bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT052 Prolonged Nursing Augments Short Chain Fatty Acid Levels And Leads To Amelioration Of Type 1 Diabetes
Authors: Imtiaz rafiqi Shafiya , Zahid Zeeshan , Lamendella Regina , aghogho olomukoro , Gionfriddo Emanuela , Tao Yang , Jaume Juan C , Imam Shahnawaz 
Published: October 2023

Abstract
Disclosure: S. rafiqi: None. Z. Zahid: None. R. Lamendella: None. O. aghogho: None. E. Gionfriddo: None. Y. Tao: None. J.C. Jaume: None. S. Imam: None.
The infant gut microbiome essentially shifts to a diverse and complex microbial system during weaning on separation from the mother and any perturbations lead to pathological imprinting with lifelong implications. Apart from breast milk, the microbiota of the skin and the intimate niche between mother and offspring contribute to gut microbial composition. Gut microbiome dysbiosis has been ascribed in the initiation and/or perpetuation of type 1 diabetes (T1D) in human and animal models. The gut microbial diversification is manifested as change in microbial metabolites particularly short-chain fatty acids (SCFAs) that have direct and indirect roles in immune regulation and epithelial barrier integrity. In this study, we try to decipher the role of prolonged nursing of newborn mice (upto 45 days) in the amelioration of type 1 diabetes in the context of changes in the gut microbiome and microbial metabolites. The humanized T1D mice used in the study spontaneously develop T1D at 3-4 weeks of age and are normally weaned at 21 days. Our results revealed mice subjected to prolonged nursing had consistent increments in levels of butyric acid from 60 to 150 days of age as compared to normal weaned mice, owing to a stable population of SCFA-producing bacteria developed during prolonged nursing with the mother. The normal weaned mice had a transient increase of butyric acid at 60 days but it didn’t sustain till the 150th day. The steady levels of butyrate in prolonged nursed mice exerted immunoregulatory roles which manifested in the enrichment of regulatory T cells (Tregs) in the intestinal mesenteric epithelium, payer’s patches, peri pancreatic lymph nodes (PLN), pancreas (PN) and spleen. The enrichment of Tregs leads to the regulation of diabetogenic Th1, Th17, and interferon gamma-producing CD8 T cells (cytotoxic lymphocytes, CTLs) at PLN, PN, and spleen. This increased immune tolerance was mirrored by improved glucose homeostasis and fasting blood glucose levels in the prolonged nursing group. Prolonged nursing preserved the pancreatic islet architecture and significantly maintained the increased number of islets per pancreas as observed in H&E sections. Also, it could be inferred from the results that SCFA’s promoted intestinal integrity with increased submucosal thickening, longer villi, and shallower crypts in the intestine of prolonged nursed mice. In conclusion, prolonged nursing accounts for gradual and steady gut microbiota succession in infants that augments SCFA production leading to enrichment of T regulatory cells and less aggressive diabetes.
Presentation: Saturday, June 17, 2023
SAT054 LivARKO Female Mice On 1-month Of High Fat Diet (HFD) Did Not Experience Insulin Resistance At The Level Of p-AKT In WAT
Authors: Frenchy Curry Dwight , Bolarinwa Elizabeth , O'neil Hill-Dick Johvan , Young Demarrius , Qutab Rabia , Carr Kiana , Falzarano Claire , Andrisse Stanley 
Published: October 2023

Abstract
Disclosure: D.F. Curry: None. E. Bolarinwa: None. J.O. Hill-Dick: None. D. Young: None. R. Qutab: None. K. Carr: None. C. Falzarano: None. S. Andrisse: None.
Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome affects up to 10% of reproductive-age adult women. The liver and white adipose tissue play an essential component in the metabolism of insulin and androgen signaling. Hyperandrogenism in females can increase predisposition to insulin resistance. Andrisse et al 2021 showed that deleting the liver androgen receptor (LivARKO) prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. The goal of this research was to determine if LivARKO prevents high fat diet (HFD) induced insulin resistance.It was hypothesized that (unlike HA-LivARKO) HFD LivARKO female mice would display impaired insulin action (lowered insulin-stimulated p-AKT) in white adipose tissue in comparison to the Control diet (CD) fed LivARKO female mice, suggesting that AR does not play a significant role in regulating HFD-induced insulin resistance. Female LivARKO mice were placed on two diets for 1 month: CD and HFD. The mice were then sacrificed. Half of the mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of the diets on insulin signaling. Western blots were used to determine protein expression in tissue from the WAT. BCA assays were used to standardize the protein concentration in each sample. Insulin action can be measured molecularly by examining p-AKT Serine 473 (positive regulator, Santa Cruz sc-514032) and p-IRS1 Serine 306 (negative regulator, Santa Cruz sc-33956). If p-AKT S473 levels increase in the presence of insulin, this indicates that insulin is likely functioning properly in the sample. Whereas if p-IRS1 S306 are elevated, this indicates malfunctioning insulin action or insulin resistance. Following a similar pattern as WT mice on a chow diet (White 2014, Fig. 4), insulin increased p-AKT in WAT of LivARKO female mice fed a CD for 1-month in comparison to LivARKO female mice not given insulin (basal). Following the pattern of WT mice on a HFD (White 2014), LivARKO female mice fed a HFD for 1-month, displayed a similar increase in insulin-stimulated p-AKT in the WAT compared to the Con-Ins group. p-IRS-1 was not detected in the WAT of LivARKO female mice fed a control diet or HFD. In conclusion, LivARKO female mice on 1-month of HFD were not experiencing insulin resistance at the level of p-AKT in WAT. Further studies in different energy storage tissues in this model are warranted.
Presentation: Saturday, June 17, 2023
SAT056 New-onset Autoimmune Diabetes After COVID-19 mRNA Vaccine: A Systematic Review
Authors: Laskova Anna , Syritsa Bohdan 
Published: October 2023

Abstract
Disclosure: A. Laskova: None. B. Syritsa: None.
Background: Vaccination against COVID-19 has become a great tool during the COVID-19 pandemic. Multiple studies have shown that vaccines are safe and effective. However, there have been reports of autoimmune diseases following the vaccination against COVID-19. One of the possible mechanisms is thought to be a reaction to adjuvants in the vaccine (ASIA syndrome). We present a systematic review of the cases of new-onset autoimmune diabetes after the COVID-19 mRNA vaccine. Methods: We included 10 patients from 6 case reports1-6 and 1 case series7 published before December 3, 2022. We analyzed demographics, results, and outcomes using descriptive statistics. Results: 60% were males, and 40% were females. The median age was 51.5 years. 70% received the BNT162b2 vaccine, 20% - the mRNA-1273 vaccine, 10% - an unnamed mRNA vaccine. 70% developed symptoms after the second dose of the vaccine. The onset was distributed from 1 week after the first dose to 8 weeks after the third dose. 30% had either personal or family history of autoimmune diseases. Among other 70%, 57% had HLA DRB1 and/or DQB1 alleles (unknown if HLA was tested in other patients). The disease manifested as diabetic ketoacidosis in 50% of the patients. Anti-GAD antibodies were elevated in 70% of the patients. 30% were weaned off insulin shortly after the diagnosis, meanwhile, the rest required insulin by the time of the articles’ writing. We noted that most of the patients who developed autoimmune diabetes after the COVID-19 vaccine had either personal or family history of autoimmune diseases or tested positive for certain pertinent HLA alleles. However, no causal relationship can be established based on the current cohort, and more research needs to be done.
References:
1. Jano M, Morioka T, Natsuki Y et al. New-onset type 1 diabetes after COVID-19 mRNA vaccination. Intern Med. 2022;61(8):1197-1200
2. Kobayashi T, Yakou F, Saburi M et al. New-onset atypical fulminant type 1 diabetes after COVID-19 vaccination: A case report. Clin Case Rep. 2022;10(10):e6473
3. Kshetree B, Lee J, Acharya S. COVID-19 Vaccine-induced rapid progression of prediabetes to ketosis-prone diabetes mellitus in an elderly male. Cureus. 2022;14(9): e28830
4. Patrizio A, Ferrari SM, Antonelli A et al. A case of Graves' disease and type 1 diabetes mellitus following SARS-CoV-2 vaccination. J Autoimmun. 2021;125:102738
5. Sasaki H, Itoh A, Watanabe Y et al. Newly developed type 1 diabetes after coronavirus disease 2019 vaccination: A case report. J Diabetes Investig. 2022;13(6):1105-1108
6. Sasaki K, Morioka T, Okada N et al. New-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination: A case report. J Diabetes Investig. 2022;13(7):1286-1289
7. Aydoğan B, Ünlütürk U, Cesur M. Type 1 diabetes mellitus following SARS-CoV-2 mRNA vaccination. Endocrine. 2022;78:42-46
Presentation: Saturday, June 17, 2023
SAT057 Hyperglycemic Emergencies Following Vaccination Against COVID-19: A Descriptive Analysis Of Crude Adverse Event Data
Authors: Laskova Anna , Syritsa Bohdan 
Published: October 2023

Abstract
Disclosure: A. Laskova: None. B. Syritsa: None.
Background: There have been case reports in the literature describing the onset of hyperglycemic emergencies after receiving the COVID-19 vaccine. One of the potential mechanisms includes hypercytokinemia leading to pancreatic damage [1]. We present a summary of cases reported to the vaccine adverse events reporting system (VAERS).
Objectives: To summarize the existent crude data about the frequency of hyperglycemic emergencies reported to the VAERS. Methods: We accessed the VAERS and searched for reports of hyperglycemic emergencies in patients who received vaccination against COVID-19 as of 12/30/2022. We manually reviewed reports and applied descriptive statistics. Results: We chose the symptoms “DIABETIC COMA; DIABETIC HYPERGLYCAEMIC COMA; DIABETIC HYPEROSMOLAR COMA; DIABETIC KETOACIDOSIS; DIABETIC KETOACIDOTIC HYPERGLYCAEMIC COMA; HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME; HYPERGLYCAEMIC UNCONSCIOUSNESS” as well as “COVID19 VACCINE”, and our search returned 455 reports. Among them, the keyword “DIABETIC KETOACIDOSIS” was used in 90% of reports, “HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME” - in 4% of reports. Pfizer-Biontech was the vaccine manufacturer in 62% of reports, Moderna - in 27%, Janssen - in 10%, and other manufacturers - in 1% of reports. In 42% of cases, the event developed after the first dose of the vaccine, 47% - after two doses, and 10% - after three doses. Males were affected in 46% of reports, females - in 54%. The onset of the symptoms was unknown in 15% of the cases. 38% of the remaining cases reported an onset within 7 days of the vaccine administration. 87% of events were categorized as “serious”. 79% of patients were hospitalized. Death was reported in 16% of cases. We reviewed the available records, and 11% of them contained no details. Among the others, 60% mentioned either history of diabetes or antidiabetic medications in the description part. About 5% of the reports contained the words “new diagnosis of diabetes” or “new-onset diabetes”. Conclusions: Our analysis of crude data reported to VAERS showed that the majority of the cases of hyperglycemic emergencies occurred in patients with a known history of diabetes. More than half of the cases occurred later than within 1 week of the vaccine administration. We would like to speculate that the later the onset is, the less likely it is associated with the vaccine. During the manual review of the records, we found that 5% of cases describe a potential new-onset diabetes event. Anyone can report to VAERS, and for any event, no causality has been established [2].
References:
1. Samuel SM, Varghese E, Triggle CR et al. COVID-19 Vaccines and Hyperglycemia-Is There a Need for Postvaccination Surveillance?. Vaccines (Basel). 2022;10(3):454.
2. https://vaers.hhs.gov/data/dataguide.html
Presentation: Saturday, June 17, 2023
SAT074 Induction Of Insulin Hypersecretion Uncovers Distinctions Between Adaptive And Maladaptive Endoplasmic Reticulum Stress Response In Beta Cells
Authors: Roy Gitanjali , dos Santos Karina Rodrigues , Kwakye Michael B , Tan Zhiyong , Johnson Travis S , Kalwat Michael A 
Published: October 2023

Abstract
Disclosure: G. Roy: None. K. Rodrigues dos Santos: None. M.B. Kwakye: None. Z. Tan: None. T.S. Johnson: None. M.A. Kalwat: None.
Pancreatic islet β-cells release insulin to maintain glucose homeostasis. β-cells must translate, package, and secrete large amounts of insulin. During this process the unfolded protein response of the endoplasmic reticulum (UPRER) is induced to maintain these functions. However, stimuli that force β-cell to secrete insulin at enhanced rates and for prolonged durations risk inducing the terminal UPRER and eventual apoptosis. In a chemical screen for insulin secretion modulators, we discovered SW016789 which caused hypersecretion of insulin and led to a transient induction of the UPRER, but not apoptosis. In contrast, SERCA2 ER Ca2+ pump inhibitor thapsigargin induces the terminal UPRER. We hypothesized that SW016789 can be used as a tool compound to discover genes involved in β-cell adaptation to hypersecretion-induced stress. We performed time course transcriptomics in MIN6 β-cells exposed to SW016789 (5 µM) or thapsigargin (100 nM) from 0-24 h. Unbiased analyses using a Dirichlet process Gaussian process (DPGP) method revealed clusters of genes temporally co-regulated and the genes within these clusters were distinct between SW016789 and thapsigargin treatments. In particular, after 6 h of SW016789-induced hypersecretion we found a highly induced cluster of genes (SW cluster 3) enriched in adaptive UPRER factors (e.g. Manf). Conversely, most of the thapsigargin-induced genes clustered at 24 h and were enriched for terminal UPRER factors (e.g. Txnip). Pathway analysis of SW cluster 3 indicated that genes involved in in regulation of mRNA methylation and ER-associated degradation were also induced by SW016789 sooner and with greater amplitude than by thapsigargin, suggesting distinct differences in the handling of protein translation and degradation. From the SW cluster 3 genes we selected proteins known to be ER-associated or secreted and generated stable transgenic or CRISPR knockout MIN6 β-cell lines for each. Our data suggest altered expression of these factors may impair glucose-stimulated insulin secretion responses and alter cell viability in presence or absence of ER stressors including cytokines, thapsigargin, and tunicamycin. In conclusion, we have successfully shown that pharmacological induction of insulin hypersecretion can induce a distinct transcriptional outcome from that of canonically-induced UPRER and that we can take advantage of this property to discover new β-cell regulatory pathways and targets. We envision this dataset as a resource for the secretory biology and islet biology communities.
Presentation: Saturday, June 17, 2023
SAT079 A Novel Variant In The Carboxyl Ester Lipase (CEL) Gene Causing MODY
Authors: Medavarapu chalapathi Rao , McNutt Markey 
Published: October 2023

Abstract
Disclosure: C.R. Medavarapu: None. M. McNutt: None.
Introduction: Maturity-onset diabetes of the young (MODY) is a group of autosomal dominantly inherited disorders of non-autoimmune diabetes mellitus. Here, we report a patient initially diagnosed with type 2 DM and later found to have carboxyl ester lipase (CEL)-MODY. Case: A 51 year-old female was diagnosed with DM at the age of 44 and initially categorized as having type 2 DM based on normal GAD-65 antibodies. The patient’s DM was well controlled on semaglutide. The patient, however, reported chronic diarrhea/steatorrhea and intermittent dull abdominal pain which was not associated with semaglutide. The patient continued to have GI symptoms despite stopping the semaglutide. Abdominal imaging was unremarkable with a normal-appearing pancreas. Interestingly, the patient's daughter had similar gastric inflammatory symptoms and multiple members of the family have early-onset DM. Due to this symptom complex and similar presentation in the family, an inflammatory pathologic syndrome was suspected. A monogenetic auto-inflammatory syndrome was also considered in differential and the whole exome was analyzed. Genetic testing identified a novel, likely pathogenic heterozygous variant in CEL(NM_001807.5): c.1875del. Pathogenic variants in CEL are associated with MODY, type VIII. Discussion: Single-base deletions in the CEL gene can cause exocrine and endocrine pancreatic dysfunction. Our patient presented with a novel c.1875del variant in CEL that has not been reported in the literature as causative of disease nor as a variant in the general population. This variant lies in the variable number of tandem repeats (VNTR)-containing exon 11 of CEL. Two other single nucleotide deletions in this exon were described in the original report of CEL-MODY. The c.1875del variant results in the deletion of one nucleotide at position c.1875 of the CEL gene, causing a frameshift in the protein reading frame. Loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay is expected. The c.1875del CEL variant is classified as likely pathogenic, and it correlated with our patient's clinical and biochemical findings. Typically, patients with CEL-MODY develop pancreatic exocrine dysfunction in early childhood and later develop DM in their 40s. A genetic diagnosis helps in determining the choice of treatment, managing associated complications, and the need for further genetic counseling for the family. Insulin is the most appropriate treatment in CEL-MODY; however, other anti-DM drugs can also be used as seen in our patient. The risk of DM complications from CEL-MODY is unknown but patients can develop pancreatic cysts and clinicians should watch for these complications. Our case highlights the need for high suspicion for possible CEL-MODY and considering genetic testing in the setting of coexistent endocrine and exocrine pancreatic insufficiency.
Presentation: Saturday, June 17, 2023
SAT081 Maturity Onset Diabetes Of The Young (MODY) Due To A New BLK Gene Mutation
Authors: Taha Doris , Thirunagari Rajeev , Adhikari Amita 
Published: October 2023

Abstract
Disclosure: D. Taha: None. R. Thirunagari: None. A. Adhikari: None.
Background: The BLK gene is a tyrosine protein kinase involved in cell proliferation and differentiation. It has been identified as a modulator of beta cell function and plays a role in the regulation of insulin synthesis and secretion. We describe the case of a patient presenting with prediabetes associated with a heterozygous c.1366 C&gt;T of the BLK gene. Case Report: We report a 10 year old Asian female who presented with a hemoglobin A1c (HbA1c) level of 6.1% (4.0-5.7), within prediabetes range. Her weight was 44 kg (Z score 1.34), height 148.2 cm (Z score 1.52) and BMI was 20 kg/m2 (85th percentile; Z score 1.06). She had no acanthosis nigricans by exam and she was at early Tanner stage 2 of puberty. Initial evaluation revealed normal C-Peptide level of 2.1 ng/mL (0.9-6.9), normal insulin level of 21.1 mcUnits/mL (3 - 25). She had normal complete blood count and comprehensive metabolic profile, and normal thyroid function tests. Glutamic acid decarboxylase (GAD65) antibodies and islet cell antibodies were negative. She had an oral glucose tolerance test which revealed a fasting glucose level of 101 mg/dL and a 2-hour glucose level of 158 mg/dL. Lipid profile was normal. She was advised regarding healthy lifestyle changes and her HbA1c level was stable. She was lost to follow-up until 16 years of age when she presented with irregular menstrual cycles and was diagnosed with polycystic ovary syndrome. Her HbA1c was elevated at 6.3% with a normal insulin level. Cortisol and thyroid function tests were normal. Pancreatic antibodies including GAD65, IA-2, insulin antibodies, islet cell antibodies, and zinc transporter 8 antibodies, were negative. C-peptide level was normal at 4.3 ng/mL (1.1-4.4). Family history was significant for patient’s father and paternal grandmother having diabetes and taking Metformin. Patient’s father was diagnosed with diabetes at 13 years of age. Maturity onset diabetes of the young (MODY) panel/ sequencing and deletion/duplication analysis was performed at GeneDx and revealed that she is heterozygous for a c.1366 C&gt;T; p.Arg456Cys (R456C) variant in exon 13 of the BLK gene. This variant has not been previously published as a pathogenic or benign variant to our knowledge. No additional variants were identified in any of the MODY genes on this panel (ABCC 8, APPL1, CEL, GCK, GLUD1, HADH, HNF1A, HNF 1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1). Conclusion: Variants of the BLK gene have been reported in association with autosomal dominant MODY, type 11. We report a pediatric patient presenting with MODY prediabetes associated with a heterozygous c.1366 C&gt;T; p.R456C variant in the BLK gene. To our knowledge, this variant has not been previously reported in MODY patients. We propose that this is a pathogenic variant and review this rare MODY form.
Presentation: Saturday, June 17, 2023