bluuebunny/crossref_metadata_2025_split huggingface dataset:
1709-P: Increased Adiponectin Levels Are Associated with Impaired Brown Adipose Tissue in Mice
Authors: CHANCLON BELEN , BAUZA-THORBRUGGE MARCO , BENRICK ANNA , WERNSTEDT-ASTERHOLM INGRID 
Published: June 2020

Brown adipose tissue (BAT) thermogenesis affects energy expenditure, as well as glucose and lipid clearance. Thus, making BAT an attractive target in obesity/type-2 diabetes. Adiponectin (Apn) regulates whole-body metabolism and lowered Apn levels are associated with obesity and increased type-2 diabetes risk. Apn has been suggested to be required for maintaining normal body temperature in cold environment, but the role of Apn in BAT functionality is not clear. Here, we have studied BAT in adiponectin overexpressing (Apn-Tg) mice. During unchallenged chow-diet conditions, BAT of Apn-Tg mice was enlarged, fibrotic and more whitish. This phenotype was, as judged by tracer experiments, associated with lower lipid and glucose uptake, decreased de novo lipogenesis and decreased fatty acid oxidation in BAT. High-fat diet (HFD)-induced obesity increased these differences between genotypes. The BAT mRNA expression of thermogenesis markers such as UCP-1 and DIO-2 were down-regulated in BAT of obese, but not lean, Apn-Tg mice. Moreover, Seahorse-based analysis revealed reduced mitochondrial function in Apn-Tg BAT in ex vivo-differentiated brown adipocytes. To test whether increased Apn levels affect cold-induced BAT activation, we exposed Apn-tg and littermate control mice to cold temperature (6°C) for four weeks. Under this setting, the BAT lipid and glucose uptake, and body temperature were similar between genotypes. Accordingly, UCP-1 and DIO-2 mRNA levels were not different between Apn-Tg and WT mice, and highly induced by chronic cold exposure. Nevertheless, Seahorse data from isolated BAT mitochondria from cold-exposed animals still indicate mitochondrial dysfunction in Apn-Tg mice. Thus, our data suggest that increased adiponectin levels are associated with metabolic dysfunction in BAT. We propose that the increased BAT expansion in Apn-Tg mice occurs at the expense of the mitochondrial function.

Disclosure
B. Chanclon: None. M. Bauza-Thorbrugge: None. A. Benrick: None. I. Wernstedt-Asterholm: None.
171-OR: Preventing Diabetes: Resource Allocation between Risk-Based and Whole Population–Based Approaches
Authors: NEUWAHL SIMON , HOERGER THOMAS J. , LAXY MICHAEL , SHAO HUI , ALBRIGHT ANN L. , ZHANG PING 
Published: June 2020

The national diabetes prevention goal set by CDC is to reduce new type 2 diabetes cases from 1.4 million in 2018 to 1.1 million in 2025 (a 21% reduction). Policymakers often debate the merits of interventions that focus on high-risk individuals vs. whole population-based interventions that benefit a broader spectrum of the population.
To resolve this debate, we use a simulation modeling approach to optimize resource allocation among a risk-based intervention (the lifestyle change intervention specified in the National Diabetes Prevention Program [National DPP]) and three whole-population interventions (e.g., sugar sweetened beverage taxes, worksite health promotion, and bike lanes or walking paths). We use the simulation model to estimate the cost and number of diabetes cases prevented by combinations of risk-based and whole population-based interventions. We then plot the prevention frontier as the least-cost combination of interventions for each prevention target. The optimal allocation of resources across interventions can be selected by choosing a prevention target or specifying the available prevention budget.
We find that neither the National DPP alone nor three whole population-based interventions combined are likely to meet the 2025 goal for type 2 diabetes prevention (Figure). Instead, a combination of the National DPP and whole population-based interventions will be needed.

Disclosure
S. Neuwahl: None. T.J. Hoerger: Research Support; Self; Centers for Disease Control and Prevention, Centers for Medicare and Medicaid Services. M. Laxy: None. H. Shao: None. A.L. Albright: None. P. Zhang: None.

Funding
Centers for Disease Control and Prevention
1719-P: Novel Mass Spectrometry–Based Selected Reaction Monitoring Proteomics for Analysis of Low Abundant Insulin Levels in Cerebrospinal Fluid
Authors: LIU QING-RONG , ZHU MIN , CHIA CHEE W. , O’CONNELL JENNIFER F. , ZHANG PINGBO , EGAN JOSEPHINE M. 
Published: June 2020

Circulating insulin levels are routinely measured using Enzyme-linked Immunosorbent Assay (ELISA). However, ELISA is not sensitive enough to measure cerebrospinal fluid (CSF) insulin levels which are 10-100 times lower than those of plasma: yet ELISA results are often reported for insulin analysis in CSF where it serves as a surrogate for brain interstitial fluid insulin levels. We developed a novel LC-MS/MS based selected reaction monitoring (SRM) proteomics assay for quantitative analyses targeting predetermined peptides derived from trypsin digests of insulin; each peptide depends on specific SRM transitions. We determined insulin levels using our novel insulin SRM proteomics method in the matching plasma and CSF samples that were from individuals fasting ≥12 hours and individuals after 2 hours of steady state hyperglycemia by clamp technology (2 hr SS HG). All samples were obtained in individuals with normal fasting glucose and HbA1C levels. Statistically significant differences were observed in both plasma and CSF between fasting and 2 hr SS HG by two tailed and unpaired student t test and 2-way matched ANOVA as shown in Table below. Our results confirmed that peripheral endogenous insulin appears in CSF at least 2 hours after steady state hyperglycemia in subjects with normal glucose tolerance. Our SRM insulin tryptic peptide panel reliably quantified insulin peptide levels in human CSF samples.

Disclosure
Q. Liu: None. M. Zhu: None. C.W. Chia: None. J.F. O’Connell: None. P. Zhang: None. J.M. Egan: None.

Funding
National Institute on Aging
172-LB: Risk of Major Congenital Malformations, Perinatal or Neonatal Death with Insulin Detemir Compared with Other Basal Insulins in Pregnant Women with Preexisting Diabetes: The EVOLVE Study
Authors: MATHIESEN ELISABETH R. , ALIBEGOVIC AMRA CIRIC , HUSEMOEN LISE LOTTE N. , KELKAR PRANAV , MCCANCE DAVID R. , DE VALK HAROLD W. , DAMM PETER ,   ON BEHALF OF THE EVOLVE STUDY GROUP
Published: June 2020

Aim: The EVOLVE study examined the risk of major congenital malformations and perinatal or neonatal deaths when using insulin detemir (IDet) versus other basal insulins in pregnant women with pre-existing diabetes.
Materials and Methods: A prospective, non-interventional, multinational study in pregnant women with type 1 or type 2 diabetes treated with IDet or other insulin treatment. In the present analysis, 727 women using IDet during pregnancy were compared with 730 women using other basal insulin, mainly insulin glargine. The primary endpoint was the number of women completing ≥22 weeks of gestation without any of the following events: major congenital malformations, perinatal or neonatal deaths.
Results: At enrolment 86% of subjects had type 1 diabetes (mean age: 31 years; BMI: 26 kg/m2) and mean A1C was 7.1%. There was no difference between treatment groups in crude or adjusted risk difference for pregnancies without major congenital malformations, perinatal or neonatal deaths (Table).
Conclusion: In pregnant women with pre-existing diabetes, IDet was not associated with excess risk of major congenital malformations, perinatal or neonatal deaths vs. other basal insulin.

Disclosure
E.R. Mathiesen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis. A. Alibegovic: Employee; Self; Novo Nordisk A/S. L.N. Husemoen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Kelkar: Employee; Self; Novo Nordisk Service Centre India Private Ltd. D.R. McCance: None. H.W. de Valk: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S.

Funding
Novo Nordisk A/S
172-OR: Diabetes Care Management (DCM) Under Total Cost of Care (TCOC) Budgeting: Insights from a Medicaid Cohort
Authors: MONTERO ALEX R. , BETLEY CHARLES , BROWN JASON R. , DELIA DEREK M. , FRANCIS NNENIA , SPICER LAURA , MAGEE MICHELLE F. 
Published: June 2020

Background: DCM interventions improve glycemic control and readmission. Cost effectiveness studies typically use only system EHR data. We implemented a 3-month technology-enabled DCM intervention (Diabetes Boot Camp (DBC)) for adults with uncontrolled T2DM in a regional health system. Using EHR data, DBC was shown to reduce A1C and hospitalizations compared to matched controls. The aim of this study was a TCOC assessment of DBC among Medicaid participants using claims data.
Methods: Medicaid-enrolled DBC completers and controls were linked to Maryland’s Medicaid Management Information System. The impact of DBC on different components of spending and TCOC at 90 days was evaluated.
Results: Among the 47 cases and 60 controls, average age was 52; 72.9% were Black; and 67.3% were female. DBC was associated with a per person reduction of $197 in ED/inpatient spending but an increase of $1,471 in TCOC, driven primarily by greater pharmacy spending and outpatient visits. Increased pharmacy spending was driven by spending on insulins and newer medication classes (Table 1).
Conclusions: In a TCOC analysis of DBC, estimated savings from reduced hospital use were more than offset by pharmacy and professional service spending. Pharmacy spending change is likely due to improved adherence/regimen intensification. To promote sustainable TCOC payment models for DCM, consideration of medication effects is needed.

Disclosure
A.R. Montero: None. C. Betley: None. J.R. Brown: Employee; Spouse/Partner; LabCorp. D.M. Delia: None. N. Francis: None. L. Spicer: None. M.F. Magee: Consultant; Self; Mytonomy. Employee; Spouse/Partner; U.S. Food and Drug Administration. Research Support; Self; AstraZeneca, Eli Lilly and Company, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; American Diabetes Association, Pri-Med LLC. Other Relationship; Self; Endocrine Society.
1720-P: The Modulation in Glucose Metabolism by B1 Kinin Receptor Does Not Depend in Hepatic Insulin Signaling
Authors: CORREIA POLIANA ESPÍNDOLA , GOMES CLARISSA B. , MERELLO PAULA N. , NATIVIDADE GABRIELLA R. , BARROS CARLOS C. , GERCHMAN FERNANDO 
Published: June 2020

Background: The kinin B1 receptor (B1R), an inducible effector of Kallikrein-Kinin System during inflammation, has been blamed also to influence glucose metabolism and leptin sensitivity.
Aim: To investigate the effects of cafeteria diet (CAF) on hepatic glucose metabolism in B1R knockout mice (B1RKO).
Methods: Two months old male C57Bl/6 wild type and B1RKO mice were fed with standard chow (SC) or CAF ad libitumfor 14 weeks (WT-SC n=7; B1RKO-SC n=8; WT-CAF n=7; B1RKO-CAF n =10). We performed glucose tolerance test (GTT) and insulin tolerance test (ITT) at the last week before organs collection. HOMA IR index was calculated. Quantitative PCR was used to determine hepatic expression of glucose-6-phospatase (G6Pase), glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase (FBPase1) and hepatocyte nuclear factor 4 alpha (HNF4A). We also performed western blot to analyze AKT phosphorylation in liver. Two-way ANOVA was used to analyze differences between groups. Values were expressed as mean ± SEM and p ≤0.05 was considered statistically significant.
Results: Although the increment of glucose area under the curve during GTT was lower in B1RKO-CAF than WT-CAF (WT-SC 46.246 ± 4.302 vs. B1RKO-SC 35.699 ± 3.383; p=0.03; and B1RKO-CAF 28.521 ± 5.338 vs. WT-CAF 56.564 ± 3.477; AUC p=0.0001), B1RKO mice presented a similar decay in glucose levels during ITT as well as HOMA-IR values . While there was a decrease in liver mRNA expression of G6Pase and PEPCK, GK expression increased in mice fed with CAF diet, without differences between genotypes. FBPase1 and HNF4A mRNA expression were not different between groups. Liver AKT phosphorylation increased with CAF in both C57Bl/6 wild type and B1RKO mice.
Conclusion: The increased glucose uptake of B1RKO mice during GTT might not be related to insulin signaling in the liver, since no changes were observed in insulin resistance or in the hepatic expression of gluconeogenesis regulatory enzymes.

Disclosure
P. Espíndola Correia: None. C.B. Gomes: None. P.N. Merello: None. G.R. Natividade: None. C.C. Barros: None. F. Gerchman: None.

Funding
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (16-0397)
1722-P: Loss of Foxos in Muscle Maintains Strength and Mitochondrial Function during Aging, but Does Not Alter Glucose or Insulin Tolerance
Authors: PENNIMAN CHRISTIE M. , BHARDWAJ GOURAV , JUNCK TAYLOR , BOYER CIERRA , JENA JAYASHREE , FUQUA JORDAN , LIRA VITOR A. , ONEILL BRIAN T. 
Published: June 2020

Muscle mitochondrial decline plays an important role in aging-related muscle weakness and is associated with insulin resistance. FoxO transcription factors are targets in insulin action and are determinants of longevity across species. However, the role of FoxOs in age-related strength and muscle mitochondrial decline is unknown. We measured strength, glucose/insulin tolerance, and muscle mitochondrial bioenergetics in 4.5- month (Young) and 24-month-old (Aged) muscle specific FoxO1/3/4 triple KO (TKO) and littermate control mice. Lean mass and muscle weights were increased 22-48% in young and aged TKO mice compared to age-matched controls. Ad libitum glucose levels were ∼12 mg/dL higher in aged groups compared to young, without differences between TKO and controls. Similarly, glucose and insulin tolerance were unchanged between TKO and control mice in both young and aged groups. While treadmill tests were not different between TKO and controls at either age, the aged control mice show a 20% decrease in max force of ankle dorsi-flexor muscles compared to young controls which was prevented in aged TKOs. Reductions in muscle mitochondrial respiration using glutamate/malate/succinate substrates were also prevented in aged TKO mice compared to aged controls. Mitochondrial Complex I activity was higher in both young and aged TKO compared to their respective controls. We did not see any differences in activity of citrate synthase, and protein expression of subunits from complex I and III, but not other complexes, showed an age-related decline in both TKO and control muscle. These data indicate that loss of FoxOs in muscle prevents age-related mitochondrial dysfunction and muscle weakness, without altering glucose or insulin tolerance, and may be a therapeutic target to prevent muscle atrophy.

Disclosure
C.M. Penniman: None. G. Bhardwaj: None. T. Junck: None. C. Boyer: None. J. Jena: None. J. Fuqua: None. V.A. Lira: None. B.T. ONeill: None.
1723-P: Transcription Factor Foxo1 Mediates TGF-ß1-Induced Apoptosis in Primary Hepatocytes
Authors: AI WEIQI , LIAO WANG , PAN QUAN , YANG WANBAO , SHEN ZHENG , GUO SHAODONG , CHEN YUNMEI 
Published: June 2020

Dysregulation of hepatocyte apoptosis or failure is associated with several types of chronic liver diseases. Transforming growth factor β1 (TGF- β1) is a well-known pro-apoptotic factor in the liver, which is constituted by a receptor complex composed of TGFβ receptor type I (TβRI) and TβRII, along with transcriptional factors Smad proteins. As a member of the forkhead box O-class transcription factors, Foxo1 is a predominant regulator for hepatic glucose production. While the role of Foxo1 in functions beyond glucose metabolism is gradually recognized, since there has been increasing evidence showing the potential relationship between TGF-β1 signaling and Foxo1. Here, we investigated whether Foxo1 mediates the pro-apoptotic effect of TGF-β1 in primary hepatocytes. By using hepatocytes isolated from both of wild type (Foxo1fl/fl) and liver specific Foxo1 knockout (LFKO, albumin-Cre+/-:: Foxo1fl/fl) mice, it was found that TGF-β1 induces hepatocytes apoptosis in a Foxo1-dependent manner. We also explored the associated molecular mechanisms and demonstrated that TGF-β1 activates protein kinase A (PKA) through TβRI-Smad3, followed by phosphorylation of Foxo1 at Ser273 to promote apoptosis of hepatocytes. The significant role of pFoxo1-S273 in mediating the pro-apoptotic effect of TGF-β1 was validated by using hepatocytes isolated from Foxo1-S273A mice, which mimics the dephosphorylation of Foxo1-Ser273. The establishment of TGF-β1-PKA-Foxo1axis in this study reveals a novel role of Foxo1 in hepatic functions.

Disclosure
W. Ai: None. W. Liao: None. Q. Pan: None. W. Yang: None. Z. Shen: None. S. Guo: None. Y. Chen: None.

Funding
American Diabetes Association (1-15-CD-09 to S.G., Sr.); National Institutes of Health (R01DK095118, R56DK11833401)
1743-P: Metabolic Characteristics of Diabetes among Low-BMI Individuals in India
Authors: YIMAGOU ERIC LONTCHI , GUPTA RIDDHI DAS , ANOOP SHAJITH , KEHLENBRINK SYLVIA , MOY JOY , MANAVALAN ANJALI , MATHIAS PRIYANKA M. , GOYAL AKANKASHA , CAREY MICHELLE , STEIN DANIEL T. , THOMAS NIHAL , HAWKINS MEREDITH 
Published: June 2020

Diabetes among low BMI individuals has been recognized globally for over 60 years, and classified by WHO as malnutrition-related diabetes mellitus in 1985. Despite its prevalence in low and middle income countries, this condition has never been comprehensively studied.
State of the art metabolic studies were performed in 20 South Indian men with Low BMI Diabetes (LD; BMI 18.3 ± 0.9 kg/m2), after excluding monogenic and immune diabetes, and visible pancreatic pathology. Other groups were studied: T1D, T2D, and nondiabetic subjects (BMI-matched to LD and T2D). Insulin secretion was assessed by C-peptide deconvolution following a mixed-meal tolerance test. Peripheral and hepatic insulin sensitivity were analyzed using tracer-based (6,6-deuterated glucose), stepped hyperinsulinemic-euglycemic pancreatic clamps following correction of glucose toxicity.
LD subjects were distinct from both T1D and T2D. Insulin secretion was significantly lower in LD than in T2D subjects, yet higher than in T1D. LD subjects were more insulin sensitive than T2D; glucose uptake and endogenous glucose production did not differ from lean nondiabetic or T1D subjects.
These comprehensive studies are the first to demonstrate that LD individuals are characterized by markedly impaired insulin secretion yet preserved insulin sensitivity. Thus, diabetes in low BMI individuals is a distinct entity that warrants further investigation.

Disclosure
E. Lontchi Yimagou: None. R. Das Gupta: None. S. Anoop: None. S. Kehlenbrink: None. J. Moy: None. A. Manavalan: None. P.M. Mathias: None. A. Goyal: None. M. Carey: None. D.T. Stein: None. N. Thomas: None. M. Hawkins: None.

Funding
National Institutes of Health (R01DK069861)
1752-P: Discovery of Targets for Insulin Resistance by Microfluidic Organ-on-Chip Models
Authors: TANATAWEETHUM NIDA , TRANG ALLYSON , ANNEPUREDDY LAASYA , MEHTA JHALAK , COHEN RONALD N. , BHUSHAN ABHINAV 
Published: June 2020

Metabolism of glucose and lipids is essential for nutrient balance and metabolic homeostasis, and is dynamically regulated by adipose tissue and liver. Dysfunction in regulation of these molecules as well as the secreted factors results in metabolic syndrome and insulin resistance (IR), which is a precursor to type 2 diabetes. Studies have shown that as the main site of adaptive thermogenesis, brown adipose tissue (BAT) improves hepatic insulin sensitivity, whereas white adipose tissue (WAT) can induce hepatic IR. However, how these organs communicate to regulate insulin sensitivity is not completely understood due to the lack of representative experimental models. Animals models are useful but suffer from confounding effects from other organs; traditional in vitro models have limited physiological representation.
We have developed an organ-on-chip platform to study the interactions between BAT/WAT and liver under different metabolic states. The adipose-liver organ-chip consists of two interconnected microfluidic devices - brown/white adipocytes were cultured in one device and hepatocytes (insulin sensitive and IR) in the other, both under perfusion. We show that (a) adipocytes exhibited higher intracellular lipid and fatty acid secretion and (b) the hepatocytes secreted higher albumin compared to traditional co-cultures. We found that brown adipocytes secretions restored insulin sensitivity, and improved glucose/lipid metabolism in IR hepatocytes. In contrast, white adipocytes worsened insulin sensitivity and glucose/lipid metabolism. IR hepatocytes lowered Akt-phosphorylation and glucose uptake while upregulated adipocyte fatty acids secretion. Through RNA-seq, we have identified adipose genes responsible for improving hepatic IR.
We have discovered potential new targets for improving hepatic insulin sensitivity. The novel organ-chip platform represented the cells physiologically and will be useful in the discovery and validation of new therapeutic targets for T2D.

Disclosure
N. Tanataweethum: None. A. Trang: None. L. Annepureddy: None. J. Mehta: None. R.N. Cohen: None. A. Bhushan: None.

Funding
DRTC (P30DK020595)
176-OR: The Impact of Chronic Kidney Disease on Commercial Payers in the U.S.
Authors: KAUF TERESA , WANG WEIYING , DILLON ALLISON , SINGH INDERJIT , ODEGARD JOHN T. , RINGEMANN CHRISTIAN , HALDRUP STEFFEN 
Published: June 2020

Objectives: While a large proportion of chronic kidney disease (CKD) cost in the U.S. is borne by Medicare, most CKD patients have commercial coverage, either as primary insurance or as a Medicare supplement. This study examines the economic impact of CKD on commercial payers in the U.S.
Methods: A retrospective cohort study using IBM MarketScan® data from January 2010 - December 2018 was conducted. Patients with ≥2 outpatient (≥30 days apart) and/or ≥1 inpatient claims containing a diagnosis code for CKD were eligible for analysis. The earliest CKD diagnosis date served as the index date. Included patients were continuously enrolled for ≥6 months pre- and post-index. Annualized progression rates and direct medical costs per patient per year (PPPY) by CKD stage were analyzed for the overall CKD population and patients with pre-existing type 1 or type 2 diabetes.
Results: Of 753,097 CKD patients identified, 310,837 (41.3%) had diabetes. More CKD patients with pre-existing diabetes had hypertension (81.7% vs. 75.7% for overall CKD). Approximately 45% of patients in both cohorts were diagnosed at Stage 3. PPPY costs for Stages 1-5 were $19,970, $26,248, $32,687, $46,091, and $61,492, respectively. For CKD patients with pre-existing diabetes, PPPY costs were $21,028, $29,941, $37,835, $50,614, and $67,160 for Stages 1-5. The increase in Stage 5 cost over Stage 1 cost was 208% and 219% for CKD overall and CKD with pre-existing diabetes, respecitvely. Annualized CKD progression was higher for CKD patients with pre-existing diabetes compared to CKD patients overall (162 vs. 130 progressions per 1000 patients in a given year).
Conclusions: Annualized rates of CKD progression are high, with the burden of CKD increasing more than 2-fold from Stage 1 to Stage 5. Earlier identification and treatment management of CKD are needed to reduce the burden of disease.

Disclosure
T. Kauf: Consultant; Self; Roche Diabetes Care. W. Wang: Consultant; Self; Roche Diabetes Care. A. Dillon: Consultant; Self; Roche Diabetes Care. I. Singh: Employee; Self; Roche Diabetes Care. J.T. Odegard: None. C. Ringemann: Employee; Self; Roche Diabetes Care. S. Haldrup: Employee; Self; F. Hoffmann-La Roche Ltd.