bluuebunny/crossref_metadata_2025_split huggingface dataset:
142-LB: Cognitive Screening among Older Adults with Diabetes
Authors: GUPTA DEEPASHREE , WILHALME HOLLY , SAUDER GABRIELA , MOIN TANNAZ 
Published: May 2022

Background: Diabetes affects approximately 24.4% of older adults in the United States and increases the risk of cognitive dysfunction and future dementia. Patients with cognitive dysfunction may find it harder to manage their diabetes and have more complications such as hypoglycemia. Yearly cognitive screening is recommended for all older adults with diabetes but may not be widely conducted.
Methods: We performed cognitive screening with the Mini-Cog test for a subset of patients with diabetes seen in Endocrine Clinics in one large healthcare system in 2020-21. We used a retrospective chart review to compare patient screening results between Endocrine (Endo) , Geriatric (Geri) and multidisciplinary Endo-Geriatric practices (Geri-Endo) . We used Chi-square tests to examine differences between clinic cohorts and a multivariate logistic regression to predict risk of cognitive dysfunction. We adjusted for age, ethnicity, sex, type of diabetes, Sulfonylurea (SU) use, ACE inhibitors (ACEI) / Angiotensin Receptor Blocker (ARB) use, smoking history, statin use, and BMI.
Findings: Among 198 patients screened (Endo=80, Geri=32, Geri-Endo=86) , those seen in Geri-endo (40.7%) and Geri (31.3%) were more likely to have lower Mini-COG scores (lower scores suggest worse cognition) as compared to those in Endo (6.3%) (p&lt;.0001) . Patients in Endo and Geri-Endo had longer duration of diabetes, were more likely to use insulin and had higher incidence of documented hypoglycemia. Higher age &gt; 75 years (p=0.0105) , previous CV events (p=0.0006) and BMI &lt;30 (p=0.0115) were significantly associated with lower Mini-COG scores.
Conclusion: Our study shows that cognitive screening can help identify older adults at risk for dementia in diabetes clinic. Patients with older age, previous CV events and lower BMI may be at higher risk for cognitive dysfunction. Older adults should be screened yearly for cognition as part of routine diabetes care.

Disclosure
D. Gupta: None. H. Wilhalme: None. G. Sauder: None. T. Moin: None.

Funding
NIH National Center for Advancing Translational Science (NCATS) , UCLA CTSI (UL1TR001881)
1440-P: Effects of Two Weight-Loss Medications, Liraglutide and Orlistat, on Liver Enzymes in Patients with Overweight or Obesity in a Real-World Setting
Authors: GORGOJO-MARTINEZ JUAN J. , CHICHARRO PABLO L. LOIS , FERREIRA-OCAMPO PABLO J. , DOEJO-MARCIALES SANDRA C. , BARRA-MALIG SOLANGE F. , ALMODOVAR-RUIZ FRANCISCA 
Published: May 2022

The aim of this analysis of the XENSOR study was to assess the effect of 2 weight-loss drugs on hepatic serum biomarkers in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification program. A retrospective real-world study (RWS) was conducted comparing the effect of orlistat 120 mg tid and liraglutide (up to 3 mg daily) on liver enzymes in adult patients with BMI &gt; 30 kg/m² (or &gt; 27 kg/m² with at least a weight-related comorbidity) . The primary endpoint was to assess in a multivariate model the differences in ALT and GGT reductions between both drugs over a median follow-up period of 7 months. A secondary endpoint was to study the impact of the amount of WL on both liver enzymes. 400 patients in the group of orlistat (BMI 41.4 kg/m2, ALT 30.1 U/L, GGT 35.7 U/L) , and 100 in the group of liraglutide (BMI 39.7 kg/m2, ALT 27.3 U/L, GGT 29.1 U/L) , were included. WL with liraglutide (−7.7 kg) was significantly greater in comparison with orlistat (−3.3 kg) , p &lt;0.0001. Treatment with both drugs significantly reduced ALT (orlistat −3.8 U/L; liraglutide −5.7 U/L, both p&lt;0.05) . ALT reduction was significantly higher with liraglutide vs. orlistat (adjusted mean difference −3.4 U/L (95% CI −6.5 to −0.2 U/L) . A significant decrease in GGT levels was observed with liraglutide (−5.8 U/L, p&lt;0.0001) , but not with orlistat. Adjusted mean differences in GGT changes between both drugs were not statistically significant. 46% of patients with high ALT levels lowered this enzyme into the normal range at the end of the follow-up, without significant differences between both drugs. When patients were split into 3 groups according to their WL (&lt;5%, 5-10% and &gt;10%) , ALT and GGT reductions were significantly higher in patients with WL&gt;10%.
In summary, in this RWS ALT reductions were significantly greater with liraglutide in comparison with orlistat. The effects of both drugs on ALT and GGT were higher in those patients with clinically relevant WL (&gt;10%) .

Disclosure
J.J.Gorgojo-martinez: Consultant; Mundipharma, Research Support; Novo Nordisk, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk. P.L.Lois chicharro: None. P.J.Ferreira-ocampo: None. S.C.Doejo-marciales: None. S.F.Barra-malig: None. F.Almodovar-ruiz: None.
1451-P: Peri-Islet Fibrosis in Cystic Fibrosis Is Associated with Altered Alpha-Cell Phenotype
Authors: KATTNER NICOLE , AL-SELWI YARA , TINIAKOS DINA , KLÖPPEL GÜNTER , SHAW JAMES A. 
Published: May 2022

Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator mutations leading to impaired epithelial cell anion transport and thickened pancreatic exocrine secretions. CF-related diabetes commonly ensues through impact of pancreatic exocrine pathology on islet cell mass and function although specific mechanisms remain unclear. Paraffin-embedded blocks obtained post mortem from pancreatic body in 9 donors with CF (6 (67%) male; age: 0-27 years) were studied. Following haematoxylin and eosin staining, CF changes were scored as early, advanced or end-stage and islet microenvironment was evaluated for presence of surrounding fibrosis and adipocyte replacement. Four donors were categorised as ‘early’ pathology with 0 (1) % (median (IQR)) of islets surrounded by uninterrupted fibrosis and 0 (0) % by adipocyte replacement; 1 donor was categorised as ‘advanced’ with 100% fibrosis, 0% adipocyte replacement; and 4 donors were categorised as ‘end-stage’ with 65 (46) % fibrosis, 12 (32) % adipocyte replacement. Presence of glucagon/vimentin co-expressing cells was demonstrated by immunofluorescence staining / confocal microscopy in 1 (25%) donor with ‘early’ CF pathology and in all with more advanced exocrine changes. All islets with altered alpha-cell phenotype had peri-islet fibrosis. In pancreata with &lt;50% fibrosis (11±17% (mean±SD) ; n=6) altered alpha-cell phenotype was seen in 11±14% of islets vs. pancreata with &gt;50% fibrosis (93±7%; n=3) with altered alpha-cell phenotype in 65±10% islets (p&lt;0.001) . Analysis of a chronic pancreatitis resection with incrementally increasing fibrosis from head to tail showed parallel increase in islet proportion with altered alpha-cell phenotype (head: 28%; body: 80%; tail: 78%) . We have demonstrated that peri-islet fibrosis is associated with aberrant islet glucagon/vimentin co-expression providing further evidence for exocrine-endocrine signalling in human pancreatic pathology.

Disclosure
N.Kattner: None. Y.Al-selwi: None. D.Tiniakos: None. G.Klöppel: None. J.A.Shaw: None.

Funding
Cystic Fibrosis Trust (SRC 019)
1474-P: Testosterone Amplifies Glucose-Stimulated Insulin Secretion from Male ß-Cells via Soluble Adenylate Cyclase
Authors: QADIR MIRZA MUHAMMAD FAHD , XU WEIWEI , NASTESKA DANIELA , BHONDELEY MANIKA , MOTA DE SA PAULA , EVANS CHARLES R. , BUCK JOCHEN , LEVIN LONNY , BURANT CHARLES , HODSON DAVID , MAUVAIS-JARVIS FRANCK 
Published: May 2022

Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS) , leading to hypoinsulinemia and hyperglycemia. We showed that dihydrotestosterone (DHT) activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of islet-derived and exogenous GLP-1 via GLP-1R in mouse and human islets. Using electron microscopy, we observe that DHT increases the size of granules and the frequency of multivesicular granules, suggesting that DHT promotes multivesicular exocytosis. Using live β cell models expressing organelle-specific cAMP sensors and novel allosteric inhibitors in human islets, we show that DHT enhances the ability of GLP-1 to produce cAMP at the plasma membrane and endosomes and enhances islet GSIS via the bicarbonate (HCO3 -) sensor, soluble adenylate cyclase (sAC) . The end-products of glucose metabolism in the TCA cycle are CO2 and H2O, which is followed by rapid conversion of CO2 to HCO3 - and H+ by carbonic anhydrase (CA) . Therefore, CO2 production is translated to HCO3 - and specifically sensed by sAC. Bioenergetics analysis of DHT-stimulated respiration in mouse islets using a Seahorse Analyser revealed that DHT decreases glycolytic acidification and increases mitochondrial acidification (H+ efflux rate) , suggesting that DHT increases mitochondrial production of CO2 followed by conversion to HCO3 - and H+, allowing HCO3 - to stimulate sAC. We discuss experiments of single-cell transcriptomics, proteomics and metabolomics dissecting the impact of DHT on human islets glycolysis and mitochondrial CO2 production. Consistent with DHT increasing production of CO2 followed by conversion to HCO3 - by CA and activation of sAC, in cultured human male islets, the CA inhibitor acetazolamide blunted DHT-enhancement of GSIS. Together these experiments provide novel insights into the role of DHT action via an extranuclear AR in enhancing GSIS.

Disclosure
M.Qadir: None. D.Hodson: Other Relationship; Celtarys Research. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical. W.Xu: None. D.Nasteska: None. M.Bhondeley: None. P.Mota de sa: None. C.R.Evans: None. J.Buck: None. L.Levin: None. C.Burant: None.

Funding
National Institutes of Health (DK107444 and DK074970) U.S. Department of Veterans Affairs Merit Award (BX003725)
15-OR: Mitochondrial NRF2 in ß-cell Oxidative Stress Response
Authors: NOVAK ALISSA , CROWDER JUSTIN , MARASCO MICHELLE , LINNEMANN AMELIA K. 
Published: May 2022

β-cells are highly metabolic and vulnerable to a variety of exogenous stressors, including excess glucose and proinflammatory cytokines. Many of these stressors elicit the accumulation of reactive oxygen species (ROS) , which can cause oxidative damage and lead to cell death. To restore homeostasis in the face of accumulating ROS, all cells, including β-cells, are equipped with adaptive stress response mechanisms such as the antioxidant response and autophagy. The antioxidant response is primarily driven by nuclear translocation of the transcription factor, NRF2. However, recently we observed a pool of NRF2 in the mitochondria that is associated with both the antioxidant response and a selective form of autophagy, known as mitophagy. We therefore hypothesized that NRF2 mediates coupling of mitophagy with the antioxidant response in the β-cell and is essential for restoration of β-cell homeostasis under conditions of increased ROS. We first asked whether loss of murine NRF2 was associated with increased susceptibility to β-cell damage induced by the toxic glucose analog, streptozotocin (STZ) . Multiple low dose STZ injections (45mg/kg for 5 consecutive days) rendered whole-body NRF2 knockout mice diabetic more quickly than wild type controls. To study the role of β-cell NRF2 in autophagy/antioxidant response coupling, we then generated a β-cell specific NRF2 knockout mouse (NRF2Δβ) by breeding NRF2 floxed mice with mice bearing the Ins1Cre/wt allele. NRF2Δβ mice appear to be phenotypically normal until at least 20 weeks of age and do not develop spontaneous diabetes. We then set out to determine how loss of β-cell NRF2 affects the mitochondria by both immunofluorescence analysis and transmission electron microscopy of isolated pancreata. We observed rounded β-cell mitochondrial morphology in the absence of NRF2. Collectively, our data are consistent with a role for NRF2 in β-cell mitochondrial function and suggest that NRF2 is required for proper response to β-cell damage.

Disclosure
A.Novak: n/a. J.Crowder: None. M.Marasco: Other Relationship; Eli Lilly and Company. A.K.Linnemann: Consultant; Janssen Research & Development, LLC.

Funding
NIDDK (R01DK124380)
159-LB: The Lipidomic Signature of Prediabetes among the Oldest Old—The Long Life Family Study
Authors: MILJKOVIC IVA , CVEJKUS RYAN , AN PING , THYAGARAJAN BHARAT , MENGEL-FROM JONAS , FEITOSA MARY , BENBOURENANE ANISA N. , ZMUDA JOSEPH M. 
Published: May 2022

The epidemiology of prediabetes and its metabolomic features remain poorly characterized in the oldest old. Therefore, we characterized the serum lipidome in 635 nonagenarians and centenarians without type 2 diabetes (T2D) from the Long Life Family Study, a multicenter study of 583 families with a clustering of exceptional longevity. Despite a low T2D prevalence and incidence in the LLFS cohort, 361 (56.9%) of participants aged 90+ years had prediabetes at study entry based on either glycated hemoglobin or fasting serum glucose levels. We used LC/MS to initially assess 193 lipid metabolites in fasting serum in those with and without prediabetes. We tested the association of log transformed lipid metabolites with prediabetes using logistic regression with the Benjamini-Hochberg false-discovery rate method (FDR&lt;0.05) , while adjusting for age, sex, fasting time, field center, and familial relatedness. 17 out of 193 annotated lipid metabolites were associated with prevalent prediabetes, with the strongest association found for phosphatidylethanolamine (PE 40:7) , which remained significant after additional adjustment for BMI (odds ratio (OR) =2.83; 95% confidence interval (CI) : 1.7-4.7) . Phosphatidylethanolamine might have proinflammatory properties and act as a positive modulator of membrane disruption induced by islet amyloid polypeptide, an amyloidogenic protein involved in T2D. Our data suggest that among the oldest old with exceptional longevity prediabetes burden is high, and that the phosphatidylethanolamine pathway might have an important role in the development of prediabetes. Future untargeted metabolomic analyses will investigate potential biomarkers that predict the transition from prediabetes to diabetes among the oldest old in this unique family study of healthy aging and exceptional longevity.

Disclosure
I. Miljkovic: None. R. Cvejkus: None. P. An: None. B. Thyagarajan: n/a. J. Mengel-from: None. M. Feitosa: None. A. N. Benbourenane: None. J. M. Zmuda: None.

Funding
National Institute of Health (U01AG023746)
159-OR: Endocrine and Metabolic Counterregulation to Standardized Postprandial Hypoglycemia after Bariatric Surgery
Authors: TRIPYLA AFRODITI , HERZIG DAVID , BRANCHAT GEMMA REVERTER , PAVAN JACOPO , SCHIAVON MICHELE , EUGSTER PHILIPPE J. , GROUZMANN ERIC , NAKAS CHRISTOS T. , VALÉRIE SAUVINET , ZEHETNER JOERG , GIACHINO DANIEL , DEL FAVERO SIMONE , THOMAS ANDREAS , THEVIS MARIO , MAN CHIARA DALLA , BALLY LIA 
Published: May 2022

Aim: To compare endocrine and metabolic counterregulation to postprandial hypoglycemia in patients with postbariatric hypoglycemia (PBH) after gastric bypass (GB) vs. surgical and non-surgical controls.
Methods: Thirty-two adults (age 42.9±12.8 years, 13% male, BMI 28.2±4.3kg/m2) of 4 matched groups (PBH patients, GB, sleeve gastrectomy [SG] and non-surgical controls [CON]) ingested 15g glucose with subsequent induction of hypoglycemia (target 2.5mM) at t150-170 min using a constant insulin infusion with controller-guided iv dextrose adjustment. Primary outcome was mean glucagon during hypoglycemia (t150-170) . Further outcomes were responses of catecholamines, cortisol, growth hormone, pancreatic polypeptide (PP) , glucagon-like peptide 1, endogenous glucose production (EGP) and exogenous insulin. Values are shown as mean±SD.
Results: Plasma glucose and insulin at t150-170 were 2.6±0.2mM and 891±382pM across all groups. Glucagon was significantly lower in all surgical groups (PBH: 12.0±8.2pM, GB: 13.4±5.7pM and SG: 11.0±6.8pM vs. CON: 23.0±6.2pM, p=0.005) . PP was significantly lower in PBH vs. CON (28.1±49.6pM vs. 146.0±93.5pM, p=0.01) . EGP did not differ significantly between groups, nor did any other hormones.
Conclusion: Our results suggest diminished glucagon response to postprandial hypoglycemia after GB and SG compared to CON, with additionally lower PP values in PBH.

Disclosure
A.Tripyla: None. J.Zehetner: None. D.Giachino: None. S.Del favero: Research Support; Dexcom, Inc. A.Thomas: None. M.Thevis: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L.Bally: None. D.Herzig: None. G.Reverter branchat: Employee; Fresenius Medical Care. J.Pavan: None. M.Schiavon: None. P.J.Eugster: None. E.Grouzmann: None. C.T.Nakas: None. S.Valérie: None.

Funding
Swiss National Science Foundation (PCEGP3_186978)
191-LB: Influenza Replication Dependent on Host Cell Pulmonary Metabolism
Authors: ROCHOWSKI MATTHEW , ALLEN SHAWN M.F. , CAMPOLO ALLISON , LACOMBE VERONIQUE 
Published: May 2022

Diabetes is an independent risk factor for severe respiratory infections, including influenza (IAV) . We hypothesize that hyperglycemia predisposes diabetic subjects to excess glucose in the airway, allowing for greater IAV replication. To test this hypothesis, type 1 (T1Dx) and type 2 (T2Dx) diabetic mouse models were intranasally infected with influenza. Subsets of T1Dx and T2Dx mice were treated with insulin or metformin, respectively, to restore euglycemia. Glucose concentrations of the bronchoalveolar lavage fluid (BALF) were measured with a glucose oxidase assay. Human bronchial epithelial cells (HBECs) were incubated with varying glucose concentrations, 2-deoxyglucose, AMPK modulators, or insulin, then infected. Viral loads were determined by immunofluorescence and/or qrtPCR for the viral protein hemagglutinin. In vivo, diabetic and infected mice demonstrated increased glucose concentrations in BALF. Viral load was significantly greater in lung homogenates of both T1Dx and T2Dx mice, which was rescued by insulin and metformin treatment. In vitro, HBECs incubated in higher [glucose] had a significantly greater percentage of cells infected than those incubated in normal [glucose]. Conversely, cells treated with 2-deoxyglucose demonstrated reduced IAV replication. Activation of glycolysis using Metformin or AICAR (i.e. AMPK activators) increased IAV replication in a time-dependent manner, while inhibition of AMPK decreased IAV replication. Finally, insulin treatment modulated IAV replication in a similar time-dependent manner. These novel findings suggest that: 1) hyperglycemia increases BALF [glucose] and 2) influenza viral replication is dependent on host-cell glycolysis. Better understanding of the mechanisms altering glucose metabolism during IAV infection may lead to the discovery of novel therapeutic targets for diabetic patients infected with IAV.

Disclosure
M. Rochowski: None. S. M. F. Allen: None. A. Campolo: Employee; Alcon Research, LLC. V. Lacombe: None.

Funding
Centers of Biomedical Research Excellence
204-OR: The Chd4 Helicase Modulates ß-Cell Function In Vivo
Authors: DAVIDSON REBECCA K. , CASEY NOLAN , KANOJIA SUKRATI , SPAETH JASON 
Published: May 2022

During diabetes progression, a subset of failing β-cells incurs a loss of transcription factors (TFs) such as Pdx1, which drives expression of numerous β-cell functional genes including Ins2, MafA, and Slc2a2. Like other TFs, Pdx1 requires the recruitment of transcriptional coregulators to modulate its transcriptional activity. It has been established that the Pdx1-bound Swi/Snf complex plays a critical role in maintaining β-cell function in part by recruiting Pdx1 to the insulin gene and facilitating its transcription. Furthermore, interactions between Pdx1 and the Swi/Snf ATPase subunit Brg1 are reduced in type 2 diabetes (T2D) β-cells. Recently, through an IP-Mass Spec approach, Pdx1 has been shown to interact with numerous other coregulatory complexes, including the Chd4 ATPase subunit of the Nucleosome Remodeling and Deacetylase complex. Here, we confirmed Pdx1 and Chd4 interact in mouse and human β-cell lines and primary β-cells using co-immunoprecipitation and proximity ligation assays (PLA) . Tissue harvested from mice injected with glucose had more β-cell nuclei containing multiple PLA signals than tissue from fasted mice. Conversely, tissue from high-fat diet mice and T2D human donors had fewer β-cell nuclei containing multiple PLA signals than tissue from control mice and nondiabetes human donors. To investigate the role of Chd4 on mature β-cell function, we generated a tamoxifen inducible, β-cell-specific Chd4 knockout mouse model (Chd4 Δβ ) . Four weeks following Chd4 removal, Chd4 Δβ mutants were glucose intolerant and had elevated ad libitum fed blood glucose levels and impaired insulin secretion from isolated islets. Bulk mRNA-sequencing from flow-sorted lineage labeled Chd4Δβ β-cells identified 1093 upregulated genes (eg Adcy1 and Rapgef3) and 438 downregulated genes (eg MafA, Robo2, and Slc2a2) . Future efforts are focused on defining the mechanisms by which Chd4 controls gene expression in the β-cell, with a current focus on how Chd4 modulates chromatin accessibility and TF recruitment.

Disclosure
R.K.Davidson: None. N.Casey: None. S.Kanojia: None. J.Spaeth: None.

Funding
National Institutes of Health (K01DK115633) Showalter Trust Award
219-OR: Intranasal Insulin Enhanced Resting-State Functional Connectivity of Medio-Prefrontal Cortex in Type 2 Diabetes: A Substudy of the Memory Advancement with Type 2 Diabetes (MemAID) Randomized Control Trial
Authors: ZHANG ZONGPAI , NOVAK VERA , NOVAK PETER , MANTZOROS CHRISTOS , NGO LONG H. , LIOUTAS VASILEIOS , DAI WEIYING 
Published: May 2022

Type 2 diabetes mellitus (T2DM) is associated with impairment of resting-state functional connectivity (rsFC) and cognition. Intranasal insulin (INI) has emerged as potential treatment for T2DM-related cognitive decline. INI treatment has increased perfusion and low-frequency fluctuations in medio-prefrontal cortex (mPFC) . We aimed to evaluate the effect of INI treatment on mPFC rsFC.MemAIDs trial consisted of 24-week of treatment with 40 IU of intranasal insulin (Novolin® R, off label use) or placebo (sterile saline) once daily and 24-week follow-up period. Of 244 randomized participants (115 T2DM and 129 controls, &gt; 50 years old) , T2DM participants (eight INI, three placebo, &gt; 50 years old) completed the baseline and end-of-treatment blood oxygen level dependent (BOLD) fMRI scans.INI treatment increased resting state mPFC-postcentral rsFC (p=0.005) and decreased mPFC-cerebellum rsFC (p&lt;0.001) . The mPFC rsFC changes after INI treatment were different from those from placebo (Figure 1) .INI treatment can modulate resting state connectivity between pre-frontal and sensorimotor cortex and cerebellum, indicating its potential effects on decision making and goal-oriented behaviors. These findings warrant further investigation.

Disclosure
Z.Zhang: None. V.Novak: None. P.Novak: Stock/Shareholder; Moderna, Inc., Novavax, Pfizer Inc., Prothena. C.Mantzoros: Advisory Panel; Novo Nordisk. L.H.Ngo: None. V.Lioutas: None. W.Dai: None.

Funding
Funded by NIH-NIDDK (1R01DK103902) , FDA (IND#107690) , Novo Nordisk, Inc. (ISS-001063) , Medtronic Inc. (NERP15-0310) and registered on www.clinicaltrials.gov (NCT02415556.)