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Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca 2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca 2+ -induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell–derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide–amino acid transporter axis. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to β-cell maintenance and function.

Introduction Endothelial dysfunction is a risk factor for cardiovascular disease in patients with diabetes. We hypothesized that imeglimin, a novel oral hypoglycemic agent, would improve endothelial function. Methods In this study, imeglimin was administered to patients with type 2 diabetes and HbA1c ≥ 6.5% who were not receiving insulin therapy. A meal tolerance test (592 kcal, glucose 75.0 g, fat 28.5 g) was performed before and 3 months after administration, and endothelial function, blood glucose, insulin, glucagon, and triglycerides were evaluated. Endothelial function was assessed by flow-mediated dilation (FMD). Results Twelve patients (50% male) with a median age of 55.5 years old (interquartile range [IQR] 51.3–66.0) were enrolled. Fasting FMD did not differ before or 3 months after imeglimin administration (from 6.1 [3.9–8.5] to 6.6 [3.9–9.0], p  = 0.092), but 2 h postprandial FMD was significantly improved 3 months after imeglimin administration (from 2.3 [1.9–3.4] to 2.9 [2.4–4.7], p  = 0.013). In terms of the glucose profile, imeglimin administration significantly improved HbA1c (from 7.2 ± 0.6% to 6.9 ± 0.6%, p  = 0.007), fasting glucose (from 138 ± 19 mg/dL to 128 ± 20 mg/dL, p  = 0.020), and 2 h postprandial glucose (from 251 ± 47 mg/dL to 215 ± 68 mg/dL, p  = 0.035). The change in 2 h postprandial FMD between before and 3 months after imeglimin administration (Δ2 h postprandial FMD) was negatively correlated with Δ2 h postprandial glucose ( r  = − 0.653, p  = 0.021) in a univariate correlation coefficient analysis. Both patients with and without decreased postprandial glucose 3 months after imeglimin administration had improved postprandial FMD. Conclusion In this small study, imeglimin administration improved 2 h postprandial FMD. Both glycemic control-dependent and -independent mechanisms might contribute to improved endothelial function. Trial Registration This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000046311).

In terms of cardiac indices of atherosclerosis, Nishikawa and colleagues suggested that we not only focus on the cardio–ankle vascular index (CAVI) and the ankle–brachial index (ABI), but also on the systolic time interval (STI). [...]we used the CAVI and ABI data to perform an additional analysis of the STI, calculated as the ratio of the pre-ejection period to the left ventricular ejection time. The results of that analysis showed that the STI did not differ significantly before and 3 months after imeglimin administration (median 0.30, interquartile range [IQR] 0.27–0.35 and median 0.33, IQR 0.31–0.36, respectively; p = 0.266); however, our patient population was small and there may have been too few participants to enable an adequate evaluation of the STI. The research was registered in the University Hospital Medical Information Network (UMIN:

Aim Education on insulin self-injection techniques is important for good glycemic control, but its effectiveness in some elderly patients is limited due to loss of cognitive function and impaired activities of daily living. We hypothesized that classification using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) would help identify elderly patients with diabetes who effectively learn self-injection techniques. Methods Diabetes patients aged ≥ 65 years who used a self-injection insulin pen were administered the DASC-8 and a questionnaire to evaluate insulin self-injection techniques, and then received technical education. The questionnaire was administered again 4 months later, and patients were classified into the education-effective and education-ineffective groups. The achievement of HbA1c targets defined for each patient according to guidelines based on DASC-8 category was examined over 12 months. Results 76 Japanese patients (median age 72.0 years and 53.9% female) with DASC-8 categories I (n = 55), II (n = 13), and III (n = 8) were enrolled. In the education-effective group, the percentage of patients in category I was significantly higher than that of patients in category II or III (92.0% to 23.8%, P < 0.001). Category I was independently associated with education effectiveness (odds ratio 14.50, 95% confidence interval: 2.110–100.0, P = 0.007). Category I patients in the education-effective group showed significantly improved achievement of target HbA1c from baseline to the 12th month (from 27.6% to 62.1%, P = 0.008). Conclusions The DASC-8 was a useful indicator for identifying elderly patients who would benefit from education on self-injection techniques.

Background Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. Methods To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. Results We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p  < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p  < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. Conclusions The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.

ContextKisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH).ObjectiveThe aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation.DesignThe patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants.ResultsA homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket.ConclusionWe identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket.We identified a novel KISS1R mutation (P147L) and demonstrated that a conformational change in the ligand-binding pocket of the mutant receptor leads to congenital hypogonadotropic hypogonadism.

Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

Purpose To compare 12-month clinical results of spatula-shaped and dual-blade microhooks ab interno trabeculotomy with phacoemulsification. Study design Retrospective comparative study. Methods We conducted a retrospective chart review of Japanese open-angle glaucoma patients who underwent ab interno trabeculotomy with phacoemulsification with a 12-month follow-up. Two types of trabecular hook were used: the spatula-shaped Tanito Trabeculotomy ab interno Micro-hook ® and the Kahook Dual Blade ® . Changes in intraocular pressure (IOP) and medication scores comprised the main outcome metrics. We also analyzed and compared patient demographics and the occurrence of complications. Results Trabeculotomy was performed using a spatula-shaped hook in 17 eyes and a dual-blade hook in 15 eyes. Significant reductions in IOP ( p  < 0.001) and medication scores ( p  < 0.001) were noted in both groups after the 1-month time point. The percentage changes of IOP from baseline at each time point were not significantly different between groups, though there was a significant difference in medication scores at 12 months ( p  = 0.0192). Postoperative complications occurred similarly in both groups; one case in the dual-blade group required additional filtration surgery. Conclusions Ab interno trabeculotomy with phacoemulsification was effective in lowering IOP both with spatula-shaped and with double-blade microhooks. At 12 months more medications were used postoperatively in the spatula-shaped microhook group; however, the reductions in the medication scores from baseline were statistically significant in both groups.

Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator–activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARγ act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation. Adipocyte differentiation is accompanied by large scale changes in the actin cytoskeleton. Here, Nobusue et al. show that binding to G-actin sequesters the transcriptional coactivator MKL1 in the cytoplasm, and triggers differentiation by inducing the expression of pro-adipogenic transcription factor PPARγ.

This study aimed to develop a poly-ε-caprolactone (PCL) material that has a low melting point while maintaining the deformation ability. The new PCL (abbreviated as 4b45/2b20) was fabricated by mixing two types of PCL with different molecular weights, numbers of branches, and physical properties. To investigate the melting point, crystallization temperature, elastic modulus, and elongation at break for 4b45/2b20 and three commercially available masks, differential scanning calorimetry and tensile tests were performed. The melting point of 4b45/2b20 was 46.0 °C, and that of the commercially available masks was approximately 56.0 °C (55.7 °C–56.5 °C). The elastic modulus at 60 °C of 4b45/2b20 was significantly lower than the commercially available masks (1.1 ± 0.3 MPa and 46.3 ± 5.4 MPa, p  = 0.0357). In addition, the elongation at break of 4b45/2b20 were significantly larger than the commercially available masks (275.2 ± 25.0% and 216.0 ± 15.2%, p  = 0.0347). The crystallization temperature of 4b45/2b20 (22.1 °C) was clinically acceptable and no significant difference was found in the elastic modulus at 23 °C (253.7 ± 24.3 MPa and 282.0 ± 44.3 MPa, p  = 0.4). As a shape memory-based thermoset material, 4b45/2b20 has a low melting point and large deformation ability. In addition, the crystallization temperature and strength are within the clinically acceptable standards. Because masks made using the new PCL material are formed with less pressure on the face than commercially available masks, it is a promising material for making a radiotherapy mask that can reduce the burden on patients.