bluuebunny/crossref_metadata_2025_split huggingface dataset:
254-LB: Characterization of Ghrelin Receptor Expression in Mouse Islets Reveals Pancreatic Polypeptide Cells as a Key Ghrelin Target
Authors: GUPTA DEEPALI , MANI BHARATH K. , SHANKAR KRIPA , OSBORNE-LAWRENCE SHERRI , METZGER NATHAN , ZIGMAN JEFFREY M. 
Published: June 2020

Objective: While expression of the ghrelin receptor, GHSR (growth hormone secretagogue receptor), by pancreatic islets has been investigated, data regarding the specific islet cell types that express GHSR are inconsistent and incomplete. For instance, transcriptomic studies indicate marked GHSR expression by somatostatin (SST)-secreting delta cells vs. little to no GHSR expression by alpha cells and beta cells, which contrasts studies suggesting direct actions of ghrelin on GHSRs expressed by alpha cells and beta cells. Also, to our knowledge, GHSR expression by pancreatic polypeptide (PP) cells has not previously been directly investigated. The aims of this study were to determine GHSR expression within the four principal islet endocrine cell types and the effects of ghrelin on circulating PP.
Methods: Ghsr-IRES-Cre mice, which express Cre recombinase directed by the GHSR promoter, crossed to Cre-dependent ROSA26-YFP reporter mice were used to histologically identify GHSR expression in islets. Double and triple labeling for YFP-immunoreactivity (IR) with insulin-IR, glucagon-IR, SST-IR, and/or PP-IR was performed to determine GHSR co-expression with islet hormones. Pharmacological manipulations were used to examine in vivo effects of acyl-ghrelin on plasma PP.
Results: Eighty-five % of YFP-IR cells expressed PP-IR, 50% expressed SST-IR, and none expressed insulin-IR or glucagon-IR. GHSR antagonist raised plasma PP in overnight-fasted C57BL/6N mice. However, acyl-ghrelin administration had no effect on plasma PP in C57BL/6N mice.
Conclusions: These results suggest that within mouse pancreatic islets, GHSR expression occurs most abundantly in PP cells and that pharmacologic blockade of ghrelin action raises plasma PP.

Disclosure
D. Gupta: None. B.K. Mani: None. K. Shankar: None. S. Osborne-Lawrence: None. N. Metzger: None. J.M. Zigman: Stock/Shareholder; Self; Medtronic.

Funding
Diana and Richard C. Strauss Professorship in Biomedical Research; Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; Kent and Jodi Foster Distinguished Chair in Endocrinology; University of Texas Southwestern Medical Center (to J.M.Z.)
256-OR: Using Human Induced Pluripotent Stem Cell Derived Organoids to Identify New Pathologies in Patients with Pdx1 Mutations
Authors: KRISHNAMURTHY MANSA , BRODA TAYLOR R. , KECHELE DANIEL O. , ZHANG XINGHAO , PALERMO JOSEPH J. , COLLINS MARGARET H. , THOMAS INAS H. , HEIDER AMER , DAUBER ANDREW , WELLS JAMES 
Published: June 2020

Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1is essential for pancreatic development and beta cell function, its role in GI development and function is not fully understood. We identified a patient with a homozygous point mutation in PDX1 causing total loss of PDX1 protein resulting in pancreatic agenesis. We differentiated induced pluripotent stem cells from the patient into human antral gastric (HAGO) and intestinal (HIO) organoids as a novel diagnostic approach to identify new GI pathologies. Immunofluorescence staining revealed that portions of the PDX1-null HAGOs lost the gastric marker claudin18 and increased intestinal villin1 expression, signifying that regions of the antrum are converting to an intestinal phenotype. Similarly, PDX1-null HIOs lost the intestinal marker cadherin17 and increased claudin18, indicating that regions of the intestine are undergoing gastric metaplasia. Examination of functional markers revealed an increase in acid producing parietal cells, complete lack of gastrin producing endocrine cells in HAGOs, and an increase in gastric surface mucin in HIOs. These in vitro results were further validated using endoscopy biopsies from two patients with PDX1 mutations, which showed a similar disruption in gastric and intestinal identity. CRISPR/Cas9-mediated correction of the PDX1 mutation reversed the observed PDX1-null metaplasic phenotypes in HAGOs and HIOs and also allowed for the successful generation of pancreatic tissue indicating unambiguously that the PDX1 mutation is responsible for these pathologies. Based on these findings, these PDX1-null patients will have additional screening to monitor the progression of metaplasia into gastric and intestinal cancer. This study further demonstrates the utility of organoids in improving patient diagnoses and treatment.

Disclosure
M. Krishnamurthy: None. T.R. Broda: None. D.O. Kechele: None. X. Zhang: None. J.J. Palermo: None. M.H. Collins: None. I.H. Thomas: None. A. Heider: None. A. Dauber: None. J. Wells: None.

Funding
American Diabetes Association (1-19-PDF-036 to M.K.)
26-LB: Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease: A Multicenter, Randomized, Parallel Study
Authors: WANG XIANGYU , ZHANG QIAN , GUAN MEIPING , SHENG SHUYUE , MO WEI , ZOU MENGCHEN , LI JIMIN , BI JIANLU , TANG XIANYU , HE JIALI , XU GUGEN , LI PING , ZHANG HUIJIE , XUE YAOMING 
Published: June 2020

Aim: This trial aimed to assess the effects of exenatide, a GLP-1RA, on renal outcomes in patients with T2DM and DKD.
Methods: We performed a randomized, parallel study conducted in 4 general hospitals. T2DM patients with an eGFR≥30mL/min/1.73m2 and macroalbuminuria, defined as 24h-urinary albumin-creatinine ratio (UAER) &gt;0.3g/24h, were randomized 1:1 to receive exenatide twice daily plus glargine or lispro insulin plus glargine for 24 weeks. The primary outcome was percentage change in 24h-UAER after 24 weeks of intervention comparing to baseline measurement. The secondary outcomes included the percentage change in urinary ACR, change in 24h-UAER, ACR, HbA1c, FPG, body weight and blood pressure. The safety outcomes include rates of hypoglycemia, adverse events and change in eGFR during the follow up.
Results: Between March 2016 and April 2019, 92 patients were randomized and took at least one dose of study drug. The mean age of the participants was 56 years. At baseline, the median 24h-UAER was 1512.0 mg/24h (IQR 782.5-2818.0), and mean eGFR was 70.4 mL/min/1.73 m2 (SD 23.4). After 24 weeks, exenatide reduced the percentage change of the 24h-UAER (difference between groups was 29.7%, p=0.0255), the percentage change of ACR (difference between groups was 28.4%, p=0.0395) and the absolute change of ACR (difference between groups was 607.8 mg/g, p=0.0209) but had no significant difference on the absolute change of 24h-UAER than the control group. Meanwhile, the body weight declined by 1.3kg with exenatide (difference between groups was 2.7kg, p=0.0001). There was no difference between two groups on the change in HbA1c, FPG, blood pressure or eGFR. Comparing to the control group, lower frequency of hypoglycemia as well as more gastrointestinal adverse events were in intervention group.
Conclusions: Exenatide twice daily plus glargine for 24 weeks resulted in significant reduction of albuminuria in T2DM patients with DKD.

Disclosure
X. Wang: None. Q. Zhang: None. M. Guan: None. S. Sheng: None. W. Mo: None. M. Zou: None. J. Li: None. J. Bi: None. X. Tang: None. J. He: None. G. Xu: None. P. Li: None. H. Zhang: None. Y. Xue: None.
261-OR: CDK4-R24C Compensates for IRS2 Deficiency by Enhancing Beta-Cell Proliferation and Restoring Signaling through the AKT-Foxo1-PDX1 Pathway
Authors: STAMATERIS RACHEL E. , SHARMA ROHIT B. , GABLASKI BRIAN , RANE SUSHIL G. , ALONSO LAURA C. 
Published: June 2020

Expanding functional beta cell mass remains a prime goal of diabetes research. We previously demonstrated that IRS2 deficient mice have reduced islet expression of cyclin D2, and that overexpressing cyclin D2 rescues proliferation in IRS2 deficient beta cells in vitro. Since cyclin D2 partners with CDK4 to drive cell cycle progression, we hypothesized that an activated form of CDK4, CDK4-R24C (resistant to inhibition by Ink4A cell cycle inhibitors) might rescue the in vivo proliferation defect in IRS2 deficient mice. Mice heterozygous for both whole body Irs2 deletion and whole body Cdk4-R24C knock-in were mated, yielding 6 genotypes of interest: Irs2+/+; Cdk4-WT, Irs2+/+; Cdk4-R24C/WT, Irs2+/+; Cdk4-R24C/R24C, Irs2-/-; Cdk4-WT, Irs2-/-; Cdk4-R24C/WT, Irs2-/-; Cdk4-R24C/R24C. Two copies, but not one, of Cdk4-R24C completely rescued fasting and non-fasting blood glucose, glucose intolerance, and beta cell mass and proliferation, without rescuing peripheral insulin resistance. Interestingly, Irs2-/-; Cdk4-WT islets contained dedifferentiated (reduced PDX1, nuclear FOXO1, ALDH1A3+) beta cells, and this was completely reversed in Irs2-/-; Cdk4-R24C/R24C islets. An in vitro primary beta cell model of increased nuclear FOXO1 activity (short-term starvation) resulted in mRNA changes consistent with nuclear FOXO1 activity (including reduced Pdx1) and mimicked IRS2 deficiency in vivo. Intriguingly, overexpressing cell cycle activators CDK4 and cyclin D2 partially rescued the mRNA changes indicative of nuclear FOXO1 activity, while expressing an inhibitor (CDKN2A/p16) did not. Overexpression of CDK4 increased FOXO1 phosphorylation. We conclude that CDK4 may play additional roles outside of the cell cycle in beta cells, by activating the insulin signaling pathway downstream of IRS2 and exerting antidiabetic action by maintaining beta cell differentiation.

Disclosure
R.E. Stamateris: None. R.B. Sharma: None. B. Gablaski: None. S.G. Rane: None. L.C. Alonso: Consultant; Self; Fairbanks Pharmaceuticals Inc. Research Support; Self; American Diabetes Association.

Funding
American Diabetes Association (1-18-IBS-233 to L.C.A.)
265-OR: Identifying Adults at Risk of Unintentional Severe Hypoglycemia in Hospital Using Artificial Intelligence (RUSHH-AI)
Authors: FRALICK MICHAEL , DAI DAVID , POU-PROM CHLOE , VERMA AMOL A. , MAMDANI MUHAMMAD 
Published: June 2020

Background: Machine learning carries great promise to improve healthcare delivery. Clinical outcomes that are routinely and objectively measured, and have serious consequences that can be prevented, are ideal targets for prediction and intervention. Hypoglycemia, defined as a blood glucose less than 3.9 mmol/L (70 mg/dL), meets these criteria. The purpose of this study was to predict hypoglycemia using artificial intelligence models in patients hospitalized to general internal medicine (GIM) and cardiovascular surgery (CV) at a tertiary-care teaching hospital in Toronto, Ontario.
Methods: Models were built using routinely-collected clinical data from the hospital’s electronic health record. Models were trained using data from Jan 2013-Apr 2017, tested using data from Apr 2017-Mar 2018, and validated using held-out test data from Apr 2018-Mar 2019. Three models were generated using supervised machine learning: LASSO regression, gradient boosted trees, and a recurrent neural network. Each model included baseline patient data and time-varying data. Natural language processing was used to incorporate text data from physician and nursing notes.
Results: We included 8492 GIM admissions and 8044 CV admissions. The average age of patients was 68 years, 35% were women, the baseline creatinine was 90 μmol/L (1.0mg/dL) and the baseline A1C was 7%. Hypoglycemia occurred in 15% of GIM admissions and 13% of CV admissions. The area under the curve for the model in the held-out validation set was approximately 0.80 on the GIM ward and 0.82 on the CV ward. When the threshold for hypoglycemia was lowered to 2.9 mmol/L (52 mg/dL), similar results were observed. Among the patients at the highest decile of risk, the positive predictive value was approximately 50% and the sensitivity was 99%.
Conclusion: Using natural language processing and machine learning we were able to accurately identify patients at high risk of hypoglycemia in hospital.

Disclosure
M. Fralick: None. D. Dai: None. C. Pou-Prom: None. A.A. Verma: None. M. Mamdani: None.
273-OR: Comparative Effectiveness of Lifestyle Intervention on Fasting Plasma Glucose in Normal Weight vs. Overweight/Obese Adults with Prediabetes
Authors: SALMON MANDY K. , WRIGHT BRENDA S. , KRIDL TERRI L. , FAIRCLOTH GEORGE C. , SALMON RICHARD D. , GORDON NEIL F. 
Published: June 2020

Almost 1 in 5 U.S. adults with prediabetes have a normal BMI. It is hypothesized that such individuals develop diabetes through different pathophysiological mechanisms and that methods of prevention may differ in the absence of overweight/obesity. Normal BMI is an exclusion criterion for many diabetes prevention programs and scarce data are available on the effectiveness of lifestyle intervention in normal weight adults with prediabetes. In this study, we compared the effect of technology-enabled lifestyle health coaching (LHC) on fasting plasma glucose (FPG) in normal weight (BMI 18.5-24.9 kg/m2; n = 188), overweight (BMI 25.0-29.9 kg/m2; n = 495) and obese (BMI &gt;30.0 kg/m2; n = 1,214) adults with prediabetes. Subjects were 1,897 consecutive adults with prediabetes (FPG = 100-125 mg/dl and not taking antidiabetic medication) who completed a baseline and follow-up evaluation as part of an LHC program (mean follow-up = 145 days). LHC included 1-on-1 behaviorally-oriented coaching, predominantly via the telephone and Internet, on exercise, nutrition and weight management. BMI decreased significantly (p &lt;0.001) in the overweight (-0.6±1.1 kg/m2) and obese (-1.3±1.8 kg/m2) participants but was unchanged (0.0±1.5 kg/m2) in the normal weight participants. In contrast, weekly aerobic exercise increased (normal weight = 77±167 min/week increase; overweight = 98±191 min/week increase; and obese = 95±146 min/week increase) and FPG decreased (normal weight = -9±9 mg/dl decrease; overweight = -7±9 mg/dl decrease; and obese = -6±10 mg/dl decrease) significantly (p &lt;0.001) in all 3 groups (p &lt;0.05 for magnitude of decrease in FPG in normal weight versus obese participants). FPG was reduced to &lt;100 mg/dl in 62.4%, 51.7% and 43.6% of the normal weight, overweight and obese participants, respectively. These data suggest that LHC is at least as effective in managing FPG in normal weight adults with prediabetes versus those who are overweight/obese.

Disclosure
M.K. Salmon: Other Relationship; Self; INTERVENT, International, LLC. B.S. Wright: Stock/Shareholder; Self; INTERVENT International, LLC. T.L. Kridl: Employee; Self; INTERVENT International, LLC. G.C. Faircloth: Stock/Shareholder; Self; INTERVENT International, LLC. R.D. Salmon: Stock/Shareholder; Self; INTERVENT International, LLC. N.F. Gordon: Board Member; Self; PrevCan. Stock/Shareholder; Self; INTERVENT International.
279-OR: Cognition in Young Adults with Youth-Onset Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth Study
Authors: SHAPIRO ALLISON , DABELEA DANA , STAFFORD JEANETTE M. , DAGOSTINO RALPH , PIHOKER CATHERINE , LIESE ANGELA D. , SHAH AMY S. , BELLATORRE ANNA , LAWRENCE JEAN M. , HENKIN LEORA , WILKENING GRETA 
Published: June 2020

Poor cognition has been observed in children and adolescents with type 1 (T1D) and type 2 (T2D) diabetes. Differences in cognition between young adults with youth-onset T1D and T2D, however, have not been explored, nor is the effect of shared etiologic processes, e.g., poor glycemic control, on cognition fully understood. Using data from SEARCH for Diabetes in Youth, a multicenter, observational cohort study, we compared cognition between young adults with youth-onset T1D and T2D, testing whether glycemic control modified the relationship between diabetes type and cognition. Cognition was assessed via the NIH Toolbox Cognition Battery and age-corrected composite Fluid Cognition scores used. Glycemic control was estimated from repeated measures of HbA1c. Linear regression modeling was used to test the interaction effect of diabetes type and glycemic control on Fluid Cognition score while controlling for sex, race/ethnicity, waist-height ratio, duration of diabetes, depression, alcohol and drug use, any hypoglycemic episode in the past year, parental highest level of education, household income, and clinic site. The T2D group (n = 254) had significantly lower Fluid Cognition scores, compared to the T1D group (n = 953) (mean [SD] 84.7 [17.3] vs. 95.4 [16.8], p&lt;0.001). Glycemic control modified the relationship between diabetes type and Fluid Cognition scores (interaction p=0.16). Using the model’s interaction estimates, at a HbA1c of 6.5%, the T2D group demonstrated significantly lower Fluid Cognition scores, compared to the T1D group (β = -6.54, 95% CI: -11.52, -1.57, p=0.01). At a HbA1c of 9.5%, Fluid Cognition scores in the T2D group differed to a lesser extent from the T1D group (β = -3.61, 95% CI: -7.16, -0.06, p=0.05). Youth with T2D had poorer cognition then youth with T1D. This effect is more pronounced at lower HbA1c levels. Our findings suggest that factors unique to youth-onset T2D may impact cognition in this specific diabetes group, warranting further investigation.

Disclosure
A. Shapiro: None. D. Dabelea: None. J.M. Stafford: None. R. Dagostino: Consultant; Self; Amgen, AstraZeneca, Celgene, Daiichi Sankyo. C. Pihoker: None. A.D. Liese: None. A.S. Shah: None. A. Bellatorre: None. J.M. Lawrence: None. L. Henkin: None. G. Wilkening: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1UC4DK108173-01)
282-OR: The Association of Age of Onset of Type 2 Diabetes with Long-Term Risk of End Stage Kidney Disease: A National Registry Study
Authors: MORTON JEDIDIAH I. , LIEW DANNY , MCDONALD STEPHEN , SHAW JONATHAN E. , MAGLIANO DIANNA J. 
Published: June 2020

This study aimed to estimate the long-term risk of End-Stage Kidney Disease (ESKD) in type 2 diabetes. We included 1,113,201 people with type 2 diabetes registered on the Australian National Diabetes Services Scheme (NDSS) followed from 2002 until 2013. The NDSS was linked to the Australia and New Zealand Dialysis and Transplant Registry and the National Death Index to obtain incident renal replacement therapy (RRT) and death, respectively. Between 2002 and 2013, 7,592 NDSS registrants initiated RRT over 7,839,075 person-years of follow up. The incidence of RRT increased with increasing duration of diabetes. In the first 10-15 years after onset of diabetes, incidence of RRT was highest in those with older age at onset of diabetes. However, over longer durations of diabetes, the cumulative incidence of RRT became higher in those with younger onset diabetes. When “total” incidence of ESKD (RRT and deaths attributed to ESKD without RRT) was considered, the predicted lifetime risks of renal failure (until age 100) were 20.1%, 16.1%, 11.6%, 7.7%, 5.4%, and 4.2% in those with diabetes onset between ages 10-29, 30-39, 40-49, 50-59, 60-69, and 70-79, respectively. Thus, the long-term risk of ESKD in type 2 diabetes is high, which disproportionately affects those with younger-onset type 2 diabetes as they are more likely to survive to longer diabetes durations.

Disclosure
J.I. Morton: None. D. Liew: None. S. McDonald: None. J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. D.J. Magliano: None.

Funding
Australian Government Research Training Program (to J.I.M.); Monash University (to J.I.M.)
284-OR: Characterization of Cognitive Changes in Type 1 Diabetes of Extreme Duration by Retinal Neural Structure and Vasculature
Authors: WOLFSON EMILY , FICKWEILER WARD , SAMPANI KONSTANTINA , SHAH HETAL , AIELLO LLOYD P. , SUN JENNIFER , KING GEORGE L. 
Published: June 2020

The risk of cognitive dysfunction in aging populations with type 1 diabetes (T1D) may be similar to that of people with type 2 diabetes, but it has not been well-characterized clinically. In the Joslin Medalist Study, a cohort of people with ≥ 50 years of T1D, cognitive dysfunction was previously shown to correlate with cardiovascular disease (CVD) and proliferative diabetic retinopathy (PDR). In a Medalist subset (n=129), we extended these findings by assessing the relationships of cognitive changes and other complications with vascular abnormalities in the retina, a developmental extension of the central nervous system. Medalists were evaluated with validated cognitive tests to assess psychomotor speed (PS), immediate memory (IM), delayed memory (DM), working memory (WM), and executive function (EF). Retinal optical coherence tomography (OCT) and OCT angiography were performed to obtain neural retinal layer thickness and vascular density for the superficial (SCP) and deep (DCP) retinal capillary plexuses. CVD and PDR were associated with worse IM (p=0.03) and decline in PS (p=0.01), respectively, adjusting for age, A1c, BMI, triglycerides and hypertension. Thinning of the retinal outer nuclear layer (ONL) was associated with PDR (p=0.04), CVD (p=0.02), worse IM (p=0.05) and PS (p=0.01), adjusted for sex, diabetes duration, PDR and visual acuity. CVD, PDR and DM severity were associated with decreased DCP density (p=0.04, p=0.0004, and p=0.002, respectively). Decreased density of the SCP was associated with worse dominant hand PS (p=0.01), adjusted for PDR, T1D duration, and visual acuity.
In summary, cognitive decline in people with long duration of T1D is associated with PDR and CVD, which is supported by shared specific retinal vascular imaging abnormalities, suggesting a potential common pathogenesis underlying these complications in T1D.

Disclosure
E. Wolfson: None. W. Fickweiler: None. K. Sampani: None. H. Shah: None. L.P. Aiello: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; KalVista Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J. Sun: Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Inc., Novo Nordisk Inc., Optovue, Inc., Roche Pharma. Other Relationship; Self; Merck Foundation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Roche Pharma. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK036836, UL1RR025758-03, R24283, DK083957-01DP3, DK094333-01, T32DK007260); JDRF (17-2013-310)