bluuebunny/crossref_metadata_2025 huggingface dataset:
8473 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
6608 Racial Disparities In Outcomes of Hyperosmolar Hyperglycemic State- A National Inpatient Sample Analysis
Authors: Karki Sunita , Neupane Shila , Neupane Binita , Chavez Luis F
Published: October 2024

Disclosure: S. Karki: None. S. Neupane: None. B. Neupane: None. L.F. Chavez: None.

Introduction: Numerous studies have explored variations in access to healthcare among racial and ethnic groups, revealing disparate challenges in insurance coverage and other healthcare services. Hyperosmolar Hyperglycemic State (HHS) or Hyperosmotic Hyperglycemic Nonketotic State (HHNK) represents a severe complication associated with type 2 diabetes mellitus. Objective of the study:To investigate if there are any racial disparities between white and black populations with the diagnosis of HHS, focusing on outcomes such as mortality rates, length of stay (LOS), hospital costs, and other outcomes. Methods: Retrospective data encompassing adult patients (age >18) with HHS between 2017 and 2020 were extracted from the National Inpatient Sample (NIS). Employing STATA as the data analysis tool, the International Classification of Diseases (ICD-10) was utilized to select disease and outcome codes. Multivariate regression analysis adjusted for relevant variables determining the adjusted odds ratio (aOR). Proportions were compared using the Fisher exact test, while continuous variables were assessed via the student t-test. The study's primary outcome was mortality, with secondary outcomes including LOS, total hospitalization costs, Acute Coronary Syndrome (ACS), septic shock, pulmonary edema, Acute Respiratory Failure (ARF), mechanical ventilation, Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI), and Cerebrovascular Accident (CVA). Results: Among 181,720 HHS-diagnosed patients, 84,140 were white, and 58,645 were black. White patients exhibited a $2,741 higher total hospital expenses compared to their black counterparts. Rates of septic shock (aOR=0.78, 5.26% vs. 4.1%, p<0.001) and ARF (aOR=0.83%, 10.54 vs. 9%, p<0.001) were elevated in whites compared to blacks. Conversely, rates of AKI were higher in blacks (aOR=1.48, 58.29% vs. 50.58%, p<0.001) compared to whites. No statistically significant differences in mortality rates, mean LOS, ACS, pulmonary edema, mechanical ventilation, ARDS, and CVA were observed. Conclusion: Whites demonstrated increased rates of total hospital expenses, septic shock, and ARF compared to blacks, while blacks exhibited higher rates of AKI. No significant differences were observed in mortality rates, LOS, ACS, pulmonary edema, mechanical ventilation, ARDS, and CVA.

Presentation: 6/2/2024
6698 Rapidly Progressive Type 1 Diabetes Mellitus Complicated By Hyperglycemic Crisis And Bowel Ischemia
Authors: Bondarenko Darya , Deyar Dylan , Nadeem Ramsha , Herrera Melanie , Arzeno Luis Enrique
Published: October 2024

Disclosure: D. Bondarenko: None. D. Deyar: None. R. Nadeem: None. M. Herrera: None. L.E. Arzeno: None.

Introduction: Type 1 diabetes mellitus (T1DM) stems from insulin deficiency due to islet-related autoantibodies. Misclassification of T1DM as type 2 diabetes mellitus (T2DM) occurs in 40% of those developing T1DM after age 30. Fulminant T1DM (FT1DM), described in East Asia, exhibits rapid progression and is diagnosed by ketosis, blood glucose ≥288 mg/dL, HgbA1c <8.7%, and fasting C-peptide <0.3 ng/mL. We present a case of rapidly progressing T1DM in a white male presenting as a hyperglycemic crisis (HC) complicated by multiorgan failure and bowel ischemia. CASE:A 52-year-old male, T2DM diagnosed by HgbA1c of 8% (normal <5.7%) 1 month prior, presented to the emergency room obtunded with two days of nausea and vomiting. Vital signs were normal other than tachycardia and tachypnea. Blood work showed pH 7.0 (normal 7.31-7.41), creatinine 4.58 mg/dL (0.7-1.3 mg/dL), glucose >1500 mg/dL (normal 65-139 mg/dL), beta-hydroxybutyrate 114.7 mg/dL (normal 0.2-2.8 mg/dL), lactate 5.7 mmol/L (normal 0.5-2 mmol/L), serum osmolarity 438 mOsmol/kg (normal 275-295 mOsmol/kg), WBC 26.2 B/L (4-11 B/L) and 4% bands (normal 0%), Hgb A1c 17.1% , C-peptide 0.11 ng/mL (0.8 - 3.85 ng/mL), GAD65 1:600 - 1:1200 (normal < 1:600). He was intubated Day 1-5. HC was treated with intravenous (IV) fluids and IV insulin infusion. He transitioned to subcutaneous insulin by Day 2. 10 days hemodialysis achieved renal recovery. He was diagnosed with latent autoimmune diabetes of adult (LADA). No triggers were identified for his HC. From Day 1, his abdominal exam was notable for guarding. Initial abdominal computed tomography (CT) was normal. Abdominal pain and distension persisted despite normalized blood work. Repeat CT showed ileus vs obstruction. Surgery on Day 12 showed multifocal bowel ischemia requiring surgical resection. Conclusion: FT1DM is a subtype of T1DM seen in Asia characterized by rapid β-cell destruction with hyperglycemia and ketoacidosis. LADA subset of T1DM manifests in adults and may take up to three years to progress to insulin dependence. Triggers for both include autoimmunity, infections, and pregnancy. HC has been associated with increased risk of occlusive and nonocclusive bowel ischemia. While this case does not meet all criteria of FT1DM, the rapid progression of the HgbA1c and disease severity is an unusual presentation of LADA. Raising awareness of the complications of this severe metabolic disorder can improve timely interventions and medical outcomes.

Presentation: 6/1/2024
7800 Real World Incidence Of Urinary Tract Infections (UTI) & Genital Tract Infections (GTI) With SGLT2 Inhibitors Alone Or In Combination With DPP4 Inhibitors In Patients With T2D In India
Authors: Gupta Arvind , Singh Nagendar Kumar , Phatak Sanjeev , Singh Akashkumar Navinprakash
Published: October 2024

Disclosure: A. Gupta: None. N. Singh: None. S. Phatak: None. A.N. Singh: None.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with urinary and genital tract infections (UTI and GTI), as they increase glucose availability in these areas, fostering bacterial growth. A study found a 26% lower occurrence of UTI and GTI in patients using a combination of Dipeptidyl Peptidase-4 inhibitors (DPP4i) and SGLT2i compared to those on SGLT2i alone. (1) The present study assessed whether patients receiving SGLT2i were at increased risk of significant UTIs & GTIs compared with those using a combination of SGLT2i & DPP-4i. A cross-sectional, multicenter, real-world study was conducted that enrolled patients with Type 2 Diabetes Mellitus (T2D) from 15th June to 30th September 2023 across 42 sites in India. The recorded data encompassed demographic information, glycemic parameters, medication use & information on hygiene practices. The sample considered for this analysis is those on SGLT2i & with or without DPPi. [Note – all patients are on other OHAs besides SGLT2i or DPP4i]. Of 10,179 patients, 2,123 were on only SGLT2i (Group A), and 8,052 were on SGLT2i and DPP4i (Group B). Group A showed a significantly higher incidence of UTI (9.09% vs. 6.11%) and GTI (6.64% vs. 5.2%). Elderly patients, especially those aged 60-69 and >70, exhibited higher UTI and GTI rates in Group A. In both genders, the incidence of UTI was higher in Group A (7.93%-males & 10.53%-females) than in Group B (5.41%-males & 7.11%-females). Amongst males, the incidence of GTI was significantly higher in Group A (5.63%) than in Group B (4.12%). In females, no significant difference was noted. Two models were developed to assess the impact of SGLT2i and insulin usage on UTI and GTI likelihood. Propensity score matching addressed confounding variables like age, gender, BMI, and comorbidities. Subsequently, logistic regression analysis focused solely on medication variables. The odds of developing UTI were calculated for various medication possibilities. As against ‘No SGLT2i’, Group A has 2.24 (CI 1.69-2.96) times higher odds of UTI, while Group B has 1.45 (CI 1.15-1.72) times. or GTI, Group A shows 3.18 (CI 2.23-4.53) times higher odds, and Group B has 2.48 (CI 1.90-3.25) times, as against ‘No SGLT2i’. In summary, DPP-4 & SGLT2 inhibitors combination therapy decreases the incidence of UTI & GTI linked to SGLT2i. Reference: (1) Fadini et al. DPP4i moderate the risk of GTI & UTI associated with SGLT2i. Diab Obes Metab. 2018 Mar;20(3):740-744.

Presentation: 6/2/2024
6774 Recurrent Hypoglycemia In Malignant Insulinoma With Multiple Liver Metastases Successfully Managed With Octreotide
Authors: Kim Keun Young , Mascarell Susana
Published: October 2024

Disclosure: K. Kim: None. S. Mascarell: None.

Introduction: Insulinoma is a rare functional pancreatic neuroendocrine tumor (pNET) with the incidence of 1-4/million person-years. Malignant insulinomas with locoregional invasion or metastases consist 10% among insulinomas. While the treatment of a single insulinoma is surgical resection, treatment of malignant insulinoma requires a comprehensive approach. Due to the low prevalence of the disease, data on therapeutic modalities of malignant insulinomas are limited. We hereby present a case of malignant insulinoma in which recurrent hypoglycemia was successfully managed with octreotide. Case: A 36 year old female diagnosed with grade III well differentiated pNET with multiple metastases to the liver and abdominal lymph nodes 1 year ago was admitted for recurrent hypoglycemic episodes. She reported progressively worsening hypoglycemia for the past 1 month. She was eating every 2 hours including her sleeping hours to prevent hypoglycemia. Due to recurrent hypoglycemia she required hospitalization with IV dextrose. After 13 hours of fasting in the ICU, hypoglycemia due to insulin hypersecretion was confirmed with blood glucose 51 mg/dL and elevated serum insulin 51.11 uIU/mL (1.9-23uIU/mL). She underwent the short octreotide test which showed suppressed insulin (5.25 uIU/mL) 6 hours after receiving 100 mcg of octreotide. She was started on octreotide 50 mcg every 12 hours and monitored for further hypoglycemic episodes. She tolerated octreotide without any side effects including hypoglycemia. She was discharged home with a continuous glucose monitor (CGM) and transitioned to intramuscular lanreotide 20mg injections every 4 weeks as an outpatient. No further hypoglycemic episodes occurred. Discussion: Few cases report treatment of hypoglycemia in malignant insulinoma with octreotide. Octreotide has the dual effect of suppressing insulin secretion and tumor growth on insulinomas that express SSTR2 receptors. However, because somatostatin agonists also inhibit the secretion of glucagon, in insulinomas without SSTR2 expression, octreotide can aggravate hypoglycemia. This was especially a concern for our patient with a large tumor burden. Thus the short octreotide test was conducted. We suggest that the octreotide test of 100 mcg SQ octreotide injection followed by hourly measurements of glucose and insulin levels is a useful and convenient test to predict efficacy while monitoring for octreotide induced hypoglycemia. Finally the use of CGM in the outpatient setting enabled successful transition to octreotide LAR which improved the patient’s quality of life greatly by enabling once a month injections.

Presentation: 6/3/2024
8537 Refractory Hypoglycemia Secondary To Metastatic Insulinoma Treated With Novel Insulin Receptor Antibody - A Case Report
Authors: Lloyd J , Abu Omar S , Lester L , Wilson L
Published: October 2024

Disclosure: J. Lloyd: None. S. Abu Omar: None. L. Lester: None. L. Wilson: None.

Introduction: Insulinoma is the most common functional pancreatic neuroendocrine tumor, characterized by hypersecretion of insulin, causing hypoglycemia. Insulinomas are mostly benign, however malignant neoplasms account for 5-10 % of cases. Surgical resection is the preferred treatment for solitary tumor, however metastatic insulinoma requires a more aggressive approach with medications to prevent hypoglycemia, resection of primary tumor, resection of metastasis, and chemoembolization. We describe a case of metastatic insulinoma with refractory hypoglycemia despite treatment with multiple medications, surgical resection of tumor, embolization of liver metastasis and successfully treated with a novel monoclonal antibody that blocks insulin receptor. Clinical Case: 43-year-old female was initially diagnosed with metastatic insulinoma in 2021. The primary tumor was pancreatic with metastasis to the liver. She was treated with surgical resection of the primary tumor and three hepatic embolizations for liver metastasis. She required a progressive number of medications to treat frequent, debilitating hypoglycemia. These medications included diazoxide, verapamil, lanreotide then changed to pasireotide, everolimus, and dexamethasone. Despite these treatments, she experienced refractory hypoglycemia and was admitted to the hospital. She required continuous dextrose infusion up to 100ml/hr of D50. Due to the large volume of fluid from dextrose infusion and other medications, she developed severe edema and AKI and required aggressive diuretic regimens and briefly intermittent CRRT. As there were no additional medications to add and prospects for future liver embolization were limited, we requested use of RZ358 through the manufacturer’s Expanded Patient Access program. This medication is a monoclonal antibody that blocks the insulin receptor to counteract the effects of insulin and thereby reduce hypoglycemia. This mechanism of action is unique from medications used to manage insulinoma induced hypoglycemia. She received her first infusion of RZ358 which she tolerated well. She had baseline elevation of ALP due to liver metastasis with further rise after liver embolizations, most recently 4 weeks prior. There was a rise in ALP levels which stabilized after 3 days. She experienced no significant side effects. For the first time in two months, five days after her first infusion of RZ358, the dextrose infusion could be stopped. She received her second infusion of RZ358 one week after first infusion. She was discharged home in a stable condition shortly after the second infusion. Conclusion: The Insulin receptor blocking monoclonal antibody, RZ358, offers a promising approach to patients with metastatic insulinoma who have refractory hypoglycemia despite maximal medical and surgical therapy.

Presentation: 6/1/2024
5154 Regulation Of T2D Genes In Human Adipocytes
Authors: Zhang Qianbin
Published: October 2024

Disclosure: Q. Zhang: None.

Type 2 diabetes (T2D) is a chronic disease that affects 415 million people around the world and was the fourth leading cause of death (2015). Insulin resistance (IR), one of the major pathophysiological mechanisms that characterize T2D, is defined as the state in which cells, tissues, or organisms no longer respond appropriately to endogenous or exogenous insulin. We have generated detailed transcriptomes and chromatin state maps from the isolated adipocytes of insulin sensitive (IS) and insulin resistant (IR) human subjects. Mapping IR/IS differentially enriched H3K27ac peaks onto T2D GWAS SNPs suggested several loci as noncoding regulatory elements (REs) of human IR. We focused on the IRS1 gene, a known T2D related locus that encodes a critical protein in the insulin signaling cascade. We developed a CRISPRi-based assay that enabled us to determine which noncoding regulatory elements are required for normal IRS1 expression in human adipocytes. Our data indicate that many IR/IS differentially regulated H3K27ac peaks are critical regulatory elements for IRS1 transcription, although we did not observe that peaks that were increased in the IS state had a larger effect, as predicted. Overall, we have developed a CRISPRi-based screening system for noncoding elements in human adipocytes, which can be deployed to study many different loci related to metabolic disease.

Presentation: 6/2/2024
8202 Retrospective Analysis of Mixed-Meal Testing in People with Suspected Spontaneous Post-Prandial Hypoglycemia
Authors: Sankaran Naveena , Jalleh Ryan , Bischoff Carmen , Marathe Chinmay
Published: October 2024

Disclosure: N. Sankaran: None. R. Jalleh: None. C. Bischoff: None. C. Marathe: None.

Introduction: While there is no consensus on the optimal confirmatory test for postprandial hypoglycemia, guidelines suggest evaluation with a mixed meal test that is most likely to provoke symptoms of hypoglycemia as nominated by the patient. However, studies evaluating post-bariatric surgery hypoglycemia indicate that meals with a lower carbohydrate content are less likely to be associated with postprandial hypoglycemia. It is hypothesized that a greater carbohydrate load may result in an excessive second-phase insulin response resulting in hypoglycemia. We evaluated the outcomes of consecutive mixed meal tests in individuals with suspected spontaneous postprandial hypoglycemia and the relationship with the percentage carbohydrate content of the test meal. Methods: We retrospectively analysed the data of 103 unselected patients who were referred to undergo a 5-hour mixed meal test following an overnight fast, between the years 2010 - 2023 at the Royal Adelaide Hospital. Correlations were determined using a linear regression model and Student’s t-test was used to compare the mean carbohydrate meal content in those with and without postprandial hypoglycemia. Outcomes: Outcomes that were measured included post-meal blood glucose, plasma insulin, plasma C-peptide levels and the macronutrient composition of the meal. Subjective reporting of symptoms during the test were also noted and correlated with the symptoms included in the Edinburgh Hypoglycemia Score. Results: 33/103 participants were excluded as they had previously undergone islet cell transplant or bariatric surgery. Out of the remaining 70 participants referred for confirmatory MMT testing, 51 were female and 19 were male. The ages of the participants ranged from 16 to 74, with the median age of 40 years. 9 participants (6 females and 3 males) had abnormal results with glucose below 3.0mmol/L. 34 participants experienced hypoglycemia with glucose levels recorded below 4.0mmol/L during the test. There was no difference in carbohydrate content consumed (61.1g, P=0.30) or percentage carbohydrate (64.5%, P=0.17) in the group without postprandial hypoglycemia compared with those with postprandial hypoglycemia (carbohydrate content 67.9 g, 69.6% carbohydrate). No correlation could be identified between the percentage of carbohydrate content of the meal with the glucose nadir (P=0.75), peak insulin concentration (P=0.99) or peak C-peptide concentration (P=0.40). The percentage of carbohydrate content of the meal was neither associated with hypoglycemia (P=0.17) or symptoms (P=0.41). Conclusion: On mixed meal testing, postprandial symptoms and hypoglycemia does not correlate with either carbohydrate load or the percentage carbohydrate content of the nominated meal.

Presentation: 6/1/2024
6769 Rhabdomyolysis In Diabetic Emergencies Highlighting The Necessity Of Prompt Creatine Kinase Monitoring
Authors: Tiwari Apoorv , Corsten Melanie , Salari Wajiha , Malik Nikhale , Dabaja Abed , Saad Chadi
Published: October 2024

Disclosure: A. Tiwari: None. M. Corsten: None. W. salari: None. N. Malik: None. A. Dabaja: None. C. Saad: None.

Rhabdomyolysis results from skeletal muscle necrosis, causing the release of intracellular contents into the bloodstream. While its association with life-threatening diabetic emergencies is rare, it remains a significant complication. We detail the case of a 37-year-old male admitted with acute pancreatitis who subsequently developed a hyperosmolar hyperglycemic state accompanied by significant electrolyte imbalances. Upon arrival at our emergency department, he displayed severe dehydration, stupor, a blood glucose level surpassing 2,000 mg/dl, and high anion gap metabolic acidosis. His condition worsened when his creatine kinase levels surged from 210 U/L to 39,000 U/L, leading to oliguric renal failure and the need for hemodialysis. His thyroid profile was unremarkable and was not on any medication. Comprehensive treatment included crystalloids, parenteral insulin, and rigorous ICU monitoring with mechanical ventilation. Following this, the patient showed rapid improvement and was discharged without requiring further dialysis. A thorough history and observation established a rare but strong link between rhabdomyolysis and hyperosmolar hyperglycemic states. These situations can intensify nephrotoxic events, especially in patients already facing severe dehydration and prerenal factors. This case emphasizes the critical need for consistent monitoring of creatine kinase levels in diabetic emergencies. Such monitoring ensures early detection and facilitates effective management of rhabdomyolysis-induced acute kidney injury, reducing potential complications and improving patient outcomes.

Presentation: 6/3/2024
12560 RIMOC1, A Novel Regulator Of Mitochondrial Function, And Its Role In Pancreatic Beta-cell Survival, Mitophagy, And Diabetogenesis
Authors: Filingeri D , Liu R , Negi V , Lee J , Kumar A , Mandi V , Moulik M , Yechoor V
Published: October 2024

Disclosure: D. Filingeri: None. R. Liu: None. V. Negi: None. J. Lee: None. A. Kumar: None. V. Mandi: None. M. Moulik: None. V. Yechoor: None.

Background: Literature supports preserving beta-cell function as an approach to slowing diabetes progression. Mitochondria emerge as an interesting area of focus, driving cellular respiration and glucose-stimulated insulin secretion (GSIS) within beta-cells in physiologic conditions, and leading to increased intracellular ROS generation when damaged. Damaged mitochondria are recycled via lysosomes by mitophagy, and defects in mitophagy have been linked to numerous disease states, with more recent data implicating impaired mitophagy with beta-cell death. Our previous work on the Hippo-TEAD pathway and beta-cell survival led to the isolation of the TEAD binding partner RIMOC1 (RAB7A-Interacting MON1-CCZ1 Complex Subunit 1), a protein highly expressed in pancreatic beta-cells, though its role in beta-cells remains unknown. The overarching hypothesis is that RIMOC1 is protective against the development of diabetes by preserving beta-cell mitophagy and mitochondrial function, and that impaired RIMOC1 function would lead to beta-cell failure and diabetes.Methods: We have generated both a stable INS2 RIMOC1 KO (knockout) cell line and an INS1-Cre RIMOC1 KO mouse model, that are beta-cell specific knockouts of RIMOC1. Mitochondrial membrane potentials were measured using TMRE and JC1 stains, and mitophagy was quantified using the mtKeima probe via flow cytometry. Protein expression was quantified via western blotting. Ongoing studies involving our mouse model include in vivo GTTs (glucose tolerance testing), ex vitro GSIS experiments to assess beta-cell function from mouse islets, and seahorse assays to quantify mitochondrial function. Results: Published GEO datasets show RIMOC1 expression is positively correlated with beta-cell maturity and negatively correlated with glucose load and HgbA1c. Our in vitro data demonstrates RIMOC1 knockout leads to decreased insulin mRNA expression, decreased insulin content, and increased beta-cell cycle inhibition. Early in vivo data shows worsened hyperglycemia with oral refeeding after fasting. In vitro mitophagy experiments demonstrate significantly diminished mitochondrial membrane potential in RIMOC1 KO INS2 cells. Conclusions: RIMOC1 is highly expressed in beta-cells and has a significant role in maintaining euglycemia through mitochondrial functioning, insulin processing, and altered mitophagy. This research highlights RIMOC1 as a promising target of further diabetes research.

Presentation: 6/2/2024
8297 Risk Of Pancreatic Cancer In Patients With Diabetes Mellitus And Pancreatitis: A Nationwide Nested Case-Control Study
Authors: Kim Young-eun , Kim Hae Kyung , Yu Min Heui , Nam Chung Mo , Kang Eun Seok
Published: October 2024

Disclosure: Y. Kim: None. H. Kim: None. M. Yu: None. C. Nam: None. E. Kang: None.

Background: Despite diabetes mellitus and pancreatitis being known risk factors for pancreatic cancer, but because of their low incidence, patients with these conditions are not included in pancreatic cancer screening. This study aimed to determine the high-risk subgroup of patients with diabetes and pancreatitis that would benefit from pancreatic cancer screening. Methods: A nested case-control study was conducted using data from the national health information database of the Korean National Health Insurance Service. Patients were categorized into the following groups: type 2 diabetes only (T2D-only), pancreatitis only (PAN-only), type 2 diabetes followed by pancreatitis (T2D-PAN), post-pancreatitis DM (PPDM), and no diabetes and no pancreatitis (NDNP). Conditional logistic regression was used to determine significant associations of each group with pancreatic cancer development risk. Results: The risk of pancreatic cancer was significantly higher in the T2D-PAN (adjusted odds ratio [AOR], 4.96; 95% confidence interval [CI], 4.48-5.49) and PPDM (AOR, 4.71; 95% CI, 4.12-5.37) groups than in the NDNP group. Furthermore, the T2D-PAN and PPDM groups had a significantly higher risk of pancreatic cancer than the T2D-only and PAN-only groups. Compared to patients in the NDNP group, patients with PPDM using insulin had a 9-fold increased risk (AOR, 9.84; 95% CI, 6.77-14.29), and patients with T2D-PAN using insulin had a 6-fold increased risk (AOR, 6.62; 95% CI, 5.33-8.20). Conclusion: Patients with both diabetes and pancreatitis had a higher risk of pancreatic cancer than those with either alone, regardless of the order of occurrence, and insulin use was associated with an additional increase in pancreatic cancer risk. These results suggest that these subgroups of patients could be considered to benefit from pancreatic cancer screening.

Presentation: 6/2/2024
12338 Risk Of Retinopathy In Patients With Type 2 Diabetes On Semaglutide
Authors: Gupta A , Nassar M , Ghanim H
Published: October 2024

Disclosure: A. Gupta: None. M. Nassar: None. H. Ghanim: None.

Title: Risk of Retinopathy in Patients with Type 2 Diabetes on SemaglutideBackground: The use of semaglutide in patients with diabetic retinopathy (DR) has raised safety concerns. While previous studies, including a meta-analysis and the SUSTAIN trial, suggested an association between rapid HbA1c reduction and retinopathy progression, recent data question the increased risk with semaglutide. Our study investigates this risk of intensive therapy benefits for the prevention of DR. Methods: This retrospective cohort study utilized TriNetX electronic health records, analyzing 117,693,426 patients with type 2 diabetes mellitus (T2DM) on anti-hyperglycemic drugs. We divided patients into those with and without a history of retinopathy, further subdividing them by treatment (Semaglutide, Sitagliptin, and Empagliflozin). After matching for confounders, we analyzed the incidence and progression of retinopathy among 336,338 Semaglutide, 578,117 Sitagliptin, and 434,552 Empagliflozin patients without a history of DR, as well as a cohort with history. Results: In patients without a prior history of DR, semaglutide showed a significant reduction in DR incidence over three years compared to sitagliptin and empagliflozin (p<0.0001). However, in those with a history, the reduction was not statistically significant (p > 0.05). Patients with mild DR on Semaglutide experienced fewer progressions to severe stages (p<0.0001), while outcomes in severe cases were inconclusive.Discussion: Semaglutide may lower the risk of developing DR in patients with T2DM without a prior history of DR and potentially stabilize or improve mild conditions without worsening severe retinopathy. The observed effects could influence treatment choices, emphasizing the need for individualized patient management. Conclusion: Semaglutide appears safe regarding retinopathy risk in patients with T2DM, offering protective benefits in those without history and not exacerbating conditions in those with prior DR. This underscores the drug's potential for comprehensive diabetes management without compromising ocular health.

Presentation: 6/3/2024
12339 Rotating Insulin Injection Sites Isn't Enough: A Challenging Case Of Insulin-Induced Lipoatrophic Panniculitis
Authors: Hand Jane , Nemiroff Samuel , Zmijewski Claudia , Levy Carol Joan
Published: October 2024

Disclosure: J. Hand: None. S. Nemiroff: None. C. Zmijewski: None. C.J. Levy: None.

Introduction: Insulin-induced localized lipoatrophy is a rare phenomenon that involves the loss of subcutaneous adipose tissue around sites of insulin injections, and it often presents as a deep, retracted scar on the skin. Its prevalence has dropped significantly given improvements in recombinant and purified insulin and its analogs, from 55% to more recently 1-2%. Lipoatrophy can cause erratic absorption of insulin, leading to suboptimal glycemic control and hypoglycemia. The pathophysiology is not completely understood but is thought to be immune-mediated. Treatment options are limited and often focus on rotating injection sites or changing the type of insulin, though some case reports alternatively describe using corticosteroid injections. Here, we report an unusual case where a patient developed a form of early, localized lipoatrophy called lipoatrophic panniculitis due to insulin. Clinical Case: A 28-year-old male with a 13-year history of type 1 diabetes presented for insulin optimization. The patient was using multiple daily injection (MDI) insulin therapy and later an insulin pump, with careful infusion site rotation. Seven years later, he experienced issues with his pump sites, developing nodules and bruises that became painful and caused labile glycemic control. He underwent dermatologic, rheumatologic, and allergic workup with two biopsies confirming insulin-induced lipoatrophic panniculitis. Immunosuppressive and varying insulin regimens were unsuccessful. Hydroxychloroquine and methotrexate showed limited improvement with intolerable gastrointestinal side effects. Trials of hydrocortisone in his insulin infusion or topical clobetasol with tacrolimus provided no benefit. Various MDI regimens with different concentrations of lispro, aspart, faster aspart, glargine, detemir, and degludec were tried; all elicited varying degrees of pain with suboptimal glycemic response. A supervised trial of inhaled insulin was associated with bronchospasms. An implantable insulin pump was sought through clinical trials but was not feasible due to eligibility. Ultimately, he was successfully referred for pancreas transplantation due to his labile and complicated diabetes, but the procedure was complicated by allograft thrombosis and failure. He is currently awaiting a second transplant. Clinical Lesson: There are few reports of patients with insulin-induced lipoatrophic panniculitis in the literature. It is an important differential to consider for a patient that is having unexpected glycemic excursions, and it is equally as challenging to select an adequate management regimen. Treatment is limited and a broad range of options need to be considered. When these patients fail mainstay immunosuppressive, corticosteroid, and insulin-based management, pancreas transplantation may be considered as an alternative feasible treatment.

Presentation: 6/1/2024
8030 Sexually Dimorphic Metabolic Consequences Of CCN5/WISP2 Gene Deletion Revealed A Male-Specific Pattern Of Gene Expression
Authors: Yang M , Xega V , Zakikhani M , Liu J L
Published: October 2024

Disclosure: M. Yang: None. V. Xega: None. M. Zakikhani: None. J. Liu: None.

Matricellular protein CCN5/WISP2 is a novel target of IGF-1 and WNT signaling within the pancreatic islets. Our previous research suggests CCN5 promotes β-cell proliferation and survival through Akt/PKB and focal adhesion kinase signaling pathways. More recently, we have reported sexual dimorphic features of CCN5 gene deletion and overexpression. Specifically, male knockout mice demonstrated improved insulin sensitivity and glucose tolerance upon high-fat diet (HFD)-induced obesity, while females were unaffected (ENDO 2022). On the other hand, male aP2-CCN5 transgenic mice that overexpress CCN5 in adipose tissues were partially protected from HFD-streptozotocin induced diabetes, with improved glucose tolerance; females exhibited impaired glucose tolerance and exacerbated diabetes (ENDO 2023). Our findings indicate that an increased level of CCN5 protects β-cells, but only in male mice. This protection cannot be solely attributed to the pro-islet effect and suggests the involvement of extra-pancreatic and sex-specific roles. This study indirectly screened normal CCN5 gene expression by detecting β-galactosidase activity, measured in X-gal-stained tissues before fixation and sectioning. In order to create the gene deletion through homologous recombination, LacZ was inserted between exons 2 and 5 of the CCN5 gene. As a result, male knockout mice exhibited a distinct blue staining in the pseudostratified columnar epithelium with stereocilia of the epididymis and vas deferens. This type of epithelium comprises a single layer of cells but appears to have multiple layers due to the nuclei being at different levels. The epithelium possesses long projections made of actin filaments and plays a crucial role in absorbing, transporting, and maturing sperm cells. The staining was also clear in Leydig cells of the testis, which produce testosterone, which was confirmed using immunohistochemistry and authentic CCN5 antibody. In female mice, however, only a few cells in the ovary and scattered staining was observed in the endometrial glands of the uterus. Since androgens promote energy expenditure, lipolysis, and insulin sensitivity, knockout or overexpression of CCN5 may potentially affect androgen and/or sperm production, leading to metabolic consequences in males. Our results from in vitro, knockout, and overexpression models support the notion that CCN5 promotes β-cell growth and survival against diabetes and further suggest that it possesses sex-specific, metabolic effects.

Presentation: 6/2/2024
7657 Single Cell RNAseq And Omics Revealed Novel Role Of Liver Group 2 Innate Lymphocytes In Regulation Of Hepatic Gluconeogenesis
Authors: Fujimoto Masanori , Tanaka Tomoaki
Published: October 2024

Disclosure: M. Fujimoto: None. T. Tanaka: None.

Background: The liver is an important organ that maintains homeostasis of glucose metabolism in the body through gluconeogenesis. It is considered that gluconeogenesis in hepatocytes is particularly active around the portal vein. However, since excessive gluconeogenesis aggravates the pathogenesis of diabetes, it is necessary to elucidate the regulatory mechanism of gluconeogenesis. Although several studies revealed that group 2 innate lymphocytes (ILC2) contribute to blood glucose maintenance in adipose and pancreatic tissues, the contribution of liver ILC2s to glucose metabolism is unknown. This study aims to elucidate the contribution of liver ILC2s to glucose metabolism and its molecular mechanism. Methods: We administered IL-33, an endogenous ILC2 activator, to BALB/c and NSG mice, and measured fasting blood glucose levels and blood glucose elevation by gluconeogenic substrate pyruvate, and blood glucose levels in liver ILC2s transplanted NSG mice. Molecular mechanisms were analyzed by single cell-RNAseq (scRNA-seq) of liver ILC2s, lung ILC2s and hepatocytes, GATA3 transcription complex, ATAC-seq, GATA3-ChIP-seq, and Metabolomics of primary hepatocytes. Results: IL-33 strongly induced IL-13 production by liver ILC2s, lowered fasting blood glucose, and suppressed pyruvate-induced glucose elevation; these effects were not observed in NSG mice lacking immune cells including ILC2s. A hypoglycemic effect of IL-33 was observed in liver ILC2-transplanted NSG mice, but not in mice transplanted with IL-13-deficient ILC2s, suggesting the effect is IL-13-dependent. scRNA-seq results showed that liver ILC2s showed higher IL-13 expression than lung ILC2s, and IL-33 treatment suppressed the expression of gluconeogenic enzymes in the G6pc-high hepatocyte population. The interaction between liver ILC2s and G6pc-high hepatocytes via IL-13/IL-13 receptors was also demonstrated; co-culture of ILC2s with primary cultured hepatocytes resulted in decreased expression of hepatocyte gluconeogenic enzymes and accumulation of multiple gluconeogenic substrates. In addition, IL-13 neutralizing antibody treatment attenuated the effect of the decreased expression of gluconeogenic enzymes in hepatocytes. Transcription factor GATA3 complex analysis and GATA3-ChIPseq suggested binding of GATA3 of the AP-1 family (JunB) in liver ILC2s. Overexpression, knockdown, and scRNA-seq results suggest that AP1 may act in a GATA3-repressive manner in liver ILC2s. Discussion The functional characteristics of liver ILC2s, hepatocyte heterogeneity and subcluster were demonstrated by scRNA-seq, suggesting that liver ILC2s may directly suppress hepatocyte gluconeogenesis via IL-13. This may play a novel role in the homeostasis of hepatic glucose metabolism.

Presentation: 6/1/2024
8722 Sodium-Glucose Cotransporter 2 Inhibitors And The Risk Of Kidney Cancer Among Patients With Type 2 Diabetes: A Population-Based Cohort Study
Authors: Lee M , Kim H , Kim R H , Yang Y , Lee S , Kang E
Published: October 2024

Disclosure: M. Lee: None. H. Kim: None. R. Kim: None. Y. Yang: None. S. Lee: None. E. Kang: None.

There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) and concomitant chronic kidney disease. Here, we investigated kidney cancer risk associated with sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with T2D, using a nationwide cohort of the Korean National Health Insurance claims and health examination database. After 1:1 propensity score matching, 83,531 SGLT2 inhibitor users and 83,531 non-users on other oral glucose-lowering drugs were selected from 814,685 cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018. During 559,738 person-years of follow-up, 143 (25.5 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 37% reduced risk of kidney cancer compared with other oral glucose-lowering drug use (18.1 vs. 29.9 per 100,000 person-years; hazard ratio [HR], 0.63; 95% CI, 0.43 to 0.92). The reduced kidney cancer risk by SGLT2 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR, 0.64; 95% CI, 0.43 to 0.93) and regardless of age, sex, BMI, comorbidities, or diabetic complications including nephropathy (all p > 0.1 for interaction). SGLT2 inhibitor use may be a preferable option for patients with T2D at high risk of kidney cancer.

Presentation: 6/3/2024
6810 Successful Insulin Allergy Desensitization To Humalog During The Second Trimester Of Pregnancy
Authors: Noreña Jairo , Seav Susan , Jiang Shirley , McGhee Sean , Tan Marilyn , Basina Marina
Published: October 2024

Disclosure: J. Noreña: None. S. Seav: None. S. Jiang: None. S. McGhee: None. M. Tan: None. M. Basina: None.

Background: Insulin allergy is rare, occurring in only 0.1 to 3% of people with insulin-treated diabetes. During pregnancy, this incidence is even lower due to a relative immunosuppressive state. Currently, there are no standardized insulin allergy desensitization protocols for this specific patient population. Clinical Case: A 39-year-old female (G4P3003) with T2DM and multiple prior medication allergies presented to the antepartum unit in her 17th week of pregnancy due to hyperglycemia and reported insulin allergy to NPH insulin.Patient was initially diagnosed with gestational diabetes during her third pregnancy, requiring NPH insulin which she seemed to tolerate well at the time. She remained medication-free for two years post-delivery but later developed T2DM with an A1c of 6.8%. Metformin and Jardiance, previously prescribed, were discontinued upon confirmation of her current pregnancy. She opted to manage her diabetes through diet and exercise alone, but her A1c rose to 7.0%, prompting the initiation of NPH.Following the first dose of NPH at home, she experienced a localized burning sensation at the injection site associated with facial flushing, followed by a diffuse, pruritic, erythematous rash on her face, chest, abdomen, and bilateral arms. Due to her history of anaphylaxis to other drugs (mainly antibiotics), she was admitted to the hospital for monitoring. Inpatient attempts with lower doses of NPH and then a trial of glargine triggered new rash episodes. Work-up revealed negative insulin antibodies, low IgG, and a normal CBC. She was started on Humalog to cover basal dose administered every 6 hours and additional prandial injections, which she tolerated prior to discharge. One week later, she developed a new local erythematous reaction at the Humalog injection site followed by a generalized rash which led to her readmission.Allergy was consulted and facilitated a successful desensitization protocol to Humalog. The protocol included escalating doses of insulin administered every 30 minutes (0.1u, 0.2u, 0.4u, 0.8u, 1u, 2u, 3u, 3u) to achieve a pre-determined cumulative dose of 10.5 units. Patient tolerated the protocol well and was discharged with q6h Humalog for basal coverage in addition to prandial doses with plan to transition to insulin pump therapy with Humalog soon. Conclusion: This unique case demonstrates how insulin desensitization can be a safe and successful strategy to help achieve insulin tolerance and glycemic control during pregnancy. Election of an insulin, such as Humalog, that can achieve the one-hour post-prandial glucose target during pregnancy and also provide effective basal coverage should be considered as desensitization can only be done with one insulin type at a time.

Presentation: 6/2/2024
8093 The Interplay Between Hypertriglyceridemia And Pancreatogenic Diabetes Mellitus
Authors: Tselovalnikova Tatiana , Bhattacharya Rajib Kumar , Drees Betty M , Tan Ngo Emmeline Monique
Published: October 2024

Disclosure: T. Tselovalnikova: None. R.K. Bhattacharya: None. B.M. Drees: None. E.T. Ngo: None.

Severe hypertriglyceridemia may induce acute pancreatitis with subsequent development of ketosis-prone pancreatogenic diabetes. This presentation is rare. We present a case of a 36-year-old female referred to our clinic for management of diabetes mellitus. At the age of 12 years, her menarche coincided with an episode of acute pancreatitis (AP) in the setting of severe hypertriglyceridemia, as well as diabetic ketoacidosis (DKA). No other causes of AP were identified - no cholecystitis, no alcohol use, no illicit substance abuse. Family history of dyslipidemia or diabetes is unclear. She was managed with insulin for hypertriglyceridemia-induced pancreatitis as well as DKA. She developed significant insulin resistance, along with elevated BMI (30.25 kg/m2), and was subsequently diagnosed with polycystic ovary syndrome, requiring metformin. Autoimmune antibodies for type 1 diabetes mellitus were all negative. Sequence analysis of the HNF1A, HNF4A, and GCK genes did not identify any sequence variants associated with maturity-onset diabetes in the young. Her diabetes has been poorly controlled with HgbA1c as high as 14.4%. Management has been complicated by non-adherence. She subsequently developed diabetic proliferative retinopathy with vitreal hemorrhages, diabetic nephropathy, and diabetic neuropathy complicated by osteomyelitis with right toe amputation. She continued to have severe hypertriglyceridemia up to 8,216 mg/dL (reference range: 0-150) associated with numerous episodes of AP with concomitant DKA, prompting frequent hospitalizations. She does not have any xanthomas or lipodystrophy on examination. No genetic testing to confirm familial causes of hypertriglyceridemia was performed as yet. There is no pre-existing cardiac conditions. She is being managed with insulin glargine, insulin aspart, metformin, pancrelipase, fenofibrate, atorvastatin, and omega-3 polyunsaturated fatty acid; however, her triglyceride level remains high at 5,353 mg/dL and diabetes remains uncontrolled with most recent HbA1c of 9%. Given the timeline of presentation in this patient, a physiological increase in estrogen level may aggravate pre-existing common or familial forms of severe hypertriglyceridemia, causing chylomicron buildup, eventually leading to recurrent pancreatitis. The manifestation of diabetes with DKA along with severe hypertriglyceridemia-induced pancreatitis is rare. Uncontrolled hypertriglyceridemia leads to frequent pancreatitis exacerbations, resulting in chronic pancreatitis and eventual overlap of pancreatogenic (Type 3c) diabetes and insulin resistance.

Presentation: 6/1/2024