clarified by examining its relationship to race/ethnicity and menopause. Therefore, we determined the relationship of BCAA with markers of insulin sensitivity (SI) in 122 federally employed women (49 White, 73 Black: 58 African American and 15 African Immigrant, age 44±10 (mean±SD) (range 24-62y); BMI 30.2±5.7 (range 20.3-45.2 kg/m2); 33% menopausal) using linear regression models adjusted for race and menopause. Fasting BCAAs were measured by nuclear magnetic resonance (NMR) spectroscopy, whole-body SI derived from the minimal model, basal hepatic insulin sensitivity (HISI) using [6,62H2]glucose, and hepatic and visceral adipose tissue (VAT) by proton NMR. BCAAs were similar in black and white women (leucine:104±30 vs. 114±37, valine:196±40 vs. 204±34, isoleucine:41±12 vs. 38±12 μmol/L, all P≥0.1) and did not differ by menopause (P>0.5). Total and individual BCAAs were associated with lower whole-body SI (Figure), weakly associated with VAT (AdjR2=0.1, P=0.01), liver fat (AdjR2=0.01, P=0.01), and there was no association with HISI (P>0.2). Overall, plasma BCAAs were not robust markers of insulin resistance in women of white or African ancestry and higher levels in women with insulin resistance may reflect a composite effect of dietary and metabolic processes.

Disclosure

S. Matta: None. C.K. Cravalho: None. A. Villalobos-Perez: None. A. Meyers: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. A.E. Sumner: None. S.T. Chung: None.

Funding

National Institutes of Health (to S.T.C., L.M., A.B.C.)
1938-P: The Gut Microbiota Is Critical for the Beneficial Metabolic Effects of Palmitic Acid Hydroxy Stearic Acids (PAHSAs) in Diet-Induced Obese Mice
Authors: LEE JENNIFER , RAHNAVARD ALI , WELLENSTEIN KERRY , NELSON ANDREW T. , CLISH CLARY B. , SIEGEL DIONICIO , KAHN BARBARA
Published: June 2020

The gut microbiome contributes to host health and has therapeutic potential to treat metabolic disease. A newer class of lipids, PAHSAs, have antidiabetic effects in high-fat diet (HFD)-fed mice. We aimed to determine whether the gut microbiome contributes to the beneficial metabolic effects of PAHSAs and if these effects are transmissible by Fecal Microbiota Transplantation (FMT) in mice. In HFD-fed germ-free (GF) mice, PAHSA treatment for 35 days did not improve glucose homeostasis vs. vehicle-treated mice, in contrast to previous data in conventional HFD mice. Feces from conventional Chow fed mice with enhanced insulin sensitivity after PAHSA treatment for 21 days were used for oral FMT in HFD-GF mice. HFD-GF mice treated with feces from PAHSA-treated chow mice gained less weight, had reduced glycemia 5-hrs after food removal, and were more glucose tolerant and insulin sensitive than HFD-GF-mice that received feces from vehicle-treated Chow mice. Metagenome sequencing and metabolomics analysis performed on cecal contents from conventional Chow-fed PAHSA- and Vehicle-treated mice showed that 26 fatty acids (out of 600 metabolites) and several microbial species and their metabolic pathways correlated most highly with PAHSA-mediated insulin sensitivity. Also, Bacteroides thetaiotaomicron (Bt), a gut microbe associated with leanness in humans, and cecal C34:2 Phosphatidylethanolamine (PE), an abundant phospholipid class that is reduced in obese humans, were most strongly associated with the beneficial PAHSA effects. Initial studies with Bt treatment in male chow mice show improved glucose tolerance and lower glycemia 5-hrs after food removal vs. controls. Thus, the gut microbiota is necessary for the effects of PAHSAs to improve glucose homeostasis in HFD-fed mice. These effects can be conferred by FMT. PAHSA-associated microbes could provide novel gut-based therapeutic strategies to treat obesity and insulin resistance.

Disclosure

J. Lee: None. A. Rahnavard: None. K. Wellenstein: None. A.T. Nelson: None. C.B. Clish: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Harrington Discovery Institute, Janssen Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK114162-01A1, DK1NADK-057521-01 to J.L.); JPB Foundation (to B.K.)