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Although the standard method to evaluate skeletal muscle protein synthesis (MPS) is muscle biopsy, the method is invasive and problematic for multisite use. We conducted a small pilot study in volunteers to investigate changes in MPS according to skeletal muscle site using a noninvasive method in which 6 healthy young men were given yogurt (containing 20 g milk protein) or water, and 1 h later, l-[11C]methionine ([11C]Met) was administered intravenously. Dynamic PET/CT imaging of their thighs was performed for 60 min. The influx constant Ki of [11C]Met in skeletal muscle protein was calculated as an index of MPS using a Patlak plot, and found to be 0.6%-28% higher after ingesting yogurt than after water in 5 of the 6 volunteer participants, but it was 34% lower in the remaining participant. Overall, this indicated no significant increase in Ki after ingesting milk protein. However, when the quadriceps and hamstring muscles were analyzed separately, we found a significant difference in Ki. This demonstrates the potential of visualizing MPS by calculating the Ki for each voxel and reconstructing it as an image, which presents unique advantages of [11C]Met PET/CT for evaluating MPS, such as site-specificity and visualization., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: [K. S., M. S., K. N., and K. A. are salaried employees of Meiji Co., Ltd., a food company, which also provided experimental funding, materials, facility, and staff assistance to this research. But, Meiji Co., Ltd. did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. K. Y., R. N., K. T., and T. H. has no conflicts of interest to declare.], (Copyright: © 2024 Sumi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Screening for undiagnosed type 2 diabetes mellitus is recommended for Asian Americans with a body mass index ≥23. However, the optimal body mass index cut-off score for predicting the risk of diabetes mellitus in Japanese people is not well known. The aim of this study was to determine the best body mass index cut-off score for predicting insulin resistance and diabetes mellitus in the Japanese population., Methods: This study had two parts, a clinical investigation and a retrospective observational investigation. In the clinical part of the study, 58 participants (26 with type 2 diabetes mellitus and 32 non-diabetics) underwent a hyperinsulinemic-euglycemic clamp from which their glucose disposal rate was measured. For the retrospective part of the study, medical check-up data from 88,305 people in the Tottori Prefecture were analyzed for clinical evidence of diabetes mellitus. The optimal BMI cut-off scores for prediction of insulin resistance and diabetes mellitus were determined., Results: In the clamp study, the optimal body mass index cut-off score to predict insulin resistance in non-diabetic patients was 22.7. All participants with type 2 diabetes mellitus were insulin resistant, and the optimal body mass index cut-off score for prediction of severe insulin resistance was 26.2. When the data from the type 2 diabetic and the non-diabetic participants were combined, the optimal body mass index cut-off score for prediction of insulin resistance was 23.5. Analysis of 88,305 medical check-up records yielded an optimal body mass index cut-off score for prediction of diabetes mellitus of 23.6., Conclusions: These results suggest that having a body mass index ≥23 is a risk factor for insulin resistance and diabetes mellitus in the Japanese population., Competing Interests: The authors have declared that no competing interests exist.

Background: Increased hepatic insulin clearance (HIC) is important in the pathophysiology of type 2 diabetes mellitus (T2DM). The aim of this study is to analyze an effective insulin resistance (IR) index that is minimally affected by HIC., Methods: Our study involved 20 participants with T2DM and 21 healthy participants without diabetes (Non-DM). Participants underwent a meal tolerance test from which plasma glucose, insulin and serum C-peptide immunoreactivity (CPR) were measured, and HOMA-IR and HIC were calculated. Participants then underwent a hyperinsulinemic-euglycemic clamp from which the glucose disposal rate (GDR) was measured., Results: The index CPR-IR = 20/(fasting CPR × fasting plasma glucose) was correlated more strongly with GDR, than was HOMA-IR, and CPR-IR could be used to estimate GDR. In T2DM participants with HIC below the median, HOMA-IR and CPR-IR were equally well correlated with GDR. In T2DM with high HIC, CPR-IR correlated with GDR while HOMA-IR did not. In Non-DM, CPR-IR and HOMA-IR were equally well correlated with GDR regardless of HIC. The mean HIC value in T2DM was significantly higher than that of Non-DM., Conclusions: CPR-IR could be a simple and effective index of insulin resistance for patients with type 2 diabetes that is minimally affected by HIC., Competing Interests: The authors have declared that no competing interests exist.

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits.

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor-1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = -0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis.

Background: The neurochemical serotonin (5-HT) is an important signaling molecule in the gastrointestinal motor and sensory functions. A key regulator of 5-HT levels is the transmembrane serotonin transporter (5-HTT; SLC6A4) that governs the reuptake of 5-HT. Recent studies have indicated 5-HTT expression may be regulated by epigenetic mechanisms. We investigated DNA methylation status of SLC6A4 gene in the gastric mucosa from functional dyspepsia (FD) because of their potential role in dyspeptic symptoms., Methods: Endoscopic gastric biopsies were obtained from 78 subjects with no upper abdominal symptoms and 79 patients with FD. Bisulfite Pyrosequencing was carried out to determine the methylation status of promoter CpG islands (PCGIs), promoter non-CpG islands (PNCGIs) and gene body non-CpG islands (NPNCGIs) in the SLC6A4 gene. Gene expression was examined by real-time PCR., Results: In overall, methylation level of PCGIs was significantly lower in FD compared to control subjects (p = 0.04). On the other hand, methylation level of NPNCGIs was significantly higher in FD compared to control subjects (p = 0.03). Lower methylation level in PNCGIs was highlighted in the patients with PDS (p = 0.01), while higher methylation level in NPNCGIs was more prominent in the patients with EPS (p = 0.017). Methylation levels of PCGIs and PNCGIs were inversely correlated, while methylation levels of NPNCGIs was positively correlated with SLC6A4 mRNA levels in FD patients., Conclusions: Our data suggest that change in DNA methylation pattern of SLC6A4 in the gastric mucosa may have a role for developing FD. A role of epigenetics for developing FD needs to be further evaluated.

The acquired mutation (V617F) of Janus kinase 2 (JAK2) is observed in the majority of patients with myeloproliferative neoplasms (MPNs). In the screening of genes whose expression was induced by JAK2 (V617F), we found the significant induction of c-Myc mRNA expression mediated by STAT5 activation. Interestingly, GSK-3β was inactivated in transformed Ba/F3 cells by JAK2 (V617F), and this enhanced the protein expression of c-Myc. The enforced expression of c-Myc accelerated cell proliferation but failed to inhibit apoptotic cell death caused by growth factor deprivation; however, the inhibition of GSK-3β completely inhibited the apoptosis of cells expressing c-Myc. Strikingly, c-Myc T58A mutant exhibited higher proliferative activity in a growth-factor-independent manner; however, this mutant failed to induce apoptosis. In addition, knockdown of c-Myc significantly inhibited the proliferation of transformed cells by JAK2 (V617F), suggesting that c-Myc plays an important role in oncogenic activity of JAK2 (V617F). Furthermore, JAK2 (V617F) induced the expression of a target gene of c-Myc, ornithine decarboxylase (ODC), known as the rate-limiting enzyme in polyamine biosynthesis. An ODC inhibitor, difluoromethylornithine (DFMO), prevented the proliferation of transformed cells by JAK2 (V617F). Importantly, administration of DFMO effectively delayed tumor formation in nude mice inoculated with transformed cells by JAK2 (V617F), resulting in prolonged survival; therefore, ODC expression through c-Myc is a critical step for JAK2 (V617F)-induced transformation and DFMO could be used as effective therapy for MPNs.