Sabyasachi Sen

Sucralose (a.k.a. Splenda when combined with dextrose and maltodextrin) is a popular nonnutritive sweetener (NNS) found in several beverages marketed for health benefits and fitness. This article examines the mechanistic aspects of sucralose’s metabolic effects on satiety, obesity, glycemic control, and adipogenesis, along with gut dysbiosis, inflammation, and disruption of intestinal permeability. Some evidence suggests that sucralose may also alter appetite regulation, taste perception, and energy intake. Additionally, there are safety concerns regarding its carcinogenic potential and its epigenetic effect on the fetus due to consistent maternal consumption. Based on current findings of NNS, it was concluded that sucralose may be of use in weight reduction in the short term as an NNS. However, this needs to be weighed against the possible long-term metabolic side effects and safety precautions.

Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it’s prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20–75 mL/min/1.73 m² with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369–384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.

Introduction: Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) has been associated with the development of COVID-19. COVID-19 may cause endothelial cell dysfunction (ECD), which can lead to cardiometabolic diseases and podocytopathy. In this study, we explored whether presence of hyperglycemia predisposes to SARS-CoV-2 infection, in vitro, and whether COVID-19 can put an individual at a higher risk of persistent renal damage in the long-term following acute COVID infection. To estimate renal damage, we evaluated albuminuria and podocytopathy. Podocytopathy was estimated by measuring podocyte-specific protein levels in urine-derived exosomes from patients who were admitted with acute COVID-19 at 10 days, 6 months, and 12 months post-acute SARS-CoV-2 infection. Methods: Blood and urine samples from patients with SARS-CoV-2 post-infection were procured from the George Washington University COVID repository. Peripheral blood mononuclear cells and urine exosomes were isolated. Podocyte-specific proteins Podocalyxin (PODXL) and Nephrin (NEPH) were identified from urine exosomes. Results: Urine exosomal podocalyxin levels were significantly high at 10 week (n = 18; P = 0.001), 6 month (n = 25; P = 0.003) and 12 month (n = 14; P = 0.0001) time points. Nephrin levels were also noted to be high at 10 week (n = 18; P = 0.001) and 12 month (n = 14; P = 0.007) time points, compared with urine samples obtained from type 2 diabetes subjects who never had COVID-19. Though urinary podocyte-specific proteins were high, compared to control, there were no significant differences noted on urine albumin:creatinine ratios (UACR) between the groups. Conclusion: Persistent high levels of podocyte-specific proteins noted in urinary exosomes even at 12 months post-Covid may lead to the development of chronic kidney disease.

Introduction: Effects of Dapagliflozin (Dapa) and Dapagliflozin-Saxagliptin combination (Combo) was examined on peripheral blood derived CD34 + Hematopoetic Stem Cells (HSCs) as a cellular CVD biomarker. Both Dapa (a sodium-glucose co-transporter 2 or SGLT2, receptor inhibitor) and Saxagliptin (a Di-peptydl-peptidase-4 or DPP4 enzyme inhibitor) are commonly used type 2 diabetes mellitus or T2DM medications, however the benefit of using the combination has not been evaluated for cardio-renal risk assessment, in a real-life practice setting, compared to a placebo. Hypothesis: We hypothesized that Dapa will improve the outcomes when compared to placebo and the Combo maybe even more beneficial. Methods: This is a pilot study evaluating low dose Dapagliflozin 10 mg or low dose Dapa + low dose Saxagliptin combination. 15 subjects were enrolled in 16 weeks, double-blind, three-arm, randomized placebo matched trial, with 10mg Dapa + Saxa placebo (n = 4), 10 mg Dapa + 5 mg Saxa (n = 5) Combo, And Dapa placebo + Saxa placebo (n = 6), Placebo groups. T2DM subjects (age 30–70 yrs) with HbA1c of 7–10%, were included. CD34 + HSC number, migration, mRNA expression along with biochemistry and urine exosomes were measured. Data were collected at week 0, 8, and 16. For statistics, a mixed model regression analysis was used. Results: Significant HbA1c (p = 0.0357) reduction was noted in Combo group versus Dapa alone and Placebo. hsCRP levels (P = 0.0317) and IL-6, two important inflammatory molecules, were significantly reduced in both Dapa and Combo vs. Placebo. Leptin levels decreased significantly in both Dapa alone (p = 0.035) and Combo group(p = 0.015), vs. Placebo, however the Adiponectin levels were higher in Dapa alone group. Dapagliflozin alone reduced lipid parameters significantly particularly triglyceride (TG) when compared to placebo, with resultant visit 3 values at 99.5 ± 7.2 vs. 129 ± 12.3 and LDL/HDL ratio values were similar at 2.18 ± 0.08 vs. 2.13 ± 0.15. CD34 + cell migration improved significantly in both Dapa alone (p = 0.05) and Combo group (p = 0.05) vs. Placebo. Conclusions: Several parameters showed significant improvement with both Dapa alone and Combo compared to placebo. However, when all outcome measures were taken into account, other than glycemic control the Combo didn’t seem to offer any further benefit, over Dapa alone. Therefore, contrary to our initial hypothesis we do not believe the more expensive Dapa + Saxa combination offers any specific cardiovascular benefit compared to Dapagliflozin alone. However it is noteworthy that both Dapa and its combination with Saxagliptin showed significant improvement compared to placebo in T2DM, particularly when progenitor cell based numbers and function were analyzed and taken into account. Trial Registration: The trial was registered with Clinical Trials.gov number NCT03660683, last updated 06052023.

Machine learning/artificial intelligence (ML/AI)-based predictive modeling is becoming increasingly popular in healthcare, particularly within the scope of precision medicine. Models based on patient data are effective tools for clinical decision-making, as well as impactful methods for researchers to expand on existing scientific and clinical understanding of biomarkers and biological pathways. We present PredictMod, an open-license platform for users to query, run, and publish electronic medical records and omics-based intervention outcome (responder vs non-responder) prediction models. The platform currently hosts several intervention outcome prediction models that utilize varied data types, conditions, and interventions, offering users insight into the kinds of information required to develop such models. Model-specific graphs and charts such as confusion matrices and feature importance facilitate user understanding of model output. Our model creation pipeline ensures comprehensive documentation using BioCompute Objects. The platform allows researchers in conjunction with clinicians to generate models using data from publications or their datasets and apply them to predict intervention outcomes for new patients or samples. PredictMod is particularly suited for small datasets, which are common in biological research. By providing a framework for pilot studies, the platform facilitates early-stage insights, helping researchers justify larger-scale data collection efforts. With its versatility and accessibility, PredictMod can advance biomedical research and precision clinical medicine by lowering technical barriers and fostering data-driven discovery approaches at the early stages of hypothesis generation using ML/AI.

Introduction: Effect of Dapagliflozin (Dapa) and Dapagliflozin-Saxagliptin combination (Combo) was examined on peripheral blood derived CD34 + Hematopoetic Stem Cells (HSC) as a cellular CVD biomarker. Both Dapa (a sodium-glucose co-transporter 2 or SGLT2, receptor inhibitor) and Saxagliptin (a Di-peptydl-peptidase-4 or DPP4 enzyme inhibitor) are type 2 diabetes mellitus or T2DM medications, but the combo has not been evaluated for cardio-renal risk assessment. Hypothesis: We hypothesized that Dapa will improve the outcomes when compared to placebo and the Combo maybe even more beneficial. Methods 15 subjects were enrolled in 16 weeks, double-blind, three-arm, randomized placebo matched trial, with 10mg Dapa + Saxa placebo (n = 4), 10 mg Dapa + 5 mg Saxa (n = 5) Combo, And Dapa placebo + Saxa placebo (n = 6), Placebo groups. T2DM (30–70 yrs) with HbA1c of 7–10%, were included. CD34 + HSC number, migration, mRNA expression along with biochemistry and urine exosomes were measured. Data were collected at week 0, 8, and 16. For statistics, a mixed model regression analysis was used. Results: Significant HbA1c (p = 0.0357) reduction was noted in Combo group versus Dapa alone and Placebo. hsCRP levels (P = 0.0317) and IL-6, two important inflammatory molecules, were significantly reduced in both Dapa and Combo vs Placebo. Leptin levels decreased significantly in both Dapa alone (p = 0.035) and Combo group(p = 0.015), vs Placebo, however the Adiponectin levels were higher in Dapa alone group. Dapagliflozin alone reduced lipid parameters significantly particularly triglyceride (TG) when compared to placebo, with resultant visit 3 values at 99.5 ± 7.2 vs 129 ± 12.3 and LDL/HDL ratio values were similar at 2.18 ± 0.08 vs 2.13 ± 0.15. CD34 + cell migration improved significantly in both Dapa alone (p = 0.05) and Combo group (p = 0.05) vs Placebo. Conclusions: Several parameters showed significant improvement with both Dapa and Combo vs placebo. However, other than glycemic control the Combo didn’t seem to offer any further benefit over Dapa alone in terms of CD34 + cell, biochemistry and podocyte markers. Moreover, the combination may have deleterious effect on renal podocyte inflammation which needs to be examined in a larger study. Trial Registration The trial was registered with Clinical Trials.gov number NCT03660683, last updated 06052023.

Disclosure: L. Esper: None. A. Ibrahim: None. S. Sen: None. Introduction: Autoimmune polyglandular syndrome type 2 (APS-2) or Schmidt's syndrome, is a rare disorder characterized by the coexistence of autoimmune adrenal and thyroid disease and/or type 1 diabetes mellitus. Clinical case: A 51-year-old woman with past medical history of depression and bipolar disorder presented to the hospital with weakness and dizziness. The patient reported increased dizziness and weakness over several months that progressed and limited her level of daily activities. She had been experiencing decreased energy, poor appetite and occasional nausea but denied vomiting or abdominal pain. She also denied any changes in her weight. She suffered from constipation but that was her baseline for many years. She was diagnosed with bipolar disorder with depression in her 20s and required multiple admissions for severe depression. She had been following up with her psychiatrist and assumed to have worsening depression. Her mood stabilizers and antidepressant medications were adjusted over several months without improvement. In the Emergency Department, her blood pressure was 98/58. Her heart rate was 57. Labs revealed Na: 115, K: 5.3 and Cr:0.87. The patient was admitted to the general medical floor for treatment of symptomatic hyponatremia. Hyponatremia was initially thought to be due to depression and decreased oral intake. She was started on fluid with slight improvement in sodium levels without significant improvement in symptoms. Further work up for the etiology of her hyponatremia and weakness elicited 2 endocrinopathies. She had a morning cortisol of 4. Cosyntropin stimulation test did not elicit a proper response. At baseline, cortisol was 4.2 and then 4.5 and 4.3 at 30 and 60 minutes, respectively. She was also found to have hypothyroidism (TSH 10, FT4: 0.4). Patient was started on hydrocortisone and fludrocortisone initially and subsequently thyroid hormone replacement was added with resolution of symptoms and hyponatremia. She reported being postmenopausal since age 41. Given that the patient had at least two endocrinopathies, 21 hydroxylase antibody testing was ordered and found to be positive. Addison's disease diagnosis is often delayed. A cross-sectional study in 2013 showed that less than 50% of patients with adrenal insufficiency were correctly diagnosed within the first half year after symptoms appeared. It however took more than 5 years until the condition was diagnosed for 20% patients. (1) The delay was primarily attributed to concomitant presence of psychiatric and gastroenterological conditions. Conclusion: Poly endocrinopathies often present with vague symptoms that need to be worked up to prevent the life-threatening effects of APS2 including adrenal crisis. We present an uncommon case of middle-aged woman with Tri-glandular syndrome with delayed diagnosis due to underlying psychiatric disease. (1) Meyer et al. Horm Metab 2013; 45:92-95 Presentation: Friday, June 16, 2023