Kenji Ashida

PaTHway Japan is an ongoing, phase 3, multicenter, single-arm, open-label trial comprised of a 26-week efficacy period with an extension period through week 182 designed to demonstrate the efficacy, safety, and tolerability of palopegteriparatide in Japanese individuals with hypoparathyroidism. Japanese men and women (≥18 years of age) with hypoparathyroidism of any etiology (≥26 weeks) taking stable doses of active vitamin D were enrolled across five sites in Japan. Once-daily palopegteriparatide was self-administered subcutaneously via a pre-filled pen injector. Titration of palopegteriparatide and conventional therapy was performed according to a protocol-specified algorithm. The main outcomes measures included the proportion of participants at week 26 who achieved albumin-adjusted serum calcium in the normal reference range, independence from active vitamin D, and independence from therapeutic doses of elemental calcium. Thirteen participants were enrolled. Hypoparathyroidism etiology was most commonly idiopathic, followed by postsurgical and genetic causes. After 26 weeks of treatment with palopegteriparatide, 92% (12/13) of participants achieved the primary multi-component endpoint. Of the participants who entered the extension period, 92% (11/12) met the multi-component endpoint at week 52. Adverse events were mild to moderate in severity; none led to discontinuation of palopegteriparatide treatment. These findings in Japanese adults are consistent with results of the pivotal phase 3 and phase 2 North American/European trials and demonstrate the reproducibility of the palopegteriparatide treatment benefit in diverse populations and geographies. Japan Registry of Clinical Trials ID: jRCT2051210058.

Objective: Preclinical studies, including animal and in vitro experiments, have suggested that imeglimin, a novel antidiabetic drug, may have beneficial effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, its effect on MASLD in individuals with type 2 diabetes remains unclear. This study aimed to evaluate whether imeglimin has beneficial effects in individuals with type 2 diabetes and hepatic enzyme abnormalities. Methods: This multicenter, retrospective, single-arm study included 49 individuals with type 2 diabetes who newly initiated imeglimin treatment and continued it for six months. Individuals with chronic liver diseases other than MASLD were excluded. Treatment efficacy for liver function was defined as an ALT reduction of ≥11 IU/L, corresponding to the upper interquartile range of ALT reduction. Logistic regression analysis was performed to identify predictors of this treatment efficacy. Results: Body mass index (BMI) and hemoglobin A1c (HbA1c) levels significantly decreased after six months of imeglimin treatment. Additionally, both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels significantly decreased (ALT: 21.0 IU/L [13.0–39.0] vs. 17.0 [12.5–28.0], p   = 0.002; AST: 21.0 IU/L [17.0–30.0] vs. 18.0 [16.0–26.0], p  =  0.010, respectively). Logistic regression analysis showed that baseline ALT and AST levels were significant predictors of treatment efficacy for liver function, after adjusting for HbA1c and BMI levels (OR 1.06, 95% CI 1.02–1.12, p = 0.006; OR 1.12, 95% CI 1.06–1.23, p = 0.002, respectively). Furthermore, the receiver operating characteristic (ROC) curve for baseline ALT as a predictor demonstrated excellent discriminatory performance (Area under the curve: 0.905, p   = 0.004). A cutoff value of 25 IU/L yielded 100% sensitivity and 77.8% specificity. Conclusion: This exploratory study suggests that imeglimin may have beneficial effects in individuals with type 2 diabetes and elevated ALT (≥25 IU/L), potentially associated with MASLD. Randomized controlled trials are needed to confirm these findings.

Purpose of Review Insulin resistance is a key component of the metabolic syndrome, type 2 diabetes mellitus (T2DM), and related cardiovascular complications. However, despite its clinical relevance, a simple and reliable surrogate marker of insulin resistance is lacking. The body muscle-to-fat ratio (BMFR) is a novel anthropometric index, and particularly in treatment-naïve patients with T2DM, BMFR correlates more closely with insulin sensitivity, assessed using the hyperinsulinemic–euglycemic clamp, than conventional indices, such as the Matsuda Index and the Quantitative Insulin Sensitivity Check Index. In this review, we critically evaluate the current evidence regarding the BMFR as an index of insulin resistance and metabolic disease risk, highlight its strengths and limitations versus conventional measures, and discuss future directions. Recent Findings Several recent studies have demonstrated the importance of body composition metrics for the evaluation of metabolic health, including those by Guan et al. (Adv Nutr), Oliver et al. (J Cachexia Sarcopenia Muscle), and Vieira et al. (Rev Endocr Metab Disord). The findings have resulted in a growing recognition of the need for reliable, accessible markers of muscle quality and metabolic risk. Summary BMFR offers advantages over the fat-to-muscle ratio and conventional anthropometric indices as an intuitive and clinically relevant marker of insulin resistance. It represents a promising method of screening for obesity-related complications, evaluating treatment responses, and guiding personalized care, including in patients with high-risk phenotypes, such as sarcopenic obesity. With further validation, BMFR could become a standard tool for the evaluation of metabolic health and risk in clinical practice.

Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the effects of Drp1 deficiency on organelle interactions, metabolism, and inflammation. Our analysis revealed disrupted interactions between mitochondria and LDs, as well as altered interactions among ER, mitochondria, and LDs in Drp1LiKO mice. Through mass spectrometry and microarray analysis, we identified changes in lipid profiles and perturbed expression of lipid metabolism genes in the livers of Drp1LiKO mice. Further in vitro experiments using primary hepatocytes from Drp1LiKO mice confirmed disturbances in lipid metabolism and increased inflammation. These findings highlight the critical involvement of Drp1 in regulating organelle interactions for efficient lipid metabolism and overall liver health. Targeting Drp1-mediated organelle interactions may offer potential for developing therapies for liver diseases associated with disrupted lipid metabolism.

Background: The coronavirus disease 2019 (COVID-19) pandemic has changed our lifestyle by imposing restrictions, such as physical distancing. The effect of COVID-19 prevalence on seasonal variations in glycemic control in patients with diabetes mellitus (DM) remains unknown. Methods: This single-center retrospective cohort study evaluated glycemic control in patients with type 2 DM who visited Sugi Cardiovascular Hospital in December 2021. We evaluated the clinical findings of all patients treated regularly between March 1, 2019, and December 31, 2021, including the periods both before and after the COVID-19 pandemic. All the standard treatments were approved. Furthermore, seasonal changes in hemoglobin A1c (HbA1c) levels were evaluated using stratified analyses based on age. Results: This study analyzed 86 patients (mean age, 69.6 ± 9.2 years; men, 57). Median HbA1c (National Glycohemoglobin Standardization Program [Union of Clinical Chemistry]) levels in spring (March) were 7.70% (interquartile range (IQR):7.23%–8.30%) [60.6 mmol/mol (IQR:55.4–67.2 mmol/mol)], 7.35% (IQR:6.90%–7.90%) [56.8 mmol/mol (IQR:51.9–62.8 mmol/mol)], and 7.50% (IQR:7.10%–8.00%) [58.5 mmol/mol (IQR:54.1–63.9 mmol/mol)] in 2019, 2020, and 2021, respectively. During these periods, HbA1c levels and body mass index (BMI) revealed significant seasonal variations “high in spring” and “low in autumn.” Median HbA1c levels in spring (March) and autumn (September) were 7.86% [61.2 mmol/mol] and 7.48% [57.4 mmol/mol] in 2019 (P < 0.001), 7.50% [57.7 mmol/mol] and 7.17% [54.2 mmol/mol] in 2020 (P < 0.001), and 7.61% [58.3 mmol/mol] and 7.19% [53.8 mmol/mol] in 2021 (P < 0.001). Seasonal variations in HbA1c levels and BMI were maintained over the past 3 years, including the pandemic period. None of the patients in this study developed COVID-19 during the study period. Conclusions: Seasonal variations in glycemic control in patients with DM were not influenced by lifestyle modifications associated with COVID-19. Maintenance of physical activity is necessary to prevent the development of sarcopenia. Moreover, seasonal variations in glycemic metabolism should be considered an independent factor for DM management. Additional extensive multifacility investigations are necessary to corroborate our findings.

Purpose Non-functioning pituitary adenomas (NFPAs) are often associated with hyperprolactinemia, which is known as the “stalk effect”. However, the relationships between hyperprolactinemia and the radiographic characteristics of the tumor that affects the pituitary stalk have not been well characterized. We aimed to identify the differences in the clinical and radiographic characteristics of patients with NFPA, with and without hyperprolactinemia. Methods We enrolled 107 patients with NFPA and allocated them to hyperprolactinemia and non-hyperprolactinemia groups using two different cut-off values: (1) the upper limit of the normal reference range, adjusted for sex and menopausal status, and (2) the upper quartile across the cohort, and compared their clinical and radiographic characteristics. These analyses were conducted to clarify the relationship between the “stalk effect” and the postoperative change in antidiuretic hormone secretion. Results The specific radiographic characteristics of the patients included the presence of a cystic or hemorrhagic tumor and the presence of pituitary stalk deviation, which were more frequent in the patients with hyperprolactinemia. Interestingly, the incidence of postoperative transient diabetes insipidus was statistically significantly higher in the hyperprolactinemia group (≥40 ng/mL) and in the group with radiologic evidence of stalk deviation, which were shown to be independent risk factors on multivariate analysis. Conclusion The presence of a “stalk effect” was associated with a higher risk of postoperative transient diabetes insipidus, reflecting perioperative pituitary stalk dysfunction following NFPA surgery, especially in patients with serum prolactin concentrations ≥40 ng/mL and radiologic evidence of stalk deviation.

Successful Superficial Blood Sampling to Localize a Fibroblast Growth Factor-23-Producing Tumor - Article abstract #943152

This study aimed to assess the efficacy of combined administration of dipeptidyl peptide-4 (DPP4) and sodium-glucose cotransporter-2 (SGLT2) inhibitors on metabolic disorders and their preferable and complementary effects. The effectiveness of a 24-week intervention on metabolic parameters (including glucose profile), physical functions (grip strength and calf circumference), and health-related quality of life (HR-QOL) was analyzed using the International Physical Activity Questionnaire and Geriatric Depression Scale 5. A total of 39 patients with type-2 diabetes mellitus (T2DM) treated with the combination of DPP4 and SGLT2 inhibitors were included in this multicenter pilot study. Combination therapy significantly reduced the HbA1c level (median [interquartile range]) after 24 weeks (pretreatment: 7.7% [7.3-8.2] vs. posttreatment: 7.1% [6.6-7.9], P < 0.001). The grip strength significantly increased after 24 weeks (1.7 ± 2.7 kg, P < 0.001), while the mean calf circumference and body mass index significantly decreased. In particular, administration of the SGLT2 inhibitor significantly increased total physical activity in participants aged ≥65 years (P = 0.003), while psychological QOL did not significantly improve. Combination therapy with DPP4 and SGLT2 inhibitors decreased HbA1c levels and improved physical function in patients with T2DM. This study confirmed the effectiveness of combination therapy for metabolic disorders and suggested its beneficial and complementary effects. Therefore, advances in treatment plans to achieve further improvements in glucose profiles using DPP4 and SGLT2 inhibitors are recommended to enhance the QOL of patients with T2DM. Clinical trial number: University Hospital Medical Information Network Center: UMIN000045375

Objective: Unusual clinical courseBackground: Immunoglobulin G4 (IgG4)-related diseases (IgG4-RD) are systemic fibroinflammatory diseases that can develop asynchronously in multiple organs. IgG4-related kidney disease (IgG4-RKD) is generally characterized by tubulointerstitial nephritis but can also manifest as membranous nephropathy without tubulointerstitial nephritis. IgG4-related membranous nephropathy can present as a phenotype of systemic disorders, including autoimmune pancreatitis-associated diabetes mellitus; however, its clinical features remain unclear.Case Report: A 56-year-old Japanese man presented to our university hospital with bilateral edema of his lower legs. He had received a diagnosis of type 1 autoimmune pancreatitis and associated diabetes mellitus 16 months prior. He was successfully treated with oral glucocorticoids 25 mg/day of prednisolone as an initial dose, followed by titration down to a maintenance dose (5 mg/day), without recurrence of autoimmune pancreatitis. The pancreas showed atrophy and required basal-bolus insulin therapy owing to insulin insufficiency. Massive proteinuria and hypoalbuminemia with nephrotic syndrome on examination led to a renal biopsy to investigate the etiology and diagnosis of IgG4-RKD. Methylprednisolone and cyclosporine A were successfully administered to ameliorate the proteinuria and control systemic IgG4-RD with IgG4-related membranous nephropathy.Conclusions: Ig4-RKD occurred despite maintenance treatment with prednisolone monotherapy and was controlled with methylprednisolone and cyclosporine A. Measurement of clinical parameters, including proteinuria, was important, and a renal biopsy finally established the diagnosis of IgG4-RKD. IgG4-RKD can present with progressive glomerular lesions and can be latent in cases diagnosed with diabetic kidney disease, particularly in patients with insulin insufficiency.

Objective: Metyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological and metabolic parameters and changes in endocrine function associated with metyrosine administration should be validated in comparison to surgery. This study was performed to confirm the effects of metyrosine on physiological, metabolic, and endocrinological functions of patients with pheochromocytoma/paraganglioma in the perioperative period. Design: This retrospective cohort study was performed at a single university hospital. Methods: We included 10 patients with pheochromocytoma/paraganglioma who received oral metyrosine after α-blocker therapy and consecutive surgeries. Urinary catecholamine metabolite levels and other clinical parameters were evaluated before and after metyrosine administration, and 1 week after surgery. Results: The mean age was 53.1 ± 16.1 years. Of the 10 participants (four men and six women), nine had pheochromocytoma and one had paraganglioma. The median maximum metyrosine dose was 750 mg/day. Urinary catecholamine metabolite levels significantly decreased in a dose-dependent manner after metyrosine administration. Both systolic and diastolic blood pressure significantly decreased after metyrosine and surgical treatment. Metyrosine administration significantly improved insulin sensitivity, although surgery improved the basal insulin secretion. Additionally, serum prolactin and thyroid-stimulatory hormone levels were significantly increased by metyrosine treatment, whereas plasma renin activity was decreased. Conclusions: Metyrosine significantly reduced catecholamines in patients with pheochromocytoma/paraganglioma and ensured the safety of the surgery. Adjustment of metyrosine administration may make surgical pretreatment more effective in achieving stabilized blood pressure and improving glucose metabolism. Endocrine parameters may manifest as the systemic effects of metyrosine administration.