Background/ObjectiveSodium-glucose cotransporter 2 (SGLT-2) inhibitors are known to increase the risk of euglycemic diabetic ketoacidosis (DKA). Hyperglycemic DKA (hDKA), however, is not a common side effect of SGLT-2 inhibitor monotherapy.Case ReportWe present a case of hyperglycemic DKA in a middle-aged Caucasian male with a history of type 2 diabetes on monotherapy with an SGLT-2 inhibitor, no history of insulin deficiency or evidence of autoimmune diabetes and no precipitating factors for DKA at presentation. The patient was discharged from the hospital on insulin therapy after resolution of DKA and was transitioned to an oral anti-hyperglycemic regimen which did not include SGLT-2 inhibitors. Close outpatient follow up subsequently revealed declining C-peptide levels and increasing hemoglobin A1C levels without any episodes of DKA.DiscussionThe mechanisms by which SGLT-2 inhibitors cause hDKA are not fully understood and likely involve hyperglucagonemia. Inhibition of SGLT-2 by dapagliflozin has been shown to paradoxically trigger glucagon secretion at higher glucose concentrations possibly due to direct effects on KATP channel activation and membrane depolarization in pancreatic α-cells.ConclusionWe conclude that monotherapy with SGLT-2 inhibitors presents a risk of not just euglycemic, but also hyperglycemic diabetic ketoacidosis in patients with type 2 diabetes and declining endogenous insulin production.

The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male Wistar rats or rat pancreatic RIN-m cells were used for in vivo and in vitro experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes

Abstract Disclosure: J. Zinn: None. L. Poretsky: None. Background: Multiple studies have demonstrated that treatment with tirzepitide results in significant improvement in HgbA1c as well as meaningful weight loss. Although the loss of skeletal muscle mass has been well described with the use of GLP-1 receptor agonists, there is little information regarding the effect of dual GLP-1/GIP receptor agonist tirzepitide on skeletal muscle mass. Clinical Case: A 68- year old male presented with a weight of 204.9 lbs and a BMI of 31.2 kg/m2. On exam, fat distribution was primarily central. Patient had a history of prediabetes, with an HgbA1c of 5.9%. He was unable to lose weight using lifestyle modifications, despite multiple meetings with a registered dietitian and consistent exercise of daily 3-6 mile walks. In the past, he used dulaglutide and semaglutide but had to discontinue these medications because of gastrointestinal side effects such as nausea and abdominal cramping. In June 2022, body composition (assessed using seca mBCA 514) demonstrated total weight of 204.9 lbs, BMI of 31.3 kg/m2, fat mass of 73.5 lbs (35.9%), fat-free mass of 131.4 lbs (64.1%), and skeletal muscle mass of 63.8 lbs (31.1%). He initiated Tirzepitide 2.5 mg weekly and maintained this dose for the duration of his treatment. Over nine months, total body weight decreased by 28.7 lbs or 13.9%. BMI decreased to 26.6 kg/m2 (at this point indicative of overweight status rather than obese). HgbA1c decreased to 5.3% (at this point no longer in the pre-diabetes range). Fat mass decreased by 18.9 lbs or 25.8%. Skeletal muscle mass decreased by 9.9 lbs or 15.5%. During this presentation we will provide a detailed time course of various metabolic and body composition parameters in this case and review relevant literature. Conclusion: We conclude that at least in some cases of patients treated with tirzepitide, up to 1/3 of lost body weight may be due to the loss of skeletal muscle mass. We suggest that, in addition to weight, serial body composition determinations should be obtained in patients on tirzepitide. It remains to be determined if adequate protein consumption and strength based exercise would ameliorate skeletal muscle mass loss observed with tirzepitide treatment. Reference: (1) Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205-216. doi:10.1056/nejmoa2206038 Presentation: 6/1/2024

Abstract Obesity is a complex chronic disease which poses a significant impact on health and wellbeing. While lifestyle modifications remain important in the treatment of obesity, incretins, such as glucagon-like peptide-1 receptor agonists and the dual incretin receptor agonist tirzepatide, have revolutionized diabetes and weight management. We report a 69-year old male initially presenting with a BMI of 31.2 kg/m2 and hemoglobin A1c of 5.9%, whose treatment with tirzepatide resulted in a reduction of weight by 28.7 lbs and a decrease in BMI to 26.8 kg/m2. Patient however, also experienced a 9.9 lb loss of skeletal muscle mass. Multiple studies have demonstrated that treatment with tirzepatide results in significant improvement in HgbA1c as well as meaningful weight loss. Although the loss of skeletal muscle mass has been well described with the use of GLP-1 receptor agonists, there is little information regarding the effect of dual GLP-1/GIP receptor agonist tirzepatide on skeletal muscle mass. We provide a detailed case study and a literature review on this topic.

This paper presents a dataset obtained from an RT2-qPCR array analysis of rat pancreatic RIN-m cells treated with two monocarbonyl analogs of curcumin (MACs), C66 and B2BrBC in the presence or absence of streptozotocin (STZ). The array quantified the expression of 84 genes associated with the onset, development, and progression of diabetes. This dataset provides information on the gene expression profiles of pancreatic cells modulated by two specific MACs in a diabetic context. The data can serve as a foundation for developing new hypotheses, designing follow-up experiments, and identifying novel targets for treatment. It can be used to investigate further the molecular mechanisms underlying the therapeutic effects of these MACs and in comparative studies using other experimental antidiabetic compounds.

Monocarbonyl analogs of curcumin (MACs) lacking a β-diketone moiety have been shown to exhibit improved stability and better bioavailability than curcumin. This study aimed to evaluate the effects of two MACs (C66 and B2BrBC) on the expression of genes related to the onset, development, and progression of diabetes in rat pancreatic RIN-m cells. The cells were cultured in complete RPMI 1640 medium and treated with C66 or B2BrBC (50 μM) or vehicle for 72 h, followed by treatment with streptozotocin (STZ) (1.5 mM) or vehicle for an additional 24 h. Quantitative PCR array analysis was performed using a rat diabetes panel comprising 84 genes. The data demonstrated that C66 and B2BrBC significantly modulated the expression of 16 genes involved in growth regulation in RIN-m cells and genes associated with inflammation, immune response, and energy metabolism. Notably, C66 and B2BrBC inhibited the STZ-induced expression of pro-inflammatory Tnf and Icam1 while increasing the expression of Ins1. Moreover, C66 pretreatment influenced Ctla4 and Serpine1 expression, and B2BrBC pretreatment affected Mapk8, Serpine1, and Igfbp5 levels compared to STZ treatment alone. Cells treated with MACs and STZ showed a different pattern of gene expression for Igfbp5, Gpd1, Agt, Serpine1, Cebpa, Retn, Ccl5, and Srebf1 compared to vehicle-treated cells. Our findings show that C66 and B2BrBC modulate the expression of essential diabetes-related genes, which may serve as a basis for further research on MACs and contribute to the development of novel therapeutic targets and strategies. Disclosure R. Stojchevski: None. J.B. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D. Avtanski: None. Funding Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research

Objective:Multiple studies have demonstrated that treatment with tirzepatide results in significant improvement in HgbA1c as well as meaningful weight loss. Although the loss of skeletal muscle mass has been well described with the use of glucagon-like peptide 1 receptor agonists, there is little information regarding the effect of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide on skeletal muscle mass. Methods:We performed serial body composition measurements in a 68-year-old male who presented with a body mass index of 31.2 kg/m2 and hemoglobin A1c of 5.9%. Treatment with tirzepatide resulted in a reduction of weight by 28.7 lbs, a decrease in body mass index to 26.8 kg/m2, and normalization of A1c (5.3%). The patient, however, also experienced a 9.9 lb loss of skeletal muscle mass, which was proportionate to a reduction in body weight - approximately 15% from the initial value for both. Muscle mass loss constituted 34% of the total body weight loss. Results:To our knowledge this is the first report of multiple serial body composition measurements in a patient on treatment with tirzepatide. The time course and the magnitude of the loss of body weight, fat mass and skeletal muscle mass are detailed. Conclusion:We propose that, in addition to weight measurements, serial body composition assessments should be obtained in patients on tirzepatide. If this is not available, our findings suggest that, at least in some cases, the percent of muscle mass lost is similar to the percent reduction of total body weight.

Abstract Disclosure: R. Stojchevski: None. A. Lavi: None. J. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. The synthesis of monocarbonyl analogs of curcumin (MACs) presents a solution to the challenges posed by curcumin, a natural polyphenol extracted from the roots of the turmeric plant (Curcuma longa), which is known for its antioxidant and anti-inflammatory properties. The limitations of curcumin, including poor stability, low bioavailability, and rapid metabolism, hinder its application, and MACs, designed without a β-diketone moiety, address these drawbacks and exhibit enhanced stability and bioavailability. This study aimed to assess the effects of two monocarbonyl analogs of curcumin, (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66) and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC), on epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cancer cells using western blot analysis. Our previous findings indicated that these analogs can potentially affect EMT by modulating the epithelial and mesenchymal gene expression. MCF-7 cells were cultured in complete medium supplemented with EMT-inducing factors for two days, followed by C66 and B2BrBC administration (100 µM) for three additional days. After the experiments, proteins were extracted, and western blot analyses were performed to measure the expression levels of various epithelial and mesenchymal markers (E-cadherin, N-cadherin, SNAI1, and Claudin-1). The results revealed that both C66 and B2BrBC increased the protein levels of the epithelial marker E-cadherin and suppressed those of the mesenchymal marker N-cadherin. Moreover, C66 and B2BrBC decreased the protein expression of the transcription factor SNAI1 and transmembrane protein Claudin-1. Between the two MACs, B2BrBC showed a more pronounced effect on N-cadherin expression, while C66 was more potent in suppressing SNAI1 protein expression. Our findings demonstrate that C66 and B2BrBC counteract EMT, contributing to the potential therapeutic applications of MACs in managing breast cancer progression. Presentation: 6/3/2024

Abstract Disclosure: S. Ahmed: None. L. Medina Mora: None. A. Sanchez Ruiz: None. L. Poretsky: None. Background: SGLT2 inhibitors have a rare but increasingly reported risk of euglycemic diabetic ketoacidosis. Hyperglycemic diabetic ketoacidosis is not an expected risk of SGLT-2 inhibitors. Clinical Case: 52-year-old male with history of type 2 Diabetes presented with progressive weakness, shortness of breath, nausea and vomiting worsening over 48 hours. He reported increased polydipsia and polyuria. Patient was found to have a blood glucose of 685 mg/dL associated with an anion gap of 28 mm/L and bicarbonate level of 6 mm/L. Beta hydroxybutyrate level was >8.0 mmoL/L. He was diagnosed with hyperglycemic diabetic ketoacidosis, given intravenous isotonic fluid and started on an insulin drip. The anion gap closed and he was successfully transitioned off the insulin drip to a basal bolus regimen of insulin. The patient improved quickly without any complication. The patient was never on insulin therapy prior to admission. No obvious source of infection was discovered to precipitate the event. The patient had a 7-year history of diabetes and was only managed on oral medications at home. He was previously on Janumet 50-1000mg twice a day and changed to only dapagliflozin 10mg 9 months prior to the current episode. He never experienced ketoacidosis or hyperosmolar hyperglycemic state. Hemoglobin A1c was found to be 8.0%. He reported that his A1c levels were always less than 8%. Autoimmune workup for type 1 Diabetes was done. C-peptide level was found to be 1.5ng/mL. Patient appeared to have an adequate insulin level despite the recent event of diabetic ketoacidosis. Patient was discharged on 10 units of Glargine® at bedtime and 3 units of Lispro® before meals. He was given glucometer teaching with an appointment for endocrine follow up. During follow up Glutamic Acid decarboxylase, Islet cell, Insulin and Zinc 8 transporter antibodies have come back negative. Patient is being planned for transition to oral antihyperglycemic agents which will not include an SGLT2 inhibitor. A MODY panel is pending results for further evaluation. Conclusion: Monotherapy of SGLT-2 inhibitors appears to not only have a risk of euglycemic diabetic ketoacidosis but also a risk of hyperglycemic diabetic ketoacidosis in type 2 diabetics. In this case we presented a case of hyperglycemic diabetic ketoacidosis in a type 2 diabetic on therapy with dapagliflozin. Presentation: Thursday, June 15, 2023

Abstract Disclosure: R. Zweifler: None. J.G. Sanchez: None. D. Kuriloff: None. E.P. Liao: None. L. Poretsky: None. Background: Alternatives to surgery for thyroid microcarcinomas and symptomatic benign thyroid nodules include active surveillance and radiofrequency ablation (RFA). However, there is paucity of information regarding these management options for Hispanic Americans. Current data suggest that non-white Americans present with larger cancer-harboring nodules making the use of active surveillance less certain. Furthermore, no RFA studies to date specifically address this population. This study will create a registry of Latinx patients with thyroid neoplasms and investigate these nonsurgical interventions for benign and malignant lesions.Methods: This study involves a registry of adult Hispanic Americans with thyroid nodules and two branching studies. The registry will collect results of FNA, prior ultrasound, and thyroid function tests. Subjects will fill out THYPRO39 (thyroid-specific quality of life questionnaire), LUMP (laryngopharyngeal measure of perceived sensation questionnaire), and have cosmetic scorings. Evaluation will recur every 6 months. Eligible subjects may enroll in one of the branching studies. The first is active surveillance for registry patients diagnosed with small, low-risk papillary thyroid carcinoma wherein subjects would be monitored every 6 months with ultrasound as an alternative to surgery. Inclusion criteria are solitary thyroid nodule ≤ 1cm, well-defined tumor margin, tumor surrounded by ≥ 2 mm of normal thyroid parenchyma, and previous ultrasound-documented stability. Exclusion criteria are metastases to regional lymph nodes, local tumor invasion, tumor growth by 3 mm or ≥50% in volume, appearance of new nodules, or other thyroid or parathyroid disease requiring surgery. The outcomes are percentage change in volume and rates of conversion to surgery. The second branching study is RFA for subjects with benign symptomatic nodules. This subset would exclude subjects who are or planning to become pregnant, breastfeeding, have a cardiac pacemaker/defibrillator, have a nodule that is not predominantly solid, or who are on anticoagulants or dual anti-platelet therapy. Subjects would have visits at 1, 3, 6, 12, and 18 months for ultrasound, thyroid function tests, questionnaires, and cosmetic scorings. The primary endpoint is percent change of nodule size from baseline to 12 months. Adverse events, total ablation time, power emitted per subject, and conversion to surgery within 18 months will also be documented. After 12 months, if a nodule has not reduced by 50%, repeat ablation will be offered. Discussion: We hypothesize that active surveillance is a valid alternative to surgery for small, low risk papillary thyroid carcinoma and that RFA is a safe and effective alternative to surgery for benign, symptomatic thyroid nodules in Hispanic Americans. Our results will broaden knowledge of a population that has been under-represented in this field. Presentation Date: Saturday, June 17, 2023

Curcumin is a natural polyphenolic compound with recognized antioxidant and anti-inflammatory effects. However, low water solubility, poor bioavailability, and rapid metabolism in vivo make its use challenging. To overcome these drawbacks, numerous curcumin analogs have been developed. The aim of the present study was to investigate the effect of two experimental curcumin monocarbonyl analogs [(2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66)] and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone) (B2BrBC)] on oxidative stress markers and antioxidant enzymes in streptozotocin (STZ)-induced diabetes rat model. The study involved a total of 53 male Wistar rats divided into two experiments in order to assess their therapeutic and preventive effects: STZ injection (60 mg/kg) followed by C66 or B2BrBC treatment (both 50 µmol/kg) daily for 30 days before the sacrifice (Experiment 1), and a single dose of C66 or B2BrBC treatment (both 125 µmol/kg) 6 hours before STZ injection, and sacrifice after 72 hours (Experiment 2). Plasma, liver, and kidney samples were obtained and used to measure the oxidative stress biomarkers [malondialdehyde (MDA) and advanced oxidation protein products (AOPP)] and the activity of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)]. The results demonstrated that both curcumin analogs displayed protective and restorative effects and counteracted the effect of STZ on the tested redox biomarkers and antioxidant enzymes, most prominently after 30 days post-treatment (Experiment 1). We conclude that the beneficial effects of C66 and B2BrBC in the STZ diabetes model provide a basis for further studies involving C66 and B2BrBC and other curcumin analogs in diabetes. Disclosure R.Stojchevski: None. M.Angelovski: None. S.Velichkovikj: None. N.Hadzi-petrushev: None. J.B.Bogdanov: None. M.Mladenov: None. L.Poretsky: None. D.Avtanski: None. Funding Gerald and Dorothy Friedman New York Foundation for Medical Research

Abstract Disclosure: R. Stojchevski: None. N. Hadzi-Petrushev: None. M. Mladenov: None. J. Bogdanov: None. S. Velichkovikj: None. L. Poretsky: None. D.B. Avtanski: None. Curcumin, a polyphenol found in turmeric (Curcuma longa), has been reported to have a range of potential therapeutic effects, including anti-inflammatory and antioxidant properties. However, curcumin’s poor bioavailability has limited its use in medicine. Monocarbonyl analogs of curcumin (MACs) have been developed to overcome this challenge and have shown promise in various medical applications, including cancer. Our previous experiments in animals showed that these two analogs possess potent antioxidant properties. The aim of this study was to investigate the in vitro effects of two experimental MACs (C66 (C22H16F6O) and B2BrBC (C20H16Br2O)) on breast cancer cell growth and epithelial-to-mesenchymal transition (EMT). Both C66 and B2BrBC significantly suppressed MCF-7 and BT-474 viability shown by MTT assay. These two analogs also suppressed breast cancer cell migration, demonstrated by scratch migration wound-healing assay using MCF-7 and MDA-MB-231 cells. Further, using qRT-PCR, we investigated the effects of C66 and B2BrBC on the expression of various epithelial (E-cadherin, cytokeratin-18) and mesenchymal (snail, slug, fibronectin, and vimentin) genes in MCF-7 cells subjected to EMT induction (a media supplement containing Wnt-5a, TGFβ1, anti-E-cadherin, anti-sFRP1, and anti-Dkk-1 antibodies). Since the EMT-induction media significantly downregulated the epithelial markers’ and upregulated the mesenchymal markers’ mRNA expression, these effects were significantly abolished when C66 or B2BrBC were introduced. Taken together, these data demonstrate that C66 and B2BrBC are potent agents for suppressing breast cancer cell growth and EMT in vitro. Further investigation is needed to determine the potential clinical use of these compounds in breast cancer treatment. Presentation: Thursday, June 15, 2023

The impact of ethnicity in patient presentation, differential diagnosis, and prognosis is well known. Thyroid neoplasia is common in the general population, and in Hispanic Americans, it is an example of potential ethnic inequality that is important in endocrinology. Given that Hispanic Americans are the second largest population group in the United States, it is necessary to investigate how the clinical impact of thyroid neoplasia in this population subgroup differs from other ethnicities.

Background/ObjectiveLyme disease, the most common vector-borne infection in the United States, causes multisystem inflammation. We describe a patient who presented with symptoms of Lyme disease, carditis, and thyroiditis.Case ReportA 53-year-old woman developed fatigue and dyspnea on exertion 1 month after returning from a trip to Delaware. Her electrocardiogram (ECG) showed first-degree atrioventricular (AV) block with a P-R interval up to 392 milliseconds, in the setting of elevated free thyroxine and undetectable thyroid-stimulating hormone levels. Lyme serology was positive. She was hospitalized and started on ceftriaxone. During the second day of hospitalization, AV block worsened to second-degree Mobitz type II but converted back to first-degree AV block after a few hours. Her 24-hour I-123 thyroid uptake and scan revealed markedly diminished I-123 uptake of 1.2%. On day 4, the P-R interval improved, and she was discharged on doxycycline for 3 weeks. P-R interval on ECG and repeated thyroid function tests were normal after finishing antibiotic treatment.DiscussionIn our patient, known exposure to the vector, a classic rash on the chest, improvement in the symptoms, and normalization of thyroid function tests after antibiotic therapy support Lyme infection as a cause of carditis and painless, autoimmune thyroiditis.ConclusionOur case highlights the importance of considering Lyme disease as a cause of painless, autoimmune thyroiditis, especially in patients with concurrent cardiovascular involvement.

Approximately 1.5 million people in the United States currently identify as transgender. The use of gender affirming hormone therapy is integral to routine clinical care of transgender individuals, yet our understanding of the effects of this therapy is limited. There are reasons to believe that gender affirming hormone therapy may have important effects on cardiovascular risk and bone health in transgender individuals. The purpose of this review article is to summarize the evidence for the cardiovascular effects (including coronary artery disease, hypertension and stroke) as well as the effects on bone metabolism associated with gender affirming hormone therapy in both transgender men and transgender women.

ABSTRACT Both obesity and the polycystic ovary syndrome (PCOS) are commonly seen in general population. Obesity is present in about 50% of women with PCOS and contributes to the development of this disorder. This article explores the influences of obesity on the pathogenesis, clinical manifestations, and treatment strategies of PCOS.