bluuebunny/crossref_metadata_2025 huggingface dataset:
7574 Diabetes Stem Cells: A Common Target for Abnormal Insulin Secretion and Insulin Resistance
Authors: Kojima Hideto , Katagi Miwako , Okano Junko , Nakagawa Takahiko
Published: October 2024

Disclosure: H. Kojima: None. M. Katagi: None. J. Okano: None. T. Nakagawa: None.

Diabetes is based on chronic inflammation and cannot be cured using only drugs that lower blood glucose levels. A culprit was lurking there that was hindering healing. We discovered abnormal hematopoietic stem cells that caused persistent chronic inflammation in the bone marrow of diabetic model animals. The real culprit is born after several days of hyperglycemia, never dies, and each time glycemic control deteriorates, it moves its progeny in large numbers throughout the body, fusing with unique cells in various organs and producing TNF-α from the organ cells. We have named these worst stem cells, which resemble cancer stem cells, "diabetes stem cells," and attempted to induce complete remission in diabetic model animals by eliminating them with drugs. In this study, we used streptozotocin (STZ)-induced insulin-deficient diabetes model mice. "Diabetes stem cells" were included in the CD106-positive short-term hematopoietic stem cell fraction, in which progenitor cells that play an important role in the regeneration of the thymus and peripheral tissues, and were characterized by abnormal expression of proinsulin and TNF-α. Furthermore, like cancer cells, the expression of histone deacetylases (HDACs) increased, and once the cells were born, they would not disappear. Therefore, we aimed to eliminate diabetes by administering an HDAC inhibitor and subcutaneously injecting insulin pellets to temporarily correct blood glucose levels. We treated diabetic mice with HDAC inhibitor for 8 weeks, along with several weeks of insulin therapy. Insulin aims to prevent the formation of new abnormal cells in the bone marrow and to prevent the inhibition of pancreatic islet wasting due to the forced insulin secretion caused by hyperglycemia. The combination therapy allowed the beta cells to regenerate and produce enough insulin to normalize blood glucose levels and maintain them even after treatment was discontinued. It also solved the mystery of how the abnormal cell population evades attacks from the T cells. In STZ diabetes, the supply of normal CD106-positive progenitor cells from the bone marrow for thymic regeneration was completely blocked, resulting in marked thymic atrophy. As a result, the thymus, which had lost its progenitor cells, was unable to establish an immune surveillance system to eliminate mutated cells throughout the body. In other words, the combination therapy completely broke the vicious cycle caused by atrophies in both the islet and the thymus. Moreover, when the thymus was surgically removed along with the adventitia to prevent regeneration, diabetes remission was completely inhibited, supporting the importance of thymic normalization. Diabetes is a hematopoietic stem cell disease accompanied by thymic dysfunction, and the removal of "diabetes stem cells" paves the way for the cure of diabetes.

Presentation: 6/2/2024
7086 Disrupted Mitochondrial Function in Alström Syndrome- A Monogenic Model of Insulin Resistance and Obesity
Authors: Ali Sadaf , Heising Silke , Veeranna Vishy , Vincent Amy , Xavier Gabriela S , Geberhiwot Tarekegn
Published: October 2024

Disclosure: S. Ali: None. S. Heising: None. V. Veeranna: None. A. Vincent: None. G.S. Xavier: None. T. Geberhiwot: None.

Alström syndrome (ALMS) is a rare monogenic disease typified by severe insulin resistance (IR) and obesity. IR and obesity are cardinal features of metabolic syndrome. The metabolic effects of insulin at key target tissues leads to metabolic haemostasis by promoting glucose and lipid uptake and metabolism to generate energy in cells. Although insulin is a major regulator of fuel metabolism, its effects on mitochondrial ATP production in severe insulin resistance are unclear. RNASeq data from adipose tissue (AT) from patients with ALMS show downregulation of the expression of genes associated with mitochondrial respiratory chain function, pointing towards possible altered mitochondrial function in ALMS. We therefore undertook a detailed assessment of mitochondrial oxidative phosphorylation capacity (OXPHOS) in skeletal muscle (SM) in ALMS. We performed SM biopsy in 10 ALMS and 10 healthy control volunteers that were age, gender and Body Mass Index matched. The SM was subjected to high resolution respirometry, the gold standard method to quantify mitochondrial function ex vivo, using OROBOROS Oxygraph -2k (O2k) system. Overall OXPHOS was higher in control SM compared to ALMS, with maximal respiration of 62.96±19.2 and 44.24 ± 12.53 pmol/(s*mg), respectively (p<0.05).Reduced oxygen influx was observed in ALMS SM in comparison to controls for fatty acid ß oxidation (6.7±5.96 vs 7.87±2.7 pmol/(s*mg);p<0.05, at complex I (19.4 ± 8.98 vs 29.7 ±5.3 pmol/(s*mg);p<0.05, and at complex II (34.98 ±11.75 vs 53.52± 13.2 pmol/(s*mg) ;p<0.05. Mitochondrial membrane integrity was unaffected during these experiments. Therefore, our analysis unveils a consistent reduction in mitochondrial respiration across all the electron transport pathway. This noteworthy finding suggests impairment in respiratory function and the electron transport chain in mitochondria, a crucial aspect of cellular energy metabolism. Several studies have previously linked IR with mitochondrial dysfunction, where insulin-resistant rodents and humans have shown blunted mitochondrial response to ATP generation. Our results align with this body of evidence emphasizing the significance of investigating the underlying mechanism contributing to this phenomenon. These findings could pave the way to exploring potential mitochondrial-targeted therapies to restore mitochondrial function and therefore, improve insulin sensitivity to tackle IR in ALMS.

Presentation: 6/2/2024
5104 Ectopic Insulinoma- a Rare Presentation of a Rare Tumor
Authors: Lavrynenko Olga , DeMarsilis Antea , Jiang Cherry , Middelbeek Roeland , Rosen Harold , Patti Mary Elizabeth
Published: October 2024

Disclosure: O. Lavrynenko: None. A. DeMarsilis: None. C. Jiang: None. R. Middelbeek: None. H. Rosen: None. M.E. Patti: None.

Background. Insulinoma is a rare, functioning neuroendocrine tumor (NET) typically localized within the pancreas, that secretes insulin, resulting in hypoglycemia. Ectopic insulinoma is even more rare than pancreatic insulinoma and is more difficult to diagnose. Case report. This 31-year-old previously healthy woman, who had an uncomplicated pregnancy and a healthy baby in October 2021, presented with intermittent hypoglycemia for more than 8 months. She denied any prior use of insulin or antidiabetic medications and was not currently taking any medications at all. There is no history of bariatric or other GI surgery. While nursing her baby in early 2022, she was noted to have a capillary blood glucose (BG) between 20-30 mg/dl, and reported both adrenergic and neuroglycopenic symptoms of hypoglycemia; these usually occurred in the morning or before lunch, especially if lunch was delayed. She wore a Libre CGM which revealed episodic hypoglycemia, which correlated with her timeline of symptoms. She reported weight gain of 8 lbs during this period. Laboratory data obtained after a 10-12 hour fast revealed hypoglycemia (venous glucose 39 mg/dL) with inappropriately high plasma insulin (42.3 mIU/ml), C- peptide (3.78 ng/ml), and proinsulin (99 pmol/L). Beta-hydroxybutyrate was 0.05 mmol/L (reference <0.28) and insulin autoantibody and sulfonylurea screen were negative. Various imaging modalities for localization revealed a solitary omental mass outside the pancreas consistent with extra-pancreatic insulinoma. No pancreatic lesion or other findings were observed with MRCP, CT C/A/P or endoscopic ultrasound. The patient underwent CT-guided biopsy of the omental mass, which confirmed a well-differentiated NET, consistent with insulinoma. Due to persistent hypoglycemia, she was started on corn starch and diazoxide. She subsequently underwent laparoscopic resection of the mass. Postoperative pathology revealed a well-differentiated NET staining positive for insulin, consistent with an extra-pancreatic insulinoma. Following surgical resection of the insulinoma, her hypoglycemia resolved even off corn starch and diazoxide. Conclusion. Ectopic insulinoma is a rare insulin-secreting NET. Only 28 ectopic insulinomas have been described in the literature to date1. We describe a patient with symptomatic hypoglycemia who was found to have an omental neuroendocrine tumor; hypoglycemia completely resolved after laparoscopic enucleation of the ectopic insulinoma. 1Fernando Guerrero-Pérez, Nuria Vialarrasa, Lidia V. Huanuco et. al. Ectopic Insulinoma: a systemic review: Reviews in Endocrine and Metabolic Disorders, 2023

Presentation: 6/1/2024
12442 Effectiveness Of An Electronic Decision Support Algorithm To Optimize Recommendation Of SGLT2i And GLP-1RA In Patients With Type 2 Diabetes Upon Discharge From Internal Medicine Wards
Authors: Jaffe E , Ayalon-Dangur I , Grossman A , Hendel H , Oved Y , Shaked A , Shimon I , Basharim B , Abo Molhem M , McNeil R , Abuhasira R , Shitrit T , Gitter L Azulay , El Saleh R , Shochat T , Eliakim-Raz N
Published: October 2024

Disclosure: E. Jaffe: None. I. Ayalon-Dangur: Grant Recipient; Self; Boehringer Ingelheim. A. Grossman: None. H. Hendel: None. Y. Oved: None. A. Shaked: None. I. Shimon: None. B. Basharim: None. M. Abo Molhem: None. R. McNeil: None. R. Abuhasira: None. T. Shitrit: None. L. Azulay Gitter: None. R. El Saleh: None. T. Shochat: None. N. Eliakim-Raz: None.

Background: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality. Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with T2DM with or at high risk for cardiovascular disease to reduce mortality. Despite the established benefit, many studies found low treatment rates with these medications in eligible patients. The aim of our study is to examine the effectiveness of a clinical decision support (CDS) algorithm that was developed in our institution, in improving the recommendation rate of SGLT2i and GLP-1RA upon discharge from hospitalization in internal medicine wards. Methods: Our algorithm was developed to automatically recommend SGLT2i and GLP-1RA for T2DM patients based on current guidelines. Data was collected from electronic medical records of all T2DM patients ≥18 years old who were eligible for SGLT2i or GLP-1RA and hospitalized for any reason in one of five internal medicine wards in Beilinson Hospital. The primary outcome was to evaluate the rate of physician recommendation of SGLT2i or GLP-1RA at hospital discharge for eligible patients pre-algorithm implementation (January 2021-December 2021) versus post-algorithm implementation (April 2023-September 2023). Results: A total of 1318 patients were included in the pre-algorithm group and 970 were included in the post-algorithm group. Median age was 75 and 73 years in the pre- and post-algorithm groups, respectively. In the pre-algorithm group, 62% were males vs 60% in the post-algorithm group. Median length of hospitalization was three days and four days in the pre- and post-algorithm groups, respectively. The rate of SGLT2i and GLP-1RA recommendation for eligible patients was 8.50% (112 of 1318 patients) in the pre-algorithm group and 22.68% (220 of 970 patients) in the post-algorithm group. The odds ratio of the recommendation rate in the post vs pre-algorithm group was 3.151, 95% confidence interval 2.467– 4.025, p<0.0001. Conclusion: The results of this study demonstrate the benefit of an algorithm as part of a CDS system to improve recommendation rates of SGLT2i and GLP-1RA for eligible patients upon discharge from hospitalization. Future studies should assess the impact of the algorithm on prescription rates, patient adherence, and long-term outcomes.

Presentation: 6/2/2024
7944 Elevated Serum Alkaline Phosphatase without other Abnormalities of Liver Associated Enzymes as an early Indicator of Glucose Intolerance: A Case Series
Authors: Bowens Brendan K , Godar Cassandra , LaChance David , Hoang Thanh Duc , Shakir Mohamed K M
Published: October 2024

Disclosure: B.K. Bowens: None. C. Godar: None. D. LaChance: None. T.D. Hoang: None. M.K. Shakir: None.

Glucose intolerance (GI) is defined as dysglycemia and includes impaired fasting glucose, impaired glucose tolerance, and prediabetes. Early detection of GI could lead to appropriate treatment and delay the progression to diabetes mellitus. The cases below detail two patients with elevated serum alkaline phosphatase (ALP) without other liver-associated enzyme abnormalities as an early indicator of GI. Case 1: A 54-year-old woman with a history of multinodular goiter status post thyroidectomy (2020), adrenal incidentaloma (2016), and asthma was incidentally found to have an elevated HbA1C (A1C) of 6.3% on screening labs in 2015. At that time, her ALP was 73 IU/L (ref 44−121). Her ALP levels slowly rose from 88 to 152 IU/L by September 2020. Work up did not reveal any etiological factors for the elevated ALP. One month later, HbA1C was found to be 7.6%. Metformin was initiated with improvement in A1C to 6.3% with an ALP of 130 IU/L. However, metformin was discontinued due to intolerance. In April 2023, her A1C was 9.3% with an ALP of 134 IU/L. A1C rose to 12.8% in Jun 2023 at which time she was started on insulin glargine, insulin aspart, sitagliptin, and was restarted on metformin. Her A1C decreased to 8.6% in August 2023 with normalization of ALP to 88 IU/L. Case 2: A 53-year-old woman with a history of hypertension, hyperlipidemia, obstructive sleep apnea, and non-ischemic cardiomyopathy in 2004 was found to have an elevated A1C of 5.8% on her screening labs in Jun 2019. Her ALP was notably in the high-normal range until Oct 2021 when it was found to be 138 IU/L. Her most recent A1C was 5.9% with an ALP of 142 IU/L. The patient was started on semaglutide (WegovyTM) briefly but was unable to tolerate the side effects. She was then started on metformin 500mg BID and dulaglutide with normalized ALP level. Discussion: Emerging evidence has shown that serum ALP activity is modestly increased in cardiometabolic diseases such as type 2 diabetes, dyslipidemia, hypertension, and peripheral arterial disease. These are increasingly being considered as inflammatory disorders and it has been shown that serum ALP level was positively and independently associated with metabolic syndrome both in men and women. It is possible that ALP could be an indicator of non-alcoholic fatty liver disease (NAFLD) which is associated with GI. Typically, NAFLD presents with higher ALT and GGT, however, occasionally isolated enzyme elevations or no elevated enzymes at all may occur. Conclusion: These cases suggest that an isolated elevation in ALP could be indicative of GI. Patients incidentally found to have an elevated ALP should be worked up further for possible evidence of GI. Early detection of GI could delay progression to diabetes and decrease morbidity.

Presentation: 6/1/2024
6869 Endocrinologist Perceptions of the Value of Digital Health Tools to Assist in the Management of Insulin Dosing
Authors: Davidson M B , Liao B , Heckman C
Published: October 2024

Disclosure: M.B. Davidson: Employee; Self; Eli Lilly & Company. B. Liao: Employee; Self; Eli Lilly & Company. C. Heckman: Employee; Self; Eli Lilly & Company.

Background and aims: Insulin management is complex for both people with diabetes (PwD) and the healthcare providers (HCP) who treat them. Digital tools, such as connected insulin pen (CIP) platforms may reduce burden and improve suboptimal insulin dosing, especially through automatic capture of insulin dose events and integration with glucose values. However, the acceptance and utilization of CIP platforms in clinical practice remains lower than expected, given this clinical care gap. This study attempted to ascertain beliefs of HCP leading to this finding. Methods: For this cross-sectional study, 190 members of The Endocrine Society who self-identified as “clinical endocrinologists who treat diabetes” completed a 10-question survey on their perception of digital health tools and their value in clinical practice. Results: In their patients using multiple daily injections (MDI), defined as three or more injections of insulin per day, documentation of insulin dosing data was identified as “important” or “very important’ to 81% of respondents. However, only 48% of respondents are “confident” or “very confident” in the reliability of manually captured insulin and glucose data. While 92% of respondents indicated that a digital platform that displays insulin and glucose data would be “beneficial” or “very beneficial” for making dosing recommendations, 60% have found that a CIP platforms had been “beneficial” or “very beneficial” in helping PwD improving their glycemic control. Conclusion: A group of almost 200 clinician members of the Endocrine Society, who actively treat PwD, indicated that in their PwD using MDI regimens, access to combined insulin and glucose data is important, and digital capture of this data would be beneficial. However, this data is often unavailable or unreliable. The survey revealed a gap between their belief that availability of glucose data and insulin dosing data can help them make dosing recommendations and their belief that these will translate into impacting glycemic control of patients. Further research would be helpful to determine how diabetes technology may better support these HCP and the PwD they treat in practice.

Presentation: 6/1/2024
12467 Ethical Challenges During Medication Scarcity
Authors: Seetharaman Kavita , Alvi Raza , Roth Virginia , Maheswaran Janane
Published: October 2024

Disclosure: K. Seetharaman: None. R. Alvi: None. V. Roth: None. J. Maheswaran: None.

Ethical considerations while rationing GLP-1 RA during medication scarcity crisis: The prevalence of type 2 diabetes and obesity have risen over the past decade. Type 2 diabetes affects nearly 29 million Americans, and one in 3 Americans are obese. Prompt treatment of type 2 diabetes can result in prevention and progression of several diabetes related complications. In the past 3 decades, advancements in scientific research has led to invention of newer therapeutic agents such as the glucagon like peptide-1 receptor agonist (GLP-1 RA) for management of type 2 diabetes and these medications have shown to provide cardiovascular benefit and renal protective effects. More recently, with increasing benefits of GLP-1 RA in treating obesity even in the absence of diabetes, the prescription rates of GLP-1 RA has increased sharply leading to acute medication scarcity and the resultant crisis has created a chaos in health care having multi-faceted repercussions.We present a short movie enacting 2 clinical scenarios with doctor and patients to initiate discussions on how to ration GLP-1 receptor agonists during times of medication scarcity crisis and the bioethical aspects to consider while making such decisions. We further include discussions by enacting pharmacy care coordinator, bioethicist, critique and defense discussion. Bioethics involved in medication scarcity crisis:https://hu-my.sharepoint.com/:v:/g/personal/kseetharaman_hsph_harvard_edu/EZIHpFRCgb5AsoKLk898TgUBsdp8JNjdAGQ6vOIpZIP1Qg?e=TkxRhz We hope our enacting of various scenarios has given you all valuable ethical perspectives to consider while rationing during times of medicine scarcity. References: National Diabetes statistics Report, https://www.cdc.gov/diabetes/data/statistics-CNN, Oprah on why she turned to weight-loss drugs. from https://www.cnn.com/videos/health/2024/03/21/oprah-weight-loss-drugs-kc-vpx.cnn Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet. 2009 Jan 31;373(9661):423-31. doi: 10.1016/S0140-6736(09)60137-9. Whitley HP, Trujillo JM, Neumiller JJ. Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages. Clin Diabetes. 2023 Summer;41(3):467-473. doi: 10.2337/cd23-0023. Epub 2023 Diabetes medications as weight loss drugs https://www.youtube.com/watch?v=VPEaLNpCzTY

Presentation: 6/3/2024
8139 Examining the Association of GLP1-RA or DPP4i with Bullous Skin Diseases in Veterans
Authors: Saad-Omer Suhail , Kinaan Mustafa , Sami Naveed , Mansi Ishak
Published: October 2024

Disclosure: S. Saad-Omer: None. M. Kinaan: None. N. Sami: None. I. Mansi: None.

Introduction: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are Autoimmune Blistering Disorders (AIBDs). GLP-1 Receptor Agonists (GLP1-RA) and Dipeptidyl peptidase 4 inhibitors (DPP4i) have been noted in various case reports and case control studies to be linked with certain AIBDs; however, their overall role in these diseases is not completely understood, despite the exponential increase in use of these medications. This study aims to be the first study to investigate the association of DPP-4 inhibitors and GLP-1 agonists with incidence of AIBD, PV, and BP in a large cohort of American veterans. Methods: This retrospective cohort study of veterans enrolled in the Veterans Health Administration (VHA) used Corporate Data Warehouse (CDW). We extracted data of patients from fiscal years (FY) 2006 to end of FY 2021 who filled either GLP1-RA or DPP4i prescriptions. CDW is a comprehensive data source that encompasses vital status, demographic data, inpatient and outpatient diagnoses and procedure codes, vital signs, laboratory data, and pharmacy fill data. The study groups included: 1) GLP1-RA group: patients who initiated GLP1-RA; and 2) DPP4i group: patients who initiated DPP4i. Our primary outcome was the incidence of AIBDs. We compared baseline characteristics of patients who experienced the outcome and those who did not among GLP1-RA or DDP4i users. We, thereafter, examined factors associated with incidence of AIBD, PV, and BP among GLP1-RA users and DPP4i users. Results: The initial cohort of GLP1-RA or DPP4i users comprised a total of 415,895 patients, from which we excluded 397 (0.095%) patients with prior bullous skin diseases before starting GLP1-RA or DPP4i medications. Overall, a total of 154 patients developed PV/BP disease after initiation of either DPP4i or GLP1-RA. Of these 154 patients, 123 of these patients were on DPP4i and 31 of these patients were on GLP1-RA. The mean age (SD) of PV/BP patients was 72 (11) years compared to an average age of 66 (10) years in patients who did not develop PV/BP. Patients were also found to be predominately white (77.9%). Factors associated with increased risk of BP were use of DPP4i (Odds Ratio [OR] 1.90, 95% confidence interval [95% CI: 1.14-3.47, p=<0.01), and older age (OR: 1.07, 95%CI: 1.04-1.09, p<0.01). Use of GLP1-RA or DPP4i was not associated with PV incidence. (OR: 1.31, 95% CI: 0.65-2.62, p=<0.45). Conclusion: In conclusion, our study supports existing literature that DPP4i use is associated with an increased risk of developing BP. Our data does not find association with GLP-1 agonists nor DPP4 inhibitors in increasing the risk of PV.

Presentation: 6/3/2024
7148 Fake Fingerstick: Artifactual Hypoglycemia in a Hospitalized patient with Systemic Sclerosis
Authors: Shteyman S , Mirza F
Published: October 2024

Disclosure: S. Shteyman: None. F. Mirza: None.

Introduction: Artifactual hypoglycemia is a problem in hospitalized patients. It often leads to unnecessary use of resources and creates anxiety for the patient and medical team. We describe a case of a 60-year-old female with history of systemic sclerosis (Raynaud, telangiectasias, esophageal dysmotility, interstitial lung disease, pulmonary hypertension), rheumatoid arthritis, autoimmune hepatitis and hypothyroidism who initially presented to the hospital emergency department with bilateral lower extremity radiculopathy, and new onset urine incontinence. She underwent spine surgery initially, followed by emergent left upper extremity thrombectomy two days later. Postoperatively, she was noted to have fingerstick glucose of 34 mg/dL. Dextrose and juice were given, and endocrinology service was consulted. The patient was monitored with 2 hourly fingerstick glucose and was noted to have frequent hypoglycemia on fingerstick monitoring. Serum glucose in AM labs was consistently within normal limits. Patient denied both adrenergic and neuroglycopenic symptoms during periods of “hypoglycemia”. She was asked to fast till fingerstick glucose was noted to be at 43 mg/dl, when blood was drawn for serum glucose, insulin, proinsulin, C-peptide, B-hydroxybutyric acid, IGF-2, insulin AB, and sulfonylurea panel, prior to giving her any dextrose. She was asymptomatic at the time. All labs were within normal limits, with serum glucose at 119 mg/dL. At that point, artifactual hypoglycemia was suspected. Serum glucose was checked twice again when fingerstick glucose was noted to be <45mg/dL, and corresponding serum glucose was noted to be normal at both times (>100 mg/dL). Decision of artifactual hypoglycemia was made and fingerstick glucose monitoring was discontinued in this non-diabetic patient, with recommendation to check serum glucose only if symptoms of hypoglycemia occur, as fingerstick glucose values were not reliable. Fasting serum glucose continued to be normal for the remainder of the hospitalization. Discussion: There have been a handful cases of artifactual hypoglycemia reported in patients with CREST, systemic sclerosis, and Raynaud’s disease. It is thought to be due to abnormal small vasculature causing delayed transit of blood through capillaries, and increased uptake of glucose into the interstitial tissue. Some recommend using earlobe sticks as a replacement for fingerstick glucose monitoring in these patients. Future research can explore if continuous glucose monitoring can be used reliably in these patients.

Presentation: 6/1/2024
6900 Fetal Abdominal Obesity in Women Exhibiting One Abnormal Value on Diagnostic Testing for Gestational Diabetes Mellitus
Authors: Kim Wonjin , Park Soo Kyung , Kim Yoo Lee
Published: October 2024

Disclosure: W. Kim: None. S. Park: None. Y. Kim: None.

Background: Fetal abdominal obesity (FAO) was already observed at the time of diagnosis of GDM in our previous study. We investigated whether fetuses of women with hyperglycemia milder than GDM showed accelerated abdominal growth, leading to adverse pregnancy outcomes. Methods: We retrospectively reviewed the medical records of 7,569 singleton pregnant women who were universally screened using a 50-g glucose challenge test (GCT) and underwent a 3-h 100-g oral glucose tolerance test (OGTT) if GCT result was ≥140mg/dL. GDM, one value abnormality (OVA), and normal glucose tolerance (NGT, NGT1: GCT negative, NGT2: GCT positive & OGTT negative) were diagnosed using Carpenter-Coustan criteria. With fetal biometry data measured simultaneously with 50-g GCT, relative fetal abdominal overgrowth was investigated by assessing the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference(AC) per actual GA by the last menstruation period(LMP), biparietal diameter (BPD) or femur length(FL), respectively. FAO was defined as FAOR ≥90th percentile Results: The FAORs of GA-AC/GA-LMP and GA-AC/GA-BPD were significantly higher in OVA subjects compared to NGT subjects but not in NGT2 subjects. Although the frequency of FAO in OVA (12.1%) was between that of NGT (9.6%) and GDM (18.3%) without statistically significant difference, the prevalence of large for gestational age at birth and primary cesarean delivery rates were significantly higher in OVA (9.8% and 29.7%) than in NGT (5.1% and 21.5%, p<0.05). Particularly, among OVA subjects with FAO, the prevalence (33.3% and 66.7%) was significantly higher than in those without FAO (9.7% and 24.2%, p<0.05). Conclusion: The degree of fetal abdominal growth acceleration in OVA subjects was intermediate between that of NGT and GDM subjects. OVA subjects with FAO at the time of GDM diagnosis were strongly associated with adverse pregnancy outcomes.

Presentation: 6/2/2024
6656 Frequently sampled HbA1c Shows Low-Sodium, High-Carbohydrate Rice Diet To Be Effective in Type 2 Diabetes
Authors: Neelon Francis A , Sanoff Scott , Lin Pao-Hwa
Published: October 2024

Disclosure: F.A. Neelon: None. S. Sanoff: None. P. Lin: None.

Hemoglobin and glucose react to form HbA1c, which persists until red blood cells (RBCs) are removed from circulation. Since RBCs survive approximately 122 days, HbA1c is usually measured at intervals of months to years, but more frequent measurement can illuminate changes in blood glucose (BG). We used Beach’s equation for the kinetics of HbA1c formation, to construct graphical depictions of how HbA1c should decline over the 122 days after a drop from constantly high to constantly normal BG levels. As part of routine patient care (not an experimental protocol), we measured HbA1c at 2-4-week intervals in a convenience sample of 10 patients (one of whom was evaluated on 2 occasions) with Type 2 diabetes, obesity, and elevated HbA1c who attended the now defunct Rice Diet Program (RDP) in Durham, NC. All were fed 3 meals/day, comprising 800-1000 kcal of rice, fruits, grains, and vegetables (70-90% carbohydrates) and 300 mg of sodium. Two patients were initially taking insulin; 1, glipizide; and 1, sitagliptin, exenatide, metformin; all hypoglycemic agents were eventually discontinued, and none added. Mean initial HbA1c of 9.7% (range, 8.3-11.7) fell to a mean of 6.2% (range 5.3-8.4) after a mean of 82 days (range, 41-139). Variability in final HbA1c values reflects, at least in part, variable duration of voluntary residence at the RDP. In 9 patients, HbA1c declined in close accordance with the course predicted for complete normalization of blood glucose from the very start of the diet; in 1 patient, HbA1c declined slowly for 25 days, after which the rate increased to near that for complete normalization of BG. Plots of Hb1c values extrapolate back through the point of origin, implying normalization of BG occurs within days of starting the RDP, and is maintained thereafter. Data from frequent measurement of HbA1c show: 1) Normalization of BG occurs almost immediately upon dietary restriction, implying that hyperglycemia in Type 2 diabetes is driven by daily calorie excess, not by accumulated calorie excess (ie, obesity). 2) Contrary to some misperceptions, a high-carbohydrate, sodium- and calorie-restricted diet is not deleterious to ― and may actually benefit ― glucose control in Type 2 diabetes.

Presentation: 6/3/2024
7555 Gender-Related Differences in Outcomes of Patients With Diabetic Ketoacidosis: An Analysis of the National Readmission Database
Authors: Ahsan E , Lesniak C , Akula M , Hu k , Chalasani K , Ong R , Holland S , Hossain M , Cheng J , Heaton J
Published: October 2024

Disclosure: E. Ahsan: None. C. Lesniak: None. M. Akula: None. K. Hu: None. K. Chalasani: None. R. Ong: None. S. Holland: None. M. Hossain: None. J. Cheng: None. J. Heaton: None.

Introduction: Diabetic ketoacidosis (DKA), one of the most serious complications of diabetes, is a significant cause of morbidity and mortality. Hospitalizations for DKA have increased significantly over the past two decades. Despite this, there is a notable absence of data on gender-related variations in the clinical characteristics and outcomes of individuals hospitalized with DKA. Understanding these distinctions is crucial for optimizing disease prevention and care. Thus, the primary aim of this study was to explore whether gender influences the outcomes of DKA. Methodology: We analyzed the National Readmissions Database (NRD) from 2016 to 2020 by evaluating patients admitted with a primary diagnosis of DKA without coma. Patients were included if they were at least 18 years old and admitted between January and November. Patients meeting inclusion criteria were stratified by sex. The groups were assessed for 30-day readmissions, all causes of mortality, length of stay, and total cost. Descriptive statistics, Cox proportional hazards, and adjusted Wald tests were used to compare the groups. Results: Between 2016 and 2020, 642,431 patients met the inclusion criteria with a median age of 44, of which 46.5% were female and 53.5% were male. Early readmission occurred in 33,639.20 females and 31,101.92 males. Cox regression analysis showed a significant difference in readmission risk for female patients than males (HR 1.20, 95% CI 1.17-1.22, P = <0.001). The length of stay was higher in male patients than in female patients (adjusted Wald test, P =<0.001). Inpatient mortality was higher in females than in males (Cox regression analysis, P = 0.009). Total cost was higher in males compared to females (adjusted Wald test, P = <0.001). Conclusion: Regrettably, the majority of studies on diabetic ketoacidosis (DKA) have not given due attention to gender differences. Our study, however, reveals statistically significant variations in in-hospital mortality and 30-day readmission rates between men and women hospitalized with DKA, with women exhibiting higher rates than men. Additionally, the length of stay and total cost were found to be higher for men. To comprehend the underlying reasons for these distinctions, further investigations are warranted. Early introduction and intensification of insulin therapy may prove beneficial for this patient group in mitigating the risk of DKA and other complications associated with diabetes mellitus.

Presentation: 6/2/2024
8731 Glucose homeostasis remains normal across a range of adiposity in fit men and women
Authors: Potter A W , Chin G C , Jacques J I , Nindl L J , Looney D P , Tharion W J , Chapman C L , Halford E N , Friedl K E
Published: October 2024

Disclosure: A.W. Potter: None. G.C. Chin: None. J.I. Jacques: None. L.J. Nindl: None. D.P. Looney: None. W.J. Tharion: None. C.L. Chapman: None. E.N. Halford: None. K.E. Friedl: None.

Introduction. Glucose dysregulation is a major obesity-related comorbidity, affecting mental and physical performance. Glycated hemoglobin (HbA1c) is a validated and stable biomarker representing glucose regulation over 2-3 months. Nearly half of American adults (41%) have elevated HbA1c concentrations representing prediabetes (≥5.7%). In a large cross-sectional sampling of the American population, HbA1c becomes elevated in 33% of individuals at >24% body fat (BF) (men) and >38%BF (women). However, daily physical activity is an important moderator of metabolic health and adiposity - the “fit fat” concept. We evaluated this effect in physically active men and women. Methods. Body composition and metabolic health data were obtained from 36,392 adults (18,130 men and 18,262 women) in the National Health and Nutrition Examination Survey (NHANES) from 1999-2018, for comparison of %BF and HbA1c relationships. Body composition and HbA1c data were obtained from 220 healthy and physically fit active-duty military men and women (188 men, mean ± SD (range): age 25.7 ± 5.9 (18-53) years; height 176.3 ± 7.7 (154.0-201.1) cm; body mass 85.3 ± 11.9 (55.7-134.7) kg, maximal oxygen uptake (VO2max) 49.1 ± 11.9 (33.8-62.5) ml/kg/min; 32 women, age 26.5 ± 7.0 (19-45) years; height 161.4 ± 5.9 (147.1-172.8) cm; body mass 63.9 ± 8.3 (46.7-86.6) kg, VO2max 42.5 ± 8.3 (29.1-52.6) ml/kg/min). Body composition was measured using DXA (iDXA, General Electric Healthcare, Madison, WI) and HbA1c was measured from capillary blood samples using a validated point-of-care analyzer (DCA Vantage Analyzer, Siemens Medical Solutions USA, Inc, Malvern, PA). Results. HbA1c remained within the normal range (<5.7%) for 98% (216/220) of a relatively wide range of %BF in a group of men (9-36%) and women (21-46%) who engaged in daily physical activity. This sample included 64 men (34%) and 4 women (12.5%) that exceeded the 24 and 38%BF thresholds where clinically high HbA1c concentrations have been observed in the civilian population. From this subset, none of the assessed women had HbA1c ≥5.7%. Three men had HbA1c 5.7-5.8% and also high measured physical fitness (VO2max, 50.1-62.5 ml/kg/min) and low %BF (15-17%); while one had lower physical fitness (VO2max 43.87 ml/kg/min) and higher body fat (26%) (HbA1c 6%). Conclusion. Glucose homeostasis remains within normal values across a range of adiposity in fit men and women. These data support the importance of daily physical activity in mitigating elevations in HbA1c, even in individuals with increased relative body fat. Physical activity appears to have a protective effect for metabolism.

Presentation: 6/3/2024
9227 Haptoglobin-related protein (HPR) new role as insulin secretion enhancer
Authors: Viesi Carlos
Published: October 2024

Disclosure: Carlos Viesi, Ph.D.[1], Ian Tamburini, BS[1], Hosung Bae, Ph.D[1]., Erwin Ilegems, Ph.D.[2], Leandro Velez, Ph.D. [1], Mingqi Zhou, BS[1], Christy Nguyen, Ph.D.[1], Casey Johnson, Ph.D.[1], Cholsoon Jang, Ph.D[1]., Erika Nishimura[2] and Marcus Seldin, Ph.D.[1]. [1]Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California, Irvine, CA, USA, [2]Departments of Diabetes Protein Engineering, Diabetes Biology & Pharmacology, Medicinal Chemistry, Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.

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
9369 Hyperglycemia On Admission And The Risk Of Complications In Patients With Hip Fractures
Authors: Hassan A , Almardini S , Arafa F , Aoun L
Published: October 2024

Disclosure: A. Hassan: None. S. Almardini: None. F. Arafa: None. L. Aoun: None.

Hyperglycemia is associated with medical complications such as poor wound healing, immunocompromised state, prolonged hospital stay, and even death. Studies have shown that patients with type II diabetes who sustain a hip fracture have an increased risk of mortality, presumably due to the increased risk of post-operative complications like postoperative pneumonia, deep surgical site infections, and postoperative delirium. Our study aims to determine if initial glucose on admission can be used as a prognostic factor for 30-day mortality and 30-day readmission in patients presenting with hip/femur fractures who also underwent surgical repair. All patients admitted to the Northwell hospital system between 6/2022 and 7/2023 for hip/femur fractures and underwent a surgical repair above the age of 50 were analyzed for this retrospective chart review study. Patients were divided into three groups based on the initial glucose value derived from BMP/CMP (ranges: glucose <140, glucose 140-200, and glucose >200). Higher glucose ranges were used as patients fasting status could not be determined. In each glucose range group, we analyzed 30-day mortality and 30-day readmission rate. Logistic regression was utilized to assess the odds of 30-day mortality and 30-day readmission as a function of initial glucose levels on admission, adjusting for BMI category, malnutrition status, and CKD stage. Adjusted odds ratios and 95% confidence intervals were computed. The original dataset contained 3158 observations. After excluding patients that did not receive a surgical intervention during their stay (n = 752), the sample size decreased to 2406. There were 50 patients that had been admitted twice during the study period, the second visit excluded from analysis, bringing the final sample size to 2356 subjects.Initial glucose on admission was not significantly associated with 30-day mortality (p = 0.8), or with 30-day readmission (p = 0.9) after adjusting for malnutrition status, BMI, and CKD. Based on the Hosmer and Lemeshow Goodness-of-Fit Test, the data fit the model well for the 30-day mortality but poorly for the 30-day readmission. Despite the well-established associations between hyperglycemia and adverse health outcomes, our study did not identify a significant association between initial glucose on admission and 30-day mortality or 30-day readmission, even after adjusting for factors such as malnutrition status, BMI, and CKD. The lack of statistical significance in the adjusted analyses suggests that other factors may play a more substantial role in predicting these outcomes in the specified patient population.

Presentation: 6/2/2024
9247 Identification of Novel Therapies for Monogenic Diabetes Using Connectivity Map (CMap)
Authors: Kreienkamp Raymond Joseph , Dos Santos Felipe R C , Bryan Christopher , Florez Jose Carlos , Claussnitzer Melina , Udler Miriam 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
7760 Identifying Conventional and Novel Biomarkers to Predict Checkpoint Inhibitor Associated Autoimmune Diabetes
Authors: Wu L , Wentworth J , Liddle C , Carlino M , Brown D , Clifton-Bligh R J , Long G , Sasson S , Tsang V , Menzies A , Gunton J E
Published: October 2024

Disclosure: L. Wu: None. J. Wentworth: None. C. Liddle: None. M. Carlino: Consulting Fee; Self; Amgen Inc, Bristol-Myers Squibb, Novartis Pharmaceuticals, Pierre Fabre, Regeneron Pharmaceuticals, Roche Pharmaceuticals, Merck, Sanofi. D. Brown: None. R.J. Clifton-Bligh: None. G. Long: Consulting Fee; Self; Amgen Inc, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis Pharmaceuticals, Pierre Fabre, Regeneron Pharmaceuticals, Sandoz. S. Sasson: None. V. Tsang: None. A. Menzies: Consulting Fee; Self; Bristol-Myers Squibb, Novartis Pharmaceuticals, Roche Pharmaceuticals, Pierre Fabre. J.E. Gunton: None.

Introduction: Checkpoint inhibitor associated autoimmune diabetes (CIADM) is a rare but highly morbid complication of immune checkpoint inhibitor (ICI) therapy. As indications for ICIs expand, the ability to predict CIADM has huge potential value and has yet to extensively explored. Aims: To identify potential biomarkers for prediction of CIADM in patients commencing ICI therapy. Methods: 14 patients with metastatic melanoma treated with ICI who subsequently developed CIADM were identified. 28 matched controls were identified (matched for ICI type, gender, cancer response and other immune related adverse events). Pre-treatment, on ICI and post CIADM serum and PBMCs were analysed. Serum was analysed for type 1 diabetes autoantibodies, C-peptide, glucose and an immune cytokine panel of TNFα, IL-2, IL-4, IL-6, IL-10, CXCL10, IL-1β, CCL2, IL-17A, CXCL8, TGF-B1, and IL-12p70. PBMCs were sorted using a BD Influx III cell sorter into 1000 CD8 cell subsets per sample. RNA was extracted and sequenced using a NovaSeq X with approximately 10 million 150bp paired end reads. RNA-Seq analysis was performed using edgeR. Results: Pre-ICI-treatment anti-GAD had a positive predictive value for CIADM prediction of 63.6% and a negative predictive value of 82.1%. Anti-IA2, anti-IAA and anti-ZnT8 were not predictive. C-peptide fell rapidly from 1.8nmol/L on treatment to 0.18nmol/L post diagnosis for CIADM and remains normal in controls. There were no significant differences in circulating cytokines between CIADM patients and controls. Pathway enrichment analysis performed on differentially expressed genes in people who developed CIADM identified significant regulation in pathways for B cell receptor and interferon signalling, RAS signalling and IGF1R signalling. These changes were not observed in controls. Conclusion: Anti-GAD has some predictive value for CIADM, but is incompletely sensitive. Further research is needed to prospectively test the predictive value of GAD Ab in combination with other potential markers such as pancreatic volumetry as we have previously published.

Presentation: 6/2/2024