Toshiaki Shimizu

Imeglimin is a novel antidiabetic agent that improves glycemic control by enhancing glucose-stimulated insulin secretion (GSIS). Although previous studies have suggested that imeglimin acts through increased NAD+ production and CD38-dependent calcium signaling, the mechanism responsible for its insulinotropic effect at clinically relevant concentrations remains incompletely understood. In particular, how clinically relevant concentrations of imeglimin affect mitochondrial bioenergetics in pancreatic beta cells remains unclear. To address this question, we examined the effects of imeglimin in normal glucose-tolerant C57BL/6 mice and isolated mouse islets using concentrations corresponding to clinically achieved plasma levels. Chronic administration of imeglimin at a pharmacological dose corresponding to clinically relevant exposure enhanced GSIS without affecting insulin sensitivity in vivo. In isolated islets, continuous exposure to imeglimin at a clinically relevant concentration (10 μmol/l) significantly enhanced GSIS, whereas supraphysiological imeglimin (1000 μmol/l) reduced GSIS. Mechanistically, 10 μmol/l imeglimin increased mitochondrial respiration, mitochondrial membrane potential, and ATP production while suppressing glucose-induced reactive oxygen species generation. Notably, blue native polyacrylamide gel electrophoresis revealed that clinically relevant concentrations of imeglimin promoted mitochondrial respiratory supercomplex formation, whereas supraphysiological concentrations did not. These findings suggest that mitochondrial respiratory supercomplex formation may contribute to the insulinotropic action of imeglimin. Our results provide new insight into mitochondrial regulation of pancreatic beta cell function and suggest that enhancement of mitochondrial supercomplex assembly represents a potential mechanism by which clinically relevant imeglimin improves beta cell function, in addition to previously proposed NAD+-dependent pathways.

Characteristics of monogenic inflammatory bowel disease in very early-onset cases: a Japanese multicenter registry study

IL-33-induced signals via membrane-bound ST2 (ST2L) are critical for allergies. However, the physiological role of endogenous soluble ST2 (sST2) remains elusive. Here, we generated sST2-deficient mice with intact ST2L using the CRISPR/Cas9 system. Skin fibroblasts constitutively released sST2 protein at extremely high levels compared to mast cells, which did not reflect the expression levels of sST2 mRNA. This discrepancy can be partly explained by the sST2 protein degradation mediated by mast cell proteases. Accordingly, sST2 deficiency did not affect IL-33- and/or IgE plus antigen-stimulated mast cell activation in vitro. We provided evidence that constitutively high levels of sST2 suppress food allergies in mice by inhibiting IL-33-dependent, both expansion of jejunum mast cells and enhancement of their degranulation. Analysis of bone marrow chimeric mice under steady-state conditions showed that circulating sST2 was derived almost equally from hematopoietic and nonhematopoietic cells. Increased circulating sST2 in food-allergic mice was possibly and partly derived from fibroblasts stimulated by locally released IL-4 and IL-13. In conclusion, endogenous sST2 contributes to the suppression of food allergies.

Orofacial granulomatosis in pediatric Crohn’s disease: clinical outcomes and genetic background in the era of biologics: a retrospective study in Japan

Shimizu T, et al. Pediatr Gastroenterol Hepatol Nutr. 2026 May;29(3):220-231. https://doi.org/10.5223/pghn.2026.29.3.220

Shimizu T, et al. Pediatr Gastroenterol Hepatol Nutr. 2026 Jan;29(1):44-54. https://doi.org/10.5223/pghn.2026.29.1.44

Fecal surrogate markers strongly correlate with endoscopic findings in pediatric onset inflammatory bowel disease: a retrospective study in Japan

Objectives: To investigate the prevalence and characteristics of growth impairment (GI) in children with inflammatory bowel disease (IBD). Methods: In this prospective observational study, 402 children with ulcerative colitis (UC, n = 257) and Crohn's disease (CD, n = 145) were enrolled from the Japanese Pediatric IBD Registry (2012–2020). GI was defined by Paris classification criteria. Longitudinal outcomes were assessed in children with ≥2 years of follow‐up ( n = 307). Results: At diagnosis, the GI prevalence was comparable between children with UC and CD (6.2% vs. 8.3%, p = 0.54). However, children with UC diagnosed at 0–4 years demonstrated significantly higher GI rates (35.3%) than older children ( p < 0.001). All children with CD experiencing GI had small intestinal lesions. Among those with GI at diagnosis, fewer children with UC (9%) recovered growth at a 2‐year follow‐up than those with CD (50%). Among children with normal growth at baseline, new‐onset GI occurred in 23% of UC and 16% of CD cases. Of these, 31% recovered within 2 years, while persistent GI was observed in 16% of UC and 11% of CD cases. Prolonged corticosteroid use at 1 year was more frequent in UC (31% vs. 19%, p = 0.02) and was significantly associated with persistent GI. Conclusions: Distinct growth patterns exist in Japanese children with IBD. Children with UC diagnosed at 0–4 years are particularly vulnerable and may benefit from early, steroid‐sparing treatment. The association between small intestinal lesions and GI in CD emphasizes the importance of small bowel evaluation. Age‐specific, patient‐centered growth monitoring is crucial to optimize long‐term outcomes.

Background: Somatic symptom disorder (SSD) in children may be influenced by stress reactivity and psychosocial factors. The glucocorticoid receptor (GR), encoded by NR3C1, is a key mediator of stress responses. However, the relationship between NR3C1 methylation and SSD remains unclear. Methods: We analyzed NR3C1 exon 1F methylation in cell-free DNA from saliva in 34 children with SSD and 29 age- and sex-matched controls using bisulfite amplicon sequencing. Psychological assessments included the Beck Depression Inventory-II (BDI-II) and KINDL questionnaires to evaluate associations with methylation patterns. Results: Methylation levels showed age-related differences. In children under 13, CpG sites displayed mixed methylation, and specific sites correlated with KINDL and BDI-II scores. KINDL physical and total well-being scores negatively correlated with CpG30 and positively with CpG35; BDI-II scores negatively correlated with CpG32 and CpG35. In children aged 13 or older, CpG sites showed uniformly high methylation with no correlation to psychological measures. The SSD group showed significantly higher average methylation across the exon 1F region than controls in the older age group. These children also had more cases of orthostatic dysregulation and longer illness duration. Conclusions: This study suggests age-dependent epigenetic regulation of NR3C1 in SSD. While younger children showed CpG-specific correlations with psychological symptoms, older children demonstrated uniformly high methylation and potentially reduced gene expression, potentially reflecting cumulative stress, autonomic dysfunction, and internalizing disorders such as anxiety and depression.

Background: Hereditary angioedema (HAE) is a rare genetic disorder that causes recurrent edema and abdominal/laryngeal attacks. However, the number of pediatric HAE cases is unknown. We aimed to assess the number of pediatric HAE and the actual status of pediatric HAE management in Japan. Methods: A mail questionnaire survey was conducted on 142 clinicians (representatives of institutes) with previous experience in HAE management. The survey items included the number of pediatric patients who were treated for HAE, history of attacks and its impact on quality of life, the presence of untested pediatric relatives of adult patients, and unmet needs. Results: In total, 69 representatives (49% of overall institutes) responded. Twenty‐five (36% of respondents) had experience in pediatric HAE management. The number of cases managed by individual faculties ranged from 1 to 6, and most physicians ( n = 16, 64% of faculties with patient(s)) reported the management of a single case only. There were 26 (8 male,16 female) patients with one or more attacks. Nineteen facilities (28% of respondents) reported one or more pediatric relative(s) of patients who were hesitant to screen. Further, physicians reported various unmet needs. Conclusions: Pediatric HAE is managed in many facilities in a dispersed manner. In some cases, the pediatric relatives of patients diagnosed with HAE did not undergo screening. This study identified unmet needs and challenges that reflect the absence of specialized pediatric management. Hence, the standardization of pediatric HAE management is an urgent concern in Japan.