For the past 100 years, insulin supplementation has been the mainstay of treatment for type 1 diabetes (T1D), which is characterized by progressive autoimmune-mediated loss of insulin-producing β cells in the islets of Langerhans over the last decades, technological advances in glucose monitoring and therapeutics have greatly improved the care and management of these patients. However, morbidity, mortality, and quality of life remain challenges for patients with T1D. Islet transplantation has been successfully performed, but there are several limiting factors, such as the lack of cadaveric donors and the need for lifelong immunosuppressive therapy. Therefore, there is a great medical need for alternative therapeutic approaches. In the current review, the current knowledge on novel approaches for the treatment of T1D with a focus on the potential of using chimeric antigen receptor (CAR)-T cells and natural killer (NK) cells is summarized.

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Artificial intelligence (AI) has gained attention for various reasons in recent years, surrounded by speculation, concerns, and expectations. Despite being developed since 1960, its widespread application took several decades due to limited computing power. Today, engineers continually improve system capabilities, enabling AI to handle more complex tasks. Fields like diagnostics and biology benefit from AI’s expansion, as the data they deal with requires sophisticated analysis beyond human capacity. This review showcases AI’s integration in endocrinology, covering molecular to phenotypic patient data. These examples demonstrate AI’s potential and power in research and medicine.

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Adult-onset testosterone deficiency (TD) in men is diagnosed by the finding of low serum testosterone levels and recognised, associated symptoms. The condition has high prevalence in men over 50 years of age, particularly those with type 2 diabetes (T2DM). Accumulating data show adult-onset TD is associated with increased mortality risk. We review the literature and consider the evidence suggesting testosterone therapy (TTh) reduces mortality, especially in men with T2DM. We previously reported that in the Burntwood Lichfield Atherstone Sutton Coldfield Tamworth (BLAST) study screened cohort of men with adult-onset TD and T2DM adult-onset TD was associated with increased mortality with TTh decreasing this higher mortality. The data hinted that the effect was greater in older men. We confirmed this observation with statistical analyses to study the effect of age on the association between adult-onset TD and mortality; Cox regression analysis demonstrated that the reduced risk (hazard ratio: 0.61, 95% CI: 0.38–0.96) following TTh was restricted to men above the median age of 65.89 years. Finally, we speculate on putative mechanisms that may mediate these associations. Heterogeneity in men with adult-onset TD is expected in view of its definition of low testosterone levels together with associated clinical phenotypes that are not always directly related. Many of these classifying phenotypes are associated with increased mortality. Thus, it is perhaps possible that mechanism(s) of all-cause mortality reduction following TTh is via the impact on these associated phenotypes such as the metabolic syndrome (MetS), hyperglycaemia, hypertension, dyslipidaemia, low haematocrit, sex hormone binding levels, erectile dysfunction, etc. We propose that further research studying the effect of TTh takes heterogeneity into account.

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to high morbidity and mortality, despite the availability of life-saving corticosteroid replacement therapy. Gene therapy represents a promising potential treatment for monogenic disorders such as congenital adrenal hyperplasia, overcoming the limitations of corticosteroid replacement approaches. Adeno-associated viral vectors are currently the leading vector for direct in vivo gene delivery. However, physiological properties of the adrenal gland limit the application of adeno-associated viral vector-based gene addition strategies. To achieve durable correction in the adrenal gland, gene editing must be employed to stably introduce a genetic modification into the CYP21A2 locus. The safety of this and other gene editing approaches could be greatly improved by using lipid nanoparticles for the delivery of editing machinery mRNA. While little data exists regarding adrenocortical lipid nanoparticle targeting, physiological features of this organ (such as high relative blood flow, fenestrated endothelium, and cholesterol uptake) indicate the promise of these delivery vectors for the treatment of monogenic diseases of the adrenal cortex. This review discusses the complexities of developing gene therapy for congenital adrenal hyperplasia and explores the viability of novel gene therapy strategies in this application.

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Stress is a state of threatened or perceived as threatened homeostasis that can be induced by various external and internal stimuli such as psychosocial factors, inflammatory or injurious conditions, and infections. In order to restore body homeostasis, adrenal glands produce and secrete glucocorticoids (GCs) and catecholamines (CAs), which are the main stress hormones that support the survival and adaptation of the organisms to the new environment. In contrast to the rather beneficial impact of acute and short-lasting stress, chronic stress and related dysregulation of the stress system is implicated in the development of many non-communicable diseases, including cancer. Particularly, ever-increasing experimental and clinical evidence implicates the involvement of CAs and GCs as well as the overexpression of their receptors in the activation of the major pathways involved in tumour development, metastasis, and resistance to various therapies. More importantly, results of experimental and epidemiological studies revealed that overexposure to stress hormones during pre- and early postnatal life might induce life-long or even transgenerational dysregulation of the stress system and predispose it to the development of various tumours. Although the exact mechanisms involved in the latter process are not yet fully known, it has been demonstrated that GC-induced epigenetic modifications can change the expression of several key genes involved in the regulation of the stress system, tumour initiation, and epigenetic imprinting. When such alterations occur in stem/progenitor cells (SPCs), this might not only lead to long-term dysfunction of the stress system but might promote the generation of cancer stem cells (CSCs). This review article discusses a hypothesis that stress hormones-mediated epigenetic reprograming of various SPCs during sensitive developmental periods, might contribute to their dysfunction and increased sensitivity to malignant transformation, thereby promoting tumorigenesis.

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The escalating prevalence of diabetes poses a significant health concern. Uncontrolled diabetes leads to a multitude of complications. A comprehensive management plan and continual adaptation of guidelines is needed. The American Diabetes Association (ADA) is a guiding force in this domain, providing diabetes care recommendations for clinicians, laboratorians, researchers, and policymakers since 1989. The latest ADA guidelines present both challenges and opportunities for laboratories. The increased emphasis on glycated hemoglobin (HbA1c) testing for early diagnosis and personalized monitoring is expected to increase testing volumes, potentially leading to a rise in point-of-care testing. Ensuring standardized testing procedures becomes paramount to maintaining consistent and reliable results across laboratories. Moreover, laboratories may need to expand their test menus to accommodate the growing demand for personalized medicine approaches and collaborate closely with healthcare providers to support informed decision-making. This commentary provides a focused analysis of the 2024 ADA guidelines for the laboratory assessment of diabetes.

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Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endogenous glucocorticoid levels are important to support bodily homeostasis, chronically elevated levels can cause damage to tissues and drive diseases including bone loss (i.e., osteoporosis), myopathy (i.e., sarcopenia) and metabolic disturbances (i.e., glucose intolerance, diabetes, and abnormal fat accrual). There is substantial evidence that basal glucocorticoid levels increase during ageing while at the same time the amplitude of the diurnal variation in glucocorticoid secretion decreases. However, the significance of these changes for skeletal health is not well understood and has only recently been studied in more detail. Evidence from genetically modified mouse models indicates that changes in glucocorticoid signaling associated with ageing induce bone loss, sarcopenia and drive osteoarthritic joint disease. These studies provide important insights into the role of glucocorticoids in age-related skeletal diseases which will aid in the development of novel treatments especially needed for osteoarthritis which disproportionally affects the elderly.

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A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019 without a history of anti-androgen therapy, and atrial fibrillation, for which he had been prescribed apixaban since 2021. Treatment with risedronate occurred from approximately 2004 to about 2011, with improvement in bone density to osteopenia. He had also taken vitamin D and calcium supplementation and engaged in regular weight-bearing exercise. The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. We propose that beta thalassemia minor is potentially a risk factor for osteopenia and osteoporosis, and that bisphosphonates can be considered for management when therapeutic intervention is indicated. Even in the absence of other known risk factors, clinicians should consider periodically screening beta thalassemia minor patients with DXA for evaluation of bone health.

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Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are uncommon neuroendocrine tumors arising from adrenal medullary chromaffin cells and sympathetic/parasympathetic paraganglia. Though PPGLs predominate in adult populations, pediatric cases of PPGLs represent more aggressive disease outcomes with 12% being diagnosed as metastatic. Metastatic disease (spread to bone, lung, lymph nodes, or liver) occurs in a subset of PPGLs, ranging from 15% to 17% depending on the underlying pathogenic variants. Historically, pulmonary metastases present clinically as multiple small lesions; however, cases of PPGLs with innumerable small metastases (a miliary pattern) overwhelming lung parenchyma define a novel yet exceptionally challenging disease presentation. This pattern of pulmonary lesions upon treatment and/or cellular lysis may lead to both respiratory decompensation as well as prolific catecholamine release, incurring significant morbidity and mortality if not appropriately managed. Of the 2,649 PPGL patients enrolled in our protocol from January 1, 2000, to April 30, 2023, 500 had metastatic disease, 122 were children/adolescents, and 3 of the 122 children/adolescents had extensive pulmonary metastatic disease. All three adolescent patients with extensive pulmonary metastases had cluster 1 PPGLs and suffered hypoxemia (due to pulmonary metastases) leading to overactive hypoxia signaling and catecholamine-induced signs and symptoms [among them hypertension and/or tachyarrhythmia(s)]. Interventions including surgery, chemotherapy, and radiotherapy were pursued. Two patients achieved disease stability, while one patient succumbed to disease. Ultimately these divergent outcomes emphasize the importance of recognizing poor prognostic factors and aggressive disease early, to select appropriate treatments. Optimal management of these patients must consider complications of catecholamine excess and the profound influence of hypoxia. Herein, we describe three adolescent cases of extensive pulmonary metastatic PPGL and the unique clinical challenges faced in treating these tumors alongside relevant literature to provide guidance on appropriate interventions (ClinicalTrials.gov identifier: NCT00004847).

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The clinical case presented describes a 44-year-old woman with a history of mucinous carcinoma in the right breast, who is diagnosed with a pituitary adenoma. Physical examination revealed signs of acromegaly, such as macroglossia and palmar hyperhidrosis. Hormonal tests were performed and showed elevated levels of insulin-like growth factor type 1 (IGF-1). The patient received GnRH analogues for breast cancer; and started medical treatment with somatostatin analogues for acromegaly, which provided improvement in symptoms. Pituitary bleeding was detected during hormone treatment, which caused the growth of the adenoma, causing it to contact the optic chiasm, although no symptoms of pituitary apoplexy were present. Transsphenoidal endoscopic surgery was performed to remove the adenoma, and the diagnosis of pituitary adenoma was confirmed by pathology. The importance of the evaluation of comorbidities in patients with acromegaly is discussed. Pituitary apoplexy as an uncommon complication of pituitary adenomas, which may be associated with the use of GnRH analogues, is addressed. Pre-surgical medical treatment in acromegaly is also discussed, highlighting the importance of a comprehensive assessment of prognostic factors and appropriate treatment selection to improve clinical outcomes. In conclusion, the importance of a multidisciplinary and personalized approach in the management of patients with GH-producing pituitary adenomas to improve quality of life and clinical outcomes is highlighted.

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Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalence of HT is increased among diabetic patients but also DM is more common in hypertensive patients. CVD risk increases multiplicatively in coexistence of HT and DM. Lowering blood pressure (BP) has been shown to be associated with improved morbidity related to both macro- and micro-vascular complications. Although there is debate about target BP levels, in many randomized controlled trials and guidelines a goal of < 130/80 mmHg is advocated in patients with DM, if well tolerated. However, an individualized approach should be cared for depending on risk factors, co-morbidities, and frailty of patients. Lifestyle modifications including weight loss, regular exercise, avoiding smoking and excessive alcohol consumption, and a healthy diet including limitation of salt and fat and total energy intake, are important both as a part of preventive therapy and treatment modality for both DM and HT. Among antihypertensive drugs angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are warranted due to their potential advantages for slowing albuminuria and progression to kidney failure which is more common in DM. Usually, their combination with calcium-channel blockers (CCBs) or thiazide/thiazide-like diuretics, in a step-wise manner, is recommended. Resistant HT is more common in DM and requires the addition of mineralocorticoid receptor antagonists (MRAs). New antidiabetic drugs like glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to lower BP. Apart from their antihypertensive effects they also improve CVD and renal outcomes. There’re ongoing new trials for new agents. Development of more potent and longer-term effective BP lowering drugs, single pill multiple drug combinations of antiHT agents and combination of antiHT agents with glucose-lowering and antilipidemic agents will probably improve compliance to treatment and achievement of goals in diabetic patients.

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Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an infant death who had been hospitalized with complicated health problems and metabolism syndrome. Whole-exome sequencing (WES) was used to screen pathogenic variants in the patient’s genome, followed by examination of variants segregation in her parents. The WES analysis identified two homozygous variants, c.[614C>G; 649A>G] in the HMGCL gene of the patient. These two variants co-locate within the exon 7 of the HMGCL gene, resulting in 2 amino acid substitutions, p.[T205S; M217V], in the conservative region of enzyme protein. Sanger sequencing showed that the patient’s unaffected mother and father carried one mutant allele of the HMGCL gene containing two c.[614C>G; 649A>G] variants. The HMGCL gene encodes the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme, which is critical in the ketogenic pathway. The deficiency of this enzyme was reported to be a life-threatening illness in the neonatal period, and two variants detected in this study were also found in a Japanese patient with sudden, unexpected death in infancy. The frequency of these two variants in the Vietnamese in-hour database and their further functional analysis were also reported in this study. The results of this study have explored the molecular etiology that causes the severe, deadly condition of the patient and provide an understanding of the risk of disease in her family.

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