bluuebunny/crossref_metadata_2025_split huggingface dataset:
246-LB: Neonatal Microbes Stimulate Beta-Cell Development
Authors: HILL JENNIFER H. , GUILLEMIN KAREN , MURTAUGH CHARLES L. , ROUND JUNE 
Published: May 2022

Newborns are exposed to environmental microbes that colonize the gut and increase in diversity during childhood to establish the resident microbiota. Concurrently, insulin-producing β-cells enter a postnatal window of proliferation and maturation. We found that germ-free animal models exhibit significant reductions in β-cell mass compared to their microbe-carrying counterparts, revealing a role for microbes in the establishment of these cells. By mining this unique source, we uncovered mechanisms of bacterially driven β-cell development.
Neonatal mice given strategically timed doses of broad-spectrum antibiotics incurred lasting reductions in β-cell mass, revealing a critical period of microbial influence on β-cells. Though reconstituted with a normal microbiota after antibiotic treatment, as adults these animals had reduced glucose tolerance and insulin secretion, and were more susceptible to metabolic disease. Treatment of neonatal mice with selective antibiotics resulted in variations in β-cell mass, blood glucose, and insulin levels, suggesting unique bacterial taxa or products influence these traits. Sequencing revealed that distinct microbes were enriched within each antibiotic treatment, allowing us to identify candidate bacterial taxa that we show are sufficient to stimulate β-cell expansion and restore insulin function. Further, we have identified multiple islet associated cell types that respond to these microbial cues. Previously, we identified the bacterial protein, BefA, that directly stimulates β-cell proliferation, and we anticipate finding additional bacterial modulators of this important tissue.
Reduced microbiota diversity can be predictive of diabetes in susceptible children, suggesting that early life microbial exposures are critical to prevent disease. Our results indicate loss of specific bacteria may result in reduced insulin production capacity prior to autoimmunity. If we can reinstate these lost microbes, we may be able to bolster the β-cell population against loss.

Disclosure
J. H. Hill: None. K. Guillemin: None. C. L. Murtaugh: None. J. Round: None.

Funding
Junior Diabetes Research Foundation (3-PDF-2019-747-A-N)
246-OR: Role of Skeletal Muscle Branched-Chain Amino Acid Metabolism in Exercise Training–Induced Insulin Sensitivity
Authors: PATAKY MARK W. , KUMAR ARATHI PRABHA , ROBINSON MATTHEW M. , KLAUS KATHERINE , DASARI SURENDRA , NAIR K. SREEKUMARAN 
Published: May 2022

Insulin sensitivity is enhanced by 3 months of either aerobic (high-intensity interval training, HIIT) or resistance exercise (RET) , but mechanisms leading to improved insulin sensitivity are not identical between modes of exercise. We sought to identify common predictors of exercise training-induced insulin sensitivity. Using RNAseq we found that branched chain amino acid (BCAA) and general amino acid metabolism were the only common pathways associated with enhanced insulin sensitivity by HIIT and RET in skeletal muscle. We explored the BCAA metabolism pathway and other amino acid metabolites as related to insulin sensitivity in response to HIIT and RET. Skeletal muscle and plasma were obtained from our previously published study which showed significantly enhanced insulin sensitivity following 12-weeks of either HIIT (n=19) or RET (n=18) . Immunoblotting was used to measure the abundance and phosphorylation of the key rate limiting enzyme in BCAA metabolism, branched chain ketoacid dehydrogenase (BCKDH) , in skeletal muscle. Liquid chromatography-mass spectrometry was used to measure amino acids and their metabolites before and after exercise training. Skeletal muscle BCKDH abundance and activity (indicated by reduced phosho/total BCKDH) were significantly increased (P&lt;0.05) by both HIIT and RET. HIIT significantly increased (P&lt;0.05) all three BCAAs (Ile +7.7 ± 2.2, Leu +18.9 ± 5.6, Val +24.5 ± 7.3 pmol/mg muscle) , as well as multiple other amino acids and metabolites in skeletal muscle. Although we did not detect an increase in amino acids or metabolites following RET in skeletal muscle, in plasma there was a significant increase (P&lt;0.05) in all three aromatic amino acids (Phe +5.1 ± 2.2, Trp +5.6 ± 2.5, Tyr +4.8 ± 1.7 µM) as well as Pro (13.0 ± 4.6 µM) , Ala (+29.3 ± 12.1 µM) , and Met (2.1 ± 0.5 µM) following RET. These results suggest activation of amino acid metabolism pathways, contributing to enhanced insulin sensitivity following different modes of exercise training.

Disclosure
M.W.Pataky: None. A.Prabha kumar: n/a. M.M.Robinson: Stock/Shareholder; GE Healthcare Systems. K.Klaus: None. S.Dasari: None. K.Nair: None.

Funding
National Institutes of Health (RAG09531) National Institutes of Health (T32 DK007352)
25-OR: Machine Learning for Early Detection of Nonresponders to Lifestyle Intervention for Prediabetes
Authors: FOPPIANI ANDREA , DE AMICIS RAMONA , LEONE ALESSANDRO , BERTOLI SIMONA , BATTEZZATI ALBERTO 
Published: May 2022

Introduction: Lifestyle intervention is the first-line treatment for prediabetes. More intensive intervention usually follows for those patients that fail to improve glycemia. We explored the possibility to early detect non-responders to lifestyle intervention from a single baseline evaluation.
Methods: The sample was composed of 738 pre-diabetic (fasting glucose 100-125 mg/dl) patients (median age 54 IQR 45-62, 57% female, median BMI 30.4 IQR 27.5, 34.2) , that were prescribed a lifestyle intervention, and were re-evaluated within 12 months. Lifestyle intervention consisted of a hypocaloric diet (based on resting energy expenditure measured by indirect calorimetry, with a Mediterranean pattern, tailored on patient habits) and WHO physical activity guidelines. The outcome was normalization of fasting glucose at follow-up (0: ≥100 mg/dl, 1: &lt;100 mg/dl) , with an historical failure rate of 44%. Baseline evaluation consisted of anthropometry, indirect calorimetry, abdominal fat ultrasound, laboratory exams, structured medical and nutritional interview, and psychological questionnaires, with a total of 114 predictors. Statistical and machine learning models were screened to select the best classifier for the outcome.
Results: The best model was a random forest model (a machine learning model) , with a validation-set accuracy of 72%, ROC AOC of 0.64, sensitivity of 55%, and specificity of 86%.
Discussion: The best developed model is able to identify more than half non-responders on the basis of a single baseline evaluation, while including few responders as false-positives. The model accuracy resulted higher than the historical rate of failure, so integrating the model suggestion in the clinical decision process should allow to more promptly treat future patients and improve the overall success rate. Machine learning models show potential in leveraging high-dimensional multi-domain routinely-collected clinical data to aid in clinical decision.

Disclosure
A.Foppiani: None. R.De amicis: None. A.Leone: None. S.Bertoli: None. A.Battezzati: None.
252-LB: GRK2 Participates in Islet Function and Glucose-Stimulated Insulin Secretory Responses
Authors: SNYDER JONATHAN W. , MONTGOMERY SARAH K. , DOLIBA NICOLAI M. , ROMAN JEFFREY , TIAN YUZHEN , SATO PRISCILA Y. , HOLLAND WILLIAM L. , HEE CHOI RAN 
Published: May 2022

Insulin deficiency is central to diabetes and diabetes-related cardiac dysfunction. GPCRs are known modulators of insulin secretion and a main pharmacological target in various tissues, including the heart. GPCR kinase 2 (GRK2) phosphorylates activated GPCRs, targeting receptors for recycling or degradation. Notably, we and others have shown that GRK2 can also localize to the cardiac mitochondria where it participates in substrate utilization, particularly in response to cellular stress. GRK2 is downregulated in the pancreas of diabetogenic mice, and we have shown that pancreatic loss of GRK2 impairs insulin secretion in normal and high fat diet. Mice with pancreatic-specific GRK2 KO showed glucose intolerance (AUC WT 8691 vs. KO 14766 mg/dl*min, n=22/group, p&lt;.05) due to significant decrease in insulin secretion following glucose administration (after 15 minutes WT 2.35 vs. KO 1.616 ng/ml, N=16-19/group, P&lt;.0001) without changes in islet size or cell distribution. Using a model of high fat diet, we observed an impairment in glucose-stimulated insulin release in pancreatic GRK2 KO animals when compared to control animals without significant changes in fasting insulin secretion or insulin sensitivity. To further dissect the role of islet GRK2 in α- or β-cells, we have constructed two novel mouse models of inducible cell type-specific GRK2 KO. Our preliminary studies reveal that β-cell GRK2 deficient animals are prone to glucose intolerance and decreased glucose-induced insulin secretion when exposed to high fat high sucrose diet. This suggests that GRK2 plays a role in islet adaptation to metabolic challenge. Further studies will delineate the mechanistic role of GRK2 in mediating metabolism and calcium influx in β-cells regulating insulin secretion, and subsequently the impact to the heart in the presence or absence of TAC. Our studies will provide new GRK2 mechanistic insight that could be explored as new pharmacological strategies to delay diabetes disease progression.

Disclosure
J. W. Snyder: None. S. K. Montgomery: None. N. M. Doliba: None. J. Roman: None. Y. Tian: None. P. Y. Sato: None. W. L. Holland: None. R. Choi: None.

Funding
National Institutes of Health (1R56HL149887) ; University of Pennsylvania Diabetes Research Center Pilot and Feasibility Grant (P30-DK019525) ; American Heart Association Scientist Development Grant (17SDG33660407)
254-OR: Glucose Response Patterns Based on 75g OGTTS during Pregnancy and Their Association with the Risk of Macrosomia: A Latent Class Analysis of TWO Cohort Studies
Authors: FRITSCHE LOUISE , HULMAN ADAM , PRYSTUPA KATSIARYNA , HENI MARTIN , BIRKENFELD ANDREAS L. , PETER ANDREAS , FRITSCHE ANDREAS , KUN ATTILA , TABAK ADAM , WAGNER ROBERT 
Published: May 2022

Background and Aims: People with different glucose response patterns during the 2-h oral glucose tolerance test (OGTT) have substantially different clinical characteristics and risk for long-term outcomes in the general population. We aimed to identify comparable glucose response patterns in pregnancy and their association with maternal and fetal outcomes.
Materials and Methods: We used latent class trajectory modelling to identify glucose response patterns using 5-point 75g OGTT in 470 pregnant women at 27.3±2.2 weeks of gestation. We assessed these classes and investigated pregnancy outcomes in an independent cohort of 7073 pregnant women with 3-point OGTTs.
Results: We identified five different glucose response patterns (classes) . Rate of gestational diabetes (GDM) was lowest in class 1 (&lt; 7%) and highest in class 5 (100%) for both cohorts. Class 3 was characterized by transient hyperinsulinemia at 30 minutes but the prevalence of GDM was only 25-36%. Compared to class 1, women in class 3 had an increased gestational weight gain (GWG, β=0.85 SE: 0.31kg, p=0.0065, adjusted for age, gestational age, pre-gestational BMI, GDM treatment and AUCGlucose) . New-borns in class 3 had the highest risk of macrosomia (OR 1.47 95% CI: [1.12, 1.93] vs. class 1) after adjustment for maternal age, parity and smoking, but this was attenuated by additional adjustment for pre-pregnancy BMI and GWG.
Conclusion: We found an easily identifiable group of pregnant women who have an increased risk of macrosomia without formally meeting GDM diagnosis. These women would most likely benefit from a therapy (e.g. nutritional counselling) aiming at preventing excessive glucose excursions and GWG.
Note: LF and AH contributed equally to this work.

Disclosure
L.Fritsche: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Hulman: None. K.Prystupa: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. A.L.Birkenfeld: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Kun: None. A.Tabak: Consultant; 77 Elektronika Kft., Boehringer Ingelheim International GmbH, Speaker's Bureau; 77 Elektronika Kft., AstraZeneca, Sanofi_aventis Zrt.

Funding
The PREG study is supported in part by a grant from the Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD)
257-LB: A Novel MODY-Associated Gain-of-Function Mutation in TALK-1 Leads to Islet Dysfunction and Glucose Intolerance
Authors: NAKHE ARYA Y. , DADI PRASANNA , ZABORSKA KAROLINA E. , JACOBSON DAVID 
Published: May 2022

The most islet-restricted and abundantly expressed K+ channel of the human ꞵ-cell, TALK-1, regulates electrical activity and glucose-stimulated insulin secretion (GSIS) . Recently we identified a gain-of-function (GOF) mutation near the pore domain of TALK-1 (Leu114Pro) that causes Maturity-Onset Diabetes of the Young (MODY) in an autosomal dominant manner, but only in a single family. To confirm TALK-1-Leu114Pro as the mutation that causes the MODY phenotype and investigate the impact of TALK-1 GOF on glucose homeostasis, a mouse model containing the TALK-1-Leu114Pro mutation was generated. Interestingly, mice with TALK-1-Leu114Pro mutation show neonatal lethality which may be due to alterations of islet hormone secretion during neonatal development (this was observed in heterozygous TALK-1-Leu114Pro C57BL/6J and homozygous TALK-1-Leu114Pro CD-1 (ICR) mice) . We first confirmed that TALK-1-Leu114Pro mutation resulted in a GOF in β-cell whole-cell K+ currents. On the ꞵ-cell plasma membrane the resulting TALK-1-Leu114Pro hyperpolarizing current blunted glucose-stimulated Ca2+ entry and subsequent Ca2+ oscillations, whereas on the endoplasmic reticulum membrane TALK-1-Leu114Pro enhanced IP3-induced Ca2+ release. TALK-1-Leu114Pro+/- islets also showed decreased GSIS and reduced plasma insulin levels in TALK-1-Leu114Pro+/- mice when compared to controls. TALK-1-Leu114Pro+/- mice exhibit a significant impairment in glucose homeostasis which is likely due to reduced islet Ca2+ influx and GSIS. However, TALK-1 activity in other islet cell types may also contribute to glucose dyshomeostasis in TALK-1-Leu114Pro+/- mice. For example, pancreatic α-cell area and islet glucagon secretion are increased TALK-1-Leu114Pro+/- mice. Taken together, these data prove that the MODY-associated TALK-1-Leu114Pro mutation disrupts glucose homeostasis and suggests that TALK-1 is an islet-restricted target for the treatment for diabetes.

Disclosure
A. Y. Nakhe: None. P. Dadi: None. K. E. Zaborska: None. D. Jacobson: None.
258-LB: ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic NOD Mice and Is Rapidly Upregulated by NF-kB in Pancreatic Beta Cells
Authors: MARTIN THOMAS , BURKE SUSAN , GHOSH SUJOY , KARLSTAD MICHAEL D. , COLLIER JASON 
Published: May 2022

Type 1 diabetes (T1D) is an autoimmune disease strongly associated with immune cell targeting of pancreatic β-cells, which ultimately produces insulin insufficiency. We identified the Icam1 gene and ICAM-1 protein, which facilitate interaction with immune cells, as elevated in female NOD mice relative to male mice. This observation is consistent with a greater frequency of diabetes onset in female mice in this well-established model of T1D. In addition, ICAM-1 protein abundance was greater in hyperglycemic female NOD compared with age-matched normoglycemic female NOD mice. Upon examining islet β-cell responses to immune cell-derived cytokines, we discovered that the Icam1 gene was rapidly (within 3h) and strongly (&gt; 20-fold) upregulated in mouse, rat, and human islets as well as 832/13 rat insulinoma cells in response to IL-1β (p &lt; 0.01) . Using chromatin immunoprecipitation (ChIP) assays, we identified rapid recruitment (within 30 minutes) of the p65 transcriptional subunit of NF-κB to κB genomic elements within the Icam1 gene promoter (3-fold; p &lt; 0.05 relative to isotype control) . ChIP assays also revealed elevated RNA polymerase II recruitment to the Icam1 gene promoter (within 30 min) in response to IL-1β (7-fold, p &lt; 0.05) . Finally, using single-cell RNA-Sequencing, we discovered that only a few clusters of β-cells expressed Icam1 at very low abundance in the basal (unstimulated) condition, while the majority of β-cell clusters in the IL-1β (3 h) stimulated condition presented with strong Icam1 positive (mRNA expressing) cells. Thus, we conclude that most, if not all, β-cells undergo rapid genetic reprogramming by IL-1β to enhance expression of the Icam1 gene and promote accumulation of the ICAM-1 protein. These findings illustrate the importance of pancreatic β-cell communication with the immune system and reveal inducible events at the β-cell level that are linked with onset and progression of T1D.

Disclosure
T. Martin: None. S. Burke: None. S. Ghosh: None. M. D. Karlstad: None. J. Collier: None.

Funding
National Institutes of Health (R03 AI151920-02)
266-OR: Dexamethasone-Induced Hyperglycemia in Nondiabetic Patients with COVID-19
Authors: RHOU YOON JI J. , HOR AMANDA , WANG MAWSON , WU YU-FANG , CHIPPS DAVID R. , CHEUNG N. WAH 
Published: May 2022

Background: Dexamethasone improves COVID-outcomes. Detailed glycemic profile for patients receiving dexamethasone for COVID-is lacking.
Methods: Our hospital recommends routine blood glucose monitoring for patients with COVID-receiving dexamethasone 6mg daily. Subjects without prior history of diabetes admitted in a non-critical care setting over a 1-month period were identified and evaluated. The primary outcome was hyperglycemia post-dexamethasone, defined as glucose ≥10mmol/L.
Results: Of 277 subjects (52% male, age 52±18 yrs, weight 90±26 kg, 7% with newly diagnosed diabetes [HbA1c ≥6.5%]) , hyperglycemia post-dexamethasone occurred in 51%, with peak glucose 12.4±2.3 (mean 2.2 tests/day) . Glucose excursions peaked 7-9 hours post-dexamethasone (figure) . Hyperglycemic subjects were older (58±17 vs. 45±7 yrs, p&lt;0.001) , had higher HbA1c (6.1±1.0 vs. 5.6±0.9%, p&lt;0.001) , higher initial venous glucose (6.7±1.7 vs. 6.0±1.5mmol/L, p&lt;0.001) , lower initial eGFR (80±18 vs. 84±15mL/min/m2, p=0.02) , higher initial CRP (969±640 vs. 791±558nmol/L, p=0.01) and greater mortality (7.7 vs. 1.5%, p=0.01) . Age, HbA1c and CRP were independent predictors of hyperglycemia.
Conclusions: Dexamethasone led to hyperglycemia in half of patients without prior diabetes admitted with COVID-19, with peak occurring 7-9 hours after dexamethasone. Older age, higher HbA1c and initial CRP predicted development of hyperglycemia.

Disclosure
Y.J.Rhou: None. A.Hor: None. M.Wang: None. Y.Wu: None. D.R.Chipps: None. N.Cheung: None.
267-OR: Diabetes, COVID-19, and All-Cause Mortality among People with Diabetes during the COVID-Pandemic in Minnesota: Population-Based Study
Authors: MCCOY ROZALINA G. , MULLAN AIDAN F. , JEFFERY MOLLY M. , BUCKS COLIN M. , CLEMENTS CASEY M. , CAMPBELL RONNA 
Published: May 2022

People with diabetes have been profoundly impacted by the COVID-pandemic. Diabetes and its comorbidities are strong risk factors for severe, including fatal, COVID-disease. People with diabetes may also have limited or delayed routine and non-emergent medical services, potentially increasing their risk of death from causes unrelated to COVID-19. Granular population-level data on rates, causes, and places (i.e. home vs. hospital) of death among people with diabetes during the COVID-pandemic is scarce. We examined Minnesota death certificates from 2020 (COVID-year) and 2018-20 (comparator years) among people with diabetes to compare changes in population-adjusted rates of diabetes-specific mortality (diabetes as a primary cause of death) , and all-cause and other disease-specific mortality (other primary causes with diabetes as a contributing cause of death) . We also assessed COVID-mortality (COVID-as a primary cause and diabetes as a contributing cause) . Analyses were adjusted for multiple comparisons using the false discovery rate correction. COVID-accounted for 246 deaths per 100,000 people with diabetes. There was no significant change in diabetes-specific mortality from 2018-20to 2020 (328 to 353 per 100,000; 2020 vs. 2018-20IRR 1.[95% CI 1.01-1.15]; p=0.08) . All-cause mortality among people with diabetes increased from 1,484 to 1,922 per 100,000 (IRR 1.30 [95% CI 1.26-1.33]; p&lt;0.001) , while non-COVID mortality among increased from 1,484 to 1,675 per 100,000 (IRR 1.13 [95% CI 1.10-1.16]; p&lt;0.001) . Deaths for cardiovascular diseases, cancers, and infectious diseases (not including COVID-19) also increased significantly, suggesting that people may have deferred care for these conditions with deadly consequences. Our findings underscore the need for uninterrupted comprehensive care for people living with diabetes to ensure that access for acute and chronic health concerns remains prioritized.

Disclosure
R.G.Mccoy: Consultant; Emmi. A.F.Mullan: None. M.M.Jeffery: Stock/Shareholder; Goodness Growth Holdings. C.M.Bucks: None. C.M.Clements: Consultant; Vail Scientific LLC. R.Campbell: Consultant; Bryn Pharma.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497)