Reviews in Endocrine & Metabolic Disorders最新文献

Poor muscle quality (MQ) is a hidden health condition in obesity, commonly disregarded and underdiagnosed, associated with poor health-related outcomes. This narrative review provides an in-depth exploration of MQ in obesity, including definitions, available assessment methods and challenges, pathophysiology, association with health outcomes, and potential interventions. MQ is a broad term that can include imaging, histological, functional, or metabolic assessments, evaluating beyond muscle quantity. MQ assessment is highly heterogeneous and requires further standardization. Common definitions of MQ include 1) muscle-specific strength (or functional MQ), the ratio between muscle strength and muscle quantity, and 2) muscle composition (or morphological MQ), mainly evaluating muscle fat infiltration. An individual with obesity might still have normal or higher muscle quantity despite having poor MQ, and techniques for direct measurements are needed. However, the use of body composition and physical function assessments is still limited in clinical practice. Thus, more accessible techniques for assessing strength, muscle mass, and composition should be further explored. Obesity leads to adipocyte dysfunction, generating a low-grade chronic inflammatory state, which leads to mitochondrial dysfunction. Adipocyte and mitochondrial dysfunction result in metabolic dysfunction manifesting clinically as insulin resistance, dyslipidemia, and fat infiltration into organs such as muscle, which in excess is termed myosteatosis. Myosteatosis decreases muscle cell function and insulin sensitivity, creating a vicious cycle of inflammation and metabolic derangements. Myosteatosis increases the risk of poor muscle function, systemic metabolic complications, and mortality, presenting prognostic potential. Interventions shown to improve MQ include nutrition, physical activity/exercise, pharmacology, and metabolic and bariatric surgery.

This review is to systematically explore the relationship between muscle dysfunction and diabetes in adults, and to examine the impact of glycemic variability on muscle health and the development of diabetes-related complications. The review was conducted using three databases: MEDLINE, Scopus, and EMBASE, targeting peer-reviewed journal articles written in English and published from January 2014 to September 2024. The methodological quality assessment of the eligible studies was conducted using Joanna Briggs Institute Critical Appraisal Checklists. A total of 17 studies were included. Most studies were undertaken in Asian countries (n = 11) and focused on adults with type 2 diabetes (n = 12). There were 8,392 adults with diabetes, and their mean age ranged from 52 to 75 years old. The measurements for muscle function and glycemic variability varied across studies. The research findings regarding the relationship between muscle dysfunction and glycemic variability metrics among adults with diabetes, both with and without complications were inconsistent. For adults with diabetes and sarcopenic obesity, poor glycemic control was identified as an independent risk factor for sarcopenic obesity. Additionally, all included studies were rated as moderate or high quality in relation to their methodology. In conclusion, this review underscores the complex and inconsistent relationship between glycemic variability and muscle dysfunction in older adults with diabetes. Poor glycemic management is a significant risk factor for sarcopenic obesity, highlighting the need for tailored interventions to improve glycemic control and muscle health in this population.

Tirzepatide, a dual GIP and GLP-1 receptor agonist, has shown significant metabolic benefits and weight reduction, but its anti-inflammatory effects have been less studied. This study was conducted in accordance with PRISMA guidelines, including observational (cohort) studies and randomized clinical trials that evaluated tirzepatide use and reported percentage changes in high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). A random-effects model was used. Seven randomized clinical trials and one observational study were included (six studies were eligible for meta-analysis). Compared to placebo, tirzepatide reduced hsCRP (mean difference [MD]: -32.9; 95% confidence interval [CI]: -33.6 to - 32.2; I²=15.3%) and IL-6 (MD: -17.8; 95% CI: -24.3 to - 11.3; I² = 1.6%). Levels of hsCRP were significantly reduced with tirzepatide at 15 mg (MD: -32.9; 95% CI: -33.6 to - 32.2; I²=4.4%), 10 mg (MD: -33.9; 95% CI: -50.3 to - 17.6; I²=41.8%), and 5 mg (MD: -20.3; 95% CI: -35.2 to - 5.3; I²=0%). Similarly, IL-6 levels were significantly reduced with tirzepatide at 5 mg (MD: -18.8; 95% CI: -32.9 to - 4.6; I²=17.2%), 10 mg (MD: -17.9; 95% CI: -28.2 to - 7.7; I²=2.1%), and 15 mg (MD: -16.8; 95% CI: -31.1 to - 2.6; I²=47.4%). This study demonstrated that tirzepatide use is associated with a significant reduction in inflammatory markers, regardless of the population studied or treatment regimen.

The development of drugs targeting Nutrient Stimulated Hormone receptors has ushered in a dramatic change in our approach to weight management because of their ability to achieve weight losses of 10%, 20%, even 30% in significant numbers of patients. Additionally, disease modifying properties of these medications are compelling. Indications now include cardiovascular risk reduction, obstructive sleep apnea and diabetes management, and emerging evidence supports efficacy for heart failure and chronic kidney disease. These medications would need to be taken long term and the population being treated will be older than the traditional weight management patient. Emerging evidence cautions that the loss of excessive lean mass with some of the newer medications may be problematic. This is not a concern for most patients who will need the medications, but it is a concern in an older population, since loss of muscle and bone accelerates and progresses past age 60. Of weight lost with semaglutide, approximately 45% is from lean mass, while with tirzepatide, it is 25%. Going forward, combining another NuSH such as glucagon or amylin with the GLP-1 receptor agonists may lessen loss of lean mass. Another approach under study is the use of MAPi - myostatin-activin pathway inhibitors. Promising results with bimagrumab are spurring investigaton in this area. For the full potential of disease modification to be achieved, it's a given that we must demonstrate safe, long term body composition improvement when the new medications are deployed, especially in the older population. This narrative review discusses the justification for focus on lean mass preservation and reviews the status of relevant drugs in development.

Obesity and type-2 diabetes mellitus (T2DM) are interrelated metabolic disorders primarily driven by overnutrition and physical inactivity, which oftentimes entails a transition from obesity to T2DM. Compromised musculoskeletal health consistently emerges as a common hallmark in the progression of these metabolic disorders. Skeletal muscle atrophy and dysfunction can further impair whole-body metabolism and reduce physical exercise capacity, thus instigating a vicious cycle that further deteriorates the underlying conditions. However, the myocellular repercussions of these metabolic disturbances remain to be completely clarified. Insulin signaling not only facilitates skeletal muscle glucose uptake but also plays a central role in skeletal muscle anabolism mainly due to suppression of catabolic pathways and facilitating an anabolic response to nutrient feeding. Chronic overnutrition may trigger different myocellular mechanisms proposed to contribute to insulin resistance and aggravate skeletal muscle atrophy and dysfunction. These mechanisms mainly include the inactivation of insulin signaling components through sustained activation of stress-related pathways, mitochondrial dysfunction, a shift to glycolytic skeletal muscle fibers, and hyperglycemia. In the present review, we aim to delve on these mechanisms, providing an overview of the myocellular processes involved in skeletal muscle atrophy and dysfunction under chronic overnutrition, and their contribution to the progression to T2DM.

Obesity is traditionally defined as "abnormal or excessive fat accumulation that presents a health risk," yet this definition lacks precision and fails to account for individual variability in body composition. The continued reliance on body mass index (BMI) as a diagnostic tool further complicates accurate assessment, as BMI does not differentiate between fat mass and lean mass. Emerging evidence highlights that health risks associated with obesity are not solely determined by fat accumulation, but also by the relative deficiency in fat-free mass, particularly muscle. Despite this, the role of muscle health in obesity management remains underappreciated in clinical practice. With the advent of potent pharmacotherapies for obesity, such as a new class of GLP-1 receptor agonists, there is growing concern about their impact on muscle mass during weight loss. This underscores the need for a more holistic understanding of body composition changes and their implications for long-term health. This special issue of Reviews in Endocrine and Metabolic Disorders addresses these critical gaps, offering diverse perspectives on integrating muscle health into the continuum of obesity care.

Obesity is a global health concern that impacts health, quality of life, and longevity in affected individuals. Comorbid cardiovascular disease, type 2 diabetes, cancer, and other conditions often accompany obesity, and researchers are actively investigating therapeutic strategies to treat obesity and mitigate the health risks associated with excess adiposity. Restrictive nutritional intake and body weight reduction through lifestyle behavioral interventions, bariatric procedures, and highly effective anti-obesity medications are all recommended treatments for obesity. Meanwhile, the caloric restriction that comes with very low-calorie diets can result in changes in body composition, most notably a progressive loss of muscle mass and/or functionality, a process that can be accelerated by aging, underlying metabolic disease, or inadequate protein intake seen with many dietary patterns. While muscle loss was previously understood as a condition only affecting older individuals, this outcome is common in patients with obesity. The term sarcopenic obesity has been used to refer to this condition, and it is now recognized as an important potential complication in all patients with obesity. Dietary challenges that influence overall body composition also have drawn attention to the gut microbiome, a topic of growing interest as there is an increasingly recognized interplay between diet, the metabolic actions of microorganisms in the gut that impact macronutrient and micronutrient production and absorption, and human health. This article will review the current understanding of obesity as a chronic disease, the impact of diet and nutritional therapy on body composition, and the potential relevance of the gut microbiome in this setting.

Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as mediators of satiety, acting in response to metabolic and hormonal cues and in opposition to Agouti-related protein (AgRP) neurons to maintain energy balance. This model, centered on the appetite-suppressant effects of the POMC-derived neuropeptide α-melanocyte-stimulating hormone (α-MSH) through its activation of melanocortin-4 receptors (MC4R), has shaped our understanding of feeding and body weight regulation for decades. However, recent discoveries have challenged and expanded this traditional view, revealing that POMC neurons are not a uniform population dedicated solely to satiety control. Single-cell transcriptomic analyses have revealed striking molecular heterogeneity, reflected in distinct anatomical distributions, receptor expression profiles, electrophysiological properties, and projection patterns - all supporting the idea of functional specialization within this neuronal population. In this review, we propose a conceptual framework that integrates POMC neuronal heterogeneity with the regulation of appetite, metabolic physiology, and behavior beyond feeding. We highlight emerging evidence showing that discrete POMC neuronal subpopulations respond to specific combinations of interoceptive and environmental cues to orchestrate diverse adaptive responses. This perspective underscores the developmental plasticity and functional versatility of POMC neurons, offering new insights into the mechanisms of obesity and potentially paving the way for novel targeted therapeutic strategies.

The regulation of energy homeostasis is an essential function of every living organism. In mammals a complex interplay of neural networks has evolved to ensure proper adaptation to energy demands, availability, consumption, storage and utilization. While a large set of parallel and redundant brain networks are functionally intertwined in these processes, a specific subset of hypothalamic neurons producing the agonist and antagonist of the anorectic signaling pathway controlled by the melanocortin receptor have been extensively studied. The anorectic/catabolic pro-opiomelanocortin (POMC) producing neurons and the orexigenic/anabolic Agouti-related peptide (AgRP) producing neurons exert opposing functions of various aspects of foraging, ingestive and post-ingestive processes. Located close to circumventricular these two populations integrate circulating reflecting energy status but are dynamically controlled by food-predicting cues. This review will be focusing on recent advances in understanding the role of the hypothalamic AgRP neurons, as critical metabolic sensors and regulators. We explore the intricate mechanisms by which these neurons integrate diverse nutritional signals and coordinate autonomic and behavioral responses to maintain metabolic equilibrium.

Childhood obesity is a global health problem, with its prevalence having tripled since 1975. The increase in its prevalence has been predominantly in developing countries, but also in those with high economic status. Nowadays, there are multiple obesity definitions, however, one of the most accurate is the one which defines obesity as the accumulation of excessive body adiposity and not as an body weight excess. Nevertheless, the body mass index (BMI) is the most frequently used tool for its classification, according to the cut-off points established by the Center for Disease Control and World Health Organization tables. In children and adolescents an adiposity excess is related to the appearance of cardiovascular disease in adulthood and with many comorbidities such as metabolic syndrome, insulin resistance, type 2 diabetes, hypertension and metabolic dysfunction-associated steatotic liver disease, among others. Currently, there is still controversy about which is the ideal indicator for measuring overweight and obesity. BMI is still used as a standardized measure but may miss cases in which body composition is pathological despite a BMI within the normal-weight category. An adequate knowledge of the impact on health of dysfunctional adiposity as well as its accurate diagnosis will allow health professionals to address this condition in a more precise and comprehensive manner, and substantially improve the associated cardiometabolic risk and prognosis.