bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth Differentiation Factor-15 (GDF-15) Inhibits Gastric Emptying in Rodents as Part of Its Anorectic Mechanism of Action
Authors: HINKE SIMON A. , CAVANAUGH CASSANDRE R. , KIRCHNER THOMAS , LANG WENSHENG , MENG RONG , WALLACE NATHANIEL H. , LIU JR. JIANYING , D'AQUINO KATHARINE E. , HO GEORGE , RANKIN MATTHEW M. , WANG SHENG-PING , CHAVEZ JOSE A. , NELSON SERENA M. , FURMAN JENNIFER , MULLICAN SHANNON , RANGWALA SHAMINA M. , NAWROCKI ANDREA R. 
Published: June 2018

GDF-15 is a secreted circulating polypeptide that regulates systemic energy balance. GDF-15 agonists may have therapeutic potential as anorectic agents in obesity and type 2 diabetes. The receptor for GDF-15, Gfral, is expressed on specific neurons in the area postrema (AP) of the hindbrain, and is necessary for the effect of GDF-15 on food intake. Given the role of the AP in vagal control of gastric motility, we sought to investigate the potential effects of GDF-15 on gastric emptying. Food intake reduction by GDF-15 was confirmed in C57Bl/6N mice using BioDAQ continuous food consumption monitoring. Animals were treated sc with recombinant His-tagged human GDF-15 prior to initiation of the dark cycle; GDF-15 treated mice showed significant reduction in food intake relative to vehicle treated controls (12 hour cumulative food intake: 3nmol/kg, -19.9±10.5%; 10nmol/kg, -58.0±10.0%; P&lt;0.0001, n=8). Gastric emptying was assessed using an oral acetaminophen (AAP) absorption test over 90 minute using LC/MS detection. This method was validated using known inhibitor of gastric emptying, Exendin-4 as a positive control; 7.2nmol/kg Exendin-4 significantly reduced integrated AAP absorption by -44.7±5.1% (P&lt;0.01, n=8). In this assay, GDF-15 caused a significant dose-dependent inhibition of gastric emptying, reducing acetaminophen AUC levels by -18.1±10.6% at 1nmol/kg, and by -36.0±9.9% at 10nmol/kg, relative to vehicle treated control mice (P&lt;0.01, n=8). Comparable results were obtained in an independent repetition of the study. We extended the results obtained in mice to SD rats, where we similarly observed a significant reduction in gastric emptying following GDF-15 treatment. Hence, GDF-15 appears to reduce gastric emptying rate in both mouse and rat, potentially contributing to the food intake suppression mechanism of action.

Disclosure
S.A. Hinke: Employee; Self; Janssen Research & Development. C.R. Cavanaugh: Employee; Self; Janssen Research & Development. T. Kirchner: None. W. Lang: None. R. Meng: None. N.H. Wallace: None. J. Liu: None. K.E. D'Aquino: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Janssen Research & Development. G. Ho: None. M.M. Rankin: Employee; Self; Janssen Research & Development. S. Wang: None. J.A. Chavez: None. S.M. Nelson: None. J. Furman: Employee; Self; Janssen Research & Development. S. Mullican: Employee; Self; Janssen Research & Development. S.M. Rangwala: Employee; Self; Janssen Research & Development. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc..
Sex-Specific Role of Adipose-Derived Lipocalin-2 in Diet-Induced Obesity and Insulin Resistance
Authors: KRISHNAN KARTHICKEYAN CHELLA , SABIR SIMON , FLOYD RAQUEL , JAYASEKERA DULSHAN , LUSIS ALDONS 
Published: June 2018

Lipocalin-2 (LCN2) is a 25-kDa secretory adipokine that is up regulated in adipose tissues of genetically obese animals and humans. LCN2 was also proposed to regulate insulin resistance (IR) in animal studies. Besides, we have shown adipose Lcn2 expression to be negatively regulated by estradiol using a mouse reference population of over ∼100 strains, the Hybrid Mouse Diversity Panel (HMDP). Recently, LCN2 has also been implicated in recruiting neutrophils to the liver in both alcoholic and nonalcoholic steatohepatitis. To further explore the causal role of LCN2 in diet-induced obesity and its metabolic complications, we carried out systems genetics analyses on multi-omics data collected from both males and females of HMDP fed a high fat/high sucrose (HF/HS) diet: Genotypes, 200,000 high-resolution SNPs; Phenotypes, obesity (fat mass, and weight of three visceral adipose depots), IR (fasting levels of glucose, insulin and HOMA-IR) and steatosis (liver triglyceride levels); and Transcriptomics, mRNA microarrays of adipose and liver tissues. Our analyses revealed female, but not male, adipose-derived LCN2 is mechanistically linked to deregulated adiposity and enhanced insulin resistance. To functionally validate the causal role of female adipose LCN2, we conditionally overexpressed either LCN2 or GFP in adipose tissues of mice of both sexes by adeno-associated viral vectors and subjected them to HF/HS diet. We demonstrated deregulated metabolic homeostasis: increased adiposity (fat mass), glucose intolerance (GTT) and insulin resistance (ITT and HOMA-IR) only in females. Follow-up ex vivo bioenergetics studies in both adipose and liver tissues demonstrated deregulated mitochondrial respiration (lowered in adipose; enhanced in liver) mediated by LCN2 overexpression only in females, thereby revealing mitochondrial dysfunction as one of the key mechanism(s) mediated by LCN2 in diet-induced obesity and its complications.

Disclosure
K. Chella Krishnan: None. S. Sabir: None. R. Floyd: None. D. Jayasekera: None. A. Lusis: None.
IKKß and Wnt/ß-Catenin Signaling Interaction Regulates Adipogenesis and Osteogenesis in Mesenchymal Stem Cells of Nonhuman Primates and Humans
Authors: SUI YIPENG , PARK SE-HYUNG , KERN PHILIP A. , TEMEL RYAN , ZHOU CHANGCHENG 
Published: June 2018

IκB kinase β (IKKβ), a central coordinator of inflammation through activation of NF-κB, has been implicated in the pathogenesis of obesity-associated metabolic disorders. We recently demonstrated that IKKβ also functions in adipose progenitors to regulate adipogenesis and adipose tissue development in mice. Deficiency of IKKβ in adipose progenitors decreased high-fat (HF)-elicited adipogenesis and protected mice from diet-induced adiposity and insulin resistance. Here we report that IKKβ can regulate both adipogenesis and osteogenesis in mesenchymal stem cells (MSCs) of non-human primates (Macaca fascicularis) and humans. Activation or overexpression of IKKβ increased adipocyte differentiation but inhibited osteoblast differentiation of MSCs isolated from adipose tissue and bone marrow of macaques and humans. By contrast, IKKβ loss of function decreased adipogenesis and increased osteogenesis in macaque and human MSCs. Mechanistically, IKKβ can directly interact with Wnt/β-catenin signaling and phosphorylate β-catenin at serine-33, -37 and -45, leading to its ubiquitination and degradation. Inhibition of canonical Wnt/β-catenin signaling then contributed to the increased adipogenesis and decreased osteogenesis in MSCs. Our findings demonstrate IKKβ as a key molecule that regulates MSC differentiation, and provide a connection between IKKβ and Wnt/β-catenin signaling which may lead to new insights into the pathogenesis of obesity and osteoporosis.

Disclosure
Y. Sui: None. S. Park: None. P.A. Kern: None. R. Temel: Research Support; Self; Ionis Pharmaceuticals, Inc., Regulus Therapeutics Inc.. Stock/Shareholder; Self; Merck & Co., Inc., Ionis Pharmaceuticals, Inc., Resverlogix Corp.. C. Zhou: None.
Relationship between Amount and Type of Dietary Fat, Postprandial Glycemia, and Insulin Requirements in Type 1 Diabetes
Authors: BELL KIRSTINE , DUKE SALLY , ALEXANDER KYLIE M. , MCGILL MARGARET , WONG JENCIA , FULCHER GREGORY , TWIGG STEPHEN M. , BRAND-MILLER JENNIE , STEIL GARRY M. 
Published: June 2018

ADA recommends individuals with type 1 diabetes (T1D) are taught to adjust insulin for dietary fat however optimal adjustments are not yet clear. This study aimed to determine 1) the relationship between the ‘amount’ and ‘type’ of dietary fat and glycemia and 2) the optimal insulin adjustments for dietary fat. Six adults with T1D using insulin pump therapy attended the research clinic on 9 to 12 occasions. On the first 6 visits, participants consumed meals containing 45g CHO with either 0g, 20g, 40g, or 60g fat and either saturated (SFA), monounsaturated (MUFA) or polyunsaturated (PUFA) fat. Insulin was dosed using individual insulin: carbohydrate ratio as a dual-wave 50/50% split over 2h. On subsequent visits, participants repeated the 20 to 60g fat meals with the insulin dose estimated using a model predictive bolus, with up to 2 repeats/meal until glycemic control achieved. With the same insulin dose, mean 5h incremental area under the curve (iAUC) was increased by 46%, 23% and 139% for the 3 fat loads relative to the 0g fat meal (0g: 509 ± 153; 20g: 742 ± 742; 40g: 626 ± 74; 60g: 1216 ± 434mmol/L.min; ns). The type of fat made small but non-significant differences to the 5h iAUC. To achieve glycemic control, on average, participants required 20-60% more insulin, delivered as a dual-wave over 1.25-2h. This study provides foundation for mealtime insulin dosing recommendations for dietary fat in T1D.

Disclosure
K. Bell: Other Relationship; Self; Novo Nordisk Inc.. S. Duke: None. K.M. Alexander: None. M. McGill: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J. Wong: Speaker's Bureau; Self; Novo Nordisk A/S, AstraZeneca, Eli Lilly and Company. G. Fulcher: Other Relationship; Self; Novo Nordisk Inc., Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp. S.M. Twigg: Advisory Panel; Self; Abbott. Consultant; Self; Abbott. Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Other Relationship; Self; Abbott. J. Brand-Miller: Board Member; Self; Glycemic Index Foundation. Other Relationship; Self; Hachette Australia. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Self; Pam Krauss Books. G.M. Steil: Consultant; Self; Profusa, Eli Lilly and Company.
A Plant-Based Diet Improves Beta-Cell Function and Insulin Resistance in Overweight Adult—A 16-Week Randomized Clinical Trial
Authors: KAHLEOVA HANA , TURA ANDREA , HILL MARTIN , HOLUBKOV RICHARD , BARNARD NEAL 
Published: June 2018

Background: The aim of this study was to test the effect of a 16-week plant-based dietary intervention on beta-cell function and insulin resistance in overweight adults with no history of diabetes.
Methods: Participants (n=75) were randomized to follow a low-fat vegan diet (n=38) or to make no diet changes (n=37) for 16 weeks. At baseline and 16 weeks, beta-cell function was assessed during standard meal tests. Insulin secretory rate was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model. HOMA-IR (The Homeostasis Model Assessment) index was used to assess insulin resistance while fasting. Repeated measure ANOVA was used for statistical analysis.
Results: A marked increase in glucose-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p&lt;0.001). HOMA-IR index fell significantly (p&lt;0.001) in the intervention group (treatment effect -1.0 [95% CI, -1.2 to -0.8]; Gxt, p=0.004). Changes in HOMA-IR correlated positively with changes in body mass index (BMI) and visceral fat volume (r=0.34; p=0.009 and r=0.42; p=0.001, respectively). The latter remained significant after adjustment for changes in BMI (r=0.41; p=0.002). Changes in glucose-induced insulin secretion correlated negatively with BMI changes (r=-0.25; p=0.04), but not with changes in visceral fat.
Conclusions: A 16-week low-fat vegan dietary intervention improved beta-cell function and insulin resistance in overweight adults. The improvement in insulin resistance was related to loss of visceral fat, independent of changes in BMI.

Disclosure
H. Kahleova: None. A. Tura: None. M. Hill: None. R. Holubkov: Other Relationship; Self; Pfizer Inc., MedImmune. N. Barnard: None.
Improved Beta-Cell Differentiation and Function in Isolated Islets Established in Dynamic Culture to Reduce Hypoxia
Authors: AL-JAHDHAMI NAJWA A. , ANDERSON SCOTT J. , ALDIBBIAT ALI , SHAW JAMES A. 
Published: June 2018

Background: Pancreatic islet transplantation effectively prevents severe hypoglycaemia in type 1 diabetes. Restoration of normal β-cell functional mass remains elusive and we have recently demonstrated loss of β-cell end-differentiation in clinical islet recipients. We hypothesised that reducing islet hypoxia in culture would restore β-cell differentiation and function.
Methods: MIN6 pseudo-islets (PI) and primary human islets (HI) were cultured in either static (SC) or horizontal rotation (RC) culture for 7 days. Hypoxia was detected by pimonidazole (Pim) adduct formation and hypoxia-induced gene expression (qPCR). β-cell end-differentiation was assessed by UCN3 expression and IF staining (urocortin-3+ insulin+ cells/total insulin+ cells) with function assayed by glucose-stimulated insulin secretion (GSIS).
Results: Hypoxia was confirmed in established PI (70±1.0% Pim+). This was reduced in rotation culture (Pim+: 15±1.5% RC vs. 80±2.5% SC; p&lt;0.05) with reduced hypoxia-induced gene expression compared with adherent MIN6 (LDHA: 6.0±2.1 RC vs. 86.0±7.8 fold SC; MCT4: RC 2.9±0.4 vs. 54.6±0.6 fold SC; p&lt;0.05). RC enhanced UCN3 gene expression (4.2±0.5 RC vs. 2.2±0.2 fold SC; p&lt;0.05) and increased UCN3/insulin co-staining (80±1.2% RC vs. 30±2.4% SC; p&lt;0.0001) with enhanced GSIS stimulation index (4.1±0.1 RC vs. 2.8±0.1 SC; p&lt;0.0001). Hypoxia-induced expression was reduced in HI RC compared with freshly isolated islets (LDHA: 0.3±0.1 RC vs. 1.8±0.04 fold SC; MCT4: 0.08±0.01 RC vs. 1.1±0.2 fold SC; p&lt;0.05) with increased UCN3 expression (5.9±1.6 RC vs. 3.3±0.9 fold SC; p&lt;0.05) and enhanced GSIS stimulation index (4.1±0.9 RC vs. 3.0±1.2 SC; p&lt;0.05).
Conclusion: Hypoxia in established PI and isolated HI was reduced over 7 days in dynamic culture. This was associated with enhanced β-cell differentiation and function providing a potential approach to maximise optimal functional mass in islet transplantation.

Disclosure
N.A. Al-Jahdhami: None. S.J. Anderson: None. A. Aldibbiat: None. J.A. Shaw: Advisory Panel; Self; Novo Nordisk A/S.
Pancreatic ß-Cell Specific Knockout of Grb10 Improves ß-Cell Function by Enhancing ß-Cell Differentiation and Suppressing ß-Cell Dedifferentiation
Authors: ZHANG JINGJING , CAI ZIXIN , LIU FENG 
Published: June 2018

Aim: Defects in β cell differentiation are associated with type 2 diabetes in humans. Understanding the basis for β cell differentiation defects may reveal new strategies for diabetes therapy.
Results: We found that Growth factor receptor binding protein 10 (Grb10) is highly expressed in mouse and human pancreas and islets and that β cell-specific knockout of Grb10 in mice increased β-cell mass and insulin content, enhanced insulin secretion from β-cells, and up-regulated mTOR and insulin signaling in islets. Pancreatic β cell-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high fat diet and protected adult mice from STZ-induced β cell death. Pancreas-specific knockout Grb10 promoted endocrine progenitors differentiate into β cells during embryonic development. In addition, knockout Grb10 in islets alleviated STZ or high fat diet-induced β cell dedifferentiation.
Conclusion: We have identified Grb10 as a key regulator of β cells differentiation/dedifferentiation and demonstrated that reducing the expression level of Grb10 has a protective effect on β-cell function. Our findings suggest a potential effective therapeutic treatment of both type 1 and type 2 diabetes.

Disclosure
J. Zhang: None. Z. Cai: None.
Immunosuppressive PLGA TGF-ß1 Microparticles Induce Antigen-Specific T-Cell Tolerance for Enhancing Islet Transplantation Outcomes
Authors: LI YING , FREI ANTHONY , BARASH STEVEN D. , STABLER CHERIE L. 
Published: June 2018

Clinical islet transplantation (CIT) is a potential therapy for type 1 diabetes. Allorejection mediated by the host CD4 T cells is a major hurdle for successful CIT, despite potent systemic immunosuppression (SI). To address these issues, we engineered PLGA microparticles (PLGA-MPs) that allow the localized delivery of TGF-β1 for regulatory T cells (TRegs) induction at the transplant site. TGF-β1 is an immunoregulatory agent that promotes the TRegs differentiation from naïve CD4 cells by inducing FoxP3 expression while suppressing inflammatory Th1 and Th2 responses. To date, we have (i) fabricated TGF-β1 loaded PLGA particles by double emulsion (PVA(aq)- CH2Cl2- PVA(aq)) with characterization in size (45±26 μm), TGF-β1 encapsulation efficiency (49.1±0.1%), and release kinetics (durable biphasic release for 14 days); (ii) proved effective TRegs conversion in OVA-OTII antigen-specific murine model (Fig.1); and (iii) shown efficacy for in vivo Treg conversion by MPs in rodent islet allografts, where accepted grafts showed improved insulin production and elevated TRegs. Future studies exploring the competency of PLGA-MPs to provide durable allograft protection in rodent models is on-going. Based on these promising preliminary results, TGF-β1 PLGA-MPs could provide a translational therapeutic strategy to minimize islet graft rejection and the dependency on SI.

Disclosure
Y. Li: None. A. Frei: Employee; Self; Medline Industries, Inc.. S.D. Barash: None. C.L. Stabler: None.
Islet Beta-Cell Specific Deletion of UBL5 Gene Associated with Mitochondrial Stress Leads to Diabetes in Mice and Beta-Cell Impairment/Death
Authors: HARALAMBOUS CHRISTIAN , NTOUMA VIKTORIA 
Published: June 2018

Hyperglycaemia has been shown to cause oxidative stress in pancreatic β-cells, leading to activation of stress responses such as the mitochondrial unfolded protein response (UPRmt). Failure of these responses to adapt to or repair damage from stress results in dysfunction and death of β-cells. Ubiquitin-like protein 5 (UBL-5) is a protein known to have a crucial role in the UPRmt in C. elegans and upregulated during the UPRmt mammals.
The aim of this study was to determine whether UBL-5 has a role in maintaining β-cell mass and function through modulating the UPRmt, by generating and characterising tamoxifen-inducible islet β-cell specific UBL-5 knockout mice. Homozygous β-cell UBL-5 knockout mice (UBL5-/-) showed glucose intolerance and lower plasma insulin levels during the OGTT while heterozygous mice (UBL5+/-) showed no difference. UBL5-/- had significantly reduced plasma insulin levels during IVGTT compared to control. Interestingly, UBL5+/- had significantly increased plasma insulin levels during IVGTT. Beta-cell mass was also significantly reduced in UBL5-/-, with most showing signs of frank diabetes (blood glucose &gt;20 mM), polyuria and polydipsia, while UBL5+/- had increased β-cell mass. One week post UBL5 deletion, UBL5-/- mice had significantly increased blood glucose levels and islet cleaved caspase-3 levels compared to controls despite no difference in β-cell mass. In addition islets taken from UBL5-/- mice 1 week post UBL5 gene deletion showed significant decrease in insulin secretion, suggesting that β-cell dysfunction precedes the decrease in β-cell mass. Islets taken from UBL5+/- mice had increased insulin secretion compared to control. Real time PCR data showed a decrease in UPRmt genes (Clpx, Clpp, CHOP, Lonp1, HSP10, HSP70, ATF5) with HSP60 showing increased expression in the UBL5-/- mice one week after gene deletion, while the UBL5+/- mice showed an overall increase in most UPRmt related genes.

Disclosure
C. Haralambous: None. V. Ntouma: None.
Cyclophilin D-Dependent Mitochondrial Proton Leak in ß Cells Promotes Basal Insulin Secretion
Authors: ALSABEEH NOUR , TADDEO EVAN , WIKSTRÖM JAKOB D. , RITOU ELENI , STILES LINSEY , KIBBEY RICHARD , LIESA MARC , SHIRIHAI ORIAN 
Published: June 2018

Prediabetic subjects display hypersecretion of insulin at basal levels of blood glucose, a phenomenon termed basal hypersecretion. The molecular mechanisms underlying basal hypersecretion and how it may lead to beta cell failure are not well understood. Islets isolated from prediabetic animals and humans have an inherently high mitochondrial proton leak. However, the molecular entity responsible for this leak and its role in basal hypersecretion are not known. We hypothesize that basal secretion is regulated by proton leak mediated by the permeability transition pore (PTP) functioning in a low conductance state. Our data indicate that islets from high fat diet animals display basal hypersecretion of insulin, increased mitochondrial proton leak, and increased expression of Cyclophilin D, a PTP regulator. Moreover, acute stimulation of islets with amino acids (leucine/glutamine) and fatty acids (oleate/palmitate) at basal glucose concentrations increases leak. Pharmacological and genetic inhibition of Cyclophilin D reverses nutrient induced islet leak and insulin secretion. Pharmacological stimulation of mitochondrial proton leak is sufficient to induce basal hyper secretion. Inhibition of CypD-mediated proton leak might constitute a novel target to test the role of basal hyperinsulinemia in the development of diabetes and obesity.

Disclosure
N. Alsabeeh: None. E. Taddeo: None. J.D. Wikström: None. E. Ritou: None. L. Stiles: None. M. Liesa: None. O. Shirihai: None.
Altered Expression of Insulin Signaling Proteins in Islets from T2DM Female Mice
Authors: SONDGEROTH KORIE L. , LEPARD KATHY 
Published: June 2018

With development and progression of T2DM in KKAy mice, pancreatic islets alter their expression of GLUT2, insulin and insulin receptor. The study’s goal was to identify glucoregulatory proteins in the insulin receptor signaling pathway that were early markers of islet dysfunction after 4 weeks of uncontrolled hyperglycemia. Isolated islets were pooled from 2 groups of 12 week old mice: insulin-resistant, euglycemic KK mice and insulin-resistant, hyperglycemic KKAy T2DM mice. Samples were analyzed for 40 proteins using 221 antibodies in an insulin phospho antibody array. After 4 weeks of hyperglycemia in KKAy mice, many proteins were not altered as compared to KK mice (ratio: 0.94-1.02) including insulin receptor (Phospho-Tyr1355), FOXO1A (Phospho-Ser329), PI3-kinase p85-alpha (Phospho-Tyr607), ERK1/2, PP1-alpha, and AMPK1. The phosphorylation states of some proteins were altered including AKT1 (Phosphor-Ser124) (0.77) and IRS-1 (Phosphor-Ser636) (1.25). Three proteins were then selected for ELISA analysis in islets isolated from 4, 8 (onset of T2DM), and 12 week old mice: GLUT2, iNOS (1.41) and CBL (Phospho-Tyr700) (0.78), an E3 ubiquitin ligase. GLUT2 was lower in KKAy mice at 4 weeks (KK, 4.0±0.5; KKAy, 2.3±0.3, p&lt;0.001), but not at 8 or 12 weeks, because GLUT2 decreased with age in both groups (12 weeks: KK, 1.0±0.1; KKAy, 1.4±0.1, p=0.31) [age*mouse: F(2,18)=11.104, p=0.001]. CBL-b was higher in KKAy mice (KK, 0.50±0.09; KKAy, 0.65±0.07) [F(1,17)=4.527, p=0.048] and decreased with age in both groups (12 week: KK, 0.30±0.02; KKAy, 0.45±0.13) [F(2,17)=12.231, p=0.001]. In contrast, iNOS was lower at 4 week (KK, 3.0±0.3; KKAy, 2.0±0.4; p=0.029), then higher at 8 and 12 week (KK, 0.8±0.4; KKAy, 2.1±0.2; p=0.007) with iNOS steady in KKAy mice [age*mouse: F(2,16)=10.902, p=0.001]. With short-term hyperglycemia in KKAy mice, many insulin signaling proteins were not altered as compared to diabetes susceptible KK mice. At onset on T2DM in KKAy mice, sustained iNOS and elevated CBL-b were early markers of islet dysfunction.

Disclosure
K.L. Sondgeroth: None. K. LePard: None.