Faculty Bibliography

The prevalence and incidence of prediabetes in children and youth continue to increase in parallel with the obesity epidemic. While prediabetes is defined by elevated HbA1c and/or impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), the risk of clinical disease is a continuum. Individuals with prediabetes are at a higher risk of developing youth-onset type 2 diabetes, which is considered a more aggressive form of the disease. This condition is associated with increased cardiovascular and metabolic risks and leads to an earlier onset of complications compared to adults with type 2 diabetes. Additionally, significant damage to beta cells may occur even before dysglycemia develops. Recent data indicate that mortality rates are higher in youths with type 2 diabetes compared to those with type 1 diabetes. Childhood prediabetes and cardiovascular complications associated with it are a significant health concern. This review provides the latest insights into this complex issue. We will present an overview of pathophysiology, screening methods, and therapeutic options to prevent the progression from prediabetes to type 2 diabetes in children. In summary, it is crucial to identify prediabetes in children, as this underscores the importance of appropriate screening and timely intervention.

BACKGROUND/OBJECTIVES/OBJECTIVE:Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia. METHODS:This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers. RESULTS:Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD. CONCLUSIONS:Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels.

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal.

Major depressive disorder is one of the most burdensome mental health disorders. Probiotics have been shown to ameliorate depressive symptoms, though the mechanism remains unclear. This study was conducted to investigate whether extracellular vesicles (EVs) extracted from the probiotic beverage water kefir could influence gene and protein expression in human-derived neuroblastoma cells in vitro. EVs were extracted from lab-cultured water kefir and a control solution without water kefir grains by ultracentrifugation. Water kefir vesicles were imaged via electron microscopy. Neuroblastoma, microglia, and neuroblastoma-microglia co-cultures were exposed to water kefir EVs or negative control medium. Uptake of water kefir EVs was identified by microscopy. All conditions were quantified for brain derived neurotrophic factor, fractalkine, and synaptophysin RNA and protein. Data were analyzed using factorial ANOVAs with significance set at 0.05. Water kefir vesicles were taken up by neuroblastoma cells, and incubation in neuroblastoma-microglia co-culture resulted in significantly higher levels of fractalkine protein compared to media-only control (p = 0.029). To our knowledge, this is the first study to identify potential interactions between EVs derived from the probiotic beverage water kefir and human neuronal cells. Further research is needed to fully elucidate the role played by probiotic-derived EVs in human health.

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study.

Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disease with increasing prevalence worldwide. Previous trials of anti-amyloid and anti-tau immunotherapy indicate that additional research needs to be conducted on other mechanisms to find curative or disease-modifying therapy. This review focuses on apolipoprotein E (ApoE), a critical protein in brain lipid metabolism that acts specifically in the clearance and transport of lipids and cholesterol. The ApoE4 allele confers substantial gene dose-dependent risk of developing AD and lowers the age of onset of AD, although the mechanisms of influence remain incompletely understood. The other isoforms bring different levels of AD risk. ApoE2 is protective while ApoE3 is the most common isoform and is considered neutral. An overview is presented of the latest information on the role of ApoE in AD pathogenesis with an emphasis on pathways that are involved in AD development and interactions with crucial processes in different cell types in the brain. Elucidating the key interactions of ApoE with multiple aspects of brain function can be useful for designing novel ApoE-targeted therapeutic approaches.