bluuebunny/crossref_metadata_2025_split huggingface dataset:
320-OR: Maternal Overnutrition Confers Increased Spare Respiratory Capacity and Glucose-Stimulated Insulin Secretion in Nonhuman Primate Offspring Islets
Authors: CARROLL DARIAN T. , ELSAKR JOSEPH M. , RICCIARDI VALERIE F. , DUNN JENNIFER C. , LINDSLEY SARAH R. , DEAN TYLER , KIRIGITI MELISSA , TAKAHASHI DIANA L. , WESOLOWSKI STEPHANIE R. , MCCURDY CARRIE E. , KIEVIT PAUL , AAGAARD KJERSTI M. , FRIEDMAN JACOB E. , GANNON MAUREEN 
Published: May 2022

The Developmental Origins of Health and Disease hypothesis states that the intrauterine environment influences postnatal health and adult disease susceptibility. In the United States, over 30% of women of childbearing age are obese, in part due to Western Style Diet (WSD) consumption. Previous data from our group using a Japanese macaque model, revealed that maternal overnutrition increases the β:α cell ratio in the islets of offspring. WSD-exposed offspring islets also exhibit inappropriate hypersecretion of insulin in response to glucose at 1 and 3 years of age. We hypothesize that fetal exposure to WSD induces a compensatory increase in β-cell fuel metabolism resulting in an inappropriate increase in insulin secretion by offspring islets. When we assessed the effect of maternal diet on mitochondrial respiration in offspring islets, we found that spare respiratory capacity is increased in islets of one year old WSD-exposed male offspring, suggesting an increased capacity to adapt to increased metabolic demand. This could be due to increased mitochondrial abundance; however, maternal overnutrition does not appear to increase β cell mitochondrial density when analyzed via transmission electron microscopy (TEM) . Insulin granule density is increased in male offspring islets in TEM micrographs, implying that insulin production is increased in response to intrauterine WSD exposure. Transcripts for CACNA1C (voltage gated calcium channel subunit) , ABCC8 (ATP-sensitive potassium channel subunit) , and VAMP2 (vesicle fusion) are increased in response to maternal WSD exposure in offspring islets. Thus, our data suggest that increases in insulin secretion in offspring exposed to maternal overnutrition result from changes in metabolic and secretion pathways. Importantly, these mechanisms could potentiate hyperinsulinism which may predispose offspring to insulin resistance and beta cell failure in adulthood.

Disclosure
D.T. Carroll: None. V.F. Ricciardi: None. J.C. Dunn: None. S.R. Lindsley: None. T. Dean: None. M. Kirigiti: None. S.R. Wesolowski: None. C.E. McCurdy: None. P. Kievit: Research Support; Novo Nordisk A/S. J.E. Friedman: None. M. Gannon: None.

Funding
NIH-NIDDK (5T32 DK7563-30, R24DK090964-06, 1R01DK128187)
34-OR: SARS-CoV-2 Infection Is Not Associated with Presence of Islet Autoantibodies in Children: Autoimmunity Screening for Kids (ASK)
Authors: RASMUSSEN CRISTY GENO , JIA XIAOFAN , SHORROSH HANAN , YU LIPING , FROHNERT BRIGITTE I. , SIMMONS KIMBER M. , STECK ANDREA , PYLE LAURA , REWERS MARIAN 
Published: May 2022

Viral infections may trigger islet autoimmunity leading to type 1 diabetes (T1D) . We hypothesized SARS-CoV-2 infection is associated with presence of islet autoantibodies (IAb) in children. Between 8/2020 and 12/2021, ASK screened 47general population Colorado children aged 1-17 y for IAb to GAD, insulin, IA-2 and ZnT8 as well as antibodies to SARS-CoV-2 receptor binding domain (CoV-2 RBDAb) - a sensitive and specific marker of infection. Of those, 4172 (89%) have not previously received SARS-CoV-2 vaccine. During the study period, prevalence of CoV-2 RBDAb increased in unvaccinated from 1% to 58% and up to 100% among vaccinated. Among all children, the prevalence increased from 1% to 72% - an estimate of herd immunity (Figure) . Among the unvaccinated, prevalence of multiple or single high-affinity IAb did not differ between children positive vs. negative for CoV-2 RBDAb, respectively 1.23% (16/1297) vs. 1.00% (29/2875) , p=0.52. In multivariate logistic regression, presence of IAb was not associated with presence of CoV-2 RBDAb (OR=1.40, p=0.31) , adjusting for age, sex, race/ethnicity, and family history of T1D. While we found no association between past SARS-CoV-2 infection and islet autoimmunity, a confirmation in a larger population is warranted. Longer follow-up will help assess whether SARS-CoV2 infection accelerates progression from islet autoimmunity to diabetes.

Disclosure
C.Geno rasmussen: None. X.Jia: None. H.Shorrosh: None. L.Yu: None. B.I.Frohnert: Advisory Panel; Provention Bio, Inc. K.M.Simmons: Advisory Panel; Provention Bio, Inc., Consultant; Dexcom, Inc. A.Steck: None. L.Pyle: None. M.Rewers: Consultant; Janssen Research & Development, LLC, Medscape, Provention Bio, Inc., Research Support; Dexcom, Inc., JDRF, Roche Diagnostics USA.

Funding
JDRF 2-SRA-2021-1065-M-N
344-OR: Body Composition Trajectories from Birth to 5 Years and Hepatic Fat in Early Childhood
Authors: COHEN CATHERINE C. , HARRALL KRISTEN K. , GILLEY STEPHANIE P. , PERNG WEI , SAUDER KATHERINE A. , SHANKAR KARTIK , GLUECK DEBORAH H. , DABELEA DANA 
Published: May 2022

Adiposity is an established risk factor for pediatric nonalcoholic fatty liver disease (NAFLD) , but little is known about the influence of body composition changes earlier in life on future NAFLD risk. Here, we examined associations of body composition trajectories from birth to early childhood with hepatic fat (HF) in early childhood in the Colorado Healthy Start cohort. Fat-free mass index (FFMI) , fat mass index (FMI) , and percent fat mass (%FM) were assessed at birth and/or ∼5 yrs in 1,235 children by air displacement plethysmography. At ∼5 yrs, HF was assessed by magnetic resonance imaging in a sub-sample of 285 children. We used a two-stage modeling approach: first, FFMI, FMI, and %FM trajectories were estimated using mixed models with random intercepts and slopes; second, associations of participant-specific deviations with HF were assessed by linear regression adjusted for confounders. As shown in Table 1, random intercepts for FFMI, FMI, and %FM at birth were all inversely associated with HF in early childhood; whereas %FM slope (i.e., velocity) from birth to ∼5 years was associated with higher HF. These findings suggest that smaller weight at birth, followed by greater gains in %FM are associated with higher HF in early childhood. This supports an influence of early life body composition patterns on HF susceptibility and the importance of perinatal strategies aiming to promote healthy adiposity in infancy/childhood.

Disclosure
C.C. Cohen: None. S.P. Gilley: None. W. Perng: None. K.A. Sauder: None. K. Shankar: None. D.H. Glueck: None. D. Dabelea: None.
345-OR: Longitudinal Changes in Arterial Stiffness and Heart Rate Variability in Youth-Onset Type 1 vs. Type 2 Diabetes
Authors: SHAH AMY S. , ISOM SCOTT , DAGOSTINO RALPH , DOLAN LAWRENCE M. , DABELEA DANA , IMPERATORE GIUSEPPINA , MOTTL AMY K. , LUSTIGOVA EVA , PIHOKER CATHERINE , MARCOVINA SANTICA M. , URBINA ELAINE M. 
Published: May 2022

Limited data exist examining arterial stiffness and heart rate variability (HRV) over time in young adults with youth-onset type 1 (T1D) and type 2 diabetes (T2D) . We compared arterial stiffness and HRV over time and by diabetes type and determined the risk factors associated with worsening arterial stiffness and HRV. Arterial stiffness (pulse wave velocity, augmentation index) and HRV (SDNN and PNN50) were measured twice (∼ 5 years apart) in the SEARCH for Diabetes in Youth Study. Linear regression models assessed risk factors overtime and with arterial stiffness and HRV at follow-up. Of 1159 participants studied, 949 had T1D (mean age 17.1 ± 4.7 years, 60.3% non-Hispanic White, 55% female) and 2had T2D (mean age 22.1 ± 3.5 years, 23.8% non-Hispanic White, 71% female) at initial assessment when diabetes duration was 7.9 years (both groups) . Participants with T2D vs. T1D had greater arterial stiffness and more abnormalities in HRV at initial and follow-up assessments (Figure) .For AIx and PNN50 T2D compared to T1D had a greater change over time (p&lt;0.05) . Risk factors associated with worse arterial stiffness and HRV at follow-up in both T1D and T2D included higher BP, HbA1c, waist circumference, and triglycerides overtime, and longer diabetes duration. Arterial stiffness and HRV worsened over time with greater changes among those with T2D and features of the metabolic syndrome regardless of diabetes type.

Disclosure
A.S. Shah: None. R. Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck & Co., Inc. L.M. Dolan: None. D. Dabelea: None. G. Imperatore: None. A.K. Mottl: Advisory Panel; Bayer AG. Board Member; Bayer AG. Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. E. Lustigova: None. C. Pihoker: None. S.M. Marcovina: None. E.M. Urbina: Advisory Panel; Astellas Pharma Inc.

Funding
NIH and CDC
358-OR: The Effect of Glucagon-Like Peptide-1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion
Authors: FARAHANI RAHELE A. , EGAN AOIFE M. , WELCH ANDREW A. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , VELLA ADRIAN 
Published: May 2022

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signalling through the Glucagon-Like Peptide-1 Receptor (GLP1R) present on β-cells. This occurs at high concentrations as are present within the islet. However, its net contribution to physiologic insulin secretion is unknown. To address this question, we studied 12 non-diabetic, weight-stable individuals (26±1 years,25±1 kg/m2) on 2 occasions. During a hyperglycemic clamp (∼8.9mmol/l) where glucose was labeled with [3-3H] glucose, glucagon was infused at 0.4ng/kg/min, for 1 hour, increasing by 0.2ng/kg/min every hour for a total of 5 hours. Subjects were studied on two occasions in random order. On one occasion Exendin-9,39 (300pmol/kg/min) was infused to block the GLP1R, while on the control day saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production (EGP) and glucose disappearance (Rd) were measured using the tracer-dilution technique. Glucagon concentrations rose from baseline (6.6±2.1 vs. 5.4±1.5 pmol/l, saline vs. exendin-9,39 respectively, p=0.22) to values that, by design, did not differ between study days (17.8±1.8 vs. 17.1±1.1 pmol/l, p&gt;0.1) . This was accompanied by a rise in C-peptide from fasting concentrations. Integrated C-peptide concentrations were slightly, but significantly, decreased during exendin-9,39 infusion (721±65 vs. 648±55 nmol per 5hr, p=0.02) . In addition, integrated insulin secretion rate was lower during exendin-9,39 infusion (213±26 vs. 191±22 nmol per 5 hr, saline vs. exendin-9,39 respectively, p = 0.03) . Both EGP and Rd did not differ significantly on either experimental day. These data show that in non-diabetic humans, during hyperglycemia as seen in the postprandial period, glucagon partially stimulates the β-cell through GLP1R. It remains to be ascertained if this also applies to individuals with type 2 diabetes.

Disclosure
R.A. Farahani: None. A.A. Welch: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S. Other Relationship; Novo Nordisk.

Funding
National Institutes of Health (DK126206)
359-OR: Imaging Pancreatic Blood Flow during Stimulation of Insulin Secretion in Humans
Authors: SIMONSON DONALD C. , TASO MANUEL , MCGRATH COLLEEN , WALDMAN STEPHANIE A. , PAPADOPOULOU FOTINI , ALSOP DAVID C. 
Published: May 2022

Non-invasive imaging of endocrine pancreatic function could provide valuable insights into the magnitude and temporal pattern of β-cell dysfunction in diabetes. Islets comprise 1-2% of pancreatic mass, but receive about 10-20% of pancreatic blood flow, which increases further during stimulation of insulin secretion. We examined the relationship between pancreatic blood flow (PBF) and insulin secretory dynamics in 12 healthy volunteers (6M / 6F, age = 29 ± 5 yrs, BMI = 24.0 ± 2.7 kg/m², HbA1c = 5.1 ± 0.3 %, FPG = 88 ± mg/dl, fasting insulin = 3.7 ± 2.3 μU/ml) . PBF was measured by pseudo-continuous arterial spin labeling (ASL) MRI, with the labeling plane positioned 5-6 cm superior to the imaging slice to label blood in the descending aorta. Fasting subjects were placed in a 3T scanner, and PBF was measured during 1) a 15 min basal period, 2) a +100 mg/dl hyperglycemic clamp for 40 min, followed by 3) a 5 gm bolus of arginine to assess maximal acute insulin response (AIRmax) . First phase (0-min) insulin response to hyperglycemia was 181 ± 96 μU/ml · min, and AIRmax after arginine + hyperglycemia (40-50 min) was 1097 ± 629 μU/ml · min. Basal PBF (188 ± 53 ml/100 gm/min) increased during first phase insulin release, peaking at 212 ± 66 at 12 min, subsequently returned to basal levels (176 ± 59) from 10-40 min during sustained hyperglycemia,and peaked again at 2± 62 at 2 min after arginine. Although there were no significant correlations between glucose, insulin or c-peptide levels and PBF, time-series Granger causality analysis demonstrated that the time-derivative of c-peptide and insulin concentrations, reflectingacute changes in insulin secretion, preceded the increase in PBF (p=0.03 for d[c-peptide]/dt, and p = 0.for d[insulin]/dt) . Conclusions: 1) Changes in PBF during stimulation of insulin secretion in humans can be imaged non-invasively by ASL, 2) Insulin secretion precedes changes in PBF, and 3) The rate of change in insulin and c-peptide release predicts subsequent modulation of PBF.

Disclosure
D.C.Simonson: Stock/Shareholder; GI Windows, Phase V Technologies, Inc. M.Taso: Research Support; GE Healthcare Systems. C.Mcgrath: None. S.A.Waldman: None. F.Papadopoulou: None. D.C.Alsop: Other Relationship; GE Healthcare Systems, Hitachi, Ltd., Philips Healthcare, Siemens, UIH America, Research Support; GE Healthcare Systems.
360-OR: Hyperglucagonemia Reduces De Novo Lipogenesis and Increases Gluconeogenesis in Healthy Subjects
Authors: CHEN XI , CARLI FABRIZIA , PEZZICA SAMANTHA , MOCCIARO GABRIELE , CIOCIARO DEMETRIO , GASTALDELLI AMALIA , DEFRONZO RALPH A. , TRIPATHY DEVJIT 
Published: May 2022

Although the effect of glucagon on glucose metabolism has been well characterized, its effect on lipid metabolism, particularly lipolysis and de novo lipogenesis, in humans in vivo has been poorly studied with controversial results. We examined the effect of short-term hyperglucagonemia on de novo lipogenesis (DNL) and endogenous glucose production (EGP) in 8 healthy normal glucose tolerant subjects (5M/3F, age=35±5, BMI= 24±1) who received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) infusion with measurement of EGP (3-3H-glucose) on the following morning 6-AM. Subjects received deuterated water (D2O, 5g/kg fat free mass) at PM on the night prior to study. 8 weeks later subjects returned for a repeat study with 12-hour infusion of normal saline. DNL was quantified by measuring the incorporation of deuterated water into circulating triglycerides. Gluconeogenic rate was measured as (EGP) x (plasma C5/C2 glucose ratio) (EGP) x (plasma C5/C2 glucose ratio) . Plasma esterified and non-esterified FFA levels were measured with gas chromatography mass spectrometry (GC-MS) . Plasma glucagon increased from 57±3 to 219±21 pg/ml within one hour and remained elevated throughout the study. DNL was significantly decreased (1.64 ± 0.58% vs. 3.± 0.98%, p&lt;0.05) after glucagon versus saline infusion. Both plasma palmitate (0.73 ± 0.vs. 0.67 ± 0.mmol/L) and total FFA (1.35 ± 0.vs. 1.21 ±0.mmol/L) concentrations were elevated after glucagon infusion (p&lt;0.05) . EGP increased following glucagon infusion (2.13 ± 0.14 vs. 1.97± 0.11mg/kg/min, p =0.006) . The increase in EGP was primarily due to increased gluconeogenesis (1.48 ± 0.14 vs. 1.27 ± 0.11, p=0.02) , while the rate of glycogenolysis did not change (0.65± 0.14 vs. 0.70± 0.11, p=ns) . Conclusion: Short-term (12-hour) physiologic hyperglucagonemia in healthy subjects reduces hepatic de novo lipogenesis, stimulates adipose tissue lipolysis, and increases hepatic glucose production by increasing gluconeogenesis.

Disclosure
X.Chen: None. F.Carli: None. S.Pezzica: None. G.Mocciaro: None. D.Ciociaro: None. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk Global Business Services, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. D.Tripathy: None.

Funding
EFSD Albert Renold Travel Fellowship; FAVHR
366-OR: 14-3-3-ζ Contributes to Effect of ß-Cell GLP1 Receptor Signaling to Alter a-Cell Proglucagon Processing
Authors: HOLTER MARLENA , PHUONG DARYL , LEE ISAAC S.H. , SAIKIA MRIDUSMITA , WEIKERT LISA A. , ANDERSON ELIZABETH T. , FU QIN , ZHANG SHENG , SLOOP KYLE , CUMMINGS BETHANY 
Published: May 2022

Glucagon like peptide 1 (GLP1) , a classically gut derived hormone, potentiates insulin secretion. New evidence suggests that α cells can produce GLP1 under certain conditions, which may offer a novel therapeutic modality for treating diabetes; however, the mechanisms regulating α cell GLP1 production are unknown. We previously found that enhanced β cell GLP1 receptor (GLP1R) signaling activates α cell GLP1 by activating prohormone convertase 1/3 (Pcsk1) expression. We tested the hypothesis that enhanced β cell GLP1R signaling activates α cell GLP1 production through paracrine factors. We studied the impact of conditioned media (CM) generated from β cell GLP1R WT and KO islets of saline (CTRL) and liraglutide (LIRA) treated mice on α cell gene expression and function. CM from LIRA treated islets increased α cell Pcsk1 expression and active GLP-1 secretion only if β cells expressed the GLP1R (Pcsk1 expression (AU) : CTRL WT=1.0±0.1, LIRA WT=2.0±0.3, CTRL KO=1.1±0.2, LIRA KO=1.1±0.2, P&lt;0.01; active GLP-1 (pg/mL) : CTRL WT=124±44, LIRA WT=682±247, CTRL KO=173±101, LIRA KO=116±30, P&lt;0.05) . Subsequent identification of the proteome secreted by mouse and human islets in response to LIRA and CTRL revealed 14-3-3-ζ as a lead candidate in the regulation of α cell Pcsk1 expression. To assess the role of 14-3-3-ζ, islets from LIRA treated mice were treated with and without 14-3-3-ζ, and islets from CTRL treated mice were treated with and without the 14-3-3 inhibitor, R18. Addition of 14-3-3-ζ ablated the effect of CM from LIRA treated islets to increase α cell Pcsk1 expression, while inhibition of 14-3-3 with R18 in CTRL islets resulted in CM that mimicked the effect of CM from LIRA treated islets to stimulate α cell Pcsk1 expression (Pcsk1 expression: CTRL=1.1±0.2, R18=2.0±0.2, LIRA=2.4±0.3, LIRA+14-3-3-ζ=1.3±0.1, P&lt;0.05) . These data refine our understanding of α cell GLP1 regulation and identify 14-3-3-ζ as a potential target with which to enhance α cell GLP1 production for diabetes treatment.

Disclosure
M.Holter: None. B.Cummings: None. D.Phuong: None. I.S.H.Lee: None. M.Saikia: None. L.A.Weikert: Stock/Shareholder; Merck & Co., Inc., Oramed Pharmaceuticals. E.T.Anderson: None. Q.Fu: None. S.Zhang: None. K.Sloop: Employee; Eli Lilly and Company.

Funding
NIH/NIDDK (F30 DK126538) Department of Defense (W81XWH-18-1-0206) The Hartwell Foundation NIH/NIDDK (R56DK124853)
368-OR: Activation of a Yap1-Dependent Mesenchymal Program Promotes ß-Cell Failure
Authors: MCKIMPSON WENDY , HOQUE NEHAN , SON JINSOOK , LEE APRIL Y. , ACCILI DOMENICO 
Published: May 2022

A critical contributor to the pathogenesis of type 2 diabetes is the failure of insulin-secreting β-cells due to loss of cell number or identity. However, the signaling pathways that trigger these events remain unclear. While β-cells are of endodermal origin, recent studies show endocrine cells that coexpress the mesenchymal marker vimentin in the pancreas with diabetes, although the functional features of these cells are not known. Here, we identify an epithelial-to-mesenchymal (EMT) -like program that is activated in islets of mice and humans with type 2 diabetes. Characteristics of this EMT-like program include increased protein and mRNA abundance of the EMT transcription factor Snail and the mesenchymal adhesion molecule N-cadherin. Lineage-tracing techniques demonstrate that this mesenchymal program is initiated in β-cells that become multi-hormonal, a hallmark of dysfunctional endocrine cells. Interestingly, EMT-like cells minimally express Aldh1a3, a marker of dedifferentiated β-cells. To determine the mechanism driving EMT-like activation in β-cells, we tested stressors that phenocopy the effects of diabetes in islets. Treatment of islets with mitochondrial decouplers as well as oxidative stress increased expression of EMT markers. The transcription factor Yap1 is a known inducer of EMT. While Yap1 is expressed at minimal levels in β-cells, its abundance increased in db/db islets and in primary cells with impaired mitochondrial function. Importantly, chemical inhibition of Yap1 in db/db islets reversed activation of EMT-like factors. Yap1 inhibition also improved insulin secretion. Taken together, we found activation of an EMT-like program in the endocrine pancreas of mice and humans with type 2 diabetes. This program is dependent on increases in Yap1 due to oxidative stress and impaired mitochondrial function, and results in disrupted β-cell function.

Disclosure
W.Mckimpson: n/a. N.Hoque: None. J.Son: None. A.Y.Lee: None. D.Accili: Advisory Panel; Lilly Diabetes.

Funding
NIDDK (1K01DK121873)
369-OR: Defining the Role of RIPK3 in Beta Cells and the Mechanism of Its Activation by ER Stress
Authors: YANG LIU , YANG BINGYUAN , TONG XIN , DAI CHUNHUA , TANG ZIHAN , CHEN WENBIAO 
Published: May 2022

Receptor interacting protein kinase 3 (RIPK3) can activate and be activated by ER stress. Islet inflammation associated with underlying activation of RIPK3 is conserved from zebrafish to humans. However, the role of RIPK3 in mammalian beta cells and the mechanism by which ER stress activates RIPK3 are not well defined. To investigate the role of RIPK3 in beta cell function, we generated beta cell specific Ripk3 knockout mice (Ripk3ßKO) in C57BL/6J background with or without the Akita mutation (Ins2C96Y/+, which causes ER stress induced beta cell apoptosis and early onset diabetes) (Ripk3ßKOAkita) . We found that the glucose tolerance was worsened in Ripk3ßKO mice than wildtype controls after 16 weeks of high fat diet. Similarly, Ripk3ßKOAkita mice had higher random blood glucose, lower circulating insulin, and worse glucose tolerance than Akita C57BL/6J mice as early as 4 weeks of age. Unexpectedly, isolated islets from Ripk3ßKO and Ripk3ßKOAkita mice have comparable glucose stimulated insulin secretion (GSIS) and are more resilient to palmitate-induced lipotoxicity than their control counterparts. Similarly, pharmacological inhibition of RIPK3 protected human islets from palmitate-induced impairment of GSIS ex vivo. We are currently investigating the role of specific islet inflammation stages in the divergent GSIS phenotypes between in vivo and ex vivo. To investigate how ER stress activates RIPK3 in beta cells, we tested the effect of inhibiting classic UPR branches on RIPK3 activation in MIN6 cells, a mouse beta cell line. We found that IRE1a activation appears to play an essential role in RIPK3 activation. Interestingly, Ripk3 knockdown in MIN6 cells also decreased IRE1a levels. We next seek to define the mechanism underlying the crosstalk between RIPK3 and IRE1a signaling pathways.

Disclosure
L.Yang: None. B.Yang: None. X.Tong: None. C.Dai: None. Z.Tang: None. W.Chen: None.

Funding
National Institutes of Health (DK117147)