OBJECTIVE:To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and type 2 diabetes mellitus (T2DM). METHODS:A nationwide cohort of dyslipidemic patients (n=311,269; age 60.8±9.2 years) was treated with statins for 6 months or longer, with no T2DM before statin initiation. All completed a standardized exercise treadmill test between October 1, 1999, and September 3, 2020, with no evidence of ischemia. We formed age- and gender-specific five CRF categories according to peak metabolic equivalents (METs) achieved, four BMI categories, and two statin intensity categories. RESULTS:During a median follow-up of 10.9 years (3,421,650 person-years of observation), 56,994 developed T2DM (incidence rate 16.7 events/1000-person-years). The adjusted risk was 23% higher in patients on high-intensity compared with those on low-intensity statins (HR, 1.23; 95% CI, 1.21 to 1.25). The T2DM risk increased progressively with higher BMI and high-intensity statin regimen to a 4.44-fold increase (HR, 4.44; 95% CI, 4.22 to 4.67) for obese patients. Conversely, the CRF-T2DM association was inverse and graded regardless of BMI or static-intensity regimen and was approximately 30% to 60% lower risk for patients achieving greater than or equal to 8.4±1.2 METs. Compared with least-fit/low-intensity statin-treated patients, T2DM risk was 21% higher for least-fit/high-intensity statin-treated patients (HR, 1.21; 95% CI, 1.18 to 1.25), and 47% lower (HR, 0.53; 95% CI, 0.51 to 0.56) in highly fit/high-intensity statin-treated patients. CONCLUSION:High-intensity statin therapy was associated with an increased risk of T2DM. The risk increased progressively with higher BMI and decreased with higher CRF. Strategies to improve fitness and weight loss in patients on high-intensity statins can potentially lower T2DM risk.

Physical inactivity and poor cardiorespiratory fitness (CRF) are strongly associated with type 2 diabetes (DM2) and all-cause and cardiovascular morbidity and mortality. Incorporating physical activity promotion in the management of DM2 has been a pivotal approach modulating the underlying pathophysiology of DM2 of increased insulin resistance, endothelial dysfunction, and abnormal mitochondrial function. Although CRF is considered a modifiable risk factor, certain immutable aspects such as age, race, and gender impact CRF status and is the focus of this review. Results show that diabetes has often been considered a disease of premature aging manifested by early onset of macro and microvascular deterioration with underlying negative impact on CRF and influencing next generation. Certain races such as Native Americans and African Americans show reduced baseline CRF and decreased gain in CRF in randomized trials. Moreover, multiple biological gender differences translate to lower baseline CRF and muted responsivity to exercise in women with increased morbidity and mortality. Although factors such as age, race, and sex may not have major impacts on CRF their influence should be considered with the aim of optimizing precision medicine.

Hoarseness due to vocal fold paresis (VFP) has a multitude of etiologies including systemic lupus erythematosus (SLE). During a clinical evaluation of a 58-year-old woman with long-standing hoarseness, an incidental finding of thyroid nodules was found to have VFP. Direct laryngoscopy and vocal fold biopsy confirmed the source was an inflammatory process involving the cricoarytenoid joint of the right hemilarynx. A presumptive diagnosis of SLE was made 3 years before meeting the clinical criteria of overt SLE. The VFP debut of SLE is extremely rare, and a literature review includes a handful of case reports (4 of a total of 37) since 1959. Only partial recovery of laryngeal function using glucocorticoids and Plaquenil was accomplished in the current case.

Abstract Disclosure: A. Parihar: None. E.S. Nylen: None. S.M. Gandhi: None. Familial Hypocalciuric Hypercalcemia (FHH) is predominantly caused by loss-of-function mutations in the calcium-sensing receptor (CaSR) characterized by a benign elevation in calcium and PTH which can be mistaken for primary hyperparathyroidism (PHPT). Missense mutations in the CaSR gene causing FHH have been documented but not much is known regarding their clinical significance. We describe a patient with FHH found to have a novel variant mutation. A 37-year-old male with hypogonadism and fatty liver was incidentally found to have hypercalcemia suggestive of PHPT with elevated PTH (102-114 pg/ml), normal vitamin D, and Fractional Excretion of Calcium (FECa) of 0.014. His father also had hypercalcemia and had undergone parathyroid surgery. The patient denied kidney stones and had a normal bone density. Subsequent Sestamibi and 4D CT scan suggested parathyroid adenoma on the left mid-lower pole of the thyroid. Neck ultrasound also showed a left 1.2 x 1 x 1 cm thyroid nodule as well as a left neck mass with calcifications. Fine needle aspiration was positive for metastatic Papillary thyroid cancer(PTC) in the left neck mass and patient underwent total thyroidectomy along with subtotal parathyroidectomy and lateral neck dissection. Thyroid pathology confirmed multifocal PTC with lymph node involvement that were BRAF V600 positive. Parathyroid pathology was benign hyperplasia. The PTH level decreased appropriately intraoperatively (69%), but postoperatively a rise was noted with levels remaining 70-90 pg/ml with normal calcium levels. Repeat FECa was 0.007, supporting the diagnosis of FHH. Given patient’s father also had hypercalcemia, genetic testing was pursued. This revealed CaSR gene missense mutation (c.1382T>C p.Leu461Pro, heterozygous). This variation is not present in population databases and has been classified as a variant of uncertain significance. It can be difficult to distinguish PHPT from FHH based on FECa as in this case. The patient also had PTC which is not known to be associated with FHH. Due to uncertain significance of this novel CaSR missense mutation, long term follow-up and further familial genetic testing will help better understand clinical implications. Presentation: 6/2/2024

INTRODUCTION:Cardiorespiratory fitness (CRF) is a stronger predictor of mortality than traditional risk factors and is a neglected vital sign of health. Enhanced fitness is a cornerstone in diabetes management and is most often delivered concurrently with pharmacological agents, which can have an opposing impact, as has been reported with metformin. Considering the rapid evolution of diabetes medications with improved cardiovascular outcomes, such as glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, it is of importance to consider the influence of these vis-a-vis effects on CRF. MATERIALS AND METHODS:Combining the words glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors with cardiorespiratory fitness, an online search was done using PubMed, Embase, Scopus, Web of Science, Scientific Electronic Library Online, and Cochrane. RESULTS:There were only a few randomized controlled studies that included CRF, and the results were mostly neutral. A handful of smaller studies detected improved CRF using sodium glucose cotransporter-2 inhibitors in patients with congestive heart failure. CONCLUSIONS:Since CRF is a superior prognosticator for cardiovascular outcomes and both medications can cause lean muscle mass loss, the current review highlights the paucity of relevant interactive analysis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is associated with abnormal accumulation of fat in the liver, which can lead to a wide variety of pathological liver defects and associated insulin resistance (IR), obesity, hypertension, dyslipidemia, diabetes, and cardiovascular disease. The molecular mechanisms that cause the initiation and progression of NAFLD are not fully understood. Increased lipolysis and de novo hepatic lipid synthesis lead to oxidative stress induced by reactive oxygen species and inflammation. Both these two entities could be interrelated and be an important mechanistic pathway, which can lead to tissue injury and hepatic cell death. Mechanisms for worsening of NAFLD include mitochondrial abnormalities, downregulation of glutathione (GSH), decreased activity of GSH-dependent antioxidants, accumulation of activated macrophages, hepatic inflammation, systemic inflammation, IR, and poorly controlled type 2 diabetes mellitus. Although no specific therapy has been approved for NAFLD, we review the latest medical therapeutics with emphasis on stem cell-based possibilities based on the presumed pathophysiology of NAFLD.

Introduction: Statin therapy and obesity are associated with increased risk of developing type 2 diabetes mellitus (T2DM). Conversely, cardiorespiratory fitness (CRF) is inversely related to T2DM incidence. The interaction between statin therapy, obesity, and CRF has not been addressed. Hypothesis: Obesity and statins will be associated with increased risk of T2DM, while CRF will mitigate this increased risk. Methods: From the ETHOS cohort, we identified 570, 054 patients (age 60.7±10.1 years) with no T2DM. All completed a standardized exercise treadmill test (ETT) with no evidence of ischemia. Subsequently, 322,805 (56.6%) were treated with statins for at least 8 months (mean 9.5±5.9 years) and 247,249 were not. Participants were classified based on body mass index (BMI) as normal weight (BMI<25.0 kg/m 2 ), overweight (BMI 25.0-29.9 kg/m 2 ), Obese-I (BMI 30.0-34.9 kg/m2), and Obese-II (BMI ≥35.0 kg/m 2 ). We established five CRF categories based on age-specific quintiles of peak metabolic equivalents achieved: Least-Fit (n=95,071); Low-Fit (n=133,404); Moderate-Fit (n=110,973); Fit (n=158,004) and High-Fit (n=72,602). Adjusted Cox proportional hazards models were constructed to evaluate the association between BMI, statin therapy and T2DM risk, and the interaction with CRF status. Results: During the follow-up period (median 10.3 years), 44,662 developed T2DM (7.4 events/1,000 person-years of observation). The risk of developing T2DM was 44% higher in those treated with statins [Hazard Ratio (HR) 1.44; 95% confidence interval (CI) 1.41-1.48)] compared to those not on statin therapy. The risk increased progressively with higher BMI levels and was nearly 3 times higher for those in the Obese-II category (HR 2.96, CI 2.85-3.06). When T2DM risk was assessed across CRF categories within BMI groups, we noted a progressive decline in T2DM risk with increased CRF regardless of statin therapy or BMI status. The adjusted risk was approximately 25% to 40% lower for those in the two highest CRF categories. Conclusions: Statin therapy and obesity were associated with increased risk of developing T2DM. This risk was mitigated significantly with increased CRF regardless of BMI status.

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. S.M. Gandhi: None. E.S. Nylen: None. Early Onset Osteoporosis (EOOP) affects children and young adults and can be caused by endocrinopathies, chronic medical conditions, nutritional deficiencies, and/or genetic mutations. The most common inherited cause is osteogenesis imperfecta(OI), and a rare variant linked to OI includes a defect in the X chromosomal gene encoding Plastin 3 (PLS3). In our case, a 34-year-old male was referred for severe osteoporosis. He had been diagnosed with osteopenia at age 21. At age 24, imaging revealed multiple vertebral compression fractures and DXA scan confirmed severe osteoporosis. He required L3-L5 kyphoplasty and started on oral bisphosphonates for presumed OI despite negative gene mutation (i.e., COL1A1/COL1A2). He continued treatment for only 2 years. 8 years later, he had persistent osteoporosis (DXA L2-4 Z-score -3.6, LFN Z-score -3.2). He had no evidence of kyphosis or scoliosis and no extraskeletal manifestations such as blue-grey sclera or any dysmorphic features. The workup was negative for secondary causes of EOOP and he denied a family history of osteoporosis. Labs showed normal 24-hour urine calcium, bone markers, and bone Alkaline Phosphatase. Karyotyping showed normal XY and gene analysis was again negative for OI. He started treatment with intravenous Zoledronic acid, however, had a 2-year gap between doses initially causing BMD to drop by 6.5% in L2-L4 (Z -4.1) and by 5.7% in LFN (Z -3.1). Subsequently, he received a total of 5 doses of Zoledronic acid to date and had no further fractures. DXA significantly improved by 10.4% in L2-4 (Z -2.6), and 16.3% in LFN (Z -2.0). Repeated expanded gene testing showed a novel PLS3 hemizygous mutation (deletion at site C.234_237+10del of Exon 3). This case demonstrates a novel PLS3 mutation variant to be a plausible cause of adulthood EOOP which was responsive to bisphosphonate treatment. PLS3 is an F-actin binding and bundling protein involved in cytoskeletal remodeling and may have roles in calcium homeostasis, cell migration, endocytosis, DNA repair, and membrane trafficking. Currently, less than 30 loss of function variants of PLS3 have been identified and all lead to severe osteoporosis- particularly in children. However, our patient’s known onset of bone loss occurred much later- in his twenties and he had no evidence of extra-skeletal manifestations. The cause for such late presentation is unclear but may be attributed to this specific variant of PLS3. This case highlights that PLS3 mutation should be on the differential for EOOP even in early adulthood. Our patient’s BMD has markedly improved with bisphosphonates and he sustained no further fractures after starting therapy. Timely diagnosis and earlier detection will allow for appropriate genetic counseling, earlier screening, and treatment of affected family members. Presentation: Thursday, June 15, 2023

Exosomes are microvesicles that constitute a non-classical mechanism for protein secretion, and they represent a sub-proteome, thus assisting in the difficult task of biomarker discovery in a biological fluid as urine, plasma, or serum. Exosomes have a proven role in regulating immune response, antigen presentation, RNA and protein transfer, and cell-cell (organ–organ) interaction/signaling. The potential role of exosomes in the cardio-renal syndromeCardio-renal syndrome currently remains underexplored. Cardiovascular pathologiesCardiovascular pathologies continue to be the leading cause of morbidity and mortality worldwide, and, particularly, rates of cardiovascular events and death consistently increase as kidney function worsens. In other words, chronic kidney disease (CKD)Chronic kidney disease (CKD) acts as a risk multiplier. This could be compounded by other metabolic dysfunction entities, such as diabetes, pre-diabetes, or overweight/obesity. Unfortunately, the relationship between markers of cardio-metabolic risk in kidney pathology often differs from that in the general population. Efforts are underway to search for the novel mechanism of action simultaneously operating in both pathologies. This book chapter will focus on the role of exosomes in cardiovascular and renal diseasesRenal disease in search for novel key targets of interaction between vascular disease and the kidneys.

OBJECTIVE:To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM). METHODS:Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test. RESULTS:During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75). CONCLUSION:In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

PURPOSE: According to the Centers for Disease Control (CDC), more than 37 million Americans have type 2 diabetes mellitus (T2D). Some studies suggest that the combination of aerobic exercise with resistance exercise may be more effective in regulating blood glucose regulation in T2D patients as compared to either mode independently. However, information on the combined effects of aerobic and resistance exercise training on hemoglobin A1C (HbA1C) levels is limited. Thus, the purpose of this study was to examine the effects of combined exercise on HbA1C changes in T2D US Veterans. In addition, we aimed to determine if baseline HbA1C level influenced the magnitude of effect of combined exercise. METHODS: Prospective waitlist-controlled intervention study in US Veterans with T2D (n = 458, EX = 344, CON = 114; age, 59 ± 8 years; HbA1C, 8.5 ± 1.6%; BMI, 35.2 ± 22.5 kg·m2). US Veterans were enrolled in an exercise program consisting aerobic and resistance exercise training. Aerobic exercise was performed for 20-40 minutes at 50-80% heart rate reserve. Resistance exercise was performed for all major muscle groups for 2-3 sets of 12-15 repetitions. Exercise duration was 12-16 weeks with a frequency of 3 times per week. Participants were grouped according to their baseline HbA1C levels using the cut point of 7.5%. Main outcome was change in HbA1C levels from baseline to post-exercise. Data were analyzed using a linear mixed model with an interaction between treatment (EX and CON) and baseline HbA1C levels (<7.5% and > 7.5%). Covariates included age and change in BMI. Significance was set at P < 0.05 (2-tailed). RESULTS: There was a significant interaction between treatment group and baseline HbA1C levels (F1, 452.0 = 4.86, p = 0.03). Mean changes in HbA1C following combined exercise were significantly greater in Veterans with HbA1C > 7.5% (-1.295) compared to those with HbA1C < 7.5% (-0.31; mean difference = 0.99) p < 0.001). There were no differences in HbA1C levels within the CON group (mean difference = 0.35; p = 0.17). CONCLUSION: The combination of aerobic and resistance exercise improved HbA1C levels in US Veterans with T2D. Greater improvements were observed in those with baseline HbA1C levels >7.5%.

Adrenal myelolipomas are benign adrenocortical tumors composed of adipose tissue mixed with hematopoietic precursor cells. An association of myelolipoma with adrenal cortical adenoma is rare and the pathogenesis of these tumors remains unclear. Here we present a case of an incidentally discovered adrenal tumor with radiologic characteristics of a myelolipoma who underwent adrenalectomy due to biochemical suspicion for pheochromocytoma. The final pathology, however, revealed a myelolipoma with a co-existing adrenal cortical adenoma without evidence of pheochromocytoma. Genetic analysis revealed the presence of a hitherto unreported heterozygous variant, c.329C>A (p.Ala110Asp), of the armadillo repeat-containing protein 5 (ARMC5) gene which when inactivated is commonly associated with bilateral adrenal nodularity.

A plethora of diabetes studies and established clinical guidelines show the strong salutary benefit of aerobic, resistance, and/or combination exercise for improved glycemic and cardiovascular outcomes. Promotion of physical fitness is a cornerstone approach to improved diabetes management especially since subjects with diabetes have reduced baseline aerobic exercise capacity (i.e., reduced cardiorespiratory fitness) with associated increased risk for premature all-cause and cardiovascular mortality. Since medications are often used in conjunction with fitness promotion this can result in complex interaction between management modalities. More recently, newer options such as glucose transporter-2 inhibitors and incretin agonists have shown to improve cardiovascular disease (CVD) outcomes in cardiovascular outcomes trials. Indeed, both classes of agents have experimentally the potential to synergize with exercise training but clinical data vis-à-vis cardiorespiratory fitness is still preliminary. Review of the interaction of exercise and metformin shows no improvement in cardiorespiratory fitness. The use of glucose transporter-2 inhibitors may improve fitness performance in those with diabetes and heart failure. Although incretin agonists have physiological effects on the vasculature and heart, they lack similar clinical supportive data.

The introduction of sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus treatment has shown an unexpectedly significant improvement in heart disease outcome trials. Although they have very different modes of action, a portion of the salutary cardiovascular disease improvement may be related to their impact on diabetic dyslipidemia. As discussed in this focused review, the sodium glucose transporter-2 inhibitors as a class show a mild increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, while triglycerides (TG) decrease inconsistently. In particular, the rise in LDL appears to be related to the less atherogenic, large buoyant LDL particles. The glucagon-like peptide-1 receptor agonists show more of an impact on weight loss and improvement in the underlying low HDL and high TG dyslipidemia. The effect of sodium glucose transporter-2 inhibitors and glucagon-like peptide 1 receptor agonists when used in combination remains largely unknown. Also unexplored is difference in effect of these medications among various ethnicities and metabolic syndrome.

We report a case of 34-year-old clinically asymptomatic woman who had been followed for 6 years for hyperthyroidism with thyroid stimulating hormone <0.006 uIU/mL, free T4 1.98 ng/mL, free T3 5.3 pg/mL, elevated thyroid stimulating immunoglobulin 1.70 IU/L, thyroid peroxidase antibody 38 IU/mL and thyroglobulin antibody 9.3 IU/mL. Radioiodine thyroid scan showed minimal uptake in both thyroid lobes (24-hour uptake was 0.3%). She subsequently underwent evaluation for lower abdominal pain and menstrual irregularities, which revealed a large left ovarian cyst measuring 15.9 cm × 10.8 cm × 13.2 cm and right-sided ovarian cyst measuring 2.7 cm × 3.3 cm × 3.5 cm. Laparoscopic bilateral ovarian cystectomy was performed and the final pathology revealed struma ovarii of the left ovarian cyst with the entire ovarian tumour made up of benign thyroid tissue. Thyroid function tests performed 3 months after surgical removal of struma ovarii showed euthyroidism. We present a rare case with detailed laboratory and immunological data before and after ovarian extirpation with resolution of hyperthyroidism associated with functional struma ovarii.

OBJECTIVES: Clinically, procalcitonin represents the most widely used biomarker of sepsis worldwide with unclear pathophysiologic significance to date. Pharmacologically, procalcitonin was shown to signal through both calcitonin receptor and calcitonin gene-related peptide receptor in vitro, yet the identity of its biologically relevant receptor remains unknown.DESIGN: Prospective randomized animal investigations and in vitro human blood studies.SETTING: Research laboratory of a university hospital.SUBJECTS: C57BL/6J mice and patients with post-traumatic sepsis.INTERVENTIONS: Procalcitonin-deficient mice were used to decipher a potential mediator role in experimental septic shock and identify the relevant receptor for procalcitonin. Cecal ligation and puncture and endotoxemia models were employed to investigate septic shock. Disease progression was evaluated through survival analysis, histology, proteome profiling, gene expression, and flow cytometry. Mechanistic studies were performed with cultured macrophages, dendritic cells, and gamma delta T cells. Main findings were confirmed in serum samples of patients with post-traumatic sepsis.MEASUREMENTS AND MAIN RESULTS: Procalcitonin-deficient mice are protected from septic shock and show decreased pulmonary inflammation. Mechanistically, procalcitonin potentiates proinflammatory cytokine expression in innate immune cells, required for interleukin-17A expression in gamma delta T cells. In patients with post-traumatic sepsis, procalcitonin positively correlates with systemic interleukin-17A levels. In mice with endotoxemia, immunoneutralization of interleukin-17A inhibits the deleterious effect of procalcitonin on disease outcome. Although calcitonin receptor expression is irrelevant for disease progression, the nonpeptide calcitonin gene-related peptide receptor antagonist olcegepant, a prototype of currently introduced antimigraine drugs, inhibits procalcitonin signaling and increases survival time in septic shock.CONCLUSIONS: Our experimental data suggest that procalcitonin exerts a moderate but harmful effect on disease progression in experimental septic shock. In addition, the study points towards the calcitonin gene-related peptide receptor as relevant for procalcitonin signaling and suggests a potential therapeutic application for calcitonin gene-related peptide receptor inhibitors in sepsis, which warrants further clinical investigation.Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. PMID: 33196529