Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.

Hypopituitarism, characterized by reduced secretion of pituitary hormones, profoundly impacts systemic metabolic homeostasis and quality of life. Its etiology ranges from congenital anomalies in pituitary development to acquired conditions involving inflammation and autoimmune processes. Despite advances in understanding its pathogenesis, diagnostic challenges persist, particularly in cases with complex extra-pituitary manifestations or novel genetic variations. Congenital hypopituitarism often stems from disruptions in transcription factors and signaling pathways critical for pituitary organogenesis. Emerging studies employing next-generation sequencing and developmental biology techniques have revealed new genetic loci and mechanisms implicated in combined pituitary hormone deficiency. However, the pathogenesis of most congenital cases remains elusive, underscoring the need for functional and phenotypic analyses of novel variants. Acquired hypopituitarism, frequently associated with pituitary tumors or systemic diseases, has also been increasingly linked to autoimmune mechanisms. Notably, the concept of paraneoplastic autoimmune hypophysitis has emerged, highlighting malignancy-driven immune responses as a novel etiological framework. Investigations into immune checkpoint inhibitor-related hypophysitis and anti-PIT-1 hypophysitis exemplify the intricate interplay between tumor immunity and endocrine dysfunction, suggesting shared mechanisms involving ectopic antigen expression and autoimmunity. This review synthesizes recent insights into the genetic, developmental, and immunological underpinnings of hypopituitarism. By exploring both congenital and acquired etiologies, we aim to bridge gaps in the current understanding of this complex disorder and provide a foundation for improved diagnostic and therapeutic strategies. Future perspectives emphasize the integration of advanced genetic tools, deeper exploration of tumor-immunity interactions, and a heightened focus on extra-pituitary phenotypes to refine clinical practice and enhance patient outcomes.

Cushing’s disease is a rare endocrine disorder that presents many systemic complications, and its initial phase management can be difficult in atypical and severe cases or at institutes with limited experience. It is a disease in which several complications may have already progressed at the time of diagnosis, and complications may become more severe during the initial management phase, potentially becoming life-threatening. In addition, many patients are young, and depending on this phase management, their quality of life will significantly decline later on. Therefore, this review summarizes the evidence accumulated to date and outlines strategies for disease management, focusing on the initial stages from detection, diagnosis, and referral of patients to surgery.

Ghrelin produced in the stomach promotes food intake and GH secretion, and acts as an anabolic peptide during starvation. Ghrelin binds to the growth hormone secretagogue receptor, a G protein-coupled receptor (GPCR), whose high-resolution complex structures have been determined in the apo state and when bound to an antagonist. Anamorelin, a low-molecular-weight ghrelin agonist, has been launched in Japan for the treatment of cancer cachexia, and its therapeutic potential has attracted attention due to the various biological activities of ghrelin. In 2019, liver-expressed antimicrobial peptide (LEAP2), initially discovered as an antimicrobial peptide produced in the liver, was identified to be upregulated in the stomach of diet-induced obese mice after vertical sleeve gastrectomy. LEAP2 binds to the GHSR and antagonizes ghrelin’s activities. The serum concentrations of human LEAP2 are positively correlated with body mass index, body fat accumulation, and fasting serum concentrations of glucose and triglyceride. Serum LEAP2 elevated and ghrelin reduced in obesity. Ghrelin and LEAP2 regulate body weight, food intake, and GH and blood glucose concentrations, and other physiological phenomena through their interactions with the same receptor, GHSR.

Androgen is widely acknowledged to regulate skeletal muscle mass. However, the specific mechanism driving muscle atrophy resulting from androgen deficiency remains elusive. Systemic androgen receptor knockout (ARKO) mice exhibit reduction in both muscle strength and muscle mass while skeletal muscle fiber specific ARKO mice have decreased muscle strength without affecting skeletal muscle mass in the limbs. Therefore, androgens may indirectly regulate skeletal muscle mass through effects on non-myofibers. Considering this, our investigation focused on blood fluid factors that might play a role in the regulation of skeletal muscle mass under the influence of androgens. Using a male mouse model of sham, orchidectomy and DHT replacement, mass spectrometry for serum samples of each group identified epidermal growth factor receptor (EGFR) as a candidate protein involving the regulation of skeletal muscle mass affected by androgens. Egfr expression in both liver and epididymal white adipose tissue correlated with androgen levels. Furthermore, Egfr expression in these tissues was predominantly elevated in male compared to female mice. Interestingly, male mice exhibited significantly elevated serum EGFR concentrations compared to their female counterparts, suggesting a connection with androgen levels. Treatment of EGFR to C2C12 cells promoted phosphorylation of AKT and its downstream S6K, and enhanced the protein synthesis in vitro. Furthermore, the administration of EGFR to female mice revealed a potential role in promoting an increase in skeletal muscle mass. These findings collectively enhance our understanding of the complex interplay among androgens, EGFR, and the regulation of skeletal muscle mass.