bluuebunny/crossref_metadata_2025 huggingface dataset:
7303 Fasting and Post-load Glucose in Exclusively Breastfeeding Women With Diabetes Risk Factors
Authors: Neamonitaki Nefeli , Thaweethai Tanayott , Pant Deepti , James Kaitlyn , Soffer Marti D , Rosenberg Emily A , Powe Camille E
Published: October 2024

Disclosure: N. Neamonitaki: None. T. Thaweethai: None. D. Pant: None. K. James: None. M.D. Soffer: None. E.A. Rosenberg: None. C.E. Powe: Consulting Fee; Self; Mediflix, Inc. Other; Self; Wolters Kluwer, Up to Date Author.

Background: Epidemiologic studies show a reduction in type 2 diabetes incidence with increased lactation duration and intensity, but physiologic mechanisms underlying this association are incompletely characterized. We examined associations between lactation and glycemic physiology in postpartum women. ​ Methods: We conducted a secondary analysis of postpartum participants in a prospective longitudinal cohort study that examined glucose and insulin physiology via serial 2-hr 75-gram oral glucose tolerance tests during pregnancy and postpartum in women with diabetes risk factors. We used linear regression to examine associations between exclusive breastfeeding and fasting glucose, adjusting for age, race/ethnicity, education, body mass index, and number of weeks postpartum. Secondary analyses examined associations with post-load glucose and insulin physiology. Additional analyses considered exclusive breastfeeding compared to exclusive formula feeding and a combination of formula and breastfeeding separately using a categorical exposure variable. Results: Of N=108 women at a mean (SD) of 11 (5.0) weeks postpartum, 56 reported exclusively breastfeeding and 52 reported not exclusively breastfeeding (15 were exclusively formula feeding and 37 were both breast- and formula feeding). Mean (SD) fasting glucose was 83 (7.0) mg/dl in those exclusively breastfeeding and 85 (8.9) mg/dl in those who were not. Fasting glucose was not significantly different in those who were exclusively breastfeeding compared to those who were not after confounder adjustment (β [95% CI] =-1.3 [-4.6, 2.0] mg/dl, P=0.45). The 60- minute post-load glucose was nominally higher in those exclusively breastfeeding, with a mean (SD) of 132 (37.5) mg/dl versus 118 (31.6) mg/dl in those who were not; this difference did not reach statistical significance in the adjusted model (β [95% CI] =12.6 [-2.1, 27] mg/dl, P=0.09). In additional analyses, fasting glucose was not significantly different between women exclusively breastfeeding, exclusively formula feeding, or both breast- and formula feeding; however, post-load glucose at 30 and 60 minutes was higher in the exclusively breastfeeding group compared to the exclusively formula feeding group (30-minute: β [95% CI]= 16 [0.36,32] mg/dl, P=0.045); 60-minute: 26 [4.0,47] mg/dl, P=0.02) in adjusted models. We did not find significant associations with insulin physiology measures. Conclusion: We did not observe lower fasting glucose with exclusive breastfeeding. Instead, glucose levels at 30 and 60 minutes after an oral glucose load were higher in exclusively breastfeeding participants compared to exclusively formula feeding participants.

Presentation: 6/2/2024
12590 Glp1 Agonists Role On Prediabetes Reversal, A Meta-analysis
Authors: Levy Sitnoveter A , de Azevedo Abrantes G , Carvalhal de Almeida Cordeiro G , Soares Azevedo V , Boccalandro C
Published: October 2024

Disclosure: A. Levy Sitnoveter: None. G. de Azevedo Abrantes: None. G. Carvalhal de Almeida Cordeiro: None. V. Soares Azevedo Junior: None. C. Boccalandro: None.

Introduction: The use of glucagon like peptide 1 (GLP-1) agonists to control type two diabetes(T2DM) is well established. However, their role on prediabetes and T2DM prevention is uncertain.This study aimed to assess GLP-1 agonists role in prediabetic patients and whether it can preventor delay new-onset T2DM in this population. Methods: We performed a systematic review and meta-analysis of randomized control trials(RCT) data on the efficacy of GLP-1 agonists in delaying T2DM in prediabetes patients. Studieswithout prediabetic patients or without GLP-1 agonists as intervention were excluded. Tworeviewers collected the data from a total of 1768 studies, of which 791 were duplicated. At the endof the review there were 41 conflicts, which were analyzed by a third reviewer. After the completereading of 13 studies, 9 were excluded. Results: We included 4 RCT comprising 1717 patients (72% women from baseline). We included4 RCT comprising 1717 patients (72% women from baseline). All patients were obese, and themean follow-up duration was 30 weeks. Overall patient's taking GLP-1 agonists showed asignificant reversal of prediabetes by achieving normoglycemia (MD +5.99 [CI +4.41, 8.12]). Thestudies displayed anConclusion: GLP-1 Agonists appear to be safe and effective in lowering the progression to T2DMin patients with prediabetes and obesity. Further trials should explore the GLP-1 agonist effect onprediabetes beyond the obese population.GLP-1 agonists appeared to be safe and effective in lowering the progression to T2DM inpatients with prediabetes.

Presentation: 6/1/2024
8258 Haptoglobin-related protein (HPR) new role as insulin secretion enhancer
Authors: Viesi Carlos , Tamburini Ian , Bae Hosung , Ilegems Erwin , Velez Leandro , Zhou Mingqi , Nguyen Christy , Johnson Casey , Jang Cholsoon , Nishimura Erika , Seldin Marcus
Published: October 2024

Disclosure: C. Viesi: None.

Type 2 Diabetes (T2D) affects over 530 million people around the globe. Insulin resistance, encompassing tissues such as muscle, adipose, and liver, is the initial step hallmarked by hyperinsulinemia. Coupled with β-cell failure, these coordinated responses progress to T2D, becoming irreversible and medically challenging. Despite the well-established requirement for communication between pancreas and peripheral tissues in T2D progression, this area remains almost entirely unexplored. Here, we performed a human population genetic screening across 310 individuals to search for new endocrine regulators of pancreas function. Specifically, global gene expression from 18 peripheral tissues was analyzed to identify potential endocrine regulators of insulin secretion. This analysis prioritized liver-specific Haptoglobin-related protein (HPR) as genetically-enriched with islet insulin responses. Mouse models using AAV technology and acute protein administration of HPR showed that this newly secreted protein is sufficient to prevent diet-induced insulin resistance through enhanced beta-cell respiration. When mice were administered soluble HPR, then pancreatic tissue subjected to global RNA-sequencing, enhanced respiration pathways were observed. Next, we generated hepatocyte-specific overexpression models using AAV, which were sufficient to rescue whole-body glucose disposal profiles and weight gain in diet-induced insulin-resistant mice. Altogether, these findings highlight HPR as a novel soluble protein which signals from liver to pancreatic islets.

Presentation: 6/3/2024
7437 Harnessing Diabetes Technology for Management of Immune Checkpoint Inhibitor Associated Diabetes
Authors: Knape Anne , Kotwal Anupam , Rohlfsen Dorotha , Patel Anery , Goldner Whitney
Published: October 2024

Disclosure: A. Knape: None. A. Kotwal: None. D. Rohlfsen: None. A. Patel: None. W. Goldner: None.

Background: Immune checkpoint inhibitors (ICIs) are a key treatment modality for many cancers. One percent of patients who receive ICIs can develop insulin deficient ICI associated diabetes (ICI-DM). These patients often have complex oncologic therapy plans making treatment of newly diagnosed insulin deficient diabetes challenging which often results in additional healthcare-related burden for the patient. Methods: This is a retrospective case series of five adults who developed ICI-DM after receiving either PD-1, CTLA-4 or PDL-1 inhibitors or a combination. Data on demographics, medical history and labs were collected in addition to mode of glucose monitoring and treatment after diagnosis of ICI-DM. Results: Patients were age 44-72 at diagnosis of ICI-DM, three were female. Two were admitted to the hospital in DKA, one was diagnosed in the ER with severe hyperglycemia without DKA, two had outpatient hyperglycemia without DKA. Glucose at diagnosis ranged from 215-510 mg/dL. C-peptide was low for all patients. Fingerstick blood sugar (FSBS) monitoring and basal/bolus insulin was immediately initiated for all patients. All were transitioned from FSBS to continuous glucose monitor (CGM) and 2/5 ultimately transitioned to sensor-augmented insulin pump therapy (AID). Time in range on CGM improved in four patients with percent time in range improving between 10-48%. In two patients, hypoglycemia frequency declined by 6% and 3%. Hyperglycemia frequency declined by 13% and 48% in patients on AID therapy and by 14% and 25% in two of those on basal/bolus insulin therapy. All patients preferred CGM over FSBS and remained on CGM therapy. Those who chose AID preferred it over basal/bolus insulin therapy stating it was less complicated than basal/bolus insulin with CGM. Conclusions: We report successful treatment of five cases of ICI-DM with CGM + basal/bolus insulin or AID. 80% demonstrated improved time in range and decreased overall frequency of hyperglycemia. 40% had decreased frequency of hypoglycemia. CGM allows for dynamic adjustment of insulin therapy in a population with complex medical regimens resulting in fluctuating glucose levels. The integrated pump and sensor technology in AID was less burdensome than basal/bolus in those who chose it. Managing ICI-DM is complicated. The burden of this entity can be lessened by harnessing the power of diabetes technology.

Presentation: 6/2/2024
8798 How Low Can You Go: Suspected Methadone-Induced Hyperinsulinemia
Authors: Ravindra L , Fernandez M G , Cheng V
Published: October 2024

Disclosure: L. Ravindra: None. M.G. Fernandez: None. V. Cheng: None.

Background: Studies have shown that methadone use can result in severe hypoglycemia. This is thought to be related to methadone having antagonistic activity at NMDA receptors, resulting in increased pancreatic insulin release, suppressed glucagon and epinephrine, and inhibition of hepatic glycogenolysis. These mechanisms affect the normal physiologic response to hypoglycemia and can result in hyperinsulinemic-induced hypoglycemia. Clinical case: We present a case of a 56-year-old male with complex regional pain syndrome managed with a high daily dose of methadone (345 mg) who presented to the hospital for evaluation of failure to thrive and hypoglycemia. During the hospital admission, evaluation of hypoglycemia included a serum blood glucose level of 41 mg/dL (normal >60 mg/dL), with an inappropriately normal level of insulin 10 (Reference Range (RR) 3-25 mU/L), C-peptide 2.9 (RR 0.5-3.3 ng/ml), Pro-insulin 2.9 (RR 3-20 pmol/L), an undetectable level of Beta-hydroxybutyrate <0.10 (RR 0.02-0.27 mMol/L) negative insulin antibodies <0.4 (RR 0.0 - 0.4 U/mL), and negative sulfonylurea screen. Additional labs included a normal TSH of 2.8 (RR 0.3-5.5 mIU/ml) and appropriate morning cortisol of 23 (RR >14-15 μg/dL). The abdominal CT and follow-up MRI did not reveal any definite abnormalities in the pancreas. Given persistent evidence of hyperinsulinemic-induced hypoglycemia, a PET Dotatate scan was performed, confirming the absence of a neuroendocrine tumor. While admitted, management included nutritional optimization, close glucose monitoring, and an intravenous dextrose infusion. Diazoxide was also initiated and gradually increased to 150 mg three times a day. Addiction Medicine assisted in tapering down the methadone dose from 115 mg to 105 mg three times a day. With these interventions, the patient had no further episodes of hypoglycemia. On discharge, the patient was provided with a continuous glucose monitor. On follow-up, the patient has continued to show improvement and the diazoxide dose has been decreased without recurrent hypoglycemia. Given this, a selective arterial calcium stimulation test was not pursued. Conclusion: Methadone is an uncommon cause of hyperinsulinemic-induced hypoglycemia. Suspicion should arise, particularly in patients on high doses. Current evidence suggests tapering methadone dosage as the primary intervention, as insulin levels can decrease drastically and improve hypoglycemia. This therapeutic approach should be considered before pursuing invasive and costly diagnostic testing.

Presentation: 6/3/2024
6452 Hybrid Closed Loop Insulin Pump Therapy (Omnipod-5, T-Slimx2, Medtronic 780G) in uncontrolled type 1 Diabetes previously treated with multiple daily injections or open loop pumps
Authors: Farhat Ilham , Drishti Shah , Bargman Renee
Published: October 2024

Disclosure: I. Farhat: None. S. Drishti: None. R. Bargman: None.

Background: Type 1 diabetes mellitus (T1DM) poses significant challenges in managing blood glucose levels, especially in adolescents and those from lower socioeconomic backgrounds. Hybrid closed-loop insulin pump systems (HCL) integrating continuous glucose monitoring (CGM) and insulin infusion have shown promise in improving glycemic control in well-controlled patients the utility of these systems is unknown in poorly controlled populations. Objectives: This study aimed to assess real-world glycemic outcomes in children, adolescents, and young adults with uncontrolled T1DM (baseline HbA1c > 9%) using HCL pump systems (Omnipod 5, Tandem t: slim X2, Medtronic 780G) after at least one year on multiple daily injections (MDI) or open loop continuous subcutaneous insulin infusion (CSI) by the impact on HbA1c levels. Methods: Descriptive, retrospective chart review within the NYCHHC hospital system (public hospital system of New York City), of patients aged 3-24 years with T1DM for at least one year. Data on HbA1c, demographics, BMI, emergency room visits, and hospital admissions were collected from the electronic medical records. Statistical analysis using paired T-tests, compared pre-HCL and post-HCL (more than 6 months) periods. Results: A cohort of 66 patients (33 males, 33 females), with average age of16 years were identified. 19 were Hispanic, 32 were Black or African American, and 15 belonged to other racial backgrounds. Baseline average A1C was 10.9. 53 patients were prescribed Omnipod-5, 12 T-slimX2, and 1 Medtronic 780G. Of these individuals, 52 started and stayed on the pump, 14 had not commenced treatment, and 5 patients discontinued the pump system prior to the end of the study. The median follows up period was 10 months and a significant improvement in glycemic control was observed with HbA1c which decreased from 10.9 (pre-HCL initiation) to 9.8 (post-HCL) (p=0.0001, 95% CI: 0.5458-1.5558). Breaking down the group into those who persisted with HCL and those who did not, it is notable that for those who discontinued HCL HbA1c levels increased not significantly from 11.6 to 12.0, (p=0.6144, 95% CI: -2.2042 to 1.4802) while in 46 patients who continued using HCL, HbA1c decreased significantly from 10.7 to 9.5 (p=0.0001, 95% CI: 0.6818-1.7337). Patients who hadn't yet initiated pump treatment displayed an average A1c of 11.9 prior to the prescription and had no further A1C measurements during the study period. Conclusion: The study demonstrates partial efficacy of HCL pump systems in improving glycemic control in individuals with poorly controlled T1DM but fails to achieve good or moderate control. This improvement could potentially reduce long term complications but further improvements are needed to bring this population’s control into target range.

Presentation: 6/2/2024
7023 Hypoinsulinemic Hypoglycemia in a Severely Malnourished Patient with an Acute Liver Injury: A Marker of Poor Outcome!
Authors: Shrestha Ganesh , Qureshi Faisal , Yadav Kritika , Shrestha Sumira , Sapkota Supriya , Saad Eltaib
Published: October 2024

Disclosure: G. Shrestha: None. F. Qureshi: None. K. Yadav: None. S. Shrestha: None. S. Sapkota: None. E. Saad: None.

Background: Hypoglycemia is commonly seen in clinical practice, mostly observed in patients using insulin or oral hypoglycemic agents which is usually associated with hyperinsulinemia. We describe a challenging case of hypoinsulinemic hypoglycemia in a severely malnourished patient with acute liver injury. This rare clinical entity is often considered a poor prognostic feature and a marker of high mortality in patients with advanced multiorgan failure. Case Presentation: A 46-year-old male with a history of Huntington's disease was brought to the ED with altered mentation and moderate hypothermia. The exam revealed a malnourished patient with a BMI of 14. The initial serum glucose was very low (< 20 mg/dl, n: 70-100 mg/dl) which improved after dextrose 50% bolus. He also had severe sepsis from aspiration pneumonia and received fluid resuscitation and broad-spectrum antibiotics. The patient had an episode of fluid-responsive hypotension on day 2 of admission, following which his liver function worsened as evidenced by elevated transaminases (AST& ALT levels were 2,000 units (n: 13-39 IU/L ) and 1,500 units (n: 7-52 IU/L ) resp compared to normal levels on admission). Additionally, deranged prothrombin time and INR on day 2 were 29 sec (n: 10-13 sec) and 2.6 (n: <1.3) resp. Diagnostic work-up for acute hepatitis depicted no specific etiology and it was attributed to a shocked liver. The patient experienced frequent episodes of symptomatic hypoglycemia (serum glucose< 20 mg/dl), necessitating a continuous infusion of dextrose-containing IV fluids. Endocrinology service recommended serum cortisol level, insulin level, and C-peptide levels to be drawn during a documented hypoglycemia episode. Serum cortisol was high at 60 mcg/dl (n: 0.4-22.6 mcg/dl) suggesting an appropriate neurohormonal stress response to the critical illness, interestingly, both insulin 0.9 (n: 1.9-23 IU/ml) and c-peptide levels 0.02 (n: 0.73-4.37 ng/ml) were below lower limits. The persistent hypoglycemia resolved when enteral feeding was initiated, and the liver function gradually improved following hemodynamic optimization. The patient, however, continued to suffer from various clinical syndromes related to poor nutrition status, and given his terminal neurologic disease he was eventually enrolled in hospice care. Conclusion: Our case reveals a rare scenario of hypoglycemia with low insulin and C-peptide levels in severely malnourished and shocked liver contrary to more commonly encountered hyperinsulinemic hypoglycemia in patients using insulin or oral hypoglycemic agents. Hypoinsulinemic hypoglycemia should be considered seriously, particularly in critically ill patients with poor nutritional status and liver injury, as it is usually associated with poor outcomes.

Presentation: 6/3/2024
7361 Identification of Novel Therapies for Monogenic Diabetes Using Connectivity Map (CMap)
Authors: Kreienkamp R J , Dos Santos F R , Bryan C , Florez J C , Claussnitzer M , Udler M S
Published: October 2024

Disclosure: R.J. Kreienkamp: None. F.R. Dos Santos: None. C. Bryan: None. J.C. Florez: None. M. Claussnitzer: None. M.S. Udler: None.

Monogenic diabetes is an underdiagnosed form of diabetes that is caused by DNA variation of strong effect in a single gene. While it is an exciting area for targeted drug development, as some forms of monogenic diabetes can be treated with gene-specific therapies, there are currently few targeted therapies available. Additionally, existing treatments are not able to cure or modify the underlying disease. Therefore, to identify novel disease-modifying therapies, we leveraged CMap, a data resource developed at the Broad Institute of MIT and Harvard that contains over one million gene expression signatures from treatment of cell types with perturbagens including drugs, bioactive small molecules, gene overexpression, and gene knockdown reagents. We analyzed the connectivity, i.e. the similarity, between two gene expression signatures, to search for perturbagen gene expression signatures opposing gene expression changes associated with monogenic diabetes. We were able to identify 15 classes of medications with significantly enriched connectivity with HNF1A-knockdown. Included in these classes were sulfonylureas, which are known to have preferential therapeutic benefit for this specific condition, supporting this method for drug discovery. Other medications included HDAC inhibitors, tyrosine kinase inhibitors, and riboflavin. We also surveyed other genes causing monogenic syndromes that include diabetes, such as PPARG, where CMap indicated high connectivity with thiazolidinediones, a type 2 diabetes drug class with known mechanism targeting PPARγ, opposing PPARγ-knockdown and beneficial for treating patients with PPARγ-driven familial partial lipodystrophy. We then validated CMap results in a high-fidelity cellular model system - primary human adipocytes constitutively expressing Cas9 - using a high-dimensional metabolic disease oriented read-out LipocyteProfiler for systematic image-based profiling of cellular phenotypes in metabolic cell types. To establish causality between the causal monogenic target PPARG and its agonizing compound effect, we performed a targeted CRISPR-Cas9 based knockout of PPARG in human adipocytes, and linked changes at the cellular level to changes related to thiazolidinediones. The data revealed a striking association between the PPARγ perturbation and the TZD effect, along with an increasing CMap absolute value and LipocyteProfiler connectivity (p=9.8 E-6). Our findings support the use of expression signature mapping as a novel approach for identifying therapies for monogenic diabetes. Further exploration of databases like CMap and validation of identified medication classes could lead to new pharmacological treatments for diabetes.

Presentation: 6/2/2024
7396 IGF-2 Induced Hypoglycemia Associated with Metastatic Hepatocellular Carcinoma
Authors: Benyaminov Fuad , Cascio Vincent , Sinha Avani G
Published: October 2024

Disclosure: F. Benyaminov: None. V. Cascio: None. A.G. Sinha: None.

Background: Non-islet-cell tumor hypoglycemia (NICTH) is a rare entity caused by tumoral secretion of IGF-2 and is associated with a wide variety of tumors. The diagnosis is made based on serum levels of IGF-1, IGF-2, and/or pro-IGF-2. Unfortunately, due to the limited access to testing in many laboratories, this pathology is often missed. We present a case of IGF-2 mediated hypoglycemia in a patient with metastatic HCC. Clinical case: A 31-year-old man with a remote history of hepatitis B infection and recently diagnosed liver and lung lesions, likely metastatic in etiology, presented to the ED with weakness, tremors, and diaphoresis. He reportedly recorded a POC glucose level of 38 mg/dL at home. Serum glucose levels in the ED confirmed severe hypoglycemia with a serum glucose level of 50 mg/dL. Laboratory workup for insulin-mediated hypoglycemia was negative, including serum insulin (<0.4 uU/mL, n 2.6-24.9 uU/mL), proinsulin (0.7 pmol/L, n 0-10 pmol/L), C-peptide (0.1 ng/mL, n 1.1-4.4 ng/mL), BHB (0.0mmol/L), and insulin antibodies (<5.0 uU/mL) in the setting a serum glucose of 48 mg/dL. Thyroid function was normal, adrenal insufficiency was ruled out, and a sulfonylurea panel was negative. Given the likely presence of metastatic cancer, NICTH was suspected. Laboratory evaluation including IGF-2 (644 ng/mL, n 333-987 ng/mL) and IGF-1 (42 ng/mL, n 82-244 ng/mL) was consistent with IGF-2 mediated hypoglycemia, due to IGF-2:IGF-1 ratio of 14, where a ratio >10 is nearly diagnostic (1). Further laboratory workup was consistent with chronic hepatitis B, and a CT scan of the chest, abdomen, and pelvis confirmed numerous liver and lung lesions. A liver biopsy was performed with pathology demonstrating HCC. Initial treatment for hypoglycemia consisted of IV dextrose-containing fluids, with improvement of hypoglycemia. In preparation for discharge, non-pharmacological treatments were initially trialed. There have been case reports where patients were successfully treated for NICTH with cornstarch. Thus, the patient was then started on 30g of cornstarch daily, however they were unable to tolerate treatment due to nausea and the hypoglycemia persisted. The patient was instructed to eat frequent, high-carbohydrate meals including a bedtime snack which also failed to improve hypoglycemia. Subsequently, the patient was started on oral prednisone. They were eventually discharged on a dose of 20mg prednisone twice per day after achieving normoglycemia. Conclusion: NICTH due to tumoral secretion of IGF-2 is a rare cause of hypoglycemia that should be considered when labs reveal a non-insulin mediated etiology in the setting of malignancy. 1. Rana P, Kim B. A Unique Case of IGF-2 Induced Hypoglycemia Associated with Hepatocellular Carcinoma. Case Rep Endocrinol. 2019 Oct 13;2019:4601484.

Presentation: 6/1/2024
12469 Impact Of Covid-19 Infection On Diabetic Ketoacidosis Severity And Outcomes In Adult Population- A Retrospective Observational Study
Authors: Niedzialkowska Ewelina Marta , Childers Karen , Qu Lihua , Misra Lynda , Brennan Michael Roger
Published: October 2024

Disclosure: E.M. Niedzialkowska: None. K. Childers: None. L. Qu: None. L. Misra: None. M.R. Brennan: Consulting Fee; Self; Insulet Corporation, Bayer, Inc., Novo Nordisk.

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM) that can be precipitated by SARS-CoV2 infection. We analyzed clinical and demographic characteristics of patients admitted with DKA to investigate if SARS-CoV2 infection affects DKA severity on admission and outcomes. Methods: We conducted a retrospective cohort study that included adult patients admitted with a diagnosis of DKA between March 1, 2020, and March 1, 2023. Patients' demographic data including age, sex, race, ethnicity, laboratory test results on admission, ICU admissions and length of hospital stay (LOS) were compared. Patient characteristics and outcomes of interest were stratified by COVID-19 test results and compared using the Kruskal-Wallis test for continuous variables and Fisher’s exact test for categorical variables. DKA severity was classified based on HCO3 values: mild 15-18 mEq/L, moderate 10-14 mEq/L, severe <10 mEq/L. Results: The study included 902 patients, of which 734 tested negative (COVID-) and 168 tested positive (COVID+) for SARS-CoV2. The mean age was significantly higher (54.09) in COVID-19+ group compared to COVID-19- group (48.25) (p<0.001). The cohort included 49.1% females, 51.7% Whites, 43.3% Blacks, 89.8% Non-Hispanic/Latino, 2.7% Hispanic/Latino. We did not find statistically significant differences in sex (p= 0.608), race (p =0.277), ethnicity (p=0.072) anion gap (p=0.783), glucose (p=0.140), hemoglobin a1c (ha1c) values on admission (p=0.876) and ICU admissions (p=0.266) between both groups. The majority (55.3%) of the patients presented with severe DKA, followed by moderate DKA in 26.6% and mild disease in 18.1% of patients without statistically significant differences between groups (p= 0.128). The mean LOS in COVID + group (11.94 days) was longer than COVID- (6.85) group (p<0.001). Mean venous pH was significantly lower in COVID-19- (7.14) compared to COVID+ (7.17) group (p= 0.016). Betahydroxybutyrate (BHB) levels on admission were higher in COVID- group (7.98 mmol/L, N 0.02-0.27 mmol/L) compared to COVID + (7.10mmol/L) cohort. Conclusion: Patients diagnosed with COVID-19 and DKA on admission did not present with more severe disease compared to patients that tested negative. COVID+ patients were older (54.09 vs 48.2) and had significantly longer LOS (11.94 vs 6.85 days). We did not identify statistically significant differences between race, ethnicity, sex, glucose, anion gap, Ha1c on admission and ICU admission rate. BHB levels on admission were higher in patients that tested negative. Interestingly, mean pH was higher in COVID-19 positive group possibly due to respiratory disorders.

Presentation: 6/1/2024
8359 Increased hepatic SGK1 activity promotes metabolic dysfunction-associated fatty liver disease in a sex-dependent manner
Authors: Vastola-Mascolo Arianna , Hernández Guadalberto , Alvarez de la Rosa Diego
Published: October 2024

Disclosure: A. Vastola-Mascolo: None. G. Hernández: None. D. Alvarez de la Rosa: None.

The serum and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr kinase with key roles in fluid and electrolyte homeostasis, blood pressure regulation and energy metabolism. Its expression is controlled by steroid hormones such as glucocorticoids, mineralocorticoids and estrogen, in addition to other stimuli such as glucose. SGK1 activation mainly depends on the PI3 kinase pathway, implicating it in insulin signaling. Previous work from our laboratory demonstrated that a systemic increase in SGK1 activity exacerbates diet-induced development of metabolic syndrome in mouse, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, a high-fat diet rapidly led to the development of hepatic steatosis. We now test the hypothesis that at least part of the effects of increased systemic SGK1 activity promoting the development of metabolic syndrome are due to alterations in liver glucose or lipid handling. To that end we developed a mouse strain with hepatocyte-specific transgenic SKG1 expression and challenged it with high-fat or high-fat/high-sucrose diets. Our results show sex differences in the development of obesity, with a marked increase in body weight in female, but not male transgenic animals. Glucose homeostasis was normal in both sexes. Increased obesity in females correlated with increased lipid accumulation in the liver. However, liver fibrosis, inflammation and dyslipidemia were more marked in male animals, further suggesting an interaction between SGK1 and sex steroid hormone signaling. Our results demonstrate a key role of SGK1 in liver lipid metabolism and suggest a crosstalk between this signaling pathway and sex hormones, which determine a more negative outcome in male animals.

Presentation: 6/1/2024
8443 Incretin-Mimetic Therapy In Hypertriglyceridemia-Induced Pancreatitis - A Case Report
Authors: Iqbal Anira , Alwahab Ula Abed
Published: October 2024

Disclosure: A. Iqbal: None. U. Alwahab: None.

Introduction The use of incretin-mimetic therapy (IMT), which includes human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonists, in patients with a history of pancreatitis is controversial. While clinical trials have demonstrated a slightly increased incidence of acute pancreatitis (AP) in patients on IMT, it is unclear if patients with hypertriglyceridemia (HTG)-induced pancreatitis areat similar risk. In patients with type 2 diabetes (T2D) and HTG, control of diabetes and improvement of metabolic profile using IMT could decrease the risk of HTG-induced pancreatitis. Case Description We report a case of a patient with diabetes and a history of HTG-induced pancreatitis where IMT was successfully used without precipitation of AP. Patient A is a 44-year-old male with obesity (BMI 38.25 kg/m2 ), T2D, and severe HTG associated with recurrent episodes of AP. His triglyceride (TG) level has ranged from 983 to >4,000 mg/dL. He is on fenofibrate, icosapent ethyl, and rosuvastatin. His last hospitalization for acute pancreatitis was 3months prior. His most recent hemoglobin A1c is 7.4%, TG is 302mg/dL, and he is being treated with glipizide, metformin, empagliflozin, and multiple daily injections of insulin. For management of his obesity and T2D, he is then started on tirzepatide, in conjunction with diet and lifestyle modification, which is slowly up-titrated to 7.5 mg weekly. After 12 months of tirzepatide treatment, he has lost 10 lbs, his A1C is now 5.9%, triglycerides have improved to 172 mg/dL, and he has had no precipitation of AP. Discussion While a history of pancreatitis is a relative contraindication to the use of IMT, attention should be paid to the cause of pancreatitis. Obesity and uncontrolled diabetes are frequent triggers of AP. IMT helps improve metabolic profile in patients with obesity, uncontrolled diabetes, and hypertriglyceridemia, thus decreasing triglyceride levels and preventing further episodes of AP as seen in our patient. The use of IMT in patients with a history of AP should be done on an individualized basis. Controlling the trigger for the AP (such as hypertriglyceridemia) should be prioritized and shared medical decision-making with the patient should be done regarding the benefits and risks of IMT.

Presentation: 6/3/2024
7923 Latent Autoimmune Diabetes of Adulthood (LADA) Complicating Common Variable Immunodeficiency (CVID)
Authors: Pathak Leilani , Jakoby Michael G
Published: October 2024

Disclosure: L. Pathak: None. M.G. Jakoby: None.

Introduction: CVID is caused by defective B-lymphocyte maturation that results in immunoglobulin deficiency. Patients with CVID are predisposed to both infections and autoimmune disorders, with approximately 20% experiencing at least one autoimmune complication. We present a patient with LADA complicating CVID. Case A 31-year-old woman was referred for newly diagnosed diabetes mellitus (DM). Medical history was notable for primary hypothyroidism and apparent chronic lymphocytic thyroiditis. A presumptive diagnosis of type 2 DM was made due to obesity, and the patient was treated with metformin. However, she could not tolerate the medication due to diarrhea. Semaglutide was substituted and tolerated without adverse effects. During the first six months of treatment with semaglutide 0.5 mg weekly, HbA1c improved from 6.4 to 5.6%. However, in the next six months, HbA1c increased to 6.6% despite full compliance with medication and stable weight. Anti-glutamic acid decarboxylase (GADA) titer was unequivocally elevated at 69.8 IU/mL (0.0-5.0), though anti-insulin and islet antigen-2 (IA-2) antibodies were undetectable. Insulin glargine was added to the patient’s diabetes regimen, and HbA1c improved to 5.5% three months later. Discussion This patient meets Immunology of Diabetes Society diagnostic criteria for LADA, namely diabetes diagnosed in adulthood (≥ 30 y), elevated diabetes-associated autoantibody titer, and insulin independence for at least six months after diagnosis. Patients with high-titer GADA tend to be younger and have more rapid and significant loss of β-cell function than patients with low GADA titers, and this patient’s rapidly waning glycemic response to semaglutide conforms with this observation. Until recently, autoimmune diabetes in the setting of CVID was thought to be an unusual complication, though the prevalence of type 1 diabetes among CVID patients in the European Society for Immunodeficiency registry is 1.6%, approximately four-fold higher than the general European population. LADA shares genetic features linked to childhood-onset type 1 DM, making it possible or evenly likely that LADA has occurred in cases of CVID, though a careful search of PubMed failed to identify reported cases. This patient illustrates the importance of considering LADA in CVID, particularly with abrupt loss of glycemic response to noninsulin therapeutic agents.

Presentation: 6/1/2024
7113 Liver Androgen Receptor Knockout Improved High-Fat Diet Induced Glucose Dysregulation in Female Mice But Not Male Mice
Authors: Andrisse S
Published: October 2024

Disclosure: S. Andrisse: None.

Previous research has indicated that liver androgen receptors may play a role in modulating disease. This study aims to investigate the pathophysiology of high fat diet (HFD) induced dysglycemia in male and female liver androgen receptor knockout (LivARKO) mice. We performed metabolic tests on LivARKO female and male mice fed a high fat diet (HFD) or a control diet (CD) (from Research Diets Inc) during months 1 or 2 after starting the diet. Additionally, we performed western blot and qRT-PCR analysis on the livers of the mice to examine intermediates in the insulin signaling pathway. LivARKO-HFD female mice displayed no difference in glucose tolerance compared to female LivARKO-Control mice. Whereas in WT female mice, HFD impaired glucose tolerance (IGT). Our data suggests that starting at one-month LivARKO may be protecting female mice from HFD-induced metabolic dysfunction. LivARKO-HFD female mice displayed significantly worse insulin sensitivity at 15 minutes compared to LivARKO-Control (Con) female mice; but, strangely, LivARKO-HFD female mice had significantly better insulin sensitivity at 60 and 90 minutes compared to LivARKO-Con female mice. Despite protecting against IGT, LivARKO did not protect against HFD-induced hyperinsulinemia (HI) in female mice. In contrast to females, male LivARKO-HFD mice displayed impaired glucose tolerance (IGT) compared to male LivARKO-Con mice. Thus, LivARKO is not protective against HFD-induced glucose metabolic dysfunction in male mice. Lastly, LivARKO-HFD female mice maintained hepatic insulin sensitivity whereas LivARKO-HFD male mice displayed hepatic insulin resistance. These findings suggest that LivARKO delayed the onset of HFD-Induced dysglycemia in female mice.

Presentation: 6/1/2024
12388 MALA: A Severe Nonfatal Case Report
Authors: Matos-Chaparro Jeysla Marie , Martinez-Aponte Victor , Velez-Maymi Sharon
Published: October 2024

Disclosure: J.M. Matos-Chaparro: None. V. Martinez-Aponte: None. S. Velez-Maymi: None.

Metformin associated lactic acidosis (MALA) is defined as altered lactate and hydrogen metabolism with pH <7.35, lactate >5 mmol/L in a patient using metformin chronically or with an overdose. MALA carries a significant mortality rate of up to 50% in metformin consumers. This is a case report of a severe non-fatal MALA that responded successfully to renal replacement therapy. We report the case of a 83-year-old female with past medical history of DMT2 and hypertension, who arrived at the urgency room due to anuria and non-radiating, lower back pain, 9/10 in intensity, with associated anorexia and general weakness, of two days of evolution. Review of systems was negative for nauseas, vomiting, and urinary symptoms. Medical reconciliation remarkable for metformin 1000 mg orally daily and losartan 100 mg orally daily. Patient was admitted to the ICU after chemistry remarkable for creatinine 6.25 mg/dL and BUN 85 mg/dL (CrCl 7 ml/min and GFR 6 ml/min). Creatine level more than 3-fold of her baseline (1.20 mg/dL). Electrolyte disturbances remarkable for severe hyperkalemia 7.30 mmol/L with peaked T waves on EKG, isotonic moderate hyponatremia (Na 128 mmol/L) and a pronounced acidosis (pH 7.28, pCO2 35, HCO3 16.20). Also, a hyperlactatemia of 9.8 mmol/L. Despite discontinuation of metformin and aggressive fluids therapy the patient progress to an oliguric state with worsening renal function (creatine 7.08 mg/dL). As per nephrology recommendations emergent renal replacement therapy was initiated. Patient underwent three consecutive days of hemodialysis that resulted in a significant improvement of renal function as well as resolution of electrolyte disturbances. The patient was transitioned to subcutaneous (Lantus) and oral therapy (Tradjenta) for DMT2 outpatient management. This case illustrates the potential for severe lactic acidosis induced by metformin toxicity. Even though most patients respond to aggressive fluid therapy and discontinuation of medication, in this case emergency hemodialysis was indicated as patient with multiple electrolyte disturbances and oliguric state. Measurements of biological parameters blood concentrations showed the effectiveness of repeated hemodialysis sessions on metformin elimination and acidosis. Patient admission was shortened due to early recognition and prompt initiation of hemodialysis, reducing hospital associated complications and cost. MALA is a fatal complication commonly seen on elderly patients on high doses of metformin. Accurate recognition and prompt initiation of dialysis and close observation in an intensive care unit leads to rapid recovery and favorable outcomes. On literature review, most cases reported with severe MALA were associated with a high mortality rate. This is a severe case of MALA with a favorable outcome due to prompt recognition and treatment with renal replacement therapy.

Presentation: 6/1/2024
8761 Marchiafava-Bignami Syndrome in a Diabetic Patient
Authors: Garg Ayushi , Chalasani Pranav , Kulairi Zain , Lawrence Lima , Sharza Jeffrey
Published: October 2024

Disclosure: A. Garg: None. P. Chalasani: None. Z. Kulairi: None. L. Lawrence: None. J. Sharza: None.

Introduction: Marchiafava-Bignami Syndrome (MBS), described as demyelination and necrosis of the corpus callosum, is a rare and fatal neurological disorder commonly caused by chronic alcoholism and malnutrition. However, there have been isolated cases of MBS reported in non-alcoholic patients, including those with uncontrolled diabetes mellitus. We report a diabetic patient who presented with anoxic hypoglycemic encephalopathy, subsequently diagnosed with MBS without a preceding history of chronic alcoholism or malnutrition. Clinical Presentation: A 56-year-old male with a past medical history of longstanding, uncontrolled type 2 diabetes mellitus, hypertension, pulmonary hypertension, congestive heart failure, chronic kidney disease(CKD), and class 3 obesity with a BMI of 43 kg/m2 was hospitalized for unresponsiveness. On arrival to the ED, his blood glucose was 37 mg/dl, and he received 1 amp of dextrose. On examination, Glasgow Coma Scale was 6 and the patient was intubated and transferred to intensive care. Labs were remarkable for hemoglobin A1c 7.0% in the setting of anemia with hemoglobin 10.4 g/dL (12.0-15.5), C-peptide 14.3 ng/ml (1.1-4.4), and insulin 4.0 uIU/mL (< 25), with a corresponding blood glucose of 141 mg/dl. MRI brain revealed necrosis and demyelination of the splenium of the corpus callosum, consistent with MBS. The patient was found to be persistently hypoglycemic, requiring IV dextrose infusion and octreotide for sulfonylurea-induced hypoglycemia, in the setting of renal dysfunction. The patient’s family corroborated noncompliance with diabetes medications. Extensive tests including CSF analysis for various infections and malignancies yielded no results. The patient was eventually transferred to hospice care and expired, after prolonged hospitalization. Conclusion: The etiology of MBS is most commonly alcoholism and malnutrition; however, there are rare case reports of MBS in patients with poorly controlled diabetes who are not alcoholic or malnourished. Wide glycemic fluctuations and subsequent osmotic changes are thought to contribute to the pathophysiology of MBS in diabetic patients. Hypoglycemia can induce osmotic stress in oligodendroglial cells, leading to the structural and functional abnormalities seen in MBS. In this patient with longstanding uncontrolled diabetes and medication noncompliance, in the setting of CKD and sulfonylurea use, wide glycemic fluctuations likely contributed to the development of this atypical case of MBS. Reference: Marchiafava-Bignami disease triggered by poorly controlled diabetes mellitus A.I. Pérez Álvarez, C. Ramón Carbajo, G. Morís de la Tassa, J. Pascual Gómez https://www.elsevier.es/en-revista-neurologia-english-edition--495-articulo-marchiafava-bignami-disease-triggered-by-poorly-S2173580816300633

Presentation: 6/1/2024
12449 Mechanisms Underlying Progressive Loss Of Sulfonylurea Sensitivity In T2D In Vivo
Authors: Patel S , Yan Z , Remedi M S
Published: October 2024

Disclosure: S. Patel: None. Z. Yan: None. M.S. Remedi: None.

Type 2 Diabetes (T2D) is characterized by a gradual loss of functional pancreatic β-cell mass, along with insulin resistance in peripheral tissues. Sulfonylureas (i.e. glibenclamide/glyburide) have long been used to treat T2D because of their ability to inhibit pancreatic β-cell KATP channels and therefore enhance insulin secretion. Although initially beneficial, sulfonylureas inevitably fail as sole therapy for unknown reasons. To determine the mechanisms underlying this secondary failure, slow-release sulfonylurea glibenclamide pellets (2.5 mg/pellet, 60-day release) were implanted in 6-week-old KK mouse model of polygenic T2D. As expected, KK mice implanted with placebo pellets (KK-Placebo) spontaneously develop hyperglycemia (230 mg/dL), glucose intolerance, impaired insulin secretion and insulin resistance. Interestingly, KK mice chronically treated with glibenclamide (KK-Glib) did not show improvement in blood glucose levels over time, nor in glucose tolerance at day 28 and 42 post treatment. Fed plasma insulin levels were decreased in KK-Glib mice compared to KK-Placebo mice. Moreover, KK-Glib mice did not show increase in plasma insulin in response to glucose challenge during glucose tolerance test at either 28- or 42-days post-treatment. Intriguingly, KK-Glib mice demonstrated improvement in insulin sensitivity at day 30 of treatment, but surprisingly not at day 45 of treatment. Fasting-refeeding study further showed decreased insulin secretion after 2 hours of feeding in KK-Glib mice compared to the KK-Placebo mice. KK-Glib mice demonstrated islet hypertrophy, and reduced β-cell number, which drive the increase in α:β cell ratio. Strikingly, islets from the KK-Glib mice showed a marked increased expression of α-cell identity markers: Gcg, Irx2, MafB and Arx with respect to KK-Placebo mice. While β-cell identity markers did not change in islets from KK-Glib mice with respect to KK-Placebo, there was a significant increase in Ngn3 mRNA levels in islets from KK-Glib mice, suggestive of β-cell dedifferentiation. Importantly, while glucose stimulated glucagon secretion was unchanged between KK-Glib and KK-Placebo islets, glucagon content was significantly increased in islets from KK-Glib mice. These findings show that secondary failure to sulfonylureas could be partly due to the increased turnover of α-cells upon treatment.

Presentation: 6/2/2024
6817 Metabolomics Analysis Reveals Disordered Serotonin Metabolism as a Novel Therapeutic Target for Post-Bariatric Hypoglycemia
Authors: Ferraz-Bannitz R , Ozturk B , Cummings C , Efthymiou V , Wang H , Navarrete V , Saeed H , Mulla C M , Sandoval D , Pan H , Dreyfuss J M , Patti M E
Published: October 2024

Disclosure: R. Ferraz-Bannitz: None. B. Ozturk: None. C. Cummings: None. V. Efthymiou: None. H. Wang: None. V. Navarrete: None. H. Saeed: None. C.M. Mulla: None. D. Sandoval: None. H. Pan: None. J.M. Dreyfuss: None. M. Patti: Advisory Board Member; Self; Fractyl Health. Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Dexcom.

Bariatric surgery is a potent approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. To identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after an oral mixed meal in 3 groups: PBH (n=13), asymptomatic post-RYGB (n=10), and non-surgical controls (n=8). In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30-80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20-50% in PBH vs. asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2-10-fold in PBH in the fasting state (p<0.01 for all). Serotonin patterns in response to meal ingestion were distinct in PBH. ELISA analysis of serotonin levels revealed 1.9-fold increase at 120 minutes after the meal (p<0.001); by comparison, serotonin levels decreased by 1.6 to 1.4-fold over the same time course in asymptomatic and nonsurgical groups (p<0.001 for both). To determine whether serotonin could modulate glucose levels, we injected wild type C57BL/6J mice with serotonin (20 mg/kg, intraperitoneal) or vehicle. Glucose levels were 39-43% lower in serotonin-injected mice (p<0.01 at 15-60 minutes). Serotonin administration also significantly increased plasma insulin by up to 5-fold at 30 minutes (p=0.004) and increased plasma GLP1 by up to 2-fold (p<0.001). Moreover, serotonin-induced hypoglycemia after mixed meal in mice was blocked by the serotonin antagonist cyproheptadine. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a new therapeutic target.

Presentation: 6/1/2024