bluuebunny/crossref_metadata_2025 huggingface dataset:
7482 Mechanisms Secondary to Biologic Sex Differences in Aldosterone and Plasma Renin Activity (PRA): Does Responsiveness to PRA/Angiotensin II differ between sexes?
Authors: Guzelce Ezgi Caliskan , heydarpour Mahyar , Romero Jose Ricardo , Pojoga Luminita , Williams Jonathan S , Adler Gail Kurr , Williams Gordon H
Published: October 2024

Disclosure: E. Caliskan Guzelce: None. M. heydarpour: None. J. Romero: None. L. Pojoga: None. J.S. Williams: None. G.K. Adler: None. G.H. Williams: None.

Men have higher baseline supine levels of Aldosterone (ALDO) than women, but women have a greater ALDO response to angiotensin II (Ang II) and greater salt sensitivity of blood pressure (SSBP). We hypothesize that the sex difference in ALDO levels is mainly driven by the response to the plasma renin activity (PRA) in men compared to women. We compared the ALDO levels of 846 individuals from the HyperPATH study to assess the potential underlying mechanism for observed sex differences in ALDO. Baseline supine ALDO levels were higher in men than women on both low and liberal salt diets (p<0.0001, p<0.0001), and baseline supine PRA levels were higher in men than women on both low and liberal salt diets (p<0.0001, p=0.003). Conversely, the change in ALDO level from baseline supine to the response to the Ang II infusion and upright posture (delta ALDO levels) were greater in women than men (p<0.0001, p<0.0001). Other potential ALDO secretagogues, ACTH, or serum potassium could not explain the sex differences. In both sexes, the basal renal plasma flow was not significantly different on both low and liberal salt diets. The Ang II administration decreased renal plasma flow but increased blood pressure. The heightened delta ALDO response to Ang II in vasculature was generalizable as delta systolic blood pressure and delta renal plasma flow were also higher in women than men both on low salt (p=0.02, p<0.0001), and liberal salt (p=0.009, p=0.0005) diets. Endogenous Ang II levels were higher in men than women on a low salt diet (p=0.01). Women had greater SSBP than men (p<0.0001), secondary to a lower BP on a low salt diet rather than an increase in BP on a liberal salt diet. In summary, 1) higher baseline supine PRA and concomitant higher baseline supine endogenous Ang II levels were associated with higher baseline supine ALDO levels in men than women on controlled sodium diets. Lower Ang II responsiveness in Ang II targeted organs was observed in men compared to women despite higher endogenous Ang II levels. This can be explained by already saturated AT1 receptors in men, resulting in less response to additional Ang II stimulation. 2) SSBP is greater in women than men because their BP is significantly lower on a low salt diet, potentially secondary to their reduced PRA-Ang II-ALDO response to the stress of a low salt diet.

Presentation: 6/3/2024
12585 Metabolic Profile In Familial Partial Lipodystrophy Type 3: Case Series Of A Family
Authors: de Souza V P , Calmon J R , Pacheco V , Muniz R d , Muniz R B , Valerio C M , Godoy-Matos A F
Published: October 2024

Disclosure: V.P. de Souza: None. J.R. Calmon: None. V. Pacheco: None. R.D. Muniz: None. R.B. Muniz: None. C.M. Valerio: None. A.F. Godoy-Matos: None.

Background: Familial partial lipodystrophy (FPLD) is a group of genetic disorders, generally autosomal dominant, caused by heterozygous pathogenic variants, characterized by abnormal distribution of body fat and metabolic complications. We will present a series of three cases of patients from the same family, with involvement of the PPARG variant c.846delC p.Leu283*, associated with type 3 FPLD. Case 1. Index patient, a 17-year-old woman hospitalized with pancreatitis. On physical examination, she presents with acanthosis nigricans, hirsutism and a skinfold measurement on the thigh of 21mm (RR < 22mm in women). At the time, she had triglycerides (TG) of 1529 mg/dL (RR < 150 mg/dL) and HbA1c of 8.4% (RR < 5.7%), and was positive for PPARG mutation. The patient started fibrate, regular and NPH insulins, metformin and pioglitazone, with good response to clinical treatment during the follow-up. Nowadays, she maintains use of oral antidiabetics, lowering TG down to 217 mg/dL and HbA1c to 6.3%. She has a recent liver ultrasound with mild steatosis - US fat fraction of 11% (RR mild 5-15%), and elastography with METAVIR F0 - 4.8 kPa (RR < 5 kPa) IQR 7.9%. Case 2. A 41-year-old female patient, mother of the index patient, has a previous history of gestational diabetes that progressed to DM with multiple complications, associated with hypertriglyceridemia and metabolic dysfunction-associated fatty liver disease (MAFLD). At the first consultation, the patient presented a TG value of 396 mg/dL and HbA1c of 10.8%, already in use of multiple-dose insulin therapy at 1.2 units/kg/day. During investigation, the patient was also confirmed to have a mutation in the PPARG. Pioglitazone was introduced and insulin adjustment was made, but the patient continued to have difficult glycemic control until the present date. Her most recent liver ultrasound reveals mild steatosis - US fat fraction of 11.5%, and elastography with METAVIR F0 - 4.0 kPa. Case 3. A 14-year-old male, brother of the index patient, was recently brought to our specialized care as an asymptomatic case without comorbidities. He presents no changes on physical examination, a HbA1c of 5.6%, but already with hypertriglyceridemia (TG 310 mg/dL). Conclusion: The clinical features of FPLD3 may exhibit significant diversity, even among individuals sharing identical mutation. However, most cases converge in the severity of metabolic impairments, although experiencing a milder reduction in adipose tissue compared to FPLD2. Mild steatosis at US-derived fat fraction in cases 1 and 2 support less severe changes in fat distribution in FPLD3, leading to suspicion about the influence of the PPARG mutation on insulin sensitivity and metabolic changes.

Presentation: 6/3/2024
12428 Modulation Of Calcium Signaling On Demand To Decipher The Molecular Mechanisms Of Primary Aldosteronism
Authors: Fedlaoui B , Cosentino T , Al Sayed Z R , Giscos-Douriez I , Hulot J S , Simon T A , Baron S , Fernandes-Rosa F L , Zennaro M C , Boulkroun S
Published: October 2024

Disclosure: B. Fedlaoui: None. T. Cosentino: None. Z.R. Al Sayed: None. I. Giscos-Douriez: None. J. Hulot: None. T. Simon: None. S. Baron: None. F.L. Fernandes-Rosa: None. M. Zennaro: None. S. Boulkroun: None.

Primary aldosteronism (PA) is the most frequent form of secondary hypertension and is due to autonomous aldosterone production by the adrenal gland. During the last decades, major advances have been made in our understanding of the disease with the identification of germline or somatic mutations in ion channels and pumps. These mutations enhance calcium signaling, the main trigger of aldosterone biosynthesis. The objective of our work was to elucidate, using chemogenetic tools, the molecular mechanisms underlying the development of PA by modulating sodium entry into the cells “on demand” leading to calcium signaling activation. We have developed an adrenocortical H295R-S2 cell line stably expressing a chimeric ion channel receptor formed by the extracellular ligand-binding domain of the α7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3a named α7-5HT3. Its activation by a selective agonist, the PSEM-817, leads to sodium entry into the cells and activation of calcium signaling. In parallel, we have developed a mouse model expressing the α7-5HT3 receptor specifically in the adrenal cortex. Cells expressing the α7-5HT3 receptor recapitulate the major characteristics of KCNJ5 mutations, the most frequent genetic alteration identified in aldosterone producing adenoma. Stimulation of the α7-5HT3 receptor by PSEM-817 resulted in a significant increase in intracellular calcium concentrations, CYP11B2 mRNA expression, and aldosterone biosynthesis and was associated with a decrease in cell proliferation. RNA sequencing and steroidome analyses revealed unique profiles associated with sodium entry. Exploration of adult mice expressing the α7-5HT3 receptor specifically in the adrenal cortex, generated in our laboratory, is ongoing. Preliminary results revealed a significant increase in plasma aldosterone and 18-hydroxycorticosterone levels in male and female mice expressing the α7-5HT3 receptor after four weeks of treatment with PSEM-817 but no major adrenal abnormalities. Our results suggest that increased sodium influx leading to increased calcium signaling is not sufficient to promote both increased aldosterone production and cell proliferation, strongly supporting the need for additional mechanisms for the development of aldosterone producing adenoma. Overall, this work provides valuable insights into the role of sodium-induced calcium signaling in the development of PA and paves the way for the development of new therapeutic strategies.

Presentation: 6/1/2024
7259 Optimizing the Aldosterone-to-Renin Ratio Cut-off for Screening Primary Aldosteronism Based on Cardiovascular Risk: A Collaborative Study
Authors: Hu J , Yang J
Published: October 2024

Disclosure: J. Hu: None. J. Yang: None.

Objectives: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cut-off covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl-[1]/mIU·l-[1]. We aimed to optimize the ARR cut-off for PA screening based on the risk of cardiovascular diseases (CVD). Methods: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl-[1]/mIU·l-[1]) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cut-off selected from FOS is applicable to PA screening. Results: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR<1.0, PA with ARR≥1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR≥1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cut-off at 2.4∼4.9, 10%∼30% of PA subjects would be unrecognized although they carried a 2.45∼2.58-fold higher CVD risk than essential hypertension. Conclusions: The CVD risk-based optimal ARR cut-off is 1.0 ng·dl-[1]/mIU·l-[1] for PA screening. The current guideline-recommended ARR cut-off may miss patients with PA and high CVD risk.

Presentation: 6/3/2024
7098 Paradoxical Worsening of Dyslipidemia with Tirzepatide
Authors: Pruett Jacob E , Carranza Leon Barbara Gisella
Published: October 2024

Disclosure: J.E. Pruett: None. B. Carranza Leon: None.

Background: While weight loss typically is associated with improvement in dyslipidemia (DLD), certain instances of extreme weight loss have been implicated in paradoxical worsening of DLD. For example, underweight women with anorexia nervosa have higher serum low-density lipoprotein cholesterol (LDL-C) than normal weight healthy counterparts (1). However, this has yet to be shown with dual incretin receptor agonist therapies such as tirzepatide. Clinical Case: A 75-year-old female with dyslipidemia treated with evolocumab (LDL-C 183 mg/dLbefore treatment), type 2 diabetes mellitus, and class 1 obesity was switched from glimepiride to tirzepatide in an effort to address the above conditions. Over the span of 6 months, tirzepatide was uptitrated to 15 mg, and the patient lost over 70 pounds with hemoglobin A1c decreasing to 5.8%. However, LDL-C more than doubled from 155 to 342, with high-density lipoprotein cholesterol (HDL-C) dropping from 57 to 42. Interestingly, triglycerides stayed the same from 124 to 122 during this timeframe. Out of concern for inefficacy of evolocumab, she was switched to inclisiran. Two months later, LDL-C was even higher at 360 with unchanged HDL-C and a moderate increase in triglycerides to 154. Given prior case reports of extreme weight loss worsening DLD along with the LDL-C skyrocketing upon tirzepatide initiation, the decision was made to decrease tirzepatide from 15 mg to 5 mg. Within the next three months, though her weight only changed by one pound, her LDL-C subsequently dropped to 114, HDL-C rose to 65, and triglycerides dropped to 71. Conclusion: To our knowledge, this is the first case report linking dual incretin receptor agonist therapy with worsening dyslipidemia. Reference: (1) Weinbrenner, T.; Züger, M; Jacoby, G.E; et al. Lipoprotein metabolism in patients with anorexia nervosa: a case-control study investigating the mechanisms leading to hypercholesterolaemia. British Journal of Nutrition. 2004;91:959-969.

Presentation: 6/3/2024
7676 Sex is An Influential Factor on the Conversion of Plasma Renin Activity and its Active Concentration
Authors: Tezuka Yuta , Omata Kei , Ono Yoshikiyo , Satoh Fumitoshi
Published: October 2024

Disclosure: Y. Tezuka: None. K. Omata: None. Y. Ono: None. F. Satoh: None.

Background: Renin is one of the essential factors to understand the cause of hypertension. In primary aldosteronism (PA), plasma renin activity (PRA) has been employed for screening and confirmation tests, while plasma active renin concentration (ARC) is being popularized due to its better reproducibility and easier technique. However, how the transition of renin measurement impacts on PA diagnosis is still unclear. Objective: To investigate the correlative relationship between PRA and ARC, and the impact of renin transition on PA screening. Methods: We retrospectively enrolled 206 hypertensive patients who underwent PA screening and/or confirmatory tests with simultaneous measurements of both PRA and ARC from 2021 to 2023. Those who had higher PRA than 3 ng/mL/h were excluded based on the context of this study. Antihypertensive drugs which interfere with renin-angiotensin-aldosterone system were withdrew before renin evaluation. Plasma samples for renin and aldosterone measurements were obtained at supine position after 30 minutes rest. PA diagnosis was established based on PRA-based confirmatory tests. The correlations between renin and other parameters were evaluated with simple linear regression and Spearman’s correlation analysis. Chi-square test was applied for categorical variables. Results: Of 206 patients, including 147 PA cases, 95 were men (46%) and, mean age and eGFR were 54 years and 72 mL/min/1.73m2, respectively. Plasma aldosterone concentrations, PRA and ARC were as follows (median [interquartile range]: 8.0 [5.4, 13.3] ng/dL, 0.40 [0.20, 0.70] ng/mL/h and 1.61 [0.79, 2.87] pg/mL, respectively. Total number of renin evaluation reviewed was 890 (median 5 times/person). PRA and ARC showed a significant positive correlation (ARC =3.97 x PRA +0.08: Spearman’s r=0.790, p<0.0001), whereas there were sex differences in the slope and the intercept, particularly in ages under 50 years old (men, 5.03 and -0.19: women, 3.11 and +0.40, respectively). The renin ratio (ARC/PRA) showed weak negative and positive correlations with age (Spearman’s r=-0.073, p=0.03) and body mass index (Spearman’s r=0.113, p=0.0007), respectively. Defining low renin status as PRA<1.0 ng/mL/h and ARC<4.0 pg/mL, 142 (97%) out of 147 PA patients showed persistent suppressed renin for both, while 15 (10%) had controversial aldosterone-to-renin ratios (ARRs) between PRA and ARC. Overall, 24 (12%) patients had controversial ARRs, and the rate was similar between men and women (11% and 13%, respectively). Conclusions: Our current study revealed the positive correlation between PRA and ARC, affected by sex. Although the renin transition could lead to different interpretation of aldosterone-to-renin ratios regardless of sex, the replacement of PRA with ARC rarely alters renin status in PA patients.

Presentation: 6/3/2024
9364 The Deleterious Synergy Of Aldosterone And LDL Cholesterol On Major Cardiovascular Events In Chronic Kidney Disease
Authors: Solomon M , Vaidya A , Waikar S S , Verma A
Published: October 2024

Disclosure: M. Solomon: None. A. Vaidya: None. S.S. Waikar: None. A. Verma: None.

Background: Elevated aldosterone and low-density lipoprotein (LDL) are both known risk factors for major cardiovascular events (MACE) in chronic kidney disease (CKD). Method: The synergistic impact of aldosterone and LDL on incident MACE was investigated among 3453 participants in the Chronic Renal Insufficiency Cohort. The primary exposure was the interaction between aldosterone and LDL as continuous variables. We also evaluated the same interaction after categorizing each variable by the median. The primary outcome was MACE [defined as the composite of heart failure (HF), myocardial infarction (MI), or stroke, whichever occurred first]. Cox proportional hazard models and confounder-adjusted survival curves were developed after adjustment for demographic, metabolic, renal, and laboratory parameters to ensure a robust interpretation of results. Results: Over a median follow-up period of 8.9 years, 1,030 participants experienced major cardiovascular events (MACE). There was a statistically significant linear interaction between aldosterone and low-density lipoprotein (LDL) in predicting incident MACE (P = 0.005). In adjusted models, participants with aldosterone and LDL levels greater than the median had a 32% increased risk of MACE (HR 1.32, 95% CI 1.08-1.61) compared to those with values below the median. The 10-year absolute risk difference for MACE was 5.8% (95% CI 1.3 -10.3) comparing individuals with aldosterone and LDL greater than the median with those below the median. Conclusion: The combination of elevated aldosterone levels and elevated LDL cholesterol imparts a heightened risk for major cardiovascular events in CKD. These findings emphasize the potential value of mineralocorticoid receptor antagonism or aldosterone synthase inhibition in combination with LDL-lowering to mitigate adverse cardiovascular events in CKD.

Presentation: 6/3/2024
6565 The NF-κB-CXCL1 Axis Mediates the Development of Nonalcoholic Steatohepatitis
Authors: Raul Mahima Chandrakant , Li Yuchang , Chen Liting , Sottas Chantal , Patel Nrupa Dinesh , Zambidis Alexander Elias , Papadopoulos Vassilios
Published: October 2024

Disclosure: M. Raul: None. Y. Li: None. L. Chen: None. C. Sottas: None. N. Patel: None. A. Zambidis: None. V. Papadopoulos: None.

The transcription factor nuclear factor kappa B (NF-κB) plays a crucial role in the pathogenesis of nonalcoholic steatohepatitis (NASH). CXC chemokine, (CXCL1) is one of the most selective and potent chemokines that effectively attracts neutrophils to the site of inflammation or infection, which is also regulated by the NF-κB signaling pathway. In the liver, when NF-κB is activated, it promotes the transcription of CXCL1 to recruit neutrophils to the site of inflammation. Moreover, induced expression of the CXCL1 gene in rat liver was accompanied by neutrophil infiltration, causing hepatic damage and dysfunction. Previous research has shown that NF-κB signaling can influence CXCL1 in vitro. However, the contribution of the NF-κB/CXCL1 axis to the progression of NASH has remained unclear. To verify the regulatory association between NF-κB and CXCL1, we conducted a luciferase assay by transiently transfecting Huh7 cells with a CXCL1-Luciferase plasmid and treating them with varying concentrations of human recombinant NF-κB protein. The results demonstrated a dose-dependent increase in CXCL1-luciferase activity in response to NF-κB, indicating that NF-κB regulates CXCL1 expression. Additionally, TNFɑ (10ng/ml)-induced CXCL1-luciferase activity was significantly and dose-dependently suppressed by celastrol (CEL), a compound known to counteract the TNFα-induced upregulation of NF-κB. To further investigate the regulation of CXCL1 by NF-κB in the liver in vivo, CEL was administered to rats fed with the Gubra-Amylin diet-induced NASH (GAN) diet. Histological studies revealed a substantial reduction in liver lipid accumulation and fibrosis, along with reduced inflammation in white adipose tissue with CEL treatment. As anticipated, NF-κB levels were significantly suppressed in GAN+CEL compared to the GAN+Veh (vehicle)-treated rats. CXCL1 expression was also diminished by the treatment, providing further confirmation of the regulation of CXCL1 by NF-κB in the liver. Moreover, the hallmarks of NASH, including inflammation, lipid accumulation, and fibrosis, were alleviated in the GAN+CEL group compared to the GAN+Veh group. In conclusion, these findings provide compelling evidence supporting the involvement of the NF-κB - CXCL1 signaling pathway in the development of NASH.

Presentation: 6/2/2024
7091 Triglyceride Glucose Index Is Strongly Associated With Nonalcoholic Fatty Liver Disease in the Normal BMI US Population
Authors: Ayesh Hazem , Niswender Kevin Dean , Carranza Leon Barbara Gisella
Published: October 2024

Disclosure: H. Ayesh: None. K.D. Niswender: None. B.G. Carranza Leon: None.

Introduction: Non-Alcoholic Fatty Liver Disease (NAFLD) poses a growing global health threat. The surge in NAFLD, often linked to metabolic disorders such as diabetes and obesity, underscores the urgency for effective screening methods. Traditional approaches rely on indicators that involve elevated BMI and/or liver function tests to identify individuals at risk of NAFLD. The Triglyceride-Glucose Index (TyG Index), calculated as ln(Fasting Triglycerides × Fasting Glucose/2), may be a promising NAFLD risk prediction tool. Our study aims to investigate the correlation between the TyG Index and NAFLD in the normal BMI population, utilizing data from the National Health and Nutrition Examination Survey (NHANES). Methods: A total of 1130 subjects with a normal Body Mass Index (BMI) (18.5 - 24.9) were selected from the NHANES study. The primary goal was to explore the correlation between hepatic steatosis and the Triglyceride-Glucose (TyG) index. The study population was categorized into TyG quartiles. Regression analysis was conducted while controlling for confounding variables such as BMI, Hemoglobin A1c, and age. Hepatic steatosis was evaluated using the Fibroscan technique, with the Median Controlled Attenuation Parameter (CAP) as the quantitative indicator. Results/Discussion: The study found a significant correlation between steatosis and the Triglyceride-Glucose Index (TyG), with an odds ratio of 3.75, a P-value < 0.001 between the lowest and highest quartile, and a confidence interval of 2.385 to 5.99. This correlation increased across higher quartiles (2-1, 3-1, 4-1) with odds ratios of 1.34, 1.91, and 3.75, revealing a dose-response relationship with higher TyG. These findings remained significant after adjusting for BMI and hemoglobin A1c, key NAFLD risk factors. The TyG index is valuable for identifying high-risk NAFLD patients, especially those with a normal BMI. Unlike other calculators like Fatty Liver Index and Hepatic Steatosis Index, TyG does not rely on BMI. The study unveiled a racial difference in the correlation between TyG and NAFLD, with a weaker TyG-NAFLD association in African Americans and a stronger one in Asians. This discovery emphasizes the need for future large-scale studies to explore potential genetic components and the potential of the TyG index to modulate genetic predisposition to NAFLD.

Presentation: 6/2/2024
7493 A Case Report of Recurrent Hypoglycemia With Polysubstance Abuse With Rhabdomyolysis and Capillary Glucose Monitoring Dilemma
Authors: Gupta Uma Datta , Prasad Parinitha , Hlaing Pwint P , Panigrahi Kalpana , Deribe Zewge
Published: October 2024

Disclosure: U.D. Gupta: None. P. Prasad: None. P.P. Hlaing: None. K. Panigrahi: None. Z. Deribe: None.

Substance use has been correlated with impaired functioning in every bodily system. Over the last two years, our investigations into polysubstance abuse patients have revealed variations in mortality risks, particularly associated with hypoglycemia. We have presented a case of 45-year-old male with a medical history encompassing Bipolar 1 disorder, Polysubstance abuse, and schizoaffective disorder presented to the Emergency Department due to bizarre behavior. On the second day of admission, the patient experienced recurrent hypoglycemia, as indicated by a finger stick blood glucose reading of 39, which was successfully corrected with 50% glucose and D5RL drip. Nevertheless, two hours later, the BG level dropped to less than 20. Despite this, the patient remained asymptomatic and alert, and oral feeding was initiated. However, an ear lobe measurement concurrently indicated a value of 122. The patient's polysubstance use had notable impacts on cardiac, respiratory, metabolic, and renal systems. Blood glucose fluctuations were influenced by both sympathomimetic drug overdoses and underlying disease processes. Instances of hypoglycemia linked to recreational drug use, particularly with substances such as ecstasy, amphetamine, eutylone, and cannabinoids, have been documented. However, there have been a few reports of persistent refractory hypoglycemia in these cases. The probable cause of refractory hypoglycemia is linked to amphetamine and synthetic cannabinoid use, accentuated by compromised elimination due to renal dysfunction. It is noteworthy that the unique recurrent hypoglycemia in our case is evident solely in peripheral finger stick measurements, with no corresponding results in ear lobe or venous blood samples. Healthcare providers may also overestimate the accuracy of portable glucose meter readings. A study revealed widening differences in meter readings (5.7% to 32%)- which needs to be re-evaluated in every instance. Recognizing and understanding cases like this will contribute to improved diagnosis in the future, facilitating the identification of reasons for the observed discrepancy. In addition, as research, papers, and case reports addressing hypoglycemia in polysubstance abuse patients, along with its management and assessment, are notably scarce that need to be addressed with proper assessment of hypoglycemia. It is imperative to conduct thorough assessments and evaluations of such cases to establish a comprehensive management plan, aiming to prevent mortality rather than merely treating symptomatic hypoglycemia.

Presentation: 6/3/2024
8704 A DREADD-base Chemogenetic Approach to Quiz the Impact of the Delta Cell Input on Islet Hormone Secretion
Authors: Rodriguez Dayleen Hakim , Tamayo Alejandro , Diaz Rayner Rodriguez , Pereira Elizabeth , Alcazar Oscar , Makhmutova Madina
Published: October 2024

Disclosure: D. Hakim Rodriguez: None. A. Tamayo: None. R. Rodriguez Diaz: None. E. Pereira: None. O. Alcazar: None. M. Makhmutova: None.

The utilization of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) that are gated by clozapine-N-oxide (CNO) enables the selective stimulation of genetically specified cell types in vivo. This chemogenetic technology has been successfully applied in various in vivo studies, including those using mice, to remotely control GPCR signaling in specific cells, such as neurons, glia cells, pancreatic β-cells, or cancer cells. Utilizing DREADDs in the study of pancreatic islets, particularly in the somatostatin-producing δ-cells, could offer insights into the complex role of this hormone. Somatostatin is known to inhibit the secretion of other islet hormones, such as insulin and glucagon, but the detailed mechanisms of its action have not been fully elucidated. To address this, we generated mice enabling the expression of either the activator-DREADD Gq or the inhibitor-DREADD Gi in the mouse somatostatin secreting cells, including the islet δ-cell. Immunohistochemical staining of pancreas sections showed that DREADD were expressed and translocated to the membrane of the islet δ-cells. Perifusion experiments with isolated islets showed that δ-cells responded to CNO stimulation as expected. Islets bearing the DREADD Gq secreted somatostatin in a dose-dependent manner, while somatostatin secretion was inhibited in those expressing DREADD Gi. Secretion of insulin and glucagon were modulated upon activation or inhibition of δ-cells via CNO/DREADD manipulation. CNO-driven pulses of somatostatin stimulation caused asynchronous off responses of neighboring α-and β-cells during the time lapses of somatostatin secretion falloff, resulting in a net increment in the magnitude of both insulin and glucagon secretion. Meanwhile, inhibition of somatostatin secretion surprisingly unleashed glucagon secretion in non-permissive 16mM glucose. These results encouraged us to explore the potential application of DREADD tools in isolated human islets. We will discuss our current approaches whilst using viral vectors to drive the expression of DREADDs in human δ-cells and its impact in the overall islet secretory output.

Presentation: 6/2/2024
8616 A Novel Mutation of Maturity Onset Diabetes of the Young
Authors: Weerasinghe K H , Branis N
Published: October 2024

Disclosure: K.H. Weerasinghe: None. N. Branis: None.

Background: Maturity onset diabetes of the young (MODY) is an autosomal dominant condition characterized by various subsets (Nkonge et al., 2020). A mutation in the glucokinase gene (GCK), otherwise known as MODY type 2, is often characterized by mild hyperglycemia managed with lifestyle modifications (Nkonge et al., 2020). Novel mutations in this gene may differ in their clinical course and need close clinical monitoring. Clinical Case: A 19 year old male presented for evaluation of his diabetes mellitus. In 2020, the patient was hyperglycemic on routine blood work, with asymptomatic features. His condition was managed with lifestyle modifications. The HbA1c was 6.8 and 7; while fructosamine was 338 mmol/L (normal 205-285 mmol/L). Subsequent workup revealed GAD 65 to be less than 5 U/ml(normal range being 0-5 U/ml) with negative islet antibodies. C-peptide was similarly measured and found to be 1.5 ng/ml, within the limits of 1.1-4.4 ng/ml, demonstrating a good pancreatic reserve. A MODY genetic profile was then conducted which revealed a novel mutation in the GCK gene, variant c.1064T>C (p.L355P). As this is a novel mutation, the probability of MODY was calculated, and found to be 75% using the Exeter maturity-onset diabetes of the young (MODY) probability calculator (EMPC).The patient’s clinical course thus far has been managed conservatively as his hyperglycemia has been mild. However, recently the patient’s post prandial sugars were found to be persistently elevated. Pharmacotherapy such as sulfonylureas was discussed however, as per the patient’s wishes, stricter dietary modifications will be applied prior to the initiation of medication. Conclusion: Patients with novel mutations should be closely monitored as the general expected clinical course may vary. These changes are demonstrated in this case report as the patient started developing elevation in postprandial sugar levels uncharacteristically. Close monitoring of the patient’s future clinical status will be essential in learning more about the differences in prognosis and long term management. References: Nkonge, K. M., Nkonge, D. K., & Nkonge, T. N. (2020a). The epidemiology, Molecular Pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clinical Diabetes and Endocrinology, 6(1). https://doi.org/10.1186/s40842-020-00112-5

Presentation: 6/2/2024
8348 A Rare Case Of Liraglutide-Associated Angioedema Requiring Emergent Intubation
Authors: Amin Tasnuva , Mararenko Anton , Cheng Jennifer , Ong Raquel , Holland Soemiwati , Hu Katherine
Published: October 2024

Disclosure: T. Amin: None. A. Mararenko: None. J. Cheng: None. R. Ong: None. S. Holland: None. K. Hu: None.

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used in the management of type 2 diabetes mellitus to enhance glycaemic control. While generally considered safe, recent reports indicate an increasing frequency of adverse drug reactions, with gastrointestinal symptoms such as pancreatitis becoming more prevalent. This case report highlights a rare occurrence of angioedema induced by the GLP-1 receptor agonist, Liraglutide. Case A 58-year-old Type 2 diabetic male presented with rapidly progressing tongue swelling, abdominal discomfort, and watery diarrhea, six hours after initiating Liraglutide therapy. On presentation, he was hemodynamically stable, afebrile, maintaining adequate oxygenation on room air. On examination, the patient was in moderate distress with generalized tongue swelling protruding out, with no swelling of eyelids or lips. No rashes were noted on exposed skin and clear breath sounds without wheezing on lung examination. Due to concern for an impending airway compromise, the patient was intubated. Chart review showed he had an episode of self-resolving tongue swelling a few months back, at which time he was taken off his Angiotensin receptor blocker. 2 weeks ago, he was started on a new brand of GLP-1 receptor agonist (Liraglutide) to achieve optimal glycemic control. No other drug allergies or allergic reactions were reported. C1-Esterase panel, eosinophil count, and inflammatory markers were within normal limits.On admission, Liraglutide was discontinued, he was placed on a basal-bolus insulin regimen, received methylprednisolone, famotidine, and diphenhydramine Subsequent improvement allowed for extubation on the third day, and the patient was discharged with plans to discontinue Liraglutide and an epinephrine pen for precautionary use. Conclusion: This case represents a rare and severe manifestation of angioedema associated with Liraglutide use in a diabetic patient. While angioedema has been infrequently reported with other GLP-1 receptor agonists such as Exenatide and Dulaglutide , our case underscores the importance of clinicians' awareness regarding this potential life-threatening complication with Liraglutide. Post-marketing surveillance data suggest that anaphylactic reactions with Liraglutide may occur rarely, emphasizing the need for vigilance among healthcare providers.

Presentation: 6/2/2024
7284 Ablation of hexose-6-phosphate dehydrogenase in mice causes skeletal muscle atrophy and dramatically impairs exercise capacity
Authors: Zogg M , Grötsch A D , Birk J , Pelczar P , Bouitbir J , Odermatt A
Published: October 2024

Disclosure: M. Zogg: None. A.D. Grötsch: None. J. Birk: None. P. Pelczar: None. J. Bouitbir: None. A. Odermatt: None.

Hexose-6-phosphate dehydrogenase (H6PD) catalyzes the first two steps of the pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER), generating the redox equivalent NADPH. It has been shown that mice lacking H6PD develop defects mainly in skeletal muscles [1]. Nevertheless, the mechanisms underlying the myopathy in H6PD KO mice is unknown. Here, we further assessed muscle responses to H6PD deficiency and aimed to uncover the mechanisms that may cause myopathy in mice. We conducted a detailed characterization of the muscle structure and function as well as energy metabolism in oxidative and glycolytic muscles of H6PD KO mice. At the age of 15 weeks, H6PD KO mice displayed lower body weight than WT mice, despite similar food and water intake. Grip strength was significantly lower in H6PD KO than in WT mice. This was associated with decreased weight of the mixed (gastrocnemius, quadriceps) and fast fiber type rich muscles of the hind leg (extensor digitorum longus, tibialis anterior) in H6PD KO animals. Atrogin1 and Murf1 mRNA expression, markers of atrophy, increased only in the white (glycolytic) quadriceps. In this context, fast-twitch fibers in WT mice displayed higher H6pd mRNA expression than slow-twitch fibers. Electron microscopy analysis of red and white gastrocnemius muscles displayed the presence of large intramyofibrillar vacuoles, and morphologic changes of the sarcoplasmic reticulum and mitochondria in H6PD KO muscle. Metabolically, H6PD KO muscles presented an accumulation of glycogen granules and significantly decreased mRNA expression of glucose transporter Glut4, glucose-6-phosphate transporter G6pt and glycogen phosphorylase Pygm. The exercise capacity, measured by maximal running distance, decreased by more than 50% in H6PD KO mice. Upon exercise, both WT and H6PD KO animals were able to mobilize the majority of glycogen stored in their muscles. However, immediately after exercise, there was a significant increase in plasma lactate and glucose levels in H6PD KO animals. Disturbances in glucose metabolism were further supported by in vitro experiments using stable C2C12 H6PD KO myoblasts, revealing a shift in basal state mitochondrial fuel oxidation usage from glucose to fatty acid and glutamine in metabolic dependency assays. In conclusion, our findings revealed that H6PD seems to play a key role in proper function and energy metabolism of skeletal muscles. References:[1] Lavery G. G. et al. 2008 J. Biol. Chem. 283, 8453-8461.

Presentation: 6/1/2024
8261 Achievement of Diabetes Treatment Goals in Mexico from 2016 to 2022
Authors: Garcia Daniel Ramirez , Fermin Martinez Carlos Alberto , Mendez Labra Padme Nailea , Antonio Villa Neftali Eduardo , Seiglie Jacqueline A , Bello-Chavolla Omar Yaxmehen
Published: October 2024

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

Background: Optimal diabetes care involves achieving goals with treatment in key metabolic parameters including HbA1c, blood pressure (BP), low density lipoprotein cholesterol (LDL-C) levels, and smoking cessation. Evaluation of diabetes care in Mexico has been incomplete, with previous studies focusing primarily on glycemic control, but not on a comprehensive analysis of combined treatment targets. Objective: To estimate achievement of diabetes treatment goals (HbA1c [A], BP [B], LDL-C [C], smoking cessation [N], and combined targets [AB, BC, AC, ABC, ABCN]) using data from nationally representative surveys from 2016-2022 among individuals with diagnosed diabetes in Mexico. Methods: We analyzed serial cross-sectional National Health and Nutrition Surveys from 2016-2022. A total of 2,689 adults with diagnosed diabetes ≥20 years were identified amongst 21,248 adults ≥20 years. Weighted prevalence estimates were obtained for glycemic control (HbA1c <7% in those <65 years, and <7.5% in those ≥65 years), BP control (<130/80 mmHg), LDL-C control (<70 mg/dL), smoking cessation, and combined targets. We also fitted logistic regression models to estimate the odds of achieving treatment targets according to age, sex, educational level, indigenous identity, and survey cycle. Results: In 2022, the prevalence of HbA1c, BP, and LDL-C control among individuals with diagnosed diabetes in Mexico was 41.2% (95% CI 30.5-52.0%), 46.0% (95% CI 36.5-55.5%), and 17% (95% CI 10.2-25.2%), respectively. Non-smoking prevalence was 92.4% (95% CI 88.6-96.2%). Combined target achievement was low, with a prevalence of 10.8% (95%CI 6.2-15.5%) for BC and 4% (95% CI 1.7-6.3%) for ABCN. The proportion of goal achievement was relatively stable across 2016-2022 for every parameter analyzed, except for LDL-C. LDL-C had the lowest proportion of control across all cycles, although a gradual increase was observed: 8.1% (95% CI 4-12.3%) in 2016 to 17% (95% CI 10.2-25.2%) in 2022. The increase in LDL-C control coincides with greater prevalence of statin use across survey cycles. Men had lower odds of achieving ABCN combined control (OR 0.49, 95%CI 0.45-0.54) than women. Similarly, compared with individuals <45 years, participants 45-64 years (OR 0.36, 95%CI 0.32-0.40) and ≥65 years (OR 0.41 95%CI 0.35-0.47) had lower odds of achieving composite control. Conclusions: Achievement of diabetes treatment goals in Mexico is suboptimal. Less than half of individuals with diagnosed diabetes achieve HbA1c or BP goals, less than a fifth achieve LDL-C control, and only 1 in 20 individuals achieve ABCN control. Greater efforts are needed to the improve the comprehensive care of individuals with diabetes in Mexico.

Presentation: 6/3/2024
7643 Acute blindness due to Metformin associated lactic acidosis
Authors: Pereira K N , Desai K , Khan T , Yong S
Published: October 2024

Disclosure: K.N. Pereira: None. K. Desai: None. T. Khan: None. S. Yong: None.

Metformin, one of the most commonly prescribed oral hypoglycemic agents, effectively lowers basal and postprandial blood glucose. However, Metformin carries a black box warning for lactic acidosis, which is more common in setting of liver and kidney dysfunction. With an incidence rate of ∼ 4.3 cases per 100,000 patient-years, Metformin associated lactic acidosis (MALA) can present with nausea, vomiting, diarrhea, encephalopathy, hypothermia, respiratory failure and hypotension. Blindness is a rarely reported outcome of MALA. We present a case of a 48 year old intellectually disabled female with a history of type 2 diabetes (on Metformin) who presented with progressive encephalopathy insetting of intractable nausea and vomiting with poor oral intake, since starting lisinopril & rosuvastatin for newly diagnosed hypertension and hyperlipidemia. She was encephalopathic, hypothermic, hypotensive, tachycardic and tachypneic. Labs were notable for leukocytosis, AKI, hyperkalemia, elevated anion gap metabolic acidosis with a lactate of 13.6 and elevated lipase. She also tested positive for Influenza A. CT head showed no acute intracranial abnormality. CT chest, abdomen & pelvis was concerning for aspiration, multifocal pneumonia or a combination of both as well as acute interstitial pancreatitis. She was admitted to the ICU for further management including hemodialysis. She continued to have improving but persistent lactic acidosis despite multiple dialysis sessions. On day 5 of ICU stay, with resolution of her encephalopathy, she reported new onset complete bilateral painless vision loss. General eye and neurologic exam was unrevealing except for sluggishly reactive pupils to light. MRI brain showed an new acute 2 mm lacunar infarct in the right temporal lobe. Neurology ruled out stroke as the cause for her vision loss. Emergent ophthalmology evaluation revealed no retinopathy, macular edema, acute glaucoma or thromboembolic event. The new onset vision loss was suspected to be due to MALA due to persistent metabolic disturbances. Some animal studies have shown that retinal horizontal cells are sensitive to low pH, resulting in interruption of signal transmission to the visual neurons and consequent blindness. The presence of factors like metformin metabolites may contribute to impaired function of retinal cells.On extensive literature review it was noted that only 5 cases of vision loss associated with MALA have been reported. However, in these cases, vision loss was transient and reversed following correction of acidosis with dialysis. Our case highlights a rare consequence of MALA, which can be irreversible and cause lifelong disability.

Presentation: 6/1/2024
8503 Analyzing Prescription Practices for Back-up Insulin and Glucagon in Type 1 Diabetes Patients Using Insulin Pumps: Findings From Cleveland Clinic
Authors: Iqbal Anira , Ambalavanan Jayachidambaram , Alkwatli Kenda , Rao Pratibha P R
Published: October 2024

Disclosure: A. Iqbal: None. J. Ambalavanan: None. K. Alkwatli: None. P.P. Rao: None.

Background: It is estimated that about 400,000 patients with type 1 diabetes (T1D) in the U.S. are using insulin pumps1. This number has been steadily increasing with expanding insurance coverage and newer, more convenient, user-friendly technology. Though these devices remarkably improve patients’ glycemic control, failure of these pumps, due to reasons such as clogging or kinking of tubing, air bubbles, pump display issues, site reaction/infection, is a frequently encountered problem. During these events, having a backup plan in the form of injectable insulin is essential to prevent severe hyperglycemia and diabetic ketoacidosis (DKA). Increasing insulin pump use also predisposes patients to severe hypoglycemia. In these cases, at-home glucagon administration can be lifesaving. Methods: Using the EPIC Cogito extracts and reporting service, data was extracted for adult patients seen at the Cleveland Clinic main campus between January 1, 2021, to January 1, 2023, using ICD codes for T1D and insulin pump status. Data collected included age, sex, prescription status for basal insulin, type of basal insulin, glucagon prescription, and current medication list.ResultsWe were able to analyze 86 patients (67% females, n=58; 33% male, n=28) with T1D utilizing an insulin pump. The average age was 48.6+18.18 years. Of the 86 patients, 51 (59%) had prescriptions for long-acting backup insulin. Only 21 patients (24%) had a prescription for glucagon. Discussion: Insulin pump failure is one of the most common causes of DKA in patients with T1D2. Educating patients on the use of long-acting injectable insulin in the event of pump failure and ensuring active prescription for every patient using an insulin pump at each visit can decrease the risk of DKA and prevent hospitalizations. Similarly, the use of a continuous subcutaneous insulin infusion (CSII) puts patients at high risk of hypoglycemia. Per Standards of Care in Diabetes 2024, glucagon should be prescribed in all patients using insulin3. Our analysis reveals that the practice of prescribing backup insulin and glucagon at Cleveland Clinic Institute needs significant improvement to potentially prevent DKA and severe hypoglycemia requiring hospitalization. References: 1Umpierrez GE, Klonoff DC. Diabetes Technology Update: Use of Insulin Pumps and Continuous GlucoseMonitoring in the Hospital. Diabetes Care. 2018 Aug;41(8):1579-1589. 2Doyle EA, Weinzimer SA, Tamborlane W. DKA Prevention and Insulin Pumps: Lessons Learned From a Large Pediatric Pump Practice. Sci Diabetes Self Manag Care. 2022. 3American Diabetes Association Professional Practice Committee; 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S111-S125.

Presentation: 6/1/2024