bluuebunny/crossref_metadata_2025 huggingface dataset:
7313 Impact of Day of Admission on Hyperosmolar Hyperglycemic State Outcomes- a National Inpatient Sample Study
Authors: Neupane Binita , Karki Sunita , Bhandari Abhishek , Rajamani Krishnakumar
Published: October 2024

Disclosure: B. Neupane: None. S. Karki: None. A. Bhandari: None. K. Rajamani: None.

Introduction: Hospital mortality and results are significantly influenced by the day of admission (weekend vs. weekday). Studies have shown there is an increase in rates of adjusted hospital mortality in various diseases. Hyperosmolar hyperglycemic state (HHS), or Hyperosmotic hyperglycemic nonketotic state (HHNK), is a serious complication associated with type 2 diabetes mellitus. There have been limited studies on how the day of admission impacts outcomes in HHS. Objective:To investigate if there are differences in weekend vs. weekday admission with the diagnosis of HHS on hospital outcomes. Methods: Retrospective data on adult patients (age >18) with a primary diagnosis of HHS was taken between 2017 and 2020 using the National Inpatient Sample (NIS). The data analysis tool utilized was STATA. Diseases and outcome codes were selected using the International Classification of Diseases (ICD-10). Multivariate regression analysis was used to adjust for potential variables and determine the adjusted odds ratio (aOR). The Fisher exact test was used to compare proportions, while the student t-test was used to compare continuous variables. The study's primary outcome was mortality; additional secondary outcomes included length of stay (LOS), total hospitalization costs, acute coronary syndrome (ACS), septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and cerebrovascular accidents (CVA). Between 2017 and 2020, the mortality rates, LOS, and total hospitalization charges of weekend and weekday admissions were analyzed. Results:181,720 patients were diagnosed with HHS; 46,100(25.36%) were admitted on the weekend. Weekend admission had increased rates of ARF (aOR =1.2, 11.15% vs. 9.57%, p<0.01) and mechanical ventilation (aOR =1.24, 7.04% vs. 5.79%, p<0.01) compared to the weekday admission. There was no difference in the outcomes of the two groups in the mortality rate, mean LOS, total hospital charges, ACS, septic shock, pulmonary edema, AKI, CVA, and ARDS. In weekend admission, there was an increase in trends of LOS and total hospitalization charges, but there were no significant outcomes in the mortality rates over the years. In weekday admission, there was an increase in mortality rate trends, LOS, and total hospitalization charges. Conclusion: There was an increase in ARF and mechanical ventilation rates on weekends compared to weekday admission. When the two groups were compared, there were no significant outcomes in mortality rate, LOS, hospital charges, and other hospital outcomes. In both weekend and weekday admissions, there was an increase in trends of LOS and total hospitalization charges; however, only admissions during the weekday showed a significant increase in mortality rate trends.

Presentation: 6/1/2024
6607 Impact of Day of Admission on Hypoglycemia
Authors: Neupane Shila , Neupane Binita , Karki Sunita , Bhandari Abhishek , Quartuccio Michael
Published: October 2024

Disclosure: S. Neupane: None. B. Neupane: None. S. Karki: None. A. Bhandari: None. M. Quartuccio: None.

Introduction: The day of admission, whether on a weekend or a weekday, plays a pivotal role in hospital mortality and outcomes, with studies indicating increased adjusted hospital mortality rates across various diseases. Hypoglycemia, a common complication seen in hospitalized patients, has not been extensively studied concerning its association with weekend admissions. Objective of the study: This research aims to investigate and compare the impact of weekend versus weekday admissions on mortality rates, length of hospital stays, total hospitalization costs, and various other outcomes related to hypoglycemia. Methods: Utilizing the National Inpatient Sample (NIS) for the years 2017 through 2020, we conducted a retrospective cohort study of adult patients (age >18) diagnosed with hypoglycemia. Disease and outcome codes were determined through the International Classification of Diseases (ICD-10), and data analysis was performed using STATA. Multivariate regression analysis adjusted for potential variables while the student t-test and Fisher exact test were employed for comparing continuous and proportional variables, respectively. The primary outcome of the study was mortality, with secondary outcomes encompassing length of stay (LOS), total hospitalization costs, acute coronary syndrome (ACS), septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and cerebrovascular accidents (CVA). Results: Among 804,164 hypoglycemia patients, 199,474 were admitted on weekends. Significant findings included higher mortality rates (adjusted odds ratio (aOR) = 1.08, 10.58% vs. 9.81%, p < 0.001), reduced mean LOS (adjusted mean difference = -0.32, 6.94 days vs. 7.3 days, p < 0.001), and lower total hospitalization charges (adjusted mean difference= -$3713, $81,026 vs. $84,471, p < 0.001) in weekend admissions. Additionally, weekend admissions exhibited increased rates of septic shock, ARF, mechanical ventilation, and AKI. There were no differences in the rates of ACS, pulmonary edema, ARDS, and CVA. Trends indicated rising mortality rates, longer hospital stays, and increased costs for weekend and weekday admissions over the three-year study period. Conclusion: Weekend admissions for hypoglycemia are associated with unfavorable outcomes, including higher mortality rates, septic shock, mechanical ventilation rates, AKI, and ARF compared to weekday admissions. However, weekend admissions showed a decrease in the mean length of hospital stay and total hospitalization charges. Ongoing analysis of the underlying causes driving these outcomes is imperative for informing state and federal planning strategies aimed at mitigating these issues.

Presentation: 6/1/2024
7306 Impact of Hypoglycemia in Heart Failure: National Inpatient Sample Analysis
Authors: Neupane Binita , Karki Sunita , Bhandari Abhishek , Farooq Umer , Rajamani Krishnakumar
Published: October 2024

Disclosure: B. Neupane: None. S. Karki: None. A. Bhandari: None. U. Farooq: None. K. Rajamani: None.

Introduction:Hypoglycemia is one of the frequently encountered phenomena in hospitalized patients, mainly with diabetes mellitus; however, it is sometimes seen in patients without diabetes mellitus. Risk factors like advanced age, comorbid diseases, aggressive hyperglycemia therapy, etc., can play a role in the contribution of hypoglycemia. Heart failure is a significant healthcare burden in the United States; mortality due to heart failure has been increasing, and the lifetime risk of heart failure has risen to 24%. There are limited studies investigating how hypoglycemia affects outcomes in heart failure. Methods: We conducted a retrospective analysis using a national inpatient sample from 2017 to 2020. For diseases/comorbidities, International Classification of Disease (ICD-10) codes were used. Data analysis was done using STATA. Multivariate regression analysis was used to calculate the adjusted odds ratio. The primary outcomes of the study were mortality, and secondary outcomes were length of stay (LOS), total cost of hospitalization, septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), and acute kidney injury (AKI). Results: There was a total of 21,258,175 patients with a diagnosis of heart failure. There were 158,175 patients with a diagnosis of hypoglycemia. There were significant outcomes in patients with hypoglycemia on rates of mortality (adjusted mean difference=3.64, 14.55% vs. 4.91%, p<0.001), LOS (adjusted mean difference =2.03, 8.50% vs. 6.22%, p<0.001), the total cost of hospital stays (adjusted mean difference=$21530, $103,773 vs. $77057, p<0.001), septic shock( aOR=4.05, 14.22% vs. 3.84%, p<0.001), ARF(aOR =1.75, 24.71% vs. 15.88%, p<0.001), mechanical ventilation (aOR=2.84, 14.84% vs. 5.21%, p<0.001), ARDS( aOR=2.15, 0.57% vs. 0.24%,p<0.001), and AKI(aOR=1.65, 41.38% vs. 29.89%,p<0.001) compared to patients without hypoglycemia. There were no significant outcomes in the rate of pulmonary edema (aOR=1.09, 0.54% vs.0.46%, p=0.24). Conclusion: Hypoglycemia increases mortality, duration of hospital stays, health care cost, and health care burden. Hypoglycemia nevertheless results in worse hospital outcomes and higher expenses as compared to non-hypoglycemia due to higher mortality rates, LOS, cost, and hospital outcomes. Blood sugar levels should be monitored frequently to minimize hospitalization complications and improve outcomes.

Presentation: 6/1/2024
8394 Increased alpha cells mass in surrounding pancreatic islet in insulinoma patients
Authors: Kim Byung Joon , Park Hee Kyung , Shin Jun-Seop , Kim Kwang-Won
Published: October 2024

Disclosure: B. Kim: None. H. Park: None. J. Shin: None. K. Kim: None.

Background: Insulin is an essential treatment for controlling blood sugar in diabetic patients. However, research on the direct or indirect effects of hyperinsulinemic states on pancreatic islets cell population is limited. We need to determine the morphology of surrounding pancreatic islets in insulinoma patients and changes in the pancreatic islet after insulin administration in mice model. Methods: Insulinoma and pancreatic tissue surrounding the insulinoma were obtained after surgery of a patient diagnosed with insulinoma due to frequent hypoglycemia. For mouse model, we administered short acting insulin for 7 days to 50% pancreatectomized mice, and then removed remnant pancreatic tissue. We performed insulin and glucagon immunofluorescent staining of the patient's insulinoma and surrounding pancreatic tissue and the mouse's pancreatic tissue. Results: In the insulinoma patients, persistent hyperinsulinemia and hypoglycemia was observed in prolonged fasting test. Alpha cells mass was increased in the surrounding pancreatic islets in insulinoma. Also, in the islets of insulin-treated mice, the number of alpha cells were increased, and the number of cells co-stained for both insulin and glucagon increased, and proliferation of alpha cells was observed. Conclusion: Although more research is needed to confirm the mechanism of effects of hyperinsulinemia on the proliferation of alpha cells, hyperinsulinemia is thought to play a role in the stimulation of increasing alpha cell mass and contributing to hyperglucagonemia in early diabetes.

Presentation: 6/2/2024
6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis
Authors: Chengappa N Kharkongor , Krug E I
Published: October 2024

Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None.

Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level < 0.1ng/ml, beta-hydroxybutyrate levels of <0.05 and insulin level <0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio>2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH. References: Soumerai TE et al. Case 20-2023: A 52-Year-Old Man with a Solitary Fibrous Tumor and Hypoglycemia. N Engl J Med 2023;388:2467-77. DOI: 10.1056/NEJMcpc2300899

Presentation: 6/1/2024
6985 Intravenous Immunoglobulin induced Type 1 diabetes remission
Authors: Shahid Nabiha , Newbern Dorothee
Published: October 2024

Disclosure: N. Shahid: None. D. Newbern: None.

Introduction: Intravenous immunoglobulin [IVIG] is an immunomodulatory agent used for treatment of autoimmune and inflammatory conditions. However, it is not indicated in patients with type 1 diabetes [T1D] as its efficacy has not been established. Clinical Case: A 9-year-old previously healthy boy presented to the Emergency Department with several days of unexplained bruising and mucosal bleeding with no prior history of trauma, bleeding disorders or other systemic symptoms. Physical examination showed generalized petechiae, ecchymosis and purpura. Vitals were normal including weight and BMI. Initial labs confirmed Immune thrombocytopenic purpura [ITP] as his platelets were less than 1K/µL with otherwise normal peripheral blood cell counts and smear. Concomitantly, labs showed significant hyperglycemia [260mg/dL] with glycosuria and trace ketonuria. Glycated hemoglobin [Hba1c] was elevated at 10.5% and ultimately Pancreatic autoantibodies [GAD65, Zinc transporter-8 and islet cell antibody] came back positive confirming T1D. Other autoimmune disorders such as adrenal insufficiency, thyroiditis, and celiac disease were ruled out. For the treatment of ITP, he the patient received 1 dose of IVIG 1g/kg and responded well with a rise in platelets to 6K/µL. The morning following the infusion, due to fasting hyperglycemia, the patient was started on basal-bolus insulin regimen. By 2nd day post IVIG, he had hypoglycemia, so insulin was discontinued with normalization of blood sugars. He is now 7 months post IVIG with no recurrent episodes of thrombocytopenia. He also remains off insulin with Hba1c in the 5.9-6.5% range. He eats a regular diet with avoidance of simple carbohydrates. He wears onwears a a continuous glucose monitor, which shows that blood sugars are in range 93% of the time He remains euglycemic overnight with transient self-resolving mild post-prandial hyperglycemia. Pancreatic autoantibodies have been reassessed and remain positive Conclusions: This case demonstrates that IVIG used for the treatment of ITP has induced a state of remission in our patient with newly diagnosed with T1D. IVIG is not a standard of treatment for T1D, however, when given for other autoantibody- or T-cell-mediated autoimmune conditions, it may reduce the insulin need in patients with known diabetes or induce remission in patients with newly diagnosed diabetes. References: 1. Colagiuri S, Leong GM, Thayer Z, et al. Intravenous immunoglobulin therapy for autoimmune diabetes mellitus. Clin Exp Rheumatol. 1996;14 Suppl 15:S93-S97.2.Vvan Megen KM, Spindler MP, Keij FM, et al. Relapsing/remitting type 1 diabetes. Diabetologia. 2017; 60(11):2252-2255. doi:10.1007/s00125-017-4403-3

Presentation: 6/2/2024
7672 Ketosis-Prone Diabetes - A Case Series
Authors: Ismail T , Farooq A , Acharya G , Snitzer J
Published: October 2024

Disclosure: T. Ismail: None. A. Farooq: None. G. Acharya: None. J. Snitzer: None.

Introduction Ketosis-prone diabetes (KPD) is a syndrome that primarily affects African Americans. It is characterized by ketoacidosis, which is like Type 1 Diabetes Mellitus (T1DM). KPD is unique because it lacks identifiable autoimmunity and has a relative insulin deficiency, resembling Type 2 Diabetes Mellitus (T2DM). Therefore, KPD is informally classified as Type 1.5 Diabetes Mellitus. However, the clinical course and outcomes of KPD are like those of T2DM, and managing blood sugar levels is possible through non-insulin antidiabetic medications and dietary interventions. Case Series: Our study involved six patients who were all of African-American ethnicity. There were an equal number of male and female patients, with ages ranging from 21 to 61 years. One patient had a BMI of 27.2, which is considered overweight, while the rest had a BMI in the obese category ory(BMI>30). Two out of six patients had a pre-existing diagnosis of type 2 diabetes mellitus (T2DM) before the initial diabetic ketoacidosis (DKA) event. One patient had prediabetes. All patients required hospitalization for ketoacidosis and hyperglycemia and were found to have a glycated hemoglobin (HbA1c) level of more than 10% during these DKA events. All patients received intravenous hydration and insulin drip treatment and were discharged with a combination of long and rapid-acting insulin regimens. Following the resolution of the first episode of diabetic ketoacidosis (DKA), all six patients experienced a decrease in their insulin requirements for optimal glycemic control. Currently, four patients have discontinued insulin entirely. Moreover, all six patients tested negative for the presence of GAD-65, insulin, and islet antigen-2 antibodies. Among the patients, only one had a previously established autoimmune disease, i.e., inflammatory bowel disease. None of the patients experienced a repeat episode of diabetic ketoacidosis. Conclusion: It is important to note that not all patients who present with Diabetic ketoacidosis have Type 1 Diabetes Mellitus (T1DM). Hence, checking auto-antibodies for T1DM before making a final diagnosis is crucial. C-peptide levels may not accurately reflect the degree of relative permanent insulin deficiency in this population if measured during or immediately after an episode of diabetic ketoacidosis due to glucose toxicity and other factors. Given its prevalence in obese individuals, weight loss through dietary modifications and GLP-1 receptor analogs may be beneficial.

Presentation: 6/3/2024
12248 Leptin Signaling Deficiency At The Central Nervous System Reduces Hepatic Glucagon Sensibility Disturbing Liver Amino Acid Metabolism Leading To Hyperaminoacidemia And Hyperglucagonemia In Male Adult Rats
Authors: Pintado Losa Cristina , Mazuecos Fernández-Pacheco Lorena , Gómez Torres Óscar , Artigas Jerónimo Sara , Burgos Ramos Emma , Ramos Inés , Poveda Colado Justa , Arribas Mocoroa Carmen , Andres Antonio , Gallardo Nilda
Published: October 2024

Disclosure: C. Pintado Losa: None. L. Mazuecos Fernández-Pacheco: None. Ó. Gómez Torres: None. S. Artigas Jerónimo: None. E. Burgos Ramos: None. I. Ramos: None. J. Poveda Colado: None. C. Arribas Mocoroa: None. A. Andres: None. N. Gallardo: None.

Leptin regulates glucagon secretion, but the contribution of central leptin resistance to circulating glucagon levels and hepatic glucagon signaling is poorly studied. To analyze the effects of deficient hypothalamic leptin signaling on glucagon levels and hepatic glucagon signaling, we infused intracerebroventricularly a rat-specific leptin receptor antagonist SLA (0,2 µg/day) for 21 days to male 3-month-old Wistar rats (n=12) or PBS (n=12). At day 21 of treatment and 30 min before sacrifice, a glucagon challenge (100 µg/kg) was performed in 16h fasted rats. After sacrifice, blood and liver samples were collected for analysis. Serum hormones, urea, and total and branched-chain amino acids (BCAA) levels were determined using commercial kits and by RP-HPLC. Hepatic neutral lipid was extracted and quantified using an enzymatic kit and the hepatic content of mRNA and proteins involved in lipid and amino acid metabolism were measured by RT-PCR and Western-Blot. Additionally, the HOMA-IR and glucagon-alanine index were determined in all rats. Blocking central leptin signaling led to impaired fat oxidation and triglyceride export capacity in the liver, resulting in a 50% increase in hepatic triglyceride content in SLA-treated rats. Glucagonemia increased in SLA-treated rats, indicating impaired hepatic glucagon sensitivity. In fact, in response to exogenous glucagon, the hepatic phosphorylation of CREB was reduced by 55% in SLA-infused compared to control rats. Importantly, SLA treatment significantly decreases the expression and the activity of BCKDH (branched-chain alpha-keto acid dehydrogenase) in the liver, leading to a reduction in the BCAA degradation in SLA-treated rats, hyperaminoacidemia, and decreased serum urea levels. In conclusion, deficient hypothalamic leptin signaling alters glucose, lipid, and amino acid homeostasis, highlighting the relevance of central leptin action in the control of peripheral metabolism and glucagon sensitivity. Funding: Work supported by Ministerio de Ciencia, Innovación y Universidades under project grants RTI2018-098643-B-I00, PID2021-128243OB-I00, and from the University of Castilla-La Mancha and the European Regional Development Fund (FEDER) under project grant 2023- GRIN-34280.

Presentation: 6/1/2024
8193 Mauriac Syndrome Uncovered, The Insulin Access Impact in Type 1 Diabetes Mellitus
Authors: Sacoto Daniel Hernan , Belokovskaya Regina , Gebran Karim , Madani Kulsum , De Rosairo Anne , Patel Dhara , Franco-Akel Alberto A
Published: October 2024

Disclosure: D.H. Sacoto: None. R. Belokovskaya: None. K. Gebran: None. K. Madani: None. A. De Rosairo: None. D. Patel: None. A.A. Franco-Akel: None.

Introduction: Mauriac syndrome is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). It is reversible with appropriate glycemic control; however, factors affecting healthcare access to insulin are leading to its re-emergence. We present a case of Mauriac syndrome as a complication of uncontrolled T1DM due to insulin access. Case: A 22-year-old Hispanic female with a history of T1DM presented to the emergency department with a two-day history of abdominal pain. She was diagnosed with diabetic ketoacidosis (DKA) (blood glucose: 802 mg/dL; pH 7.14; bicarbonate: 7 mmol/L; anion gap: 34; positive serum ketones). Incidental transaminitis was noted. R factor showed a cholestatic pattern of 0.6 (AST: 136 U/L, ALT: 49 U/L, alkaline phosphatase:286 U/L). US liver revealed an enlarged liver (craniocaudal: 16.5 cm) without biliary obstruction. Her phenotype consisted of short stature (4.8 feet) with a moon face and a protuberant abdomen. Her records revealed a normal karyotype 46 XX, with a bone age of 4 years, pubertal delay, low insulin-like growth factor-1 levels (58 ng/mL), and long-standing hyperlipidemia. Over the years, she experienced multiple DKA episodes in the context of uncontrolled T1DM (hemoglobin A1c:11-13 %). The main problem identified included difficulty with insulin access, specifically related to insurance coverage as well as managing her disease. Glycemic control has significantly improved with continuous glucose monitoring and updated insurance status. Discussion: Mauriac syndrome is characterized by hepatomegaly, transaminitis, delayed pubertal maturation, growth failure, and cushingoid features. Hyperglycemia leads to intrahepatic glycogen deposition and the lack of insulin to lipolysis and ketosis, leading to high cortisol levels and growth delay. Factors leading to uncontrolled T1DM include lack of insulin access. The high cost is considered a major barrier, with an average price per millimeter of insulin tripled from 231 to 736 US dollars. Even patients with insurance tend to have high co-pays and deductibles, with a 61% chance of delay or denial due to pre-approval requirements. Lower socioeconomic status, lack of access to devices such as insulin pumps, migratory status, social support, and ethnic background are other factors related to glycemic control. Our patient belongs to a family of immigrants with low socioeconomic status, which might have contributed to the development of Mauriac syndrome. Since clinical and laboratory abnormalities are reversible with appropriate glycemic control, advocating for policies that facilitate better insulin access is paramount.

Presentation: 6/2/2024
8182 New Mouse Model Mirrors Human MODY8: Opening Doors to Understanding Exocrine-Endocrine Crosstalk in the Diabetic Pancreas
Authors: Jellas Khadija El , Salerno Valeria , Katz Liora S , Hu Jiang , Fogarty Garrett , Mandal Ankita , DiStefano-Forti Ava , Scott Donald , Lowe Mark , Molven Anders , Kulkarni Rohit N
Published: October 2024

Disclosure: K. El Jellas: None. V. Salerno: None. L.S. Katz: None. J. Hu: None. G. Fogarty: None. A. Mandal: None. A. DiStefano-Forti: None. D. Scott: None. M. Lowe: None. A. Molven: None. R.N. Kulkarni: None.

Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited form of monogenic diabetes, caused by heterozygous mutations in the carboxyl ester lipase (CEL) gene expressed in pancreatic acinar cells. MODY8 is characterized by chronic pancreatitis and exocrine dysfunction. Despite the intimate anatomical relationship between the endocrine and exocrine pancreas, little is known about the biological components mediating exocrine-endocrine communication in regulating glucose homeostasis. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. Examination of glucose homeostasis revealed that inducing stress (e.g. by high-fat diet) leads to glucose intolerance in MODY8/16R mice and a blunted glucose-stimulated insulin-secretion compared to their control littermates. Histopathological analyses demonstrated features of chronic pancreatitis in some pancreatic lobes, including inflammation, acinar atrophy, acinar-to-ductal metaplasia, fibrosis and fat infiltration, mirroring the morphology of the human disease. Moreover, we applied immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) to intact pancreata and found that beta-cell mass was significantly decreased in the MODY8/16R mice, with a large number of islets located within fatty lobes. These results are coupled with comparative proteomics and lipidomic profiling with the aim of understanding the molecular signatures of exocrine and endocrine cells during pathogenesis. In conclusion, we have generated a mouse that recapitulates several features of the exocrine and endocrine phenotype characteristic of human MODY8. This novel model provides a unique opportunity, not possible in humans, to characterize pancreatic endocrine-exocrine communication in a longitudinal manner as a response to diverse environmental stressors.

Presentation: 6/2/2024
6370 New-Onset Autoimmune Diabetes Following COVID-19 Infection and its Implications for Identical Twin Siblings
Authors: Wintermyer Gelareh , Gillis-Funderburk Sheri
Published: October 2024

Disclosure: G. Wintermyer: None. S. Gillis-Funderburk: None.

COVID-19 patients face many post-recovery complications,including autoimmune disorders. Late autoimmune diabetes ofadults (LADA) is one such disorder. Studies suggest that SARS-CoV may trigger proinflammatory cytokines that damage beta cellsand impair insulin secretion. Here, we explore a case of new-onsetLADA in a patient after recovery from COVID-19. Further, asidentical twins of LADA patients have a higher risk of developingit, we discuss how we approached the patient’s identical twin.A 29-year-old female with history of obesity (BMI 32.3) presentedto our endocrinology clinic. She complained of difficulty losingweight and fatigue and reported having COVID-19 three monthsearlier. She also mentioned having polyuria. She underwent labtests, including CBC, CMP, TSH, A1C, and a lipid panel. The testresults were within normal limits, except for her A1C of 11.3%.She was started on metformin and weekly Semaglutide injections.Given her recent COVID-19 history, she was assessed for LADA.Anti-GAD-65 and ZNT8 antibodies were 120 U/mL and 150U/mL, respectively. Serum C-peptide and IA-antibodies werewithin normal ranges. The patient informed us of her twin sister’sconcurrent COVID-19 infection. Due to the risk of LADA in hertwin sister, we recommended an evaluation by our clinic. Duringthe sister’s first visit, her BMI was 37.5, and she asked for weightloss medication. Comprehensive testing, including LADAantibodies, was conducted, with results within normal ranges andA1C level of 4.9%. The sister was also started on Semaglutide forweight management.The patient had quarterly follow-up appointments at the clinic.After a year, her A1C and continuous glucose monitoring machine(CGM) readings showed improvement. Her BMI decreased to 24.She never required insulin therapy, as her diabetes was well-managed and her average monthly glucose level on GCM readings were 125, 123 and 119 mg/dL in three different periods. Antibodieswere retested. This time IA-2 antibody was also elevated.Similarly, her twin sister continued to follow-up at our clinic. Thesister achieved significant weight loss without complications. HerLADA antibodies remained negative, and her A1C remainednormal. Clinicians should be vigilant for post-COVID LADA. In this case,Semaglutide aided weight loss, which benefits diabetesmanagement. Ongoing studies explore the potential of GLP-1medications in early-stage LADA. Historically, LADA patientswere started on insulin. However, CGM has enabled close glucosemonitoring, offering management of LADA with non-insulinmedications. It is also important to remember that autoimmunedisease risk is elevated in identical twins. In this case, although thetwin sister did not develop antibodies, the risk remains. Regularevaluation of high-risk patients is crucial for early detection ofantibodies, facilitating timely treatment to prevent adverseoutcomes.

Presentation: 6/3/2024
8813 Nivolumab-Induced Diabetes: A Hidden Danger
Authors: Case James , Chemitiganti Ramachandra Rahul V , Suravajjala Devi
Published: October 2024

Disclosure: J. Case: None. R.V. Chemitiganti: None. D. Suravajjala: None.

Immunomodulating therapy as utilized in chemotherapy for malignancy may lead to potential adverse events including immune-related adverse events(IRAEs). One such pathway by which this may occur is through alteration of the programmed cell death as affected by drugs such as nivolumab which inhibits appropriate matching of PD-1 and PD-L1 and may lead to a robust immune response with collateral damage to nontumor tissue. Multiple downstream effects may be seen leading to other pathologies including development of autoimmune diabetes as noted in the patient described herein. A 61 year old female presented to establish care for suspected type one diabetes mellitus. She had a history of renal cell cancer diagnosed about one year prior for which she was treated with nivolumab. She was found to have hyperglycemia on routine labwork with further labwork revealing inappropriately low c-peptide as measured at less than 0.10 ng/mL (0.8-3.85ng/mL) with a coincident glucose of 566mg/dL (74-106mg/dL). Further workup revealed no measurable presence of GAD65, antipancreatic islet cell or ZNT8 antibodies. Diagnosis was made of insulinopenic diabetes or otherwise autoimmune diabetes induced as an IRAE subsequent nivolumab use. She was subsequently started on a basal bolus regimen with insulin achieving blood glucose control. IRAEs are an unfortunate, albeit rare consequence of immune checkpoint inhibitors including nivolumab. Depending on the toxicity grade and prognosis the offending agent may be discontinued and steroids initiated to mitigate adverse effects. However sometimes the occurrence of an IRAE may go undetected until too late as noted in the above patient. Her presentation was atypical considering many present with DKA and as well IRAEs are less likely in monotherapy. Education of IRAEs as well as appropriate screening would aid in recognition of potential IRAEs at which time appropriate measures may be taken to alleviate collateral damage. Further elucidation of the mechanism by which this autoimmune response is activated against nontumor tissue may also lead to better understanding of autoimmune diabetes caused by other etiologies.

Presentation: 6/2/2024
8262 Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) after gastric sleeve surgery
Authors: Thomas Renu Eugene , Charales Ashley , Bangash Bushra , Haider Syed Basit , Ouais Samir , Ali Zuhair
Published: October 2024

Disclosure: R.E. Thomas: None. A. Charales: None. B. Bangash: None. S. Haider: None. S. Ouais: None.

Introduction: Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a rare condition characterized by endogenous hyperinsulinemic hypoglycemia after meals. This article explores NIPHS, emphasizing its occurrence post-gastric sleeve surgery. We delve into clinical features, diagnosis, treatment, and challenges, using a case presentation to illustrate complexities.Clinical Features and Classification:NIPHS entails endogenous hyperinsulinemic hypoglycemia without islet cell neoplasms, featuring islet cell hypertrophy. Formerly "Nesidioblastosis," post-RYGB cases constitute a distinct diagnosis. Common features include postprandial hyperinsulinemic hypoglycemia, negative radiologic localization, and a positive calcium stimulation test.Patients present postprandial hypoglycemia 2-4 hours after meals, with symptoms like tachycardia, tremors, confusion, and occasional seizures. Lab findings include elevated insulin, C peptide, and pro-insulin, low beta-hydroxybutyrate, and negative sulfonylurea/meglitinide screen.Diagnostic Workup:Evaluate glucose, insulin, pro-insulin, C peptide, beta-hydroxybutyrate, and sulfonylurea/meglitinide. Ultrasound differentiates insulinoma from diffuse processes. If negative, conduct SACST for localization.Case Presentation:A 37-year-old female post-gastric sleeve surgery presented with severe hypoglycemia. Symptoms included confusion, nausea, and palpitations, occurring postprandially, relieved by food or juice. Glucagon was administered, and consultations sought. Diazoxide stabilized blood glucose.Treatment Modalities:Dietary modifications reduce free carbohydrate intake, spaced meals minimize hyperinsulinemic episodes. Medical management (octreotide, verapamil, diazoxide, acarbose) proves effective, especially post-gastric bypass. Sub-total pancreatectomy is considered in severe refractory cases.Multidisciplinary Approach:Management involves endocrinologists, surgeons, radiologists, and dietitians. Regular monitoring assesses efficacy, adjusts medications, and addresses complications. Challenges and Future Perspectives: NIPHS complexities include variable presentation and diagnostic challenges. Research should refine criteria, explore interventions, and understand pathophysiology. Conclusion: Non-insulinoma pancreatogenous hypoglycemia syndrome, especially post-gastric sleeve surgery, presents complexities. This exploration highlights clinical aspects, diagnostics, and management challenges, emphasizing the need for a multidisciplinary approach. Continued research aims to enhance diagnostic precision and improve outcomes for those affected by this intriguing syndrome.

Presentation: 6/3/2024
7260 Nuclear Corepressor 1 (NCoR1) plays important role in the regulation of insulin gene transcription in mouse Min6 pancreatic beta cells
Authors: Shimizu Hiroaki , Horibata Yasuhiro , Amano Izuki , Ritter Megan J , Ohyama Masahide , Domae Mariko , Sugimoto Hiroyuki , Hollenberg Anthony Neil
Published: October 2024

Disclosure: H. Shimizu: None. Y. Horibata: None. I. Amano: None. M.J. Ritter: None. M. Ohyama: None. M. Domae: None. H. Sugimoto: None. A.N. Hollenberg: None.

Background: Nuclear Corepressor 1 (NCoR1) is a transcriptional corepressor which has been recognized as an important player in the regulation of hepatic lipogenesis and hematopoiesis in mouse embryo. NCoR1 is also widely expressed in mouse insulin sensitive organs, for instance adipocyte, skeletal muscle, and hepatocytes. Mouse genetic deletion strategies of either NCoR1 or SMRT(NCoR2; an ortholog corepressor of NCoR1) demonstrated that each corepressor effects the insulin sensitivity in the tissues. However, the role of each corepressor in pancreatic beta cell is not still elucidated. Methods: To clarify this, we took the gene-targeting strategy for NCoR1 using CRISPR Cas-9 and made the pancreatic beta Min6 clone which lacks NCoR1 protein (Min6-NCoR1KO; NKO cells). For this study, wild type Min6 cells (WT) and NKO cells were cultured in the Dulbecco's DMEM medium with 10% fetal bovine serum for 4-5 days, and the expression analyses compared between two cell types were performed. Results: Both comprehensive proteomics and following expression analyses compared between WT and NKO cells demonstrated that NKO cells have significantly lower expression level of insulin (INS-1 and INS-2), accompanied with high expression of histone deacetylase 6 (HDAC6). For further analyses, we also made the Min6 clone which lacks SMRT(Min6-SMRTKO; SKO cells). Interestingly, SKO cell had higher insulin and lower HDAC6 levels, accompanied with significant up-regulation of NCoR1. Conclusion: Taken together, these data indicate that NCoR1 has dominant effects in the regulation of both histone deacetylation and insulin gene transcription in Min6 cells. Further investigations for the function of NCoR1 in the insulin gene transcription observed in Min6 cells will be needed.

Presentation: 6/2/2024
9185 Pembrolizumab-Induced New-Onset Type 1 Diabetes Mellitus: A Case Report
Authors: Teng David , Connelly Tessa L , Ahmad Mobeen , Saeed Rehan
Published: October 2024

Disclosure: D. Teng: None. T.L. Connelly: None. M. Ahmad: None. R. Saeed: None.

Introduction: Immune checkpoint inhibitors are becoming essential in the treatment of various cancers. Pembrolizumab is a monoclonal antibody that binds PD-1 receptors, thereby enabling an anti-tumor response by preventing T-cell suppression. Common side effects associated with pembrolizumab include thyroid disorders, hepatitis, pneumonitis, and acute kidney injury, among others. We describe an interesting case of a woman presenting with diabetic ketoacidosis (DKA) in the setting of pembrolizumab-associated new-onset type 1 diabetes mellitus, which was reported at 0.1% during initial clinical trials but is now being increasingly recognized as a complication of immune checkpoint therapy. Case Description: The patient is a 70-year-old female with past medical history notable for stage IIIA vulvar squamous cell carcinoma initially diagnosed and treated in 2017, with recurrence in 2022 and in 2023, at which point pembrolizumab therapy was initiated. Approximately one month after her first dose, the patient presented to the emergency department with palpitations, nausea, non-bloody vomiting, polydipsia, and non-bloody diarrhea. On arrival, the patient’s vital signs were as follows: 97.2 °F, BP 128/74 mmHg, heart rate 80 bpm, respiratory rate 18 per minute, and SpO2 100% on room air. No acute findings were noted on physical exam. Initial blood work was notable for: pH 7.146, lactate 2.4 mmol/L, bicarbonate 8 mmol/L, anion gap 37 mmol/L, creatinine 1.59 mg/dL, glucose 563 mg/dL, C-peptide 0.16 ng/mL, HbA1c 6.9%, and WBC 18.8 B/L with neutrophilic predominance. Urinalysis was notable for 4+ glucose and 4+ ketones. The patient was admitted to the progressive care unit and DKA protocol was initiated including the administration of IV fluids, insulin infusion, and electrolyte replacement. Additional blood work was unrevealing, including insulin autoantibodies <0.4 U/mL, negative islet cell IgG cytoplasmic autoantibodies, and negative anti-GAD65 antibodies. The patient was eventually discharged with outpatient Endocrinology follow-up. Discussion: Immunotherapy is quickly redefining the standard of care in the treatment of several types of malignancies through the leveraging of the body’s immune defense apparatus. Pembrolizumab prevents the deactivation of T-cells via the PD-1/PD-L1 pathway. Unfortunately, this also predisposes non-cancerous cells to autoimmune destruction by these T-cells. It is proposed that such is the mechanism by which pancreatic beta islet cells are destroyed in the setting of pembrolizumab use, thereby resulting in a rapid reduction in insulin production capability. New-onset type 1 diabetes complicated by DKA is potentially life-threatening, and so we believe this case highlights the need for both pre-treatment counseling as well as follow-up screening following initiation of pembrolizumab therapy.

Presentation: 6/2/2024
8241 Post-Covid complications in patients with diabetes mellitus are high during 24 month after acute infection
Authors: Alieva Anna
Published: October 2024

Disclosure: A. Alieva: None.

The consequences of coronavirus infection in patients with diabetes have not been fully studied. The purpose of the work was to study post-Covid complications in patients with diabetes. Materials and methods. We examined 188 patients with diabetes mellitus who had a coronavirus infection in 2020 and applied to the RSSPMCE clinic for inpatient treatment within 1-24 months after the acute period of viral infection. The criteria for inclusion in the study were: the presence of type 2 diabetes mellitus (DM), diagnosed before 2020, a history of COVID-19 infection confirmed by PCR. Exclusion criteria were pregnancy and diabetes diagnosed in 2020 and later. Results and discussion. An increase in D-dimer levels was observed at 0-3, 7-9 and 19-24 months, which was accompanied by an increase in von Willebrand factor at 4-9 months and thrombosis at 4-6 months after COVID-19. The period of 4-6 months after coronavirus infection was also characterized by an increase in inflammatory markers and the development of purulent complications. The progression of polyneuropathy was noted during the first 6 months after COVID-19; for periods of 6-12 months, the development of vasculitis was typical. In the periods of 1-3 months and 10-24 months after COVID-19, cases of the development of newly registered hypertension were observed. Conclusion. Patients with type 2 diabetes mellitus for 2 years after coronavirus infection remain at risk of developing thrombotic complications, new-onset arterial hypertension and accelerated progression of chronic complications of diabetes mellitus, which requires careful targeted monitoring of such patients.

Presentation: 6/3/2024
8010 Potent MSB-61 as Type 1 Diabetes (T1D) therapy: mechanism of action in insulin secretion
Authors: Ajmal Nida , Bogart Maisy , Corbin Kathryn , Khan Palwasha , Shafqat Mariam , Bergmeier Stephen , Gu Guoqiang , Tong Xin , Nunemaker Craig S
Published: October 2024

Disclosure: N. Ajmal: None. M. Bogart: None. K. Corbin: None. P. Khan: None. M. Shafqat: None. S. Bergmeier: None. G. Gu: None. X. Tong: None. C.S. Nunemaker: None.

Type 1 diabetes (T1D) is a chronic autoimmune disorder caused by proinflammatory cytokines (Interleukin 1-beta; IL1-β, Tumor Necrosis Factor-alpha; TNF-α, and Interferon-gamma; IFN-ϒ) from immune cells that destroy insulin-producing beta cells in pancreatic islets and lead to hyperglycemia. The development of possible treatments to cure T1D is needed besides intensive insulin therapy that does not halt disease progression. We have identified a small molecule called MSB-61 that can protect islet cells from endoplasmic reticulum stressors (66% protection) and cytokines (33% protection) as measured by propidium iodide in islets isolated from mice using 50uM MSB-61. Importantly, we observed large increases in insulin secretion during overnight exposure to 50uM MSB-61. Insulin secretion began to increase in response to MSB-61 at ∼4h, reaching a plateau at ∼8h of greater than 4-fold insulin release compared to controls. The Kegg pathway analysis of RNA-seq data on MSB-61 suggested that multiple genes upregulated by MSB-61 are involved in insulin secretion through an amplifying pathway that includes cAMP/PKA and Pi3k/Akt signaling cascades. Based on RNA sequencing data, this study aimed to test MSB-61 for identifying pathway by which it potentiates insulin secretion. Islets from CD-1 mice and mouse insulinoma Min-6 cell lines were used to test amplifying pathways by using cAMP/PKA and Pi3k/Akt analogs and antagonists with and without MSB-61, and overnight insulin secretion and insulin content will be measured by enzyme-linked immunosorbent assay (ELISA). MSB-61 showed no potential effects on insulin secretion when tested for Pi3k/Akt pathway in the presence of analogs and antagonists such as 740-Y-P and wortmannin. It further suggests MSB-61 might potentiate insulin secretion through the cAMP/PKA pathway, which is still under investigation. RNA sequencing analysis of mouse islets showed several genes that belong to Ras family member-2 and have GTPase activity. Genes with GTPase activity will be further investigated to help identify if MSB-61 stimulates insulin secretion through an amplifying pathway involving the cAMP/PKA downstream signaling cascade. Identifying the mechanism of action and signaling pathway by which MSB-61 potentiates insulin secretion will open new ways of identifying T1D therapeutic interventions that would help replace standard insulin therapy.

Presentation: 6/3/2024