bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Dysfunction within Brown Adipose Tissue and Skeletal Muscle Caused by Complete Hepatic Insulin Resistance Is Reversible by FGF-21 Treatment
Authors: STOEHR OLIVER , TAO RONGYA , COPPS KYLE D. , WHITE MORRIS F. 
Published: June 2018

Hepatic Irs1/Irs2 double knockout mice (LDKO) developed severe systemic insulin resistance, glucose intolerance, and dysregulated gluconeogenesis and hyperinsulinemia—which was largely normalized upon deletion of FoxO1. Although hepatic insulin resistance was established genetically in the LDKO mice, altered hepatokine secretion can dysregulate the metabolism of other tissues—including white (WAT) and brown (BAT) adipose tissues, and skeletal muscle. Compared against control mice, glucose uptake into BAT and various skeletal muscles of LDKO-mice was reduced strongly before and during insulin stimulation. Moreover, BAT exhibited higher gene expression levels of muscle and white adipose tissue markers, whereas expression of BAT and thermogenesis markers were decreased. This indicated immature BAT development, and consequently LDKO-mice failed to maintain body core temperature when exposed to a 4°C environment. Among the dysregulated hepatokines in LDKO-mice, FGF-21 (fibroblast growth factor 21) was reduced significantly. As circulating FGF-21 is produced almost entirely in the liver, LDKO-mice treated by hepatic infection with FGF-21AdV (adenoviral FFG-21) displayed better glucose tolerance, insulin sensitivity, and glucose uptake into BAT and skeletal muscle. FGF-21 also restored normal cold sensitivity. On a high fat diet (HFD) LDKO mice developed severe hyperglycemia; however LDKO•FGF-21AdV-mice lost weight and glucose tolerance improved. These results suggest that reduced FGF-21 contributed to BAT and skeletal muscle dysfunction in LDKO-mice, which can dysregulate systemic glucose homeostasis during hepatic insulin resistance. Expression of FGF-21 can restore and improve glucose metabolism despite the persistent hepatic insulin resistance and uncontrolled gluconeogenesis in these mice.

Disclosure
O. Stoehr: None. R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.
Differential Effects of Niacin on High-Fat Diet–Induced Adipose Tissue Inflammation and Nonalcoholic Fatty Liver Disease in C57BL6/J and B6129SF2/J Mice
Authors: FANG HAN , GRAFF EMILY , LI ZHUOYUE , JUDD ROBERT L. 
Published: June 2018

Pharmacological doses of niacin improve adipose tissue (AT) inflammation and nonalcoholic fatty liver disease (NAFLD) in rodents chronically fed a high-fat diet (HFD). However, recent mouse studies have demonstrated significant metabolic changes in different strains of mice fed a HFD. Therefore, the aim of this study was to assess the effect of niacin on both AT inflammation and liver steatosis in two mouse strains, C57BL6/J (B6) and B6129SF2/J (B6129), under HFD feeding. Thirty-two male B6 and 32 male B6129 mice were randomized into four groups: Chow/Vehicle (CV), Chow/Niacin (CN), HFD/Vehicle (HV), and HFD/Niacin (HN). They were fed either a chow (10% fat) or HFD (60% fat) for 20 weeks. Niacin (360 mg/kg/day) or vehicle was added to the drinking water from week 5 until the end of the study. As expected, HFD-fed mice gained more weight than chow-fed mice in both strains, with no difference in weight gain between strains. Crown-like structure (CLS) number, a hallmark of AT inflammation, was increased in HV mice of both strains compared to CV mice. In addition, HV B6 mice had higher CLS number than HV B6129 mice. In B6129 mice, niacin decreased CLS number in HN compared to HV mice, while this decrease was not observed in B6 mice. Liver weight to body weight (L/B) ratio, liver triglyceride (TG) content and NASH score was increased in HV compared to CV B6 mice. In contrast, in B6129 mice, only NASH score was increased in HV compared to CV controls. Niacin had no impact on L/B ratio, TG content, or NASH score in B6 mice. However, in B6129 mice, niacin increased all three parameters in HN compared to HV mice.
In conclusion, there are strain differential effects on AT inflammation and NAFLD induced by HFD feeding. Interestingly, liver steatosis is significantly increased in HFD-fed B6129 mice treated with niacin. This increase is potentially due to methyl deficiency, as niacin is a potent hepatic methyl consumer and 129 mice are more sensitive to methyl deficiency.

Disclosure
H. Fang: None. E. Graff: None. Z. Li: None. R.L. Judd: None.
Glutathione Deficiency Induces Epigenetic Alterations of Vitamin D Metabolism Genes in the Liver of High-Fat Diet–Induced Type 2 Diabetic Mice
Authors: PARSANATHAN RAJESH , JAIN SUSHIL K. 
Published: June 2018

Vitamin D (VD) deficiency is an epidemic health problem. Over a billion people worldwide are VD-deficient or insufficient. VD-regulates the functions of over 200 genes and is essential for growth and development. VD-deficiency can result in diabetes, hypertension, heart disease and stroke. VD levels correlate positively with GSH and negatively with insulin resistance in type 2 diabetic patients. HFD-fed mice exhibited elevated blood glucose, and decreased blood GSH and 25(OH)VD with reduced GSH and increased oxidative stress in the liver. We investigated whether GSH deficiency induces epigenetic alterations in VD-metabolism genes in the high-fat diet (HFD) fed mice. The levels of VD-metabolism genes (CYP2R1, CYP27A1, CYP27B1, and VDR) and GSH biosynthesis pathway genes (GCLC, GCLM, GSS, and GSR) were significantly (p&lt;0.005) down-regulated in the liver of HFD-fed mice. Conversely, CYP24A1 which metabolizes the active VD was significantly (p&lt;0.005) increased. In vitro mouse hepatocyte GCLC knockdown decreases GSH and alters VD-regulatory genes in the similar pattern of HFD-fed mice. Further, significant increased DNMTs (1, 3a and 3b) and global DNA methylation levels with decreased TET1 (p&lt;0.005) but not TET2/3 were observed in the cultured hepatocytes and liver. Notably, significant (p&lt;0.005) gene-specific hypermethylation of CYP2R1 (1.71, 2.55; Control vs. HFD), CYP27A1 (7.58, 8.68), CYP27B1 (0.11, 0.77), VDR (0.16, 0.46) and hypomethylation of CYP24A1 (0.59, 0.33) was observed in the liver of HFD-fed (16 weeks) mice compared with control (normal diet) group. GSH deficiency-induced epigenetic alterations (methylation status) of VD-metabolism enzyme genes and the VDR gene appear to play a significant role in the circulating VD. These findings indicate that GSH epigenetically regulates VD-metabolism genes in obesity/T2DM and a novel adjuvant therapeutic target for restoring VD-deficiency in susceptible populations.

Disclosure
R. Parsanathan: None. S.K. Jain: None.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Acutely Inhibits Food Intake in Leptin-Deficient ob/ob Mice and Leptin Receptor–Deficient fa/fa Rats
Authors: HOWARD VICTOR G. , OLDHAM STEPHANIE , KONKAR ANISH , TREVASKIS JAMES , WILL SARAH 
Published: June 2018

MEDI0382 is a potent glucagon-like-peptide-1 (GLP-1) and glucagon receptor dual agonist that inhibits feeding and induces weight loss in mice. To test whether MEDI0382-mediated improvements in metabolism require leptin signaling, we determined its acute effects on food intake in rodents lacking either leptin (ob/ob mice) or the leptin receptor (fa/fa rats). An acute dose response study in ob/ob mice was performed with mice dosed subcutaneously (SC) with GLP-1 receptor agonist liraglutide (30 nmol/kg), glucagon receptor agonist G1437 (30 nmol/kg), or MEDI0382 (1, 3, 10 or 30 nmol/kg). At 24 h, liraglutide and G1437 treatment reduced food intake by 50% and 16% vs. controls, respectively. MEDI0382 inhibited food intake in a dose-dependent manner, and exerted superior inhibition of food intake compared to equimolar doses of liraglutide and G1437. The fa/fa rats were also dosed once with liraglutide, G1437 (both at same doses as above), or MEDI0382 (3, 10 and 30 nmol/kg) and food intake measured. Liraglutide and G1437 treatment decreased 24 h food intake by 55% and 27% respectively and MEDI0382 dose-dependently decreased food intake (32%, 67% and 77%). Also, fa/fa rats treated with MEDI0382 had an additional reduction in food intake than equimolar doses of either liraglutide or G1437. Finally, lean C57BL/6 mice housed in the BioDaq food intake monitoring system were dosed SC once with MEDI0382 (0.3, 1, 3, 10 and 30 nmol/kg), and a dose-dependent effect on inhibition of food intake was observed. Further analysis showed MEDI0382 decreased total meal number and increased satiety ratio.
In summary, MEDI0382 exerted potent anorexigenic effects in mice independent of the leptin pathway, characterized by decreased number of meals consumed and increased satiety.

Disclosure
V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Regeneron Pharmaceuticals, Inc., AstraZeneca. S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. A. Konkar: Employee; Self; Sanofi. Other Relationship; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Dietary Supplementation with Galactooligosaccharide (GOS) Attenuates High-Fat, High-Cholesterol Containing Western Diet (WD)–Induced Glucose Intolerance
Authors: HE HONGLIANG , GHOSH SIDDHARTHA S. , YANNIE PAUL J. , WANG JING , GHOSH SHOBHA 
Published: June 2018

WD induces the development of type 2 diabetes (T2DM). In addition to the direct effects on gut dysbiosis, we have shown that WD also affect intestinal barrier function leading to increased release of LPS into circulation resulting in chronic inflammation that underlies the development of T2DM; oral supplementation with curcumin attenuate these WD-induced effects. Herein we examined the effects of GOS supplementation on WD induced changes. C57BL/6 mice were either fed a standard chow or WD or WD+GOS or WD+Curcumin (WD+C) for 16 weeks. Glucose tolerance tests were performed and while no significant differences were seen in female mice (Panels A and C), WD-induced glucose intolerance was significantly attenuated by GOS or curcumin supplementation in male mice (Panels B and D). Although plasma LPS levels were not significantly affected, a significant decrease in circulating macrophages (Panel E) as well as neutrophils (Panel F) was noted with GOS or Curcumin supplementation indicating a reduction in systemic inflammation. Gene expression and histological changes in the ileum and colon indicate GOS or curcumin-mediated increase in mucin production and maintenance of mucous layer integrity. Dietary supplementation with GOS or Curcumin, therefore, represents a simple strategy to ameliorate the metabolic/diabetogenic effects of WD.

Disclosure
H. He: None. S.S. Ghosh: None. P.J. Yannie: None. J. Wang: None. S. Ghosh: None.
Genetically-Regulated Mechanisms of Insulin Resistance in Adipose Tissue
Authors: SHARMA NEERAJ K. , KEY CHIA-CHI C. , COMEAU MARY E. , LANGEFELD CARL D. , PARKS JOHN S. , DAS SWAPAN K. 
Published: June 2018

Insulin resistance (IR) is a harbinger of type 2 diabetes (T2D) and partly determined by genetic factors. However, genetically-regulated mechanisms of IR remain poorly understood. Using gene expression, genotype, and insulin sensitivity (SI and Matsuda index from FSIVGT and OGTT) data from an African American cohort (AAGMEx, N=256), we performed transcript-wide association and expression quantitative trait loci (eQTL) analyses to identify IR-associated cis-regulated transcripts (cis-eGenes) in adipose tissue. Data from a European ancestry cohort (METSIM, N=770) was used for testing replication of Matsuda index-associated cis-eGenes. In vitro genetic silencing studies were performed in a human adipocyte model to define the molecular mechanism of selected genes. Expression level of 2724 transcripts in adipose were negatively (1338) or positively (1386) associated (p&lt;0.001) with Matsuda index in both cohorts. In the AAGMEx cohort, we identified cis-eQTLs (FDR&lt;1%) for 786 Matsuda index-associated transcripts. Cis-eQTLs for 510 Matsuda index-associated genes were identified in both the AAGMEx and METSIM cohorts. These genes were enriched for mitochondrial dysfunction, phagosome maturation, and branched-chain amino acid degradation pathways. The enoyl-CoA hydratase domain-containing 3 (ECHDC3) was the top ranked Matsuda index-associated cis-eGene. ECHDC3 expression level was positively correlated with Matsuda index (r=0.47, p=5.3x10-15) and rs200943982 was the top ECHDC3 cis-eSNP (p=1.94x10-9) in AAGMEx. The shRNA-mediated silencing of ECHDC3 in SGBS adipocytes reduced insulin-stimulated Akt phosphorylation. RNA-seq analysis identified 691 differentially-expressed genes in ECHDC3 knockdown cells, which were enriched in γ-linolenate and cholesterol biosynthesis, LXR/RXR activation pathways, and known IR genes.
In summary, variation-based genomic analysis with concurrent in vitro genetic silencing studies identified novel genetic regulatory mechanisms of IR.

Disclosure
N.K. Sharma: None. C.C. Key: None. M.E. Comeau: None. C.D. Langefeld: None. J.S. Parks: None. S.K. Das: None.
National Trends and Outcomes in Patients with Uncontrolled Diabetes and Related Complications
Authors: JAIN NIDHI , AGARWAL MANYOO , KADARIA DIPEN , STEINBERG HELMUT O. , DAGOGO-JACK SAMUEL 
Published: June 2018

Introduction: Patients with uncontrolled DM can present to the hospital with life threatening complications: DKA, hyperosmolar syndrome and coma. There is a paucity of data on the contemporary trends and outcomes of uncontrolled diabetes related hospitalizations (UDH).
Methods: We analyzed the 2003 to 2011 Nationwide Inpatient Sample database (https://www.hcup-us.ahrq.gov) to examine the trends and in-hospital outcomes in patients with UDH aged ≥18 years in the U.S. All patients with primary diagnosis of uncontrolled DM were identified using ICD-9 CM codes- 250.02-250.03, 250.10 -250.13, 250.20 -250.23 and 250.3.
Results: From 2003 to 2011; 1,690,457 patients had UDH. The yearly hospitalization increased from 171,408 (2003) to 216,965 (2011)(ptrend &lt;0.001). Breakdown by sex, race, income and insurance status are in Table 1. The in-hospital mortality decreased from 0.8% to 0.4% (adjusted odds ratio [per year] 0.90; 95% confidence interval 0.89 to 0.91; ptrend &lt;0.001). The average hospital charges increased from $14,370 to $22,897 (ptrend &lt;0.001), whereas the average length of stay decreased from 3.9 to 3.4 days (ptrend &lt;0.001).
Conclusion: Hospitalizations with UDH increased by ∼25% in all U.S demographic groups between 2003 and 2011. However, outcomes improved during the same period, with decreases in length of stay and risk-adjusted in-hospital mortality.

Disclosure
N. Jain: None. M. Agarwal: None. D. Kadaria: None. H.O. Steinberg: None. S. Dagogo-Jack: None.
Txnip Deficiency in the Intestinal Epithelial Cells Prevents against the High-Fat Diet-Induced Fructose Uptake
Authors: SHAH ANU , DAGDEVIREN SEZIN , HUNDAL HENNA , LEE RICHARD 
Published: June 2018

Thioredoxin interacting protein (Txnip) has emerged as a key player in nutrient sensing and carbohydrate metabolism. Our lab recently discovered that Txnip binds to the fructose transporters, Glut 2 and Glut 5, to increase the fructose uptake by enterocytes. Additionally, we demonstrated that Txnip was required for the streptozotocin-induced diabetic mice to exhibit a significant increase in fructose absorption. In the present study, we explored the effects of high fat diet (HFD) on fructose uptake in mice with fasting euglycemia and elucidated the role of Txnip in this process. We hypothesized that jejunal uptake of fructose would increase in the HFD-fed mice as compared to the regular diet (RD)-fed controls, and this rise would be prevented in mice with intestinal epithelium knockout of Txnip, despite being on a HFD. To test this hypothesis, C57BL/6J wild type mice were kept on HFD for 16 weeks. At the end of this period, the HFD-fed mice not only exhibited a fasting euglycemia, but also displayed significantly higher fructose absorption (hepatic portal vein blood: p&lt;0.01 and liver: p&lt;0.vs. RD-fed mice, n=6-7 mice/group). Interestingly, gene and protein expressions of Txnip were also significantly higher in the jejunal samples from these mice. Since fructose absorption primarily occurs in the jejunum, we generated a Txnip villin-cre mice that lacks Txnip in the intestinal epithelial cells; and then subjected these mice and their cre counterparts to RD/HFD. The preliminary data at one month post-diet shows a reduced trend of fructose absorption in both RD-fed and HFD-fed Txnip villin cre mice compared to the cre-controls. Thus, our data demonstrates that HFD facilitates fructose uptake by the intestine, and the targeted deletion of Txnip at the intestinal level can decrease the absorption of dietary fructose. This outcome implies a molecular mechanism by which high fat diet can promote excess hepatic lipid synthesis via enhanced fructose uptake.

Disclosure
A. Shah: None. S. Dagdeviren: None. H. Hundal: None. R. Lee: None.
Overexpression of Perilipin 2 Induces Cardiac Steatosis and Atrial Fibrillation via Connexin 43 Remodeling
Authors: SATO SATSUKI , SUZUKI JINYA , HIROSE MASAMICHI , NAKAYA TAKAHIRO , YAMADA MIKA , ICHIKAWA MAI , IMAGAWA MICHIKO , ZENIMARU YASUO , TAKAHASHI SADAO , KRAEMER FREDRIC B. , KONOSHITA TADASHI , ISHIZUKA TAMOTSU 
Published: June 2018

Atrial fibrillation (AF) is prevalent among diabetic patients. Diabetes is also associated with myocardial lipid droplet accumulation (steatosis), which is thought to be a source of intracellular lipotoxicity. Since the relative contribution of cardiac steatosis per se to AF has not been elucidated, the current study was designed to clarify the causal effect of cardiac steatosis on AF using an aged mouse model of cardiac steatosis. Cardiac-specific perilipin (PLIN) 2-overexpressing mice (PLIN2-Tg) were created and maintained on a chow diet for &gt;12 months. Cardiac steatosis was assessed by electron microscopy and triacylglycerol (TAG) content. AF was induced by transesophageal electrical burst pacing, and the duration of AF was measured. Atrial impulse conduction patterns were analyzed in Langendorff-perfused hearts using optical mapping technique. Myocardial localization of a gap junction protein, connexin (Cx) 43, was analyzed by confocal microscopy. Electron microscopy of the atrium of PLIN2-Tg revealed accumulation of small lipid droplets around clusters of mitochondria, and the atrial TAG content in PLIN2-Tg was 4- to 8-fold higher than that in wild type (Wt) atrium. Electrocardiograms showed significantly longer RR intervals in PLIN2-Tg compared to Wt mice. The prevalence of sustained (&gt;5min) AF was significantly greater in PLIN2-Tg compared with Wt mice (69% vs. 24%). Confocal microscopy revealed that Cx43 was distributed at the intercalated discs in Wt atria, whereas it was heterogeneously redistributed to the lateral side of the cardiomyocytes in PLIN2-Tg atria. Isochrone mapping showed slow and heterogeneous impulse propagation in PLIN2-Tg atria compared with Wt atria. These results indicate that PLIN2-induced steatosis causes Cx43 remodeling, impaired conduction propagation, and a higher incidence of AF. Controlling cardiac steatosis might be an important target for inhibiting AF in patients with cardiac steatosis.

Disclosure
S. Sato: None. J. Suzuki: None. M. Hirose: None. T. Nakaya: None. M. Yamada: None. M. Ichikawa: None. M. Imagawa: None. Y. Zenimaru: None. S. Takahashi: None. F.B. Kraemer: None. T. Konoshita: None. T. Ishizuka: None.
Heart-Specific Overexpression of HMG-CoA Synthase 2 Induces Mitochondrial Stress—Adaptation via the ATF4 Pathway
Authors: ZENIMARU YASUO , SUZUKI JINYA , NAKAYA TAKAHIRO , YAMADA MIKA , ICHIKAWA MAI , SATO SATSUKI , IMAGAWA MICHIKO , KRAEMER FREDRIC B. , KONOSHITA TADASHI , ISHIZUKA TAMOTSU 
Published: June 2018

The liver is the central organ for ketone body production, and HMG-CoA synthase2 (HMGCS2) is a rate-limiting enzyme involved in this process. We reported that fasting markedly increased mRNA expression of HMGCS2 in mouse heart, whereas its protein expression was faint and increased only marginally with fasting. To clarify the pathophysiological role of HMGCS2 in the heart, we generated transgenic (Tg) mice with heart-specific HMGCS2 overexpression and analyzed the effects on metabolic status in the myocardium. Plasma concentrations of β-hydroxybutyrate (βOHB), glucose and free fatty acids were comparable between Tg and wild type (Wt) mice, whereas the cardiac βOHB content in Tg mice was increased 10-fold (fed state) or 2-fold (24h-fasted state) over that of Wt mice. Confocal microscopy demonstrated that the HMGCS2 protein co-localized with a mitochondrial protein, ATP5A, in cardiomyocytes of Tg mice. Transmission electron microscopy showed many swollen mitochondria, some of which contained vacuole-like vesicles and decreased cristae in Tg hearts, and ultrasonography showed impaired systolic function. Microarray gene expression analysis revealed that approximately 800 genes were altered &gt;2-fold in Tg hearts compared with Wt hearts. Among the altered genes, ATF4 and its target genes, including PHGDH, MTHFD2 and ASNS which promote glutathione production, were upregulated in Tg hearts. Consistent with this result, a metabolome analysis performed by capillary electrophoresis-mass spectrometry demonstrated that glutathione was increased in Tg hearts, suggesting an adaptation to mitochondrial stress. In addition, 3 branch-chain amino acids were increased in Tg hearts compared with Wt hearts. These results indicate that myocardial HMGCS2 can produce ketone bodies in mitochondria, leading to mitochondrial stress and cardiac dysfunction. The limited induction of HMGCS2 protein upon fasting might constitute a protective mechanism for cardiomyocytes.

Disclosure
Y. Zenimaru: None. J. Suzuki: None. T. Nakaya: None. M. Yamada: None. M. Ichikawa: None. S. Sato: None. M. Imagawa: None. F.B. Kraemer: None. T. Konoshita: None. T. Ishizuka: None.
Foxo1 Corepressor (FCoR) and Foxo1 Regulate a-Cell and ß-Cell Identity
Authors: KODANI NORIKO , NAKAE JUN , ITOH HIROSHI 
Published: June 2018

We previously identified a Foxo1 binding protein; Foxo1 CoRepressor (FCoR), in adipocytes. FCoR inhibits Foxo1 activity by enhancing its acetylation. FCoR is expressed in pancreatic α- and β-cells from the embryonic stage. Fcor knockout mice (FcorKO) show impaired glucose tolerance, decreased insulin secretion, increased glucagon secretion and increased α-cell mass. We have shown that FCoR suppresses the expression of master α-cell regulatory transcription factor Aristaless-related homeobox (Arx) by increasing the methylation of the CpG-rich promoter region, while Foxo1 induces Arx expression by hypomethylation of this area. These results suggest that FCoR and Foxo1 have an opposing action in the regulation of Arx expression and α-cell mass. We studied how Foxo1 regulates Arx expression. Arx promoter region contains a conserved forkhead responsive element (FRE). Foxo1 binds to the FRE and induces Arx expression. Binding of Foxo1 to the Arx promoter dissociates binding of DNA methyltransferase 3a (Dnmt3a), and this may result in hypomethylation of the CpG rich region. Our results suggest that Arx is the target gene of Foxo1. Immunohistochemical staining of FcorKO islets showed Foxo1 nuclear localization and decreased Foxo1 in the cytosol. In isolated islets from FcorKO, we observed significant deacetylation of Foxo1, and decreased endogenous Foxo1 protein compared to control. These results are consistent with the previous finding that deacetylated Foxo1 is the active form, and is quickly ubiquitinated and degraded. To study the relationship between FCoR and Foxo1, we generated β-cell-specific Foxo1 knockout mice in the background of FcorKO (DKO). DKO showed further aggravation of glucose tolerance and insulin secretion compared to FcorKO. Foxo1 single knockout has normal glucose metabolism, thus, our results suggest that Foxo1 is activated to maintain β-cell function in FcorKO. We provide evidence that FCoR and Foxo1 function in harmonization to regulate pancreatic α-cell and β-cell identity.

Disclosure
N. Kodani: None. J. Nakae: None. H. Itoh: None.