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.

Adult growth hormone deficiency (AGHD) is often accompanied with metabolic dysfunction-associated steatotic liver disease (MASLD). Although some studies reported that MASLD is ameliorated by growth hormone replacement therapy (GHRT), the characteristics of AGHD that are associated with an improvement of hepatic steatosis by GHRT remain unknown. We aimed to investigate whether GHRT affects hepatic lipid accumulation as well as biochemical parameters, and investigated the association between these parameters (UMIN000044989). Thirty people with AGHD were recruited, and assigned to either the GHRT group or the non-GHRT group. Serum laboratory data were analyzed before and after GHRT. Hepatic lipid content was evaluated using magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Correlations between MRI-PDFF and other clinical parameters were investigated. Twenty-nine people completed this study (19 in the GHRT group and 10 in the non-GHRT group). In the GHRT group, significant decreases in MRI-PDFF and serum levels of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase were observed after the treatment. The decrease in MRI-PDFF levels after GHRT significantly correlated with initial MRI-PDFF, triglyceride (TG), lactate dehydrogenase, and ALT levels, and age. Multiple regression analysis demonstrated that younger age and high serum TG levels were independent predictors of a decrease in MRI-PDFF levels. GHRT in people with AGHD significantly reduced lipid accumulation in the liver on MRI, and improved serum liver parameters. Age and serum TG levels were found to be associated with the effectiveness of GHRT.

Although antithyroid drugs (ATDs) are the first-line treatment for patients with Graves’ disease (GD) in Japan and other countries, some patients do not achieve remission due to drug resistance, leading to surgery. Even if ATD doses are increased, they often have uncontrolled thyroid function and enlarged goiters, necessitating high-risk emergency surgical treatment. In this study, we aimed to identify the characteristics of patients resistant to ATDs who underwent thyroidectomy and those who achieved remission. We retrospectively analyzed 45 patients with GD who underwent thyroidectomy and 73 patients who achieved remission with ATDs at Shinshu University Hospital between April 1, 2015 and September 30, 2023. In patients who underwent surgery, the drug-resistant patients (DR group; n = 15) had longer disease durations (8.0 vs. 3.0 years, respectively; p = 0.013), higher free triiodothyronine (FT3) / free thyroxine (FT4) ratios (5.54 vs. 3.52, respectively; p = 0.005), higher anti-TSH receptor antibody (TRAb) levels (39.16 vs. 13.31 IU/L, respectively; p = 0.002), and larger thyroid glands (251.00 vs. 54.80 g, respectively; p < 0.001) than non-drug-resistant patients (NDR group; n = 30). Compared with patients who achieved remission with ATDs (Remission group; n = 73), the DR group had higher FT3/FT4 ratios (5.54 vs. 2.99, respectively; p < 0.001) and higher TRAb levels (39.16 vs. 5.9 IU/L, respectively; p < 0.001). Notably, most of the patients in the DR group had a combination of these factors. This suggests that in patients with large thyroid, high FT3/FT4 ratios, and high TRAb levels, early consideration of definitive-curative treatment such as surgery or RI therapy may be warranted instead of continuing prolonged ineffective ATDs treatment.

Nerve conduction studies (NCS) are the standard method for diagnosing diabetic polyneuropathy. Because a clear association between handgrip strength and diabetic neuropathy can serve as a screening tool, the present study evaluated the association between handgrip strength and NCS and diabetes-related complications. A total of 436 patients with type 2 diabetes (T2D) who were admitted to our hospital between April 1, 2018 and March 31, 2023, and evaluated using Baba’s diabetic neuropathy classification (BDC) were included. The participants were grouped by sex using the grip strength tertile method to assess correlations with the prevalence of diabetic microvascular complications in the high-handgrip group (HG), middle-handgrip group (MG), and low-handgrip group (LG). The percentage of BDC-0 was 65% in the HG, 54% in the MG, and 36% in the LG. Furthermore, none of the participants in the HG had BDC-3/4, whereas 4% in the MG and 15% in the LG had BDC-3/4. The morbidity progression of diabetic neuropathy was seen in the order of LG, MG, and HG (p < 0.001). Patients with T2D and advanced diabetic neuropathy had decreased handgrip strength. Early evaluation of BDC and other NCS should be considered if decreased handgrip strength is evident.

Insulin resistance (IR) is the core for type 2 diabetes and metabolic syndrome. The homeostasis assessment model is a straightforward and practical tool for quantifying insulin resistance (HOMA-IR). Multiple adaptive regression spline (MARS) is a machine learning method used in many research fields but has yet to be applied to estimating HOMA-IR. This study uses MARS to build an equation to estimate HOMA-IR in pre-menopausal Chinese women based on a sample of 4,071 healthy women aged 20–50 with no major diseases and no medication use for blood pressure, blood glucose or blood lipids. Thirty variables were applied to build the HOMA-IR model, including demographic, laboratory, and lifestyle factors. MARS results in smaller prediction errors than traditional multiple linear regression (MLR) methods, and is thus more accurate. The model was established based on key impact factors including waist-hip ratio (WHR), C reactive protein (CRP), uric acid (UA), total bilirubin (TBIL), leukocyte (WBC), serum glutamic oxaloacetic transaminase (GOT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), serum glutamic pyruvic transaminase (GPT), and triglycerides (TG). The equation is as following:

HOMA-IR = 6.634 – 1.448MAX(0, 0.833 – WHR) + 10.152MAX(0, WHR – 0.833) – 1.351MAX(0, 0.7 – CRP) – 0.449MAX(0, CRP – 0.7) + 1.062MAX(0, UA – 8.5) + +1.047(MAX(0, 0.83 – TBIL) + 0.681MAX(0, WBC – 11.53) – 0.071MAX(0, 11.53 – WBC) + 0.043MAX(0, 24 – GOT) – 0.017MAX(0, GOT – 24) + 0.021MAX(0, 59 – HDL) – 0.005MAX(0, HDL – 59) – 0.013MAX(0, 141 – SBP) – 0.033MAX(0, 100 – GPT) + 0.013MAX(0, GPT – 100) – 0.004MAX(303 – TG)

Results indicate that MARS is a more precise tool than fasting plasma insulin (FPI) levels, and could be used in the daily practice, and further longitudinal studies are warranted.

Pediatric patients with pheochromocytoma (PCC)/paraganglioma (PGL) (PPGL) are rare, and clinicopathological investigations, especially the relationship between gene analysis and histological features, are insufficient. We comprehensively examined the clinical data, germline/somatic variants (mutations), and pathological characteristics of operated tumors using immunohistochemical expression and histological grading by Grading of Adrenal PCC and PGL score. This study included 28 patients (15 males and 13 females) aged <19 years. The age at the diagnosis was 12.8 ± 4.5 years. The included patient often had multiple PPGLs, with 39 tumors, including 21 PCCs and 18 PGLs, with average tumor sizes of 45.0 ± 22.8 and 42.6 ± 23.6 mm, respectively. Genomic types examined by gene mutations and immunohistochemistry of CA9 for VHL, SDHB for SDHx, and MAX for MAX, classified them into 14 VHL (50%), ten SDHx (35.7%), one MAX (3.6%), and three unknown (10.7%) types. Tumor metastasis was limited to two SDHB-related PPGLs, but not to VHL-related PPGLs. In both patients, the metastatic sites were the bones. The average GAPP score of the PPGLs was 2.9 ± 1.5 in VHL and 5.3 ± 1.7 in SDHB, and histological grades were well-differentiated in VHL and moderately differentiated in SDHB. SSTR2 expression was positive in 90% of SDHB-related PPGLs, but negative in 75% and weakly or focally positive in 25% of VHL-related PPGLs. Most pediatric PPGLs (90%) demonstrated mutations in VHL, SDHB, and MAX, with histological features depending on the mutation type. Combined genetic and immunohistochemical examination is desirable for accurate genomic diagnosis, and clinicopathological study.

Over 70 intragenic copy-number variations (CNVs) of PHEX have been identified in patients with X-linked hypophosphatemia (XLH). However, the underlying mechanism of these CNVs has been poorly investigated. Furthermore, although PHEX undergoes X chromosome inactivation (XCI), the association between XLH in women with heterozygous PHEX variants and skewed XCI remains unknown. In this study, we determined the precise genomic structure and the XCI status of a girl with XLH who showed short stature and bowing of the legs at 2 years old. Laboratory tests revealed low levels of serum phosphate and elevated levels of alkaline phosphatase and fibroblast growth factor 23. Multiplex ligation-dependent probe amplification and targeted long-read sequencing revealed that she carried a 24.6-kb intragenic duplication of PHEX. The duplication was tandemly aligned in a head-to-tail orientation. The duplication breakpoints shared a 2-bp microhomology, indicating that this CNV resulted from a replication-based error. Trio sequencing results showed that the duplication was a de novo CNV that occurred on the paternally-derived allele. DNA methylation analysis demonstrated random XCI. A literature review of 12 previously reported cases of intragenic CNVs of PHEX revealed that the deletions/duplications can be ascribed to replication-based errors. Our findings and those of previous studies indicate that XLH-causative CNVs in PHEX predominantly arise from replication-based errors. Thus, the genomic region surrounding PHEX may be vulnerable to replication-based errors during gametogenesis or early embryogenesis. Our study provides supporting evidence that heterozygous PHEX variants can lead to XLH in women with random XCI.

Pasireotide (PAS), a multireceptor somatostatin analog, has been demonstrated to effectively control hormone levels, including those of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), in patients with acromegaly. However, it induces hyperglycemia by inhibiting insulin secretion via somatostatin receptor 5 (SSTR5). Despite the extensive literature on the occurrence of PAS-induced hyperglycemia, there is still no consensus on the optimal first-line treatment for this complication. Herein, we present two cases of acromegaly treated with PAS and highlight its short- and long-term effects on glucose metabolism. In the first case, postprandial hyperglycemia manifested rapidly following the commencement of PAS treatment and was effectively managed with dulaglutide under continuous glucose monitoring (CGM). In the second case, long-term PAS therapy resulted in a dose-dependent glycemic response that was controlled by different GLP-1 receptor agonists (GLP-1RAs), including semaglutide. CGM facilitated the early detection of significant glycemic fluctuations, underscoring the necessity for close monitoring in patients receiving PAS therapy. These cases demonstrate the efficacy of GLP-1RAs in managing PAS-induced hyperglycemia and highlights the value of CGM in early detection and intervention. Our findings suggest that GLP-1RAs, particularly semaglutide, are a valuable treatment option for this condition. Further research is needed to determine the optimal treatment strategy, particularly in East Asian populations, and to establish a clear consensus on the first-line therapy for PAS-induced hyperglycemia.

The use of asfotase alfa, a bone-targeted recombinant alkaline phosphatase (ALP) enzyme, for the treatment of adult-onset hypophosphatasia (HPP) remains controversial, particularly in patients without evident bone abnormalities. We report the case of a 41-year-old woman with a history of Graves’ disease, who presented with progressive joint pain and severe fatigue. Despite the absence of bone lesions, the patient was diagnosed with HPP based on persistently low alkaline phosphatase levels, family history, and a novel heterozygous ALPL variant (p.Ala205Thr). Functional analysis revealed a dominant-negative effect for this variant. Her symptoms significantly interfered with her daily activities owing to uncontrolled pain and loss of motor function and were so exacerbated that high doses of acetaminophen and NSAIDs were ineffective. Treatment with asfotase alfa was initiated based on multidisciplinary team consensus. Within 3 months of treatment initiation, her pain improved significantly, as indicated by reduced scores on the visual analog scale from 6.6 to 0.9, and elimination of the need for analgesics. Additionally, her grip strength increased, and her urinary phosphoethanolamine levels and serum pyridoxal 5'-phosphate/pyridoxal ratio decreased from 90.4 to 57.8 μmol/g·creatinine and from 4.6 to 0.4, respectively. These improvements have been maintained for more than 2 years. This case highlights the potential of asfotase alfa in effectively alleviating symptoms in patients with adult-onset HPP without bone lesions, emphasizing the importance of patient selection and outcome monitoring. We also discuss the key considerations for future treatment, supported by a literature review of asfotase alfa in adult patients with HPP.