bluuebunny/crossref_metadata_2025 huggingface dataset:
7309 Moderate ER Stress, Facilitated by IL-1β, Initiates Protective Mechanisms in Pancreatic β-Cells Ameliorating Dysfunction and Diminishing Death Induced by Inflammatory Cytokines
Authors: Sétula C , Orellano M S , Argañarás M , Scelza-Figueredo A , Spinedi E , Andreone L , Perone M J
Published: October 2024

Disclosure: C. Sétula: None. M.S. Orellano: None. M. Argañarás: None. A. Scelza-Figueredo: None. E. Spinedi: None. L. Andreone: None. M.J. Perone: None.

Type 1 and type 2 diabetes share common features, encompassing islet inflammation, β-cell dysfunction and the eventual reduction in both the number and mass of β-cells. The organism's resilience against higher doses of a harmful substance can be bolstered through the induction of mild stress responses, achieved by exposing it to low concentrations of the said agent. Our objective was to evaluate whether physiological concentrations of IL-1β prompt adaptive mechanisms that protect β-cells from the distinctive inflammatory milieu associated with diabetes.We employed INS-1E insulinoma and isolated mouse islets and measured NO by Griess, cell viability (MTT) and death (Hoechst/PI, microscopic fluorescence and Annexin V-PE/7-AAD, flow cytometry), mRNA by RT-qPCR, NF-κB (immunofluorescence), insulin (ELISA) and proteins by Western blot (WB). GSIS (glucose-stimulated insulin secretion) index was calculated as the ratio of insulin released during 1h under stimuli of 20mM/2mM glucose. Results are presented as mean ± SD, n≥3 independent experiments. Comparison between groups was carried out using paired or unpaired Student's t-test or ANOVA followed by Bonferroni's multiple comparison test, as appropriate. Mild endoplasmic reticulum (ER) stress was induced in β-cells through a 72h incubation with 10 pg/ml IL-1β (IL-1βlow). Cytokine-induced damage was triggered by 100 pg/ml IL-1β + 5 ng/ml IFNγ for 16h (CYT). IL-1βlow protects INS-1E from the decrease in mitochondrial reduction potential triggered by CYT, diminishes cell death (p<0.05 vs CYT) and improves GSIS (p<0.05 vs CYT), the latter in pancreatic islets as well (p<0.05 vs CYT). IL-1βlow reduces NO production (p<0.001 vs CYT) through a decrease in iNOS mRNA (p<0.01 vs CYT) and its protein expression (p<0.01 vs CYT). IL-1βlow reduces CYT-triggered NF-κB nuclear translocation (p<0.05 vs CYT). IL-1βlow hampers the increase in CHOP expression (p<0.001 vs CYT; by WB), decreases the mRNA expression of DP5 (p<0.05 vs CYT), PUMA (p<0.05 vs CYT), Bax/Bcl-2 ratio (p<0.01 vs CYT) and cleaved caspase-3 (p<0.001 vs CYT; by WB). Our study demonstrates that β-cells possess the capability to activate an adaptive stress response mediated by IL-1β in response to inflammatory stimuli. Approaches aimed at bolstering this resilient response provide a novel therapeutic avenue to enhance the functionality and viability of β-cells, ultimately mitigating the adverse inflammatory conditions associated with diabetes.Supported by ANCYPT-FONCYT (PICT -2018-1577 / -2018-0719), and partially by FPREDM 2023.

Presentation: 6/2/2024
12622 Molecular Physiology And Compensatory Response In Maladapted Pancreatic Islets Of Humanized Mice Model For Type 1 Diabetes
Authors: Hussain Ashaq , Aldasouqi Ahmad , Rafiqi Shafiya Imtiaz , Khan Saira Saeed , Paparodis Rodis , Jaume Juan Carlos , Imam Shahnawaz
Published: October 2024

Disclosure: A. Hussain: None. A. Aldasouqi: None. S. Rafiqi: None. S.S. Khan: None. R. Paparodis: None. J.C. Jaume: None. S. Imam: None.

Genetic predisposition linked with specific HLA (DR and DQ) alleles, environmental factors, and other uncharacterized physiological aberrations triggers an autoimmune attack and depletion of β cells in pancreatic islets, leading to decreased insulin secretion and diabetes. Our laboratory has generated humanized mice carrying the antigen-presenting HLA-DQ8 diabetes-linked haplotype and expressing the human autoantigen GAD65 in pancreatic beta cells. These humanized mice spontaneously develop type 1 diabetes (T1D) and represent the full spectrum of pathophysiological conditions experienced in T1D. Using humanized mice as a model of study, we studied the molecular physiology and compensatory response in maladapted pancreas under normal physiological conditions and hyperglycemic stress of T1D. We studied the differential expression of some important genes by quantitative PCR in maladapted islets to identify the physiological processes affected during the initial oxidative stress exerted by autoimmune conditions. Our results confirmed that levels of cyclin B, cMyc, Cyc D, Cyc E, PDGFRA, and NOTCH are reduced during autoimmune insult, reflecting the poor regenerative capacity of islet cells. However, Cyc A has an elevated expression, reflecting that islet cells, particularly the β cells of Type 1 diabetic mice, may have regenerative potential that may be explored. The genes for Desmin and Survivin showed decreased expression, whereas genes for Smad and Synuclein displayed increased expression. The genes for insulin and somatostatin showed elevated expression, whereas the gene for glucagon displayed reduced expression. The results suggest that during autoimmune insults, the β cells moderately whip up the synthesis of insulin-specific RNA to maintain the requirements. Among the endoplasmic reticulum-specific molecular chaperones, Calnexin showed an elevated expression, whereas calreticulin displayed a reduced expression. Among the genes involved with the architecture of the islet, Lamin and Integrin both display increased expression, reflecting the dynamic change in islet architecture during the autoimmune depletion of β cells. We also investigated the expression of ER-specific stress genes both at RNA and protein levels. Our preliminary results have confirmed that ER-specific stress genes showed an elevated expression during oxidative stress mediated by autoimmune T1D conditions.

Presentation: 6/3/2024
6684 Multi-Dose BCG Vaccination for Protection Against COVID-19 Disease and Other Respiratory Infections in Subjects with Type 1 Diabetes Late in the US Pandemic
Authors: Kühtreiber Willem , Hostetter Emma , Wolfe Grace E , Vaishnaw Maya , Goldstein Rachel , Bulczynski Emily , Hullavarad Neeshi , Braley Joan E , Zheng Hui , Faustman Denise L
Published: October 2024

Disclosure: W. Kühtreiber: None. E. Hostetter: None. G.E. Wolfe: None. M. Vaishnaw: None. R. Goldstein: None. E. Bulczynski: None. N. Hullavarad: None. J.E. Braley: None. H. Zheng: None. D.L. Faustman: None.

A Phase II clinical trial previously reported that multiple doses of the bacillus Calmette-Guerin (BCG) vaccine, originally developed for tuberculosis prevention, could protect at-risk individuals with type 1 diabetes (T1D) against COVID-19 disease and infectious diseases early in the pandemic in the United States (US) (Cell Rep Med 2022). As SARS-CoV-2 evolved, COVID-19 disease became more transmissible, but less lethal. In a new, Phase III, randomized, double-blinded, placebo-controlled trial, we tested whether at-risk individuals with T1D given multi-dose, intradermal BCG would be protected against COVID-19 and other infectious diseases (2:1 randomization; BCG: n=93; placebo: n=48). The trial was conducted late in the COVID-19 pandemic during sequential dominance of Beta, Gamma, Delta and Omicron variants. All participants were US citizens and were negative for prior BCG vaccination and negative for tuberculosis. Two co-primary endpoints were protection from COVID-19 disease and platform protection from all infectious diseases. From April 2021 to November 2022, Tokyo-strain BCG vaccination provided significant protection against COVID-19 disease (p=0.023) and strong platform protection against all infectious diseases (p<0.0001). Over the 19-month course of the study, commercial COVID-19 vaccines were rolled out. An observational analysis of the placebo control group (i.e., no BCG vaccination) showed that COVID-19 mRNA vaccination alone provided no protection from COVID-19 disease in the enrolled population (p=0.43). BCG vaccination efficacy against COVID-19 and infectious disease in T1D was unaffected by concurrent COVID-19 vaccinations (observational analysis). These data suggest that BCG has efficacy against a range of SARS-CoV-2 variants, in contrast to current COVID-19 vaccines, which have narrow efficacy against specific viral variants. Further, it shows that individuals with T1D represent a vulnerable population for whom BCG appears to be the only effective vaccine against COVID-19 disease and confirms that, in the US, BCG vaccination protects against infectious disease as well.

Presentation: 6/3/2024
6536 National Trends in Prevalence of Prediabetes and Diabetes Among Women With Low Bone Mineral Density: 2009-2018
Authors: Atri Avica , Anastasopoulou Catherine
Published: October 2024

Disclosure: A. Atri: None. C. Anastasopoulou: None.

Introduction: In recent years, bone fragility has emerged as a complication of prediabetes (preDM) and diabetes mellitus (DM), resulting in reduced bone mass and increased fracture risk, and is an important, though under-studied risk factor for osteoporosis. However, the converse relationship, trends in prevalence of preDM and DM in women with low bone mineral density (BMD) in the United States, are not well established. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) for the years 2009-10, 2013–14 and 2017–18 to include U.S. women aged ≥ 50 years with T-score ≤ -1. Osteoporosis assessment in NHANES was not completed in 2011–12 and 2015–16, and therefore not included in the analysis. Osteopenia and osteoporosis were defined by a femoral neck BMD ≤1 to 2.5, and ≤2.5 standard deviations (SDs) below the BMD of a young female adult mean (T-score). Femur neck BMD was measured by dual energy x-ray absorptiometry (DEXA). PreDM and DM were defined using HbA1c values of 5.7 - 6.4% and ≥ 6.5% respectively. Participants with missing HbA1c and BMD data were excluded. Descriptive statistics were used for comparing means and medians. The Cochran-Armitage test was utilized for trend analysis. Results: In this nationally representative sample of US women with low BMD, the median (IQR) T-score at femoral neck worsened from -1.74 (-1.4 to -2.17) in 2009-10 to -1.87 (-1.43 to -2.32) in 2017-18 (trend p = 0.001). Similarly, the prevalence of osteoporosis increased from 13.7% to 16.9% (trend p = 0.001). Overall, in this cohort, the national prevalence of both preDM and DM decreased from 40% to 32.9% and 9.6% to 9%, respectively (trend p = 0.001). Along with a reduction in the overall prevalence of osteopenia (86.3% to 83.1%, p=0.001), the prevalence of both preDM and DM decreased from 39.2% to 32.6% and 10% to 9% (p = 0.001). In those with osteoporosis, the prevalence of preDM decreased from 45.2% to 34.4% (p trend=0.001), however, the prevalence of DM increased from 7.5% to 8.7% (p trend =0.001). Overall rates of uncontrolled DM (HbA1c > 7%) in women with osteoporosis showed significant improvement (5.8% to 3.5%, p = 0.001). Discussion Despite worsening trend in femoral neck BMD among US women age ≥ 50 years from 2009-10 to 2017-18, the overall prevalence of preDM and DM improved by 7.1% and 0.6% respectively. However, this favorable trend was not observed among women with osteoporosis, where the overall prevalence of DM increased by 1.2%, though the rate of uncontrolled DM significantly decreased by 2.3%. Targeted interventions to improve blood glucose control among women with low BMD, especially those with osteoporosis are warranted, to improve bone health, as well as reduce fall and fracture risk.

Presentation: 6/2/2024
7799 Nesidioblastosis Concurrent with Anatomically Confirmed Metastatic Gastric Cancer
Authors: Cho Y , Jo K , Han J H , Moon S d , Kim E
Published: October 2024

Disclosure: Y. Cho: None. K. Jo: None. J. Han: None. S. Moon: None. E. Kim: None.

Background: Nesidioblastosis is a rare condition that should be considered in cases of pancreatogenic hyperinsulinemic hypoglycemia without evidence of insulinoma on imaging. We present the first case of nesidioblastosis concomitant with anatomically confirmed metastatic gastric cancer of the pancreas. Case Report A 57-year-old male presented with recurrent episodes of loss of consciousness and hypoglycemia, with a glucose level of 26 mg/dl upon arrival at the emergency room. Despite a history of advanced gastric cancer and previous chemotherapy, the patient had not been diagnosed with diabetes and was not taking medications associated with hypoglycemia. Four months prior, he underwent total gastrectomy. The fasting plasma glucose levels was 38 mg/dl, accompanied by C-peptide levels of 6.10 ng/mL, insulin levels exceeding 1000 uIU/ml, and proinsulin levels at 8.8 pmol/L. The insulin antibody level was more than 100%, and the highest cortisol level reached 15.60 ug/dL during the rapid ACTH stimulation test. The patient's postprandial 2-hour glucose level reached 233 mg/dl during the 75g glucose tolerance test. Imaging studies, including whole-body PET CT and abdominal CT, showed no evidence of suspected metastatic lesions, and the pancreas appeared normal on MRI. Endoscopic ultrasound could not be performed due to anatomical changes following the surgery. A selective arterial calcium stimulation test demonstrated a substantial over twofold increase in insulin concentrations in the gastroduodenal artery, splenic artery, and superior mesenteric artery. The patient received methylprednisolone 125 mg once daily but insulin levels remained elevated, exceeding 1000 uIU/ml, requiring continuous dextrose infusion. Octreotide therapy was initiated, resulting in an improvement in insulin levels to 589 uIU/ml, although discontinuation of dextrose fluid remained unfeasible. After consultation with the surgeon, a open subtotal pancreatectomy was performed, allowing discontinuation of dextrose on the second post-surgery day, with improved glucose and insulin levels. Histological examination showed three clusters of atypical cells with perineural infiltration. Immunostaining indicated negative synaptophysin and positive CK20, suggesting possible gastric cancer metastasis, consistent with prior gastrectomy findings. Moreover, an increased number of variable-sized Langerhans islets exhibited positive insulin and glucagon immunostaining within the islets, indicative of nesidioblastosis. Conclusion: Nesidioblastosis should be considered in cases of unexplained post-surgery hypoglycemia following metastatic gastric cancer treatment. Furthermore, given the potential link with metastatic gastric cancer, which may elude detection via imaging alone, aggressive surgical intervention should be contemplated as a nesidioblastosis treatment strategy.

Presentation: 6/3/2024
6984 New Onset Diabetes After Transplant: Need for Strict Glucose Monitoring
Authors: Chaudhary Taibah , Syed Omar , Nawaz Maria , Kaur Ravleen , Iqbal Aimen , Deck Charles
Published: October 2024

Disclosure: T. Chaudhary: None. O. Syed: None. M. Nawaz: None. R. Kaur: None.

Introduction: Immunosuppressant use comes at a cost of challenging side effects, which are being discovered more as its use increases. One such example is our case of new-onset diabetes after transplant (NODAT).Patient presentation: A 36-year-old male with a past medical history of end-stage renal disease status post renal transplant (6/2023), hypertension, and hyperlipidemia who presented to the hospital in 10/2023 with fever, chills, and diarrhea. His vitals at that time were as follows: temperature 36.1C, blood pressure 148/84 mmHg, pulse 87 bpm, and a respiratory rate of 22. Lab work was significant for blood glucose 1144, anion gap 22, bicarbonate 13, potassium 7.3, Sodium 135, lipase 427, pH 7.3, urine ketones 80, HbA1C 11.5 %. CT scan of the abdomen revealed loss of peripancreatic fat and inflammatory changes surrounding the pancreas. His medication review included Tacrolimus 12 mg daily, Mycophenolate 500 mg BID, Valtrex 500mg daily, and fluconazole 200mg every other day. He was treated with 2 liters of normal saline bolus and started on maintenance fluid, and insulin drip as per DKA protocol. Calcium gluconate and an albuterol nebulizer were given for hyperkalemia. Tacrolimus and prednisone were held. Endocrinology and Nephrology were consulted. The patient was thought to have diabetes due to steroid use which were discontinued and the patient was discharged on subcutaneous insulin regimen and lower dose of tacrolimus. Despite discontinuation of steroids, patients continued to have raised glucose readings confirming the causative agent as tacrolimus. Conclusion: The current guidelines for post-kidney transplant patients recommend checking fasting blood glucose weekly for the first four weeks, then biweekly for two months, and then monthly thereafter. HbA1C should be checked every 3 months and if it is >6% then home glucose monitoring should be done as well. Although the frequency of these check-ups decreases, it is imperative for physicians to remember that patients can still develop NODAT months post-transplant. It is also essential to reinforce the importance of these glucose checks for the patient as missed diagnosis can lead to dangerous complications such as DKA.

Presentation: 6/2/2024
7431 Non-Insulin Treatment of Type 1 Diabetes Mellitus: The Power of GLP-1 and GLP-1/GIP RA
Authors: Ferri-Guerra J , Kasper-Guerra E , Abdulhussein O , Madrigal Loria G , Ambalavanan J , Zhou K
Published: October 2024

Disclosure: J. Ferri-Guerra: None. E. Kasper-Guerra: None. O. Abdulhussein: None. G. Madrigal Loria: None. J. Ambalavanan: None. K. Zhou: None.

Background: Insulin is the mainstay of treatment of patients with type 1 diabetes mellitus (T1D). However, patients with T1D can also potentially benefit from adjunctive therapies such as GLP-1 receptor agonists or GLP-1/GIP receptor agonists, especially when obesity and elevated cardiovascular risk are present. Case 1: A 64-year-old male with severe coronary artery disease requiring revascularization and obesity with T1D has been wearing a pump for insulin delivery since the age of 43, started on closed loop system Control IQ with Tandem in April 2022. In December 2022, patient had myocardial infarction. At that time, Hba1c was elevated at 7.6% and BMI was elevated at 32.5 kg/m2, and patient was considered a good candidate for tirzepatide, which was prescribed. The tirzepatide dose was slowly increased, up to 10 mg weekly. The new therapy resulted in loss of 17 kg (20.1% decrease of body weight) with only some mild nausea. There was an improvement in HbA1c to 7.1% and a dramatic reduction in daily average insulin use from 90 units to 52 units. Case 2: A 59-year-old female with obesity and T1D diagnosed at the age of 8 had been wearing insulin pump, Medtronic 670G in manual mode, for insulin delivery for the past few years with poor glycemic control. In August 2021, patient was prescribed semaglutide for post prandial hyperglycemia and obesity management (BMI at 31.6kg/m2). Since being on the medication, she lost 12kg (16.8% decrease in body weight), despite being on the lowest dose of 0.25 mg (maximum tolerated). Her HbA1c has improved from 8.2% when therapy was initiated, to 7% with just the introduction of semaglutide to her insulin regimen. Conclusion: Although insulin is a required therapy for patients with T1D, adjunctive therapies may improve glycemic control, reduce insulin requirements and promote weight loss. GLP-1 and dual GLP-1/GIP receptor agonists should be considered for these patients.

Presentation: 6/1/2024
7187 Non-islet Cell Tumor Hypoglycemia in a Patient With Metastatic Renal Cell Carcinoma
Authors: Bao Ginny W , Yin Anthony Y
Published: October 2024

Disclosure: G.W. Bao: None. A.Y. Yin: None.

We report a rare case of non-islet cell tumor hypoglycemia (NICTH) in a patient with metastatic renal cell carcinoma. NICTH is a paraneoplastic syndrome due to increased production of an incompletely processed form of insulin-like growth factor 2 (“big IGF-2”). It requires a high-level of suspicion for diagnosis and is challenging to manage. Our patient is a 69 year old gentleman with a history of deceased donor renal transplant in 1994 and 2008. He was diagnosed with renal cell carcinoma (RCC) metastatic to bone, lymph nodes, and lungs, which was initially treated with cabozantinib, later switched to lenvatinib and everolimus due to disease progression. On admission, he presented with anasarca and weakness. He had recurrent fasting hypoglycemia associated with confusion and lethargy. The lowest serum glucose was 28 mg/dL. He was also diagnosed with primary hypothyroidism (TSH 25.1 uIU/mL and free T4 0.31 ng/dL), suspected to be due to tyrosine kinase inhibitor therapy. Levothyroxine was initiated. Cosyntropin stimulation resulted in a post-stimulation cortisol of 7 ug/dL, although this was felt not to be reliably diagnostic of adrenal insufficiency in the setting of profound hypoalbuminemia. IGF-1 and IGF-2 were 16 ng/mL and 388 ng/mL, respectively; IGF-2: IGF-1 ratio was 24.3. He was treated with intravenous dextrose and prednisone 30mg daily with stabilization of glucoses for a few days. On hospital day 19, he acutely decompensated and passed away shortly after being transitioned to comfort-focused care. Non-diabetic hypoglycemia is relatively uncommon, and may be seen in patients with liver disease, sepsis, adrenal insufficiency, and malignancy. We report a case of NICTH in a patient with metastatic RCC, which is a particularly rare cause of hypoglycemia. NICTH is due to tumor production of “big IGF-2”, a precursor of IGF-2, which mimics the effects of insulin and causes fasting hypoglycemia. NICTH is more commonly associated with mesenchymal and epithelial tumors such as fibromas, fibrosarcomas, and hepatocellular carcinomas. NICTH due to RCC appears to be a much more rare entity, with as few as four cases reported in the literature. Laboratory findings of NICTH include low insulin, pro-insulin, C-peptide, and β-hydroxybutyrate during hypoglycemia. An IGF-2: IGF-1 ratio >10 is considered virtually diagnostic. Surgical excision is curative, although often delayed or not feasible, and patients frequently require intravenous dextrose. High-dose steroids (ie, prednisone 30-60mg daily) can be used, which promotes “big IGF-2” clearance. NICTH is likely under-recognized in patients with advanced malignancies. This diagnosis should be considered in those with refractory hypoglycemia, although management is challenging if tumor control cannot be achieved.

Presentation: 6/1/2024
8538 Pancreatic Islet Adaptations to Hyperglycemia Are Prevented by Glycolytic Inhibition and Amplified by Inhibiting Membrane Depolarization
Authors: Whitticar N B , List B P , Bruce N , Bertram R , Nunemaker C S
Published: October 2024

Disclosure: N.B. Whitticar: None. B.P. List: None. N. Bruce: None. R. Bertram: None. C.S. Nunemaker: None.

Long before type 2 diabetes ensues, pancreatic islets undergo functional changes to compensate for increasing insulin resistance. Primarily, the islets increase their ability to secrete insulin by augmenting the glucose-stimulated insulin secretion (GSIS) pathway. As metabolic syndrome worsens, islets become functionally exhausted, leading to cellular dysfunction and apoptosis. To avoid the negative consequences of this compensatory response, various steps of the GSIS pathway can be attenuated to restore normal functional levels before the islets fail. Determining which inhibitors can prevent the earliest adaptations to hyperglycemia may reveal the processes that play a causal role in islet failure. The chemicals mannoheptulose (MH), diazoxide (DZ), and nifedipine (NP) were chosen to inhibit the glucokinase enzyme, KATP-channel closure, and voltage-gated calcium channels, respectively. CD-1 mouse islets were placed in 20 mM glucose to simulate hyperglycemia along with a concentration of each inhibitory drug that reduced insulin secretion by 30-40%. After 48-hour treatment, glucose-stimulated calcium tests were performed to determine if the treatments could prevent the negative adaptation to hyperglycemia. Only islets treated with MH to reduce glycolytic activity maintained a normal calcium response. Islets in the MH group also retained a strong insulin response to glucose and were not depleted of insulin content. Unexpectedly, inhibition of calcium influx and insulin secretion with DZ or NF caused a substantial increase in basal insulin secretion compared to islets in standard culture (P<0.01, n=6; P=0.06, n=6, respectively). These results indicate that the signaling pathway that causes the adaptation to hyperglycemia lies upstream of KATP channels and downstream of glucokinase. Mathematical modeling using the Integrated Oscillator Model was able to replicate our results and suggests that high rates of glycolytic and mitochondrial metabolism are associated with the signal that adapts islets to hyperglycemia, and that reducing intracellular calcium in the face of high glucose further increases basal insulin secretion. Ongoing studies will determine if metabolic acceleration or altered membrane conductance are responsible for the earliest islet adaptations to hyperglycemia. Our results suggest that reducing metabolic activity, but not calcium influx, prevents adaptations to hyperglycemia in mouse islets. These findings can be applied to potentially prevent the progression of obesity and hyperinsulinemia into type 2 diabetes.

Presentation: 6/2/2024
8330 Pancreatic neurons in neuron-islet complexes and activation of these neurons promotes insulin secretion under high glucose level
Authors: Liu Y , Yang Z , Feng Q , Hu M , Sha L
Published: October 2024

Disclosure: Y. Liu: None. Z. Yang: None. Q. Feng: None. M. Hu: None. L. Sha: None.

Islets are rich in pancreatic nerve innervation. Pancreatic ganglionic neurons, as an integrating center, receive central and peripheral nerve innervation regulating endocrine and exocrine of pancreas. Neurons in pancreatic ganglia have been studied intensely in our lab and a few other labs. Neurons located in islets forming neuron-islet complexes have been demonstrated. However, the properties and function of these neurons has not been studied. In this study, pancreatic neurons in the neuron-islet complex and the effects of activation of these neurons on insulin release were investigated. Methods: Eight week old rats were used. Pancreas was digested and a method was developed to identify neuron-islet complexes from islets. Results: CHAT and TUBB3 were co-localized in nearly all neurons in the neuron-islet complex indicating that these neurons were mainly cholinergic neurons. A small portion (<10%) of TUBB3 positive cells were also positive for nNOS. Nicotinic tartrate was used to activate neurons in the complexes. After one hour of administration of nicotinic tartrate, with 5.6 mM glucose, ACh level was increased significantly from 15.26±5.46 μM to 23.24±4.18 μM and insulin level were slightly increased from 37.21±2.04 μM to 39.27±1.23μM (P > 0.05). With 16.7 mM glucose, ACh level were increased significantly from 23.83±2.28 μM to 30.92±1.03 μM and insulin increased significantly from 41.93±1.30 μM to 49.04±1.68 μM. Conclusion: The neurons in neuron-islet complexes are mainly cholinergic neurons and activation of these neuron under high glucose level stimulate insulin secretion.

Presentation: 6/2/2024
9337 Postprandial And “Fasting” Hypoglycemia In A Patient With A History Of Gastric Bypass Surgery And Carcinoid Syndrome
Authors: Ntelis Spyridon , Pennant Marjorie
Published: October 2024

Disclosure: S. Ntelis: None. M. Pennant: None.

Background: Hypoglycemia is an increasingly recognized complication of bariatric surgery that can occur years after the procedure. Episodes most commonly occur 1-3 hours after meals. Fasting hypoglycemia is not typical and raises concerns for other etiologies, including adrenal insufficiency and other causes of endogenous hyperinsulinism. Clinical Case: A 51-year-old woman with a history of carcinoid tumor of unknown origin with liver metastases, treated with monthly octreotide injections, and history of Roux-en-Y gastric bypass presented with multiple episodes of symptomatic hypoglycemia up to 24 mg/dl. Symptoms included tremor and diaphoresis and improved with juice. Morning cortisol was 22.7 mcg/dL (n > 19.4 mc/dL), ruling out adrenal insufficiency. A continuous glucose monitor (CGM) was placed, and she was advised to have frequent low-carbohydrate meals mixed with healthy fats and protein. She was also advised to add cornstarch to meals, until mixed-meal testing could be performed. She was hospitalized for a seizure provoked by hypoglycemia after a heavy high-carbohydrate meal, and treatment with acarbose 25 mg three times daily was started. Mixed-meal testing was consistent with post-prandial hyper-insulinemic hypoglycemia, with elevated insulin (58 mcIU/ml, n: 2.6-24.9 mcIU/ml) and c-peptide (11.2 ng/ml, n: 1.1-4.4 ng/ml) levels during an episode of symptomatic hypoglycemia (glucose 22 mg/dL) 2.5 hours after the patient’s meal. CGM showed hypoglycemia mostly occurring after meals and some episodes of hypoglycemia early in the morning, that occurred after late-night snacks. Clinical picture and laboratory testing were suggestive of post-bariatric surgery hypoglycemia. Poor hepatic glycogen reserve, secondary to the liver metastases, was considered a contributing factor. Interestingly, although hypoglycemia was mediated by hyperinsulinemia, treatment with a somatostatin analogue provided no benefit. The frequency of hypoglycemia decreased with adherence to a low-carbohydrate diet, and episodes mostly occurred when acarbose use was delayed. Octreotide was transitioned to lantreotide. Due to persistence of early-morning low glucose values on follow-up, further work-up was pursued to rule out etiologies of fasting hypoglycemia. Glucose values remained >70 mg/dl during 72 hours of fasting. IGF-I (115 ng/ml, n: 53-287 ng/ml) and IGF-II (608 ng/ml, n: 267-616 ng/ml) levels were normal, and insulin antibodies were undetectable. Post-bariatric surgery hypoglycemia was confirmed and acarbose dose was increased to 50 mg three times daily. Conclusion: Postprandial hypoglycemia is a late complication of bariatric surgery. Early-morning hypoglycemia can also be seen after bariatric surgery in patients who have late-night meals and snacks.

Presentation: 6/1/2024
9253 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City
Authors: Fermin-Martinez Carlos Alberto , Bello-Chavolla Omar Yaxmehen , Antonio-Villa Neftali Eduardo , Garcia Daniel Ramirez , Seiglie Jacqueline A
Published: October 2024

Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None.

Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population.

Presentation: 6/1/2024
12524 Predictive Factors For Type 2 Diabetes Remission: Insights From A Digital Twin Intervention Program At 18 Months
Authors: Shamanna P , Dharmalingam M , Vadavi A , Keshavamurthy A , Bhonsley S , Thajudeen M , Balasubramanian A , Joshi S R
Published: October 2024

Disclosure: P. Shamanna: None. M. Dharmalingam: None. A. Vadavi: None. A. Keshavamurthy: None. S. Bhonsley: None. M. Thajudeen: None. A. Balasubramanian: None. S.R. Joshi: None.

Background and aims: Digital twin (DT) platform uses Artificial Intelligence (AI) and Internet of Things, to integrate multi-dimensional data for precision nutrition and health recommendations via the mobile app. Remission was defined as A1C levels less than 6.5% without medication for over 3 months. Evidence suggests that remission is more likely in individuals with early type 2 diabetes (T2D) who are not using insulin therapy and who can engage in significant weight loss. We evaluated the predictive value of baseline parameters on T2D remission, including duration of diabetes, HbA1c levels, diabetic medications as drug count, and CGM metrics, with the objective to improvise the patient selection strategies for remission Methods We analyzed T2D patients (n=209) who completed 18 months of digital twin intervention. Potential predictors were examined by logistic regression analyses, with model performance evaluated by accuracy, precision, recall, and Area under the Receiver Operating Characteristic Curve (AUC-ROC) metrics. Results The model achieved an accuracy of 78.57%, precision of 79.41%, recall of 93.10%, and AUC-ROC of 0.745. Significant inverse associations with remission were observed for the duration of diabetes (OR: 0.74), baseline HbA1c (OR: 0.76), and the number of anti-diabetic medications as oral drugs (OR: 0.77), indicating decreased odds of remission with increasing values. Conversely, positive associations were found for Time Below Range 2 at baseline (OR: 1.22) and HOMA2IR at baseline (OR: 1.24), suggesting increased odds of remission with higher values in these metrics. We describe the Receiver Operating Characteristic (ROC) curve for the diabetes remission prediction model, with the area under the curve (AUC) indicating the model's discriminatory ability. The duration of diabetes emerged as the most significant negative predictor, followed by baseline HbA1c and the number of diabetic drugs, while counterintuitive findings like the positive association of baseline HOMA2IR with remission suggest areas for further investigation. Conclusion We identified baseline parameters significantly influencing the likelihood of T2D remission in people undergoing digital twin intervention. The odds ratios indicate the effect sizes of these predictors, highlighting the importance of personalized, data-driven treatment approaches that potentially enhance remission outcomes. Further validation of these findings in larger external cohorts would be useful.

Presentation: 6/1/2024
12600 Predictors Of Diabetes Remission: The Impact Of Early Intervention Through A Digital Twin Platform
Authors: Joshi S R , Dharmalingam M , Vadavi A , Keshavamurthy A , Bhonsley S , Thajudeen M , Balasubramanian A , Panandikar M , Shamanna P
Published: October 2024

Disclosure: S.R. Joshi: None. M. Dharmalingam: None. A. Vadavi: None. A. Keshavamurthy: None. S. Bhonsley: None. M. Thajudeen: None. A. Balasubramanian: None. M. Panandikar: None. P. Shamanna: None.

Introduction and Objective: Digital twin (DT) platform uses Artificial Intelligence (AI) and Internet of Things, to integrate multi-dimensional data for precision nutrition and health recommendations via the mobile app. We aimed to identify the pre-intervention anthropometric and biochemical parameters that predict diabetes remission (HbA1c < 6.5% without medications for over 3 months). Methods: 209 patients with T2D completed 540 days (18 months) of DT intervention. Results: 129 (61.7%) achieved remission of T2DM (R group). At baseline, patients in R group, compared with patients in the Non-remission Group (group NR) (n=80) had shorter duration of diabetes (yrs) (R: 2.9±2.6, 95% CI 2.5 to 3.4) vs. (NR: 4.7±2.2, 95% CI 4.2 to 5.2), p= <0.0001; lower baseline HbA1c % (R: 8.6±1.9, 95% CI 8.3 to 9) vs. (NR: 9.5±1.7, 95% CI 9.1 to 9.9), p=0.0008; lower estimated HbA1c (eA1C) (R: 7.6±2.2, 95% CI 7.2 to 8) vs. (NR: 8.9±2.3, 95% CI 8.4 to 9.4), p= <0.0001; lower glucose management indicator (GMI) % (R: 7.5±1.6, 95% CI 7.2 to 7.8) vs. (NR: 8.4±1.8, 95% CI 7.9 to 8.8), p=0.0006; ; lower Time Above Range level 1 (TAR1 %; target 180-250 mg/dl < 25% time) (R:21.3±17.6, 95% CI 18.2 to 24.4) vs. (NR: 31.2±17.2, 95% CI 27.3 to 35), p<0.0001; lower Time Above Range level 2 (TAR2 %; target >250 mg/dl < 5% time) (R: 15±24.5, 95% CI 10.8 to 19.3) vs. (NR: 24.2±26.3, 95% CI 18.2 to 29.9), p=0.01; higher Time In Range (TIR; target 70-180 mg/dl >70% time) (R: 59.5±31.5, 95% CI 54 to 65) vs. (NR: 43.3±30.9, 95% CI 36.4 to 50.2), p=0.0003; lower fasting plasma glucose (mg/dl) (R: 161±53.4, 95% CI 151.7 to 170.3) vs. (NR: 186.4±69.3, 95% CI 171 to 201.8), p=0.003; higher HOMA2B (%) (R: 56.6±31.7, 95% CI 51.1 to 62.1) Vs (NR: 43.6±27.5, 95% CI 37.4 to 49.6), p=0.002; and comparable fasting insulin (mIU/L) (R: 13.9±10.1, 95% CI 12.2 to 15.7) vs. (NR: 11.8±7.2, 95% CI 10.2 to 13.4), p=0.09 (ns), HOMA2IR (%) (R:1.9±0.93, 95% CI 1.8 to 2.1) vs (NR:1.8±0.84, 95% CI 1.6 to 2), p=0.33 (ns); weight (kg) (R:78.9±14.4, 95% CI 76.2 to 81.6) vs (NR:78.1±12.8, 95% CI 75.3 to 81), p=0.71 (ns). The mean baseline anti-diabetic drug count was lower in R (1.4) Vs NR (2.1). At 540 days the change was as follows: comparable Time Below Range1 - TBR1 %(< 70-54 mg/dl) < 4% (R: 3.5±14.9, 95% CI 0.92 to 6.1) Vs (NR: 1.9±8.3, 95% CI 0.07 to 3.8), p=0.38 (ns); lower HbA1c (R: 5.9±0.35, 95% CI 5.8 to 6) Vs (NR: 7.2±1.1, 95% CI 7 to 7.5), p<0.0001. Conclusion: Shorter diabetes duration, lower baseline HbA1c, eA1C, GMI, and TAR, higher TIR, lower fasting plasma glucose, and higher beta-cell function are key predictors of diabetes remission.

Presentation: 6/3/2024
12397 Predictors Of Hospital Readmission Within Three Months Among Patients Admitted For Diabetic Ketoacidosis (dka)
Authors: Onwudiwe O , Yerashevich L , Onwudiwe C , Baral B , Acharya A , Nguyen H
Published: October 2024

Disclosure: O. Onwudiwe: None. L. Yerashevich: None. C. Onwudiwe: None. B. Baral: None. A. Acharya: None. H. Nguyen: None.

Purpose: Diabetic ketoacidosis (DKA) represents a critical, life-threatening complication of diabetes, with higher rates of re-admission noted among individuals from lower socioeconomic backgrounds, those lacking insurance coverage, and those with suboptimal follow-up care. This study seeks to identify predictors of hospital readmission within three months among patients admitted for DKA in a community hospital setting. Methods: Patient data were extracted from electronic medical records from 2019 to 2021 for individuals admitted due to DKA using ICD codes. DKA diagnosis was based on the presence of hyperglycemia, high anion gap metabolic acidosis, and ketonemia. Demographic information, results of routine biochemical tests, insurance status, follow-up with primary care providers (PCP) or endocrinologists, and clinical progression were retrospectively collected from patients' records. Multivariable logistic regression analyses were conducted to identify predictors of readmission. Results: A total of 222 unique DKA admission visits were analyzed. The mean age (standard deviation) of the patients was 48 (16) years, and 58% of them were male. Among these visits, 39% had type 1 diabetes, 43% had type 2 diabetes, and 18% were newly diagnosed diabetes cases. The majority of patients were overweight, with a mean body mass index (BMI) of 27, and the mean glycated hemoglobin level was 10.8. Common triggers for DKA included insulin non-adherence (52%), infection (37.8%), and alcohol use (8.6%). Logistic regression analysis revealed that lack of follow-up significantly increased the odds of readmission within three months (B = 2.025, p = .003, Exp(B) = 7.576, 95% CI [1.952, 29.401]), as did having type 1 diabetes (B = 1.473, p = .019, Exp(B) = 4.364, 95% CI [1.272, 14.978]). However, the association between insulin adherence and readmission was not statistically significant at the conventional alpha level of 0.05 (B = 1.329, p = .112, Exp(B) = 3.777, 95% CI [0.733, 19.458]). Other demographic (age, gender, employment status, insurance status, medication compliance,) and clinical [insulin adherence, presence of infection, blood glucose level at diagnosis of DKA, and level of glycated hemoglobin (Hba1c)] variables did not significantly predict readmission within 3 months. Conclusion: DKA, being preventable with adequate insulin adherence, is also influenced by factors such as infection and lifestyle choices. The findings highlight the critical role of post-discharge follow-up care in reducing readmission rates among DKA patients. Healthcare providers should prioritize ensuring timely and comprehensive follow-up, particularly for patients with type 1 diabetes, to optimize post-hospitalization management and prevent avoidable readmissions.

Presentation: 6/3/2024
8681 Preoteogenomic Identification Of Novel Translated And Regulatory Open Reading Frames In Human Beta-Cells
Authors: Walters K , Guiterrez R C , Sakhar S , Baldwin A , Nakayasu E S , Russ H , Mukherjee N
Published: October 2024

Disclosure: K. Walters: None. R.C. Guiterrez: None. S. Sakhar: None. A. Baldwin: None. E.S. Nakayasu: None. H. Russ: None. N. Mukherjee: None.

Preoteogenomic Identification of Novel Translated and Regulatory Open Reading Frames in Human Beta-cells The discovery of novel autoreactive T cells that target β cells during type 1 diabetes (T1D) has been challenging due to our limited knowledge in autoreactive β cell antigens. Most of these antigens are derived from canonical open reading frames (ORFs) of protein coding genes, such as preproinsulin and chromogranin A. However, a defective ribosomal product (DRiP) was recently identified from the insulin mRNA (INS-DRiP). This antigen is the result of translation from a novel or unannotated open reading frames (nuORFs). nuORFs have a range of functions from regulating translation to encoding novel small bioactive peptides to producing neoantigens. In this study, we use a transcriptome-wide approach to identify nuORFs in human β cells in an unbiased manner. We performed ribosome profiling (ribo-seq) in stem cell derived β cells (sBCs). Human pluripotent stem cells were differentiated into sBCs expressing a flag-tagged ribosomal protein (RPL22-Flag) driven by the rat insulin promoter. We performed IP-ribo-seq on sBCs enriching for RPL22-Flag containing ribosomes. These data exhibited high-resolution 3-nucleotide periodicity consistent with translating codons and identified sequencing reads consistent with translation of the INS-DRiP. We performed de novo ORF-calling using two software using complementary statistical approaches (RiboCode and ORFQuant). We identified over 12,000 canonical annotated ORFs of which ∼85% were had protein level support from matched proteomics confirming the high specificity of our approach. Of nearly 1000 nuORFs identified in sBCs, over half had protein level support in sBCs and cadaveric human islets. We found that 149 nuORFs were associated with Type-1 Diabetes (T1D) genes, including a novel upstream ORF (uORF) in TYK2, which had the strongest association with T1D and is a promising therapeutic target to halt T1D progression. Using reporter assay, we show that the novel uORF in TYK2 is a translational activator and warrants further investigation. Finally, our data represents a valuable database for the search of novel autoreactive antigens in β cells and accelerate the discovery of novel autoreactive T cells implicated in T1D pathogenesis.

Presentation: 6/2/2024
7513 Presence Of Hispanic/Latino Physicians In Academic Research. Are We There Yet?
Authors: Guillen Lopez Claudia Estefania , Patel Aesha , Rocha Andrea , Arima Chloe , Molkina Angelina , Robles Lydia , Gastelum Alheli Arce
Published: October 2024

Disclosure: C.E. Guillen Lopez: None. A. Patel: None. A. Rocha: None. C. Arima: None. A. Molkina: None. L. Robles: None. A. Arce Gastelum: None.

Hispanic/Latino endocrinologists' presence and active involvement in diabetes research play a pivotal role in shaping the trajectory of healthcare initiatives in the United States. Diabetes, a prevalent and complex health condition, disproportionately affects diverse communities, with Hispanics/Latinos being among the groups facing higher incidence rates. In this context, the significance of Hispanic/Latino endocrinologists cannot be overstated, as their unique perspectives and cultural insights contribute to a more nuanced understanding of the multifaceted factors influencing diabetes prevalence, management, and outcomes in the U.S. By actively involving Hispanic/Latino endocrinologists in diabetes research, we not only enhance the representation of diverse patient populations but also foster a more comprehensive approach to addressing the intricate intersections of genetics, lifestyle, and socio-cultural factors contributing to diabetes disparities in the nation. In the 2021 Physician Specialty Data Report, the Association of American Medical Colleges (AAMC) incorporated physician race and ethnicity information for the first time. Within the 7,354 actively practicing endocrinologists surveyed, only 636 individuals identified as Hispanic/Latino. The majority of these endocrinologists were predominantly dedicated to clinical practice. A descriptive analysis of 1011 abstracts on diabetes and glucose metabolism presented at the Endo Society from 2021 to 2023 revealed that 549 were authored by women and 458 by men. The majority (705 posters, 69.7%) originated from the U.S., and 306 (30.26%) were classified as international posters. Among these, 152 posters (15%) were associated with the Hispanic or Latino authors, but only 91 (9%) were published in the U.S. In conclusion, the engagement of Hispanic/Latino physicians in endocrinology is indispensable for advancing healthcare. Their participation brings diverse perspectives, facilitates a better understanding of health disparities, and promotes innovative research and patient care strategies. By actively involving Hispanic/Latino physicians, we contribute to a more comprehensive understanding of endocrine disorders and work towards a healthcare system that prioritizes inclusivity, cultural sensitivity, and collaboration, ultimately benefiting the well-being of individuals across diverse communities.

Presentation: 6/2/2024