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Abstract Detection and diagnosis of colon polyps are key to preventing colorectal cancer. Recent evidence suggests that AI-based computer-aided detection (CADe) and computer-aided diagnosis (CADx) systems can enhance endoscopists' performance and boost colonoscopy effectiveness. However, most available public datasets primarily consist of still images or video clips, often at a down-sampled resolution, and do not accurately represent real-world colonoscopy procedures. We introduce the REAL-Colon (Real-world multi-center Endoscopy Annotated video Library) dataset: a compilation of 2.7 M native video frames from sixty full-resolution, real-world colonoscopy recordings across multiple centers. The dataset contains 350k bounding-box annotations, each created under the supervision of expert gastroenterologists. Comprehensive patient clinical data, colonoscopy acquisition information, and polyp histopathological information are also included in each video. With its unprecedented size, quality, and heterogeneity, the REAL-Colon dataset is a unique resource for researchers and developers aiming to advance AI research in colonoscopy. Its openness and transparency facilitate rigorous and reproducible research, fostering the development and benchmarking of more accurate and reliable colonoscopy-related algorithms and models.

Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.

Abstract Objectives Since carbonized clots and tissue (debris) tend to adhere firmly to the tip of the endoscopic submucosal dissection (ESD) knife as the procedure proceeds, manual removing the firm debris is often challenging and time‐consuming. Recently, effective ultrasonic cleaning for other medical devices has been reported. The aim of the present study was to clarify whether ultrasonic cleaning is effective in removing the debris on the insulation‐tipped diathermic (IT) knife‐2. Methods This study was an ex‐vivo experimental randomized study. A total of 40 IT knife‐2 knives with debris on their tip surfaces were prepared and randomly assigned to two groups (Group A and Group B). The knives in Group A were cleaned using the conventional scrubbing method for 30 s (conventional cleaning method), while those in Group B were cleaned using a combined method of scrubbing for 20 s and ultrasonic cleaning for 10 s (combined ultrasonic cleaning method). The tip electrode of the knife after cleaning was photographed under a microscope (40x). The 40 images of the knives were evaluated by independent three endoscopists and two clinical engineers using the five‐step evaluation criteria ranging from cleaning score 1 (dirty) to 5 (clean). Results The mean cleaning score of 3.78 (range: 2.33–4.67) in Group B was significantly higher than that of 1.68 (range: 1.00–2.83) in Group A. Conclusions The combined ultrasonic cleaning method could remove debris adhering to the IT knife‐2 more effectively than the conventional cleaning method. Ultrasonic cleaning may be applied for real‐world ESD.

Abstract Background Hematopoiesis is a model-system for studying cellular development and differentiation. Phenotypic and functional characterization of hematopoietic progenitors has significantly aided our understanding of the mechanisms that govern fate choice, lineage specification and maturity. Methods for progenitor isolation have historically relied on complex flow-cytometric strategies based on nested, arbitrary gates within defined panels of immunophenotypic markers. The resulted populations are then functionally assessed, although functional homogeneity or absolute linkage between function and phenotype is not always achieved, thus distorting our view on progenitor biology. Method In this study, we present a protocol for unbiased phenotypic identification and functional characterization which combines index sorting and clonogenic assessment of individual progenitor cells. Single-cells are plated into custom media allowing multiple hematopoietic fates to emerge and are allowed to give rise to unilineage colonies or mixed. After colony identification, lineage potential is assigned to each progenitor and finally the indexed phenotype of the initial cell is recalled and a phenotype is assigned to each functional output. Conclusions Our approach overcomes the limitations of the current protocols expanding beyond the established cell-surface marker panels and abolishing the need for nested gating. Using this method we were able to resolve the relationships of myeloid progenitors according to the revised model of hematopoiesis, as well as identify a novel marker for erythroid progenitors. Finally, this protocol can be applied to the characterization of any progenitor cell with measurable function.

Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts. We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performed a head-to-head comparison of hESC-CMs and hESC-CVPs and compared these with the most commonly used clinical cell type, human bone marrow mononuclear cells (hBM-MNCs). In a nude rat model of myocardial infarction, hESC-CMs and hESC-CVPs generated comparable grafts. Both similarly improved systolic function and ventricular dilation. Furthermore, only rare human vessels formed from hESC-CVPs. hBM-MNCs attenuated ventricular dilation and enhanced host vascularization without engrafting long-term or improving contractility. Thus, hESC-CMs and CVPs show similar efficacy for cardiac repair, and both are more efficient than hBM-MNCs. However, hESC-CVPs do not form larger grafts or more significant numbers of human vessels in the infarcted heart.

Narrow-band imaging (NBI) is a new imaging technology that was developed in 2006 and has since spread worldwide. Because of its convenience, NBI has been replacing the role of chromoendoscopy. Here we review the efficacy of NBI with/without magnification for detection, characterization, and management of colorectal polyps, and future perspectives for the technology, including education. Recent studies have shown that the next-generation NBI system can detect significantly more colonic polyps than white light imaging, suggesting that NBI may become the modality of choice from the beginning of screening. The capillary pattern revealed by NBI, and the NBI International Colorectal Endoscopic classification are helpful for prediction of histology and for estimating the depth of invasion of colorectal cancer. However, NBI with magnifying colonoscopy is not superior to magnifying chromoendoscopy for estimation of invasion depth. Currently, therefore, chromoendoscopy should also be performed additionally if deep submucosal invasive cancer is suspected. If endoscopists become able to accurately estimate colorectal polyp pathology using NBI, this will allow adenomatous polyps to be resected and discarded; thus, reducing both the risk of polypectomy and costs. In order to achieve this goal, a suitable system for education and training in in vivo diagnostics will be necessary.

Background and study aims: Sessile serrated adenoma/polyps (SSA/Ps) are considered precursors of colorectal cancers with microsatellite instability. However, it is still difficult to differentiate SSA/Ps from hyperplastic polyps endoscopically; therefore, the prevalence of SSA/Ps remains uncertain in clinical practice. This study aimed to clarify the proportion of SSA/Ps in endoscopically diagnosed colorectal polyps with hyperplastic features (E-HPs). Patients and methods: Patients aged ≥ 40 years undergoing colonoscopy for standard clinical indications at our center were prospectively enrolled between June 2013 and May 2014. During colonoscopy, 0.05 % indigo carmine dye was sprayed throughout the colorectum to highlight lesions. All detected lesions were diagnosed by high definition magnifying narrow-band imaging and were resected endoscopically or surgically, apart from rectosigmoid E-HPs ≤ 5 mm. The number of rectosigmoid E-HPs ≤ 5 mm was recorded, and some were resected for use as tissue samples. Results: A total of 343 patients (male: 42.9 %; mean age: 61.5 years) were included. Among 3838 E-HPs (distal: 96.4 %) detected in 294 patients, 792 were resected and analyzed. All of 21 SSA/Ps identified in 17 patients were included in E-HPs, and the overall proportion of SSA/Ps in E-HPs was 2.7 %. However, this proportion increased with the size of E-HPs (≤ 5 mm: 0.7 %; 6 – 9 mm: 29.0 %; ≥ 10 mm: 70 %) and was higher in the proximal colon than in the distal colorectum (10.9 % vs. 0.9 %). In addition, no SSA/P was found in the rectum, and no SSA/P had cytological dysplasia. Conclusions: The overall proportion of SSA/Ps in E-HPs was 2.7 %, although this proportion was higher in the proximal colon and increased with the size of E-HPs. SSA/Ps were common in routine colonoscopy, with a prevalence of at least 5.0 %. Study registration: UMIN000010832.

Background and study aims: The real-time optical diagnosis of colorectal polyps with high confidence predictions can achieve high levels of accuracy. Increasing the rates of high confidence optical diagnosis can improve the clinical application of real-time optical diagnosis in routine practice. The primary aim of this prospective study was to evaluate whether high magnifying endoscopy improves the rates of high confidence narrow-band imaging (NBI) – based optical diagnosis for differentiating between neoplastic and non-neoplastic colorectal lesions according to the NBI international colorectal endoscopic (NICE) classification. Patients and methods: Consecutive adult patients undergoing colonoscopy with a high magnifying (maximum, × 80) colonoscope between April and August 2012 were recruited. The optical diagnosis for each polyp was evaluated during colonoscopy in two consecutive stages by the same endoscopist, who first used NBI with non-magnifying endoscopy (NBI-NME), then NBI with magnifying endoscopy (NBI-ME). A level of confidence was assigned to each prediction. Results: The analysis included 124 patients (mean age, 56.4 years; male-to-female ratio, 72:52) with 248 polyps smaller than 10 mm. Of the 248 polyps, 210 were 1 to 5 mm in size and 38 were 6 to 9 mm in size; 77 polyps were hyperplastic, 4 were sessile serrated adenomas/polyps, 160 were low grade adenomas, 5 were high grade adenomas, and 2 were deep submucosal invasive carcinomas. The rate of high confidence optical diagnosis when NBI-ME was used was significantly higher than the rate when NBI-NME was used for diminutive (1 – 5 mm) polyps (92.9 % vs 79.5 %, P

In vitro expanded bone marrow stromal cells contain at least two populations of fibroblasts, a CD146/MCAM positive population, previously reported to be critical for establishing the stem cell niche and a CD146-negative population that expresses CUB domain-containing protein 1 (CDCP1)/CD318. Immunohistochemistry of marrow biopsies shows that clusters of CDCP1+ cells are present in discrete areas distinct from areas of fibroblasts expressing CD146. Using a stromal cell line, HS5, which approximates primary CDCP1+ stromal cells, we show that binding of an activating antibody against CDCP1 results in tyrosine-phosphorylation of CDCP1, paralleled by phosphorylation of Src Family Kinases (SFKs) Protein Kinase C delta (PKC-δ). When CDCP1 expression is knocked-down by siRNA, the expression and secretion of myelopoietic cytokines is increased. These data suggest CDCP1 expression can be used to identify a subset of marrow fibroblasts functionally distinct from CD146+ fibroblasts. Furthermore the CDCP1 protein may contribute to the defining function of these cells by regulating cytokine expression.

In the current study, we used a canine model of radiation-induced lung injury to test the effect of a single i.v. infusion of 10×10(6)/kg of marrow fibroblasts on the progression of damage following 15 Gy exposure to the right lung. The fibroblasts, designated DS1 cells, are a cloned population of immortalized cells isolated from a primary culture of marrow stromal cells. DS1 cells were infused at week 5 post-irradiation when lung damage was evident by imaging with high-resolution computed tomography (CT). At 13 weeks post-irradiation we found that 4 out of 5 dogs receiving DS1 cells had significantly improved pulmonary function compared to 0 out of 5 control dogs (p = 0.047, Fisher's Exact). Pulmonary function was measured as the single breath diffusion capacity-hematocrit (DLCO-Hct), the total inspiratory capacity (IC), and the total lung capacity (TLC), which differed significantly between control and DS1-treated dogs; p = 0.002, p = 0.005, and p = 0.004, respectively. The DS1-treated dogs also had less pneumonitis detected by CT imaging and an increased number of TTF-1 (thyroid transcription factor 1, NKX2-1) positive cells in the bronchioli and alveoli compared to control dogs. Endothelial-like progenitor cells (ELC) of host origin, detected by colony assays, were found in peripheral blood after DS1 cell infusion. ELC numbers peaked one day after infusion, and were not detectable by 7 days. These data suggest that infusion of marrow fibroblasts stimulates mobilization of ELC, which is associated with a reduction in otherwise progressive radiation-induced lung injury. We hypothesize that these two observations are related, specifically that circulating ELC contribute to increased angiogenesis, which facilitates endogenous lung repair.

Neuroendocrine neoplasms can produce multiple hormones that are released into the bloodstream, causing symptoms that vary depending on the type and quantity of hormones involved. We herein report a 63-year-old asymptomatic patient with pancreatic insulinoma who showed marked elevations in circulating calcitonin and procalcitonin levels that returned to normal following surgery. Immunohistochemical analyses confirmed the co-staining of calcitonin and insulin immunoreactivity in the tumor cells, suggesting a calcitonin-producing insulinoma. This insulinoma released calcitonin and a considerable amount of its precursor peptide, procalcitonin, resulting in both hyperprocalcitoninemia and hypercalcitoninemia.

Hyperinsulinemia is often observed in obese subjects because of insulin resistance, but it may occur in nonobese subjects with unknown etiology. A 72-year-old man was admitted to our hospital for the examination of hyperinsulinemia, reactive hypoglycemia, and liver dysfunction. The patient's body mass index was 23.7 kg/m 2 , but he had an elevated visceral fat area (125 cm 2 ). His laboratory data showed mildly elevated liver enzymes, whereas plasma fasting glucose and serum insulin levels were 91 mg/dL and 52.3 μU/mL, respectively. In a 75-g oral glucose tolerance test, the serum insulin level reached the highest value of 1124 μU/mL at 180 minutes. There was no obvious etiology except for mild liver steatosis shown by liver biopsy. We suspected genetic abnormalities related to hyperinsulinemia. We performed whole-exome sequencing (WES) analyses and identified a heterozygous nonsense variant p.R924X in the insulin receptor ( INSR ) gene, a novel heterozygous missense variant p.V416M in the AKT1 gene, and a novel hemizygous missense variant p.R310Q in the PHKA2 gene, which is the causative gene of hepatic injury as glycogen storage disease type IX. It was speculated that the INSR gene variant, in addition to visceral fat accumulation, was the main cause of hyperinsulinemia and reactive hypoglycemia, and the remaining 2 variants were also partly responsible for hyperinsulinemia. WES analysis revealed candidate gene variants of hyperinsulinemia and hepatic-type glycogenosis. Thus, WES analysis may be a useful tool for clarifying the etiology when unexplained genetic pathophysiological conditions are suspected., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

We report the case of a 52-year-old woman with Prader-Willi syndrome (PWS) and diabetes. Her diabetes was managed with sulfonylurea followed by premixed insulin; however, her glycemic control gradually worsened and became unstable. Her urine and blood C-peptide levels were undetectable. She tested positive for anti-GAD antibodies, and had a high-risk genotype - DRB1*09:01-DQB1*03:03 - for slowly progressive insulin-dependent diabetes mellitus (SPIDDM) in the HLA-DR/DQ region, confirming the diagnosis of SPIDDM. Dysglycemia in PWS is thought to be attributable to hyperphagia and obesity. However, the possibility of SPIDDM might be considered if the insulin secretory capacity is almost lost in patients with PWS.

We herein report the case of a 37-year-old man with both pheochromocytoma and visceral fat accumulation and describe the sequential changes in his adiponectin levels throughout the clinical course from catecholamine crisis until the follow-up for adrenalectomy. His adiponectin level decreased during catecholamine crisis and increased after adrenalectomy. However, his adiponectin level decreased again at two years postoperatively when his visceral fat area greatly increased. This case suggests that catecholamines and visceral fat volume may affect adiponectin metabolism in subjects with pheochromocytoma, which may precipitate cardiovascular complications in this endocrine disease.

Insulin autoimmune syndrome (IAS) involves not only fasting hypoglycemia, but also postprandial hyperglycemia. In the present study, we hypothesized that glycated albumin (GA) levels and the GA/HbA1c ratio, which reflect fluctuations in plasma glucose levels, are elevated in IAS patients. Four IAS patients were enrolled in the present study. Thirty-two non-diabetic subjects matched for gender, age, and BMI were used as the control group. The fasting plasma glucose levels in the IAS patients were significantly lower than in the control group. However, the oral glucose tolerance test (OGTT) revealed impaired glucose tolerance or diabetes mellitus in all the IAS patients, and thus the OGTT 2-h plasma glucose levels were significantly higher than in the control group. The GA levels and the GA/HbA1c ratio in the IAS patients were significantly higher than in the control group, despite no significant difference in the HbA1c levels between the two groups. In one case in which IAS spontaneously went into remission, there was a significant correlation between anti-insulin antibodies and GA, but not HbA1c. Improvement in glucose fluctuations was observed by continuous glucose monitoring in another patient along with improvement in the clinical symptoms. Furthermore, anti-insulin antibodies, GA, and the GA/HbA1c ratio decreased, but HbA1c did not change significantly in three IAS patients along with the improvement in clinical symptoms. These results suggest that GA and the GA/HbA1c ratio are useful indicators for determining the level of disease activity in IAS patients., Competing Interests: The authors declare that they have no conflicts of interest.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients prior to their participation in this study.

Aim: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels., Methods: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals., Results: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P ＜ 1 × 10 (-14)), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) scores, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels, similar to increasing VFA and decreasing adiponectin levels., Conclusion: These results suggested that CDH13 SNPs cause an adiponectin-resistant status to compensate for increasing adiponectin levels and could result in the deterioration of metabolic syndrome traits.

The aim of this study was to investigate the clinical and endocrinological characteristics of adrenal incidentalomas in Osaka region, Japan. The study was a multicenter retrospective analysis of 150 patients with adrenal incidentalomas who underwent radiographic and endocrine evaluations between 2005 and 2013. Most adrenal incidentalomas were discovered by computed tomography (77.0%) and the rest were identified by abdominal ultrasonography (14.6%), magnetic resonance imaging (4.2%), or positron emission tomography (4.2%). Adrenal incidentalomas were more frequently localized on the left side than on the right. The average diameter of tumors was 21 ± 11 mm. On endocrinological evaluation, 14 patients were diagnosed with primary aldosteronism (9.3%), 10 with subclinical Cushing's syndrome (6.7%), 7 with pheochromocytoma (4.7%), 7 with Cushing's syndrome (4.7%), 2 with both subclinical Cushing's syndrome and primary aldosteronism (1.3%), and 110 with non-functioning tumors (73.3%). Patients with functioning tumors were significantly younger and had larger tumor diameters than those with non-functioning tumors. Except for hypertension, complications were comparable between patients with functioning and non-functioning tumors, including the presence of glucose intolerance, cardiovascular disease, and dyslipidemia. In conclusion, a higher prevalence of primary aldosteronism was observed compared with a previous report. Complications were comparable between patients with functioning and non-functioning tumors, including the frequencies of glucose intolerance, cardiovascular disease, and dyslipidemia. Long-term follow-up is required in patients with non-functioning tumors because the frequency of complications, such as glucose intolerance, cardiovascular disease, and dyslipidemia, was equal to that in patients with functioning tumors.

Objective: We assessed the efficacy and adverse effects of febuxostat in male hyperuricemia patients., Subjects and Methods: This was a 12-week, multicenter, open-label, uncontrolled study. The enrolled subjects were 89 hyperuricemic male patients (12 overexcretors, 56 normal excretors, and 21 underexcretors). The endpoint was percent change in serum urate level., Results: The concentration of urate in serum before and 12 weeks after beginning administration of febuxostat in the overexcretors was 9.34 ± 1.48 and 5.59 ± 1.17 mg/dl, respectively, while those were 8.59 ± 1.24 and 5.41 ± 1.35 mg/dl, respectively, in the normal excretors, and 8.29 ± 1.01and 5.11 ± 1.71 mg/dl, respectively, in the underexcretors. After 12 weeks, the rate of change in serum urate after beginning administration of febuxostat was - 0.384 ± 0.186 in the overexcretors, - 0.368 ± 0.128 in the normal excretors, and - 0.365 ± 0.217 in the underexcretors, with no significant differences among them. A common adverse event related to febuxostat was gout flare., Conclusion: Febuxostat effectively reduced the concentration of urate in serum in hyperuricemic patients regardless of the level of uric acid excreted in urine without severe adverse effects.

Insulinoma and insulin or insulin receptor (IR) autoantibodies are the main causes of hyperinsulinemic hypoglycemia in adults, but the exact cause in other cases remains obscure. This study is to determine the genetic basis of hyperinsulinemic hypoglycemia in two cases without the above abnormalities. Sequence analysis of IR gene in two patients with adult-onset hyperinsulinemic hypoglycemia and their relatives were performed, and the mutant gene observed in one case was analyzed. Both cases had normal levels of fasting plasma glucose (FPG), fasting hyperinsulinemia, low insulin sensitivity, and hypoglycemia with excessive insulin secretion during oral glucose tolerance test (OGTT). Both reported adult-onset postprandial hypoglycemic symptoms. In one patient, a missense mutation (Arg256Cys) was detected in both alleles of the IR gene, and his parents had the same mutation in only one allele but no hypoglycemia. The other had a novel nonsense mutation (Trp1273X) followed by a mutation (Gln1274Lys) in one allele, and his 9-year old son had the same mutation in one allele, together with hyperinsulinemic hypoglycemia during OGTT. Overexpression experiments of the mutant gene found in Case 1 in mammalian cells showed abnormal processing of the IR protein and demonstrated reduced function of Akt/Erk phosphorylation by insulin in the cells. In two cases of hyperinsulinemic hypoglycemia in adults, we found novel mutations in IR gene considered to be linked to hypoglycemia. We propose a disease entity of adult-onset hyperinsulinemic hypoglycemia syndrome associated with mutations in IR gene.

Visceral fat accumulation contributes to the development of insulin resistance, leading to metabolic syndrome. Adiponectin provides a link between visceral fat accumulation and insulin resistance. In addition to environmental factors, genetic factors play important roles in visceral fat accumulation and circulating adiponectin levels. Genome-wide association studies (GWASs) have identified genetic variations in the adiponectin, C1Q and collagen domain containing (ADIPOQ) gene that are associated with adiponectin levels. In this study, we investigated whether ADIPOQ single nucleotide polymorphisms (SNPs) were associated with visceral fat accumulation and insulin resistance. We measured the visceral fat area (VFA) by computed tomography (CT) and examined the presence of the insulin resistance-related phenotype (fasting plasma glucose, fasting insulin, and homeostasis model assessment-insulin resistance [HOMA-IR]) in a set of Japanese individuals (731 men and 864 women) who were genotyped for seven ADIPOQ SNPs reported by recent GWASs (namely, rs6810075, rs10937273, rs1648707, rs864265, rs182052, rs17366568, and rs6773957). SNPs associated with the phenotype (P < 0.05) were then evaluated by association analysis using a second set of the study participants (383 men and 510 women). None of the SNPs was associated with body mass index (BMI) or VFA in men or women. However, the adiponectin-decreasing alleles of rs10937273 and rs1648707 were significantly associated with HOMA-IR (P = 0.0030 and P = 0.00074, respectively) in women, independently of BMI. These SNPs were significantly associated with decreased adiponectin levels in women. Our results suggested that rs10937273 and rs1648707 may affect insulin sensitivity by regulating adiponectin production by adipose tissue in women.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference, waist-hip ratio measurements and visceral fat area (VFA); the latter can be accurately measured by performing computed tomography (CT). In addition to environmental factors, genetic factors play an important role in obesity and fat distribution. New genetic loci associated with body mass index (BMI) and adiposity have been identified by genome-wide association studies (GWASs). This study utilized CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to higher BMI are associated with VFA, subcutaneous fat area (SFA), and the ratio of VFA to SFA (V/S ratio). We measured the VFA and SFA of 1424 obese Japanese subjects (BMI ≥ 25 kg/m(2), 635 men and 789 women) who were genotyped for 13 single nucleotide polymorphisms (SNPs) reported by recent GWASs, namely, TNNI3K rs1514175, PTBP2 rs1555543, ADCY3 rs713586, IRS1 rs2943650, POC5 rs2112347, NUDT3 rs206936, LINGO2 rs10968576, STK33 rs4929949, MTIF3 rs4771122, SPRY2 rs534870, MAP2K5 rs2241423, QPCTL rs2287019, and ZC3H4 rs3810291. The G-allele of NUDT3 rs206936 was significantly associated with increased BMI (P = 5.3 × 10(-5)) and SFA (P = 0.00039) in the obese Japanese women. After adjustment with BMI, the association between rs206936 and SFA was not observed. This significant association was not observed in the men. The other SNPs analyzed were not significantly associated with BMI, VFA, SFA, or V/S ratio. Our results suggest that NUDT3 rs206936 is associated with BMI in Japanese women.

Aim: Visceral fat accumulation plays an integral role in morbidity and mortality rates by increasing the risk of developing metabolic disorders such as type 2 diabetes, dyslipidemia, and hypertension. New genetic loci associated with fat distribution, measured by waist-hip ratios and computed tomography (CT), have recently been identified by genome-wide association studies in European-descent populations. This study used CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to fat distribution are associated with visceral fat area (VFA) and subcutaneous fat area (SFA) in the Japanese population., Methods: We measured the VFAs and SFAs of 1424 obese Japanese subjects (BMI≥25 kg/m(2), 635 men and 789 women) that were genotyped at 15 SNPs, namely, TBX15 rs984222, DNM3 rs1011731, LYPLAL1 rs4846567, GRB14 rs10195252, NISCH rs6784615, ADAMTS9 rs6795735, CPEB4 rs6861681, LY86 rs1294421, VEGFA rs6905288, RSPO3 rs9491696, NFE2L3 rs1055144, ITPR2 rs718314, HOXC13 rs1443512, ZNRF3 rs4823006 and THNSL2 rs1659258., Results: The G-allele of LYPLAL1 rs4846567 was borderline associated with an increased ratio of VFA to SFA (V/S ratio; p= 0.0020). LYPLAL1 rs4846567 had a stronger effect on the V/S ratio in women (p= 0.0078) than in men (p= 0.12); however, neither result was significant after Bonferroni correction for multiple comparisons. NISCH rs6784615 was nominally associated with increased VFA (p=0.040) and V/S ratio (p= 0.020). The other SNPs analyzed were not significantly associated with body mass index (BMI), VFA, or SFA., Conclusion: Our results suggest that LYPLAL1 rs4846567 and NISCH rs6784615 may influence fat distribution in the Japanese population.

A 70-year-old woman with no history of diabetes was admitted to the hospital for the management of hypoglycemia. Her fasting plasma glucose level was 54 mg/dL with an extremely high serum immunoreactive insulin level (1210 μU/mL). She had high titers of anti-insulin antibodies and exhibited the DRB1*0406 genotype for HLA-DR4, leading to a diagnosis of insulin autoimmune syndrome. She had been taking several health preparations for approximately 10 years; however, all were thiol group-free. Due to frequent episodes of nocturnal hypoglycemia, the health preparations were discontinued and the patient was treated with cornstarch. This protocol successfully ameliorated the hypoglycemic episodes and normalized the patient's laboratory and serological test results.

Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.

Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 × 10(-5)) and rs1421085 (P=7.4 × 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP × SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2β (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P=0.0039 and 0.0039, respectively), SFA (P=0.0027 and 0.0023, respectively) and VFA (P=0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects.

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) > or =30 kg m(-2)) and normal-weight control subjects (n=1736, BMI <25 kg m(-2)). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects.