担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65-80 years with moderately controlled glycemic levels (HbA1c 7.4-10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were - 27.2 mg/dL, - 0.61%, and - 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, - 0.29%, and - 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients.Trial registration number: UMIN000010376.

DOI： 10.1038/s41598-022-27301-9

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Type 2 diabetes (T2D) is a polygenic disease and studies to understand the etiology of the disease have required selectively bred animal models with polygenic background. In this review, we present two models; the Goto-Kakizaki (GK) rat and the Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mouse. The GK rat was developed by continuous selective breeding for glucose tolerance from the outbred Wistar rat around 50 years ago. The main cause of spontaneous hyperglycemia in this model is insulin secretion deficiency from pancreatic β-cells and mild insulin resistance in insulin target organs. A disadvantage of the GK rat is that environmental factors have not been considered in the selective breeding. Hence, the GK rat may not be suitable for elucidating predisposition to diabetes under certain environmental conditions, such as a high-fat diet. Therefore, we recently established two mouse lines with different susceptibilities to diet-induced diabetes, which are prone and resistant to the development of diabetes, designated as the ON-DP and ON-DR mouse, respectively. The two ON mouse lines were established by continuous selective breeding for inferior and superior glucose tolerance after high-fat diet feeding in hybrid mice of three inbred strains. Studies of phenotypic differences between ON-DP and ON-DR mice and their underlying molecular mechanisms will shed light on predisposing factors for the development of T2D in the modern obesogenic environment. This review summarizes the background and the phenotypic differences and similarities of GK rats and ON mice and highlights the advantages of using selectively bred rodent models in diabetes research.

DOI： 10.1507/endocrj.EJ22-0253

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of this retrospective multicenter study was to clarify the antifibrotic effect and long-term outcome of sodium glucose cotransporter 2 inhibitors (SGLT2-Is) in patients with nonalcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM). Of the 1262 consecutive patients with T2DM who recently received SGLT2-Is, 202 patients with NAFLD had been receiving SGLT2-Is for more than 48 weeks and were subjected to this analysis. Furthermore, 109 patients who had been on SGLT2-I therapy for more than 3 years at the time of analysis were assessed for the long-term effects of SGLT2-Is. Significant decreases in body weight, liver transaminases, plasma glucose, hemoglobin A1c, and Fibrosis-4 (FIB-4) index were found at week 48. Overall, the median value of FIB-4 index decreased from 1.42 at baseline to 1.25 at week 48 (p < 0.001). In the low-risk group (FIB-4 index < 1.3), there was no significant change in the FIB-4 index. In the intermediate-risk (≥1.3 and <2.67) and high-risk (≥2.67) groups, the median levels significantly decreased from 1.77 and 3.33 at baseline to 1.58 and 2.75 at week 48, respectively (p < 0.001 for both). Improvements in body weight, glucose control, liver transaminases, and FIB-4 index were found at 3 years of SGLT2-I treatment. In the intermediate-risk and high-risk groups (≥1.3 FIB-4 index), the FIB-4 index maintained a significant reduction from baseline throughout the 3 years of treatment. Conclusion: This study showed that SGLT2-Is offered a favorable effect on improvement in FIB-4 index as a surrogate marker of liver fibrosis in patient with NAFLD complicated by T2DM, especially those with intermediate and high risks of advanced fibrosis, and this antifibrotic effect is sustained for the long term.

DOI： 10.1002/hep4.2069

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type 2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin-secreting cells. METHODS: Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-βH1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch-clamp was used for single-cell electrophysiology. Confocal microscopy was used to determine intracellular localization. RESULTS: Human islet expression of the transcription factor PDX1 was positively correlated with SYT11 (p = 2.4e-10 ) and SYT13 (p < 2.2e-16 ). Syt11 and Syt13 both co-localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS-1 832/13 cells (siSYT11) resulted in increased basal and glucose-induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K+ . Interestingly, the cAMP-raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage-gated Ca2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells. CONCLUSION: SYT11 and SYT13 have similar localization and transcriptional regulation, but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type-2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.

DOI： 10.1111/apha.13857

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD). DESIGN AND METHODS: Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population. RESULTS: Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls. CONCLUSIONS: ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

DOI： 10.1007/s11102-022-01231-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Background and Aim: This study aimed to clarify the efficacy and safety of oral semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM). Methods: This was a single-arm, open-label pilot study. Sixteen patients with NAFLD who received oral semaglutide for T2DM were included in the analysis. Oral semaglutide was initiated at a dose of 3 mg once daily, and the dose was sequentially increased to 7 mg at 4 weeks and 14 mg at 8 weeks (maintenance dose) until the end of the 24-week trial. Results: Body weight and levels of liver-related biochemistry, plasma glucose, and hemoglobin A1c decreased significantly from baseline to 12 weeks. These significant decreases were maintained until the end of the trial. Additionally, levels of the homeostasis model assessment-insulin resistance and triglyceride significantly decreased at 24 weeks. Controlled attenuation parameter (CAP) values significantly decreased from baseline to 24 weeks. Changes in body weight were correlated with those in levels of alanine aminotransferase (r = 0.52) and CAP (r = 0.72). As for liver fibrosis markers, significant decreases from baseline to 24 weeks in levels of the fibrosis-4 index, ferritin, and type IV collagen 7 s were found; however, the liver stiffness measurement did not significantly decrease. Most adverse events were grade 1-2 transient gastrointestinal disorders. Conclusions: Oral semaglutide treatment in patients with NAFLD complicated by T2DM improved impaired liver function, hypertriglyceridemia, insulin resistance, and hepatic steatosis, as well as improving diabetic status and reducing body weight.

DOI： 10.1002/jgh3.12780

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12780

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The sequence of events for secreting insulin in response to glucose in pancreatic β-cells is termed "stimulus-secretion coupling". The core of stimulus-secretion coupling is a process which generates electrical activity in response to glucose uptake and causes Ca2+ oscillation for triggering exocytosis of insulin-containing secretory granules. Prior to exocytosis, the secretory granules are mobilized and docked to the plasma membrane and primed for fusion with the plasma membrane. Together with the final fusion with the plasma membrane, these steps are named the exocytosis process of insulin secretion. The steps involved in the exocytosis process are crucial for insulin release from β-cells and considered indispensable for glucose homeostasis. We recently confirmed a signature of defective exocytosis process in human islets and β-cells of obese donors with type 2 diabetes (T2D). Furthermore, cyclic AMP (cAMP) potentiates glucose-stimulated insulin secretion through mechanisms including accelerating the exocytosis process. In this mini-review, we aimed to organize essential knowledge of the secretory granule exocytosis and its amplification by cAMP. Then, we suggest the fatty acid translocase CD36 as a predisposition in β-cells for causing defective exocytosis, which is considered a pathogenesis of T2D in relation to obesity. Finally, we propose potential therapeutics of the defective exocytosis based on a CD36-neutralizing antibody and on Apolipoprotein A-I (ApoA-I), for improving β-cell function in T2D.

DOI： 10.1007/s13340-022-00580-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

Pheochromocytomas can present with various symptoms. Nonspecific manifestations of pheochromocytoma include intestinal pseudo-obstruction and weight loss. Here, we present a case of pheochromocytoma in which prolonged intestinal pseudo-obstruction due to excess catecholamines was one of the factors leading to the development of a liver abscess. An 18-year-old male patient with a history of status epilepticus and severe intellectual disability was transferred to our hospital for a thorough examination of fever and constipation that had lasted for 2 months. When admitted to our hospital, he had fever, and his body mass index was 9.5 kg/m². Upon comprehensive examination of the patient’s fever, the blood culture was found positive for Bacteroides. Computed tomography showed findings of intestinal pseudo-obstruction and a low density region in the liver that indicated a liver abscess. Imaging studies also revealed a right adrenal mass and endocrinological test showed elevated plasma norepinephrine and urine normetanephrine levels. In addition, the right adrenal mass showed uptake on ¹²³I-metaiodobenzylguanidine scintigraphy. These findings led to a definite diagnosis of pheochromocytoma. The patient was eventually diagnosed with a pheochromocytoma coexisting with a liver abscess. After treating the liver abscess with antibiotics and ultrasound-guided drainage, an adrenalectomy was performed. The pathological findings were consistent with pheochromocytoma. Postoperatively, the catecholamine excess normalized and intestinal pseudo-obstruction and weight loss improved. We suspected that prolonged intestinal pseudo-obstruction resulted in bacterial translocation and development of a liver abscess. To the best of our knowledge, this is the first report of a pheochromocytoma associated with a liver abscess. Moreover, the clinical presentation of this patient was unusual for pheochromocytoma, as the patient did not have typical symptoms such as hypertension or tachycardia, but rather presented with constipation, intestinal pseudo-obstruction, and weight loss. This case provides valuable insight regarding the impact of catecholamine excess on the intestinal tract and body weight.

DOI： 10.1177/20420188221139652

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/20420188221139652

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D. Materials and Methods: Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis. Results: Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85-0.98), P = 0.01) and mean postoperative BG (1.11 (1.05-1.18), P < 0.001) were independently associated with postoperative complications. Conclusion: Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

DOI： 10.1177/20420188221099349

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets is not clear. Here we report increased expression of miR-200c in islets from T2D as compared with non-diabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on protein level in EndoC-βH1 cells overexpressing miR-200c and Luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c (LNA200c) increased glucose-stimulated insulin secretion in islets from T2D donors ∼3-fold. Our data reveal a vital role of the miR-200c-ETV5 axis in beta cell dysfunction and pathophysiology of T2D.

DOI： 10.2337/db21-0077

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.

DOI： 10.1038/s41598-021-95581-8

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH. Design: Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting. Results: Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II. Conclusion: The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

DOI： 10.1530/EJE-20-0706

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Smoking during pregnancy is one of the causes of low birthweight. Ingestion of nicotine during pregnancy has various metabolic impacts on the fetus and offspring. According to the developmental origins of health and disease theory, low birthweight is a risk factor for developing various non-communicable diseases, including diabetes. We hypothesized that when nicotine-induced low-birthweight rats, when exposed to a high-fat diet (HFD) after growth, are predisposed to glucose intolerance as a result of a mismatch between the eutrophic environment and small body size. Therefore, we investigated whether hyperinsulinemia was caused by exposure of nicotine-induced low-birthweight rats to HFD, including whether this phenomenon exhibited possible sex differences. The average birthweight and body weight at weaning day of offspring from nicotine-administered dams was lower than those of controls. The offspring from nicotine-administered dams did not show rapid fat accumulation after exposure to HFD, and weight and body fat ratio of these animals did not differ from those of the controls. Blood glucose levels did not differ between the groups, but insulin levels increased only in male HFD-exposed offspring from nicotine-administered dams. Similarly, only in HFD-exposed male from nicotine-administered dams showed decreases in the insulin receptor expression in the liver. We conclude that male rats subjected to prenatal nicotine exposure develop hyperinsulinemia when exposed to HFD after growth. Our results suggest that decreased expression of insulin receptors in the liver may be involved in the mechanism underlying hyperinsulinemia in low-birthweight offspring, a phenomenon that appeared to exhibit a sex-specific bias.

DOI： 10.3389/fendo.2021.694336

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1-6.7 kPa) (p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.

DOI： 10.1177/20420188211000243

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A prolonged QT interval plays a causal role in fatal arrhythmia and is known to be a risk factor for sudden cardiac death. Although diabetic patients with microvascular complications tend to have a longer QT interval, the therapeutic effect of diabetes on the QT interval remains unclear. Here, we assessed the changes in QT interval in patients with type 2 diabetes (T2D) who received multiple daily insulin injections. Materials and methods: Patients with T2D (n = 34) who were admitted to our hospital and initiated multiple daily insulin injections for glycemic control were enrolled in this study. Clinical measurements, including electrocardiogram, were taken on admission and discharge. The QT interval was measured manually in lead II on the electrocardiogram, and corrected QT interval (QTc) was calculated using Bazett's formula. The change in QTc (ΔQTc) during hospitalization (median, 15 days) and clinical parameters affecting ΔQTc were investigated. Results: QTc was shortened from 439 ± 24 to 427 ± 26 ms during hospitalization (p < 0.0001). ΔQTc was positively correlated with the changes in fasting plasma glucose (ΔFPG, r = 0.55, p = 0.0008) and glycated albumin (r = 0.38, p = 0.026) following insulin therapy, but not with the final dose of insulin (r = -0.20, p = 0.26). The multiple regression analyses revealed that ΔFPG was independently associated with ΔQTc. Conclusions: Multiple daily insulin injections can ameliorate QT interval by lowering the blood glucose levels in T2D, suggesting that glycemic control is important for preventing patients with T2D from sudden cardiac death.

DOI： 10.1177/20420188211010057

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/HYPOTHESIS: Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice. METHODS: Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro. RESULTS: ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice. CONCLUSIONS/INTERPRETATION: The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.

DOI： 10.1007/s00125-020-05191-8

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Obesity is a risk factor for type 2 diabetes (T2D); however, not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI ≥30 kg/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased β-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human β-cell line EndoC-βH1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that β-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit β-cell function in T2D associated with obesity.

DOI： 10.2337/db19-0944

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/INTRODUCTION: An increased risk of diabetes mellitus has been reported in primary aldosteronism, but the pathogenesis of glucose intolerance between the primary aldosteronism subtypes remains unclear. This study aimed to evaluate glucose metabolism in oral glucose tolerance test between aldosterone-producing adenoma and idiopathic hyperaldosteronism, and characterize patients with improved glucose intolerance after primary aldosteronism treatment. MATERIALS AND METHODS: Oral glucose tolerance test was carried out in 116 patients who were diagnosed with primary aldosteronism and received adrenal venous sampling for subtyping. Oral glucose tolerance test was re-evaluated after starting the treatment of primary aldosteronism for those who had glucose intolerance before the treatment. RESULTS: A total of 46.4% and 52.3% of patients with aldosterone-producing adenoma and idiopathic hyperaldosteronism, respectively, were diagnosed with impaired glucose tolerance or diabetes. The insulinogenic index was significantly lower in aldosterone-producing adenoma than in idiopathic hyperaldosteronism (P = 0.045), whereas the Matsuda insulin sensitivity index was significantly higher in aldosterone-producing adenoma than in idiopathic hyperaldosteronism (P = 0.022). After the treatment of primary aldosteronism, glucose intolerance was improved in 66.6% and 45.8% of aldosterone-producing adenoma and idiopathic hyperaldosteronism, respectively. The presence of obesity and central obesity were significantly lower in patients who improved glucose intolerance after the treatment of primary aldosteronism as compared with those not improved (P = 0.013 and P = 0.033, respectively). CONCLUSIONS: Insulin secretion impairment and insulin resistance play pathogenic roles for glucose intolerance in aldosterone-producing adenoma and idiopathic hyperaldosteronism, respectively. In addition, primary aldosteronism treatments can ameliorate glucose intolerance more effectively in patients without obesity and/or central obesity.

DOI： 10.1111/jdi.13312

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 38-year-old woman with type 1 diabetes, whose fasting plasma glucose levels were >500 mg/dL under 176 U/day of subcutaneous insulin injection, was admitted to Nippon Medical School Hospital, Tokyo, Japan. When insulin was administered intravenously, she was able to maintain favorable glycemic control even under 24 U/day of regular insulin, showing that she was accompanied by subcutaneous insulin resistance. To choose an optimal insulin regimen, we carried out subcutaneous insulin challenge tests without or with heparin mixture, and found a cocktail of insulin lispro and heparin could reduce blood glucose levels markedly. As a consequence, she achieved favorable blood glucose control by continuous subcutaneous insulin infusion of the cocktail. In summary, the insulin and heparin challenge tests are useful for choosing an optimal insulin regimen in cases of subcutaneous insulin resistance.

DOI： 10.1111/jdi.13266

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aims to evaluate the effect of dipeptidyl peptidase-4 inhibitors on lipid metabolism in patients with type 2 diabetes mellitus (T2D). METHODS: This is a multicenter, open-labeled, randomized controlled study. T2D patients with HbA1c 6.9-8.9% (52-74 mmol/mol) who were under treatment with sulfonylurea were randomly allocated to either the sitagliptin group or the non-sitagliptin group. Glucose and lipid metabolism parameters including apolipoproteins (apo), sterols, and urinary albumin were assessed at baseline, 3, and 6 months of the treatment. RESULTS: A total of 164 patients completed the 6-month observation (n = 81 for sitagliptin and n = 83 for non-sitagliptin). HbA1c decreased in the sitagliptin group but not in the non-sitagliptin group. Serum TG and total, LDL and HDL cholesterol levels did not change in either group. Apo B-48, apo CII, and apo CIII levels decreased in the sitagliptin group, but not in the non-sitagliptin group. The change in urinary albumin was significantly different between the groups with a preferable change in the sitagliptin group. There were no changes in serum sterols levels in the two groups. CONCLUSIONS: The treatment of sitagliptin for 6 months improves the metabolism of glucose and chylomicron and reduces plasma levels of atherogenic lipoproteins in patients with T2D.

DOI： 10.1016/j.diabres.2020.108119

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The increase of plasma levels of high-density lipoproteins and Apolipoprotein A-I (ApoA-I), its main protein component, has been shown to have a positive action on glucose disposal in type 2 diabetic patients. The current study investigates the unexplored function of ApoA-I to prime beta cells for improved insulin secretion. INS-1E rat clonal beta cells as well as isolated murine islets were used to study the effect of ApoA-I on responsiveness of the beta cells to high glucose challenge. Confocal and transmission electron microscopy were used to dissect ApoA-I mechanisms of action. Chemical endocytosis blockers were used to understand the role of ApoA-I internalization in mediating its positive effect. Pre-incubation of beta cells and isolated murine islets with ApoA-I augmented glucose stimulated insulin secretion. This effect appeared to be due to an increased reservoir of insulin granules at the cell membrane, as confirmed by confocal and transmission electron microscopy. Moreover, ApoA-I induced pancreatic and duodenal homeobox 1 (PDX1) shuttling from the cytoplasm to the nucleus, with the subsequent increase in the proinsulin processing enzyme protein convertase 1 (PC1/3). Finally, the blockade of ApoA-I endocytosis in beta cells resulted in a loss of ApoA-I positive action on insulin secretion. The proposed mechanisms of the phenomenon here described include ApoA-I internalization into beta cells, PDX1 nuclear translocation, and increased levels of proinsulin processing enzymes. Altogether, these events lead to an increased number of insulin granules.

DOI： 10.1016/j.bbadis.2019.165613

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell function and elucidate the role of riborepressor GAS5 lincRNA in the GC signaling pathway in human pancreatic beta cells. METHODS: Patients undergoing two weeks of high-dose prednisolone therapy were monitored for C-peptide levels. Human pancreatic islets and the human beta cell line EndoC-βH1 were incubated in pharmacological concentrations of dexamethasone. The GAS5 level was modulated using anti-sense LNA gapmeR or short oligonucleotides with GAS5 HREM (hormone response element motif). Immunoblotting and/or real-time PCR were used to assess changes in protein and RNA expression, respectively. Functional characterization included glucose-stimulated insulin secretion and apoptosis assays. Correlation analysis was performed on RNAseq data of human pancreatic islets. RESULTS: We found reduced C-peptide levels in patients undergoing high-dose GC therapy. Human islets and the human beta cell line EndoC-βH1 exposed to GC exhibited reduced insulin secretion and increased apoptosis. Concomitantly, reduced expression of important beta cell transcription factors, PDX1 and NKX6-1, as well as exocytotic protein SYT13 were observed. The expression of the glucocorticoid receptor was decreased, while that of serum and glucocorticoid-regulated kinase 1 (SGK1) was elevated. The expression of these genes was found to significantly correlate with GAS5 in human islet transcriptomics data. Increasing GAS5 levels using GAS5 HREM alleviated the inhibitory effects of dexamethasone on insulin secretion. CONCLUSIONS: The direct adverse effect of glucocorticoid in human beta cell function is mediated via important beta cell proteins and components of the GC signaling pathway in an intricate interplay with GAS5 lincRNA, a potentially novel therapeutic target to counter GC-mediated beta cell dysfunction.

DOI： 10.1016/j.molmet.2019.12.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/HYPOTHESIS: Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. METHODS: Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. RESULTS: Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.

DOI： 10.1007/s00125-019-05037-y

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The polygenic background of selectively bred diabetes models mimics the etiology of type 2 diabetes. So far, three different rodent models (Goto-Kakizaki rats, Nagoya-Shibata-Yasuda mice, and Oikawa-Nagao mice) have been established in the diabetes research field by continuous selective breeding for glucose tolerance from outbred rodent stocks. The origin of hyperglycemia in these rodents is mainly insulin secretion deficiency from the pancreatic β-cells and mild insulin resistance in insulin target organs. In this chapter, we summarize backgrounds and phenotypes of these rodent models to highlight their importance in diabetes research. Then, we introduce experimental methodologies to evaluate β-cell exocytosis as a putative common defect observed in these rodent models.

DOI： 10.1007/978-1-0716-0385-7_3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 21-year-old man presented with hyperthyroidism and hypokalemia and was treated for thyrotoxic hypokalemic periodic paralysis caused by Graves' disease. Thyroid function soon normalized but hypokalemia persisted. Laboratory data revealed hyperreninemic hyperaldosteronism and metabolic alkalosis consistent with Gitelman Syndrome. The patient was found to have a previously unreported compound heterozygous mutation of T180K and L858H in the SLC12A3 gene, and Gitelman Syndrome was diagnosed. He was started on eplerenone to control serum potassium level. Alternative diagnoses should be considered when electrolyte imbalances persist after disease resolution.

DOI： 10.1272/jnms.JNMS.2019_86-505

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Although metformin treatment has been reported to reduce the risk of cardiovascular events in patients with type 2 diabetes, the underlying mechanisms have not been elucidated fully. Here we assessed atherosclerotic lesion formation in newly established 2 mouse lines with different blood glucose levels (Oikawa-Nagao Diabetes-Prone [ON-DP] and -Resistant [ON-DR]) to evaluate the effect of metformin on early-stage atherosclerosis. METHODS: Mildly hyperglycemic ON-DP and normoglycemic ON-DR female mice fed an atherogenic diet for 20 weeks (8-28 weeks of age). During the feeding period, one group of each mouse line received metformin in drinking water (0.1%), while another group received water alone as control. Atherosclerotic lesion formation in the aortic sinus was quantitively analyzed from the oil red O-stained area of the serial sections. RESULTS: Metformin treatment did not affect food intake, body weight, and casual blood glucose levels within each mouse line during the 20-week feeding period. Nevertheless, metformin treatment significantly reduced atherosclerotic lesion formation in the ON-DP mice (59% of control), whereas no significant effect of metformin was observed in the lesion size of the ON-DR mice. CONCLUSION: Metformin can attenuate early-stage atherogenesis in mildly hyperglycemic ON-DP mice. Pleiotropic effects of metformin, beyond its glucose-lowering action, may contribute to the antiatherogenic property in the early-stage atherosclerosis.

DOI： 10.5551/jat.48223

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suitable for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as "housekeeping genes" in the context of hormone secretion. Despite the abundance and importance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR-152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electrical activity and Ca2+ -influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunction underlying T2D pathogenesis.

DOI： 10.1111/dom.13382

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/INTRODUCTION: A prolonged QT interval plays a causal role in life-threatening arrhythmia, and becomes a risk factor for sudden cardiac death. Here, we assessed the association between microvascular complications and the QT interval in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes (n = 219) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control were enrolled. QT interval was measured manually in lead II on the electrocardiogram, and corrected for heart rate using Bazett's formula (QTc). Diabetic neuropathy, retinopathy and nephropathy were assessed by neuropathic symptoms or Achilles tendon reflex, ophthalmoscopy and urinary albumin excretion, respectively. RESULTS: In univariate analyses, female sex (P = 0.025), duration of type 2 diabetes (P = 0.041), body mass index (P = 0.0008), systolic blood pressure (P = 0.0011) and receiving insulin therapy (P < 0.0001) were positively associated with QTc. Patients with each of the three microvascular complications had longer QTc than those without: neuropathy (P = 0.0005), retinopathy (P = 0.0019) and nephropathy (P = 0.0001). As retinopathy or nephropathy progressed, QTc became longer (P < 0.001 and P < 0.001 for trend in retinopathy and nephropathy, respectively). Furthermore, QTc was prolonged with the multiplicity of the microvascular complications (P < 0.001 for trend). Multiple regression analyses showed that neuropathy, nephropathy and the multiplicity of the microvascular complications were independently associated with QTc. CONCLUSIONS: Patients with type 2 diabetes with severe microvascular complications might be at high risk for life-threatening arrhythmia associated with QT interval prolongation.

DOI： 10.1111/jdi.12772

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Atherosclerosis Society  

AIM: We studied the frequency of Achilles tendon xanthoma (ATX) in patients with acute coronary syndrome (ACS). Furthermore, we investigated the differences in clinical findings between ACS patients with and without ATX. METHODS: Patients with ACS (n=335) were admitted to the coronary care unit of Nippon Medical School between July 2011 and December 2014. Informed consent for the measurement of Achilles tendon thickness (ATT) on a radiograph was obtained from 228 patients without tendon rupture. ATT of each side was measured on the radiograph in patients with ACS and in those with acromegaly (n=18), non-familial hypercholesterolemia (non-FH; n=96), and familial hypercholesterolemia (FH; n=31). RESULTS: ATT of the right and left side in ACS patients were 6.9±1.3 and 7.0±1.6 (mm; mean± SD). In acromegaly, non-FH, and FH patients, ATT of the right/left side were 6.6±1.1/6.7±1.1, 6.2±0.9/6.6±1.0, and 9.4±3.3/10.0±3.1, respectively. ATX (ATT ≥9 mm) was found in 26 (11.4%) patients with ACS. Patients with acromegaly and non-FH had no ATX, whereas all patients with FH had ATX. No differences in age and serum lipid profiles were observed between ACS patients with and without ATX. The levels of body mass index and glycated hemoglobin of ACS patients with ATX were significantly greater than those in ACS patients without ATX (26.8±4.0 vs. 23.9±3.3, p＜0.05, and 6.9±1.4% 6.3±1.3%, p＜0.05, respectively). CONCLUSION: This is the first report in which the frequency of ACS patients with ATX was 11.4%. The serum lipid profiles of ACS patients with ATX were similar to those without ATX. In the future, ACS patients with ATX will be diagnosed as having FH.

DOI： 10.5551/jat.37770

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記述言語：英語   出版者・発行元：SPRINGER  

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記述言語：英語   出版者・発行元：SPRINGER  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

AIM: The clinical significance of energy expenditure (EE) in the treatment of type 2 diabetes has not been fully elucidated. Here we analyzed the relationships between EE and clinical measurements in patients with type 2 diabetes receiving diet therapy. METHODS: A total of 100 patients (34 women and 66 men) with type 2 diabetes admitted to our hospital for glycemic control were enrolled. The participants received an energy-restricted diet during their hospitalization (median, 15 days). EE was measured in the fasted (FEE) and postprandial (PPEE) states using indirect calorimetry. The postprandial increment of EE (ΔEE) was calculated from the FEE and PPEE (ΔEE=PPEE-FEE). RESULTS: FEE, PPEE, and ΔEE were 0.997±0.203, 1.104±0.213, and 0.107±0.134 kcal/min, respectively. Body weight decreased from 68.7±16.6 to 66.8±16.0 kg (p＜0.0001) during hospitalization. FEE and PPEE showed positive correlations with height, body weight, body mass index, and abdominal circumference at admission, but ΔEE was not correlated with these anthropometric measurements. On the other hand, ΔEE was inversely correlated with the body weight change. The association between ΔEE and the body weight change was independent of age, sex, and HbA1c. CONCLUSIONS: Postprandial increase in energy expenditure may be a determinant of individual differences in weight reduction in patients with type 2 diabetes on diet therapy. As a simple surrogate for diet-induced thermogenesis, ΔEE may serve as a useful predictive marker for the efficacy of diet therapy.

DOI： 10.5551/jat.35303

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

MicroRNAs have emerged as important players of gene regulation with significant impact in diverse disease processes. In type-2 diabetes, in which impaired insulin secretion is a major factor in disease progression, dysregulated microRNA expression in the insulin-secreting pancreatic beta cell has been widely-implicated. Here, we show that miR-130a-3p, miR-130b-3p, and miR-152-3p levels are elevated in the pancreatic islets of hyperglycaemic donors, corroborating previous findings about their upregulation in the islets of type-2 diabetes model Goto-Kakizaki rats. We demonstrated negative regulatory effects of the three microRNAs on pyruvate dehydrogenase E1 alpha (PDHA1) and on glucokinase (GCK) proteins, which are both involved in ATP production. Consequently, we found both proteins to be downregulated in the Goto-Kakizaki rat islets, while GCK mRNA expression showed reduced trend in the islets of type-2 diabetes donors. Overexpression of any of the three microRNAs in the insulin-secreting INS-1 832/13 cell line resulted in altered dynamics of intracellular ATP/ADP ratio ultimately perturbing fundamental ATP-requiring beta cell processes such as glucose-stimulated insulin secretion, insulin biosynthesis and processing. The data further strengthen the wide-ranging influence of microRNAs in pancreatic beta cell function, and hence their potential as therapeutic targets in type-2 diabetes.

DOI： 10.1038/srep44986

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ENDOCRINE SOC  

The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.

DOI： 10.1507/endocrj.EJ16-0297

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記述言語：英語  

DOI： 10.1111/1346-8138.13265

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記述言語：英語   出版者・発行元：SPRINGER  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Accumulation of phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine, in blood plasma has been observed in various pathological conditions, including atherosclerosis. In this study, we investigated the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to develop a method for accurate quantification of PCOOH (1-palmitoyl-2-hydroperoxyoctadecadienoyl-sn-glycero-3-phosphocholine, 16:0/HpODE PC), focusing on isomers such as 16:0/13-HpODE PC and 16:0/9-HpODE PC. Sodiated PCOOH ([M+Na](+), m/z 812) provided not only a known product ion (m/z 147) but also characteristic product ions (m/z 541 for 16:0/13-HpODE PC and m/z 388 for 16:0/9-HpODE PC). Thus, three multiple reaction monitorings (MRMs) could be performed. MRM (812/147) enabled determination of 16:0/HpODE PC, and MRM (812/541) and MRM (812/388) allowed specific measurement of 16:0/13-HpODE PC and 16:0/9-HpODE PC, respectively. By using this method, we could determine plasma PCOOH concentrations in healthy subjects and patients with angiographically significant stenosis. In healthy subject and patient plasma, the concentration of 16:0/HpODE PC was close to the sum of the concentrations of 16:0/13-HpODE PC and 16:0/9-HpODE PC. This finding shows that radical and/or enzymatic oxidation, rather than singlet oxygen oxidation, is recognized to cause peroxidation of PC. The newly developed LC-MS/MS method appears to be a powerful tool for developing a better understanding of in vivo lipid peroxidation and its involvement in human diseases.

DOI： 10.1016/j.ab.2014.10.017

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ENDOCRINE SOC  

We recently established 2 mouse lines with different susceptibilities (prone and resistant) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R], respectively). In the present study, we analyzed transgenerational changes in metabolic phenotypes in these 2 mouse colonies to explore how the distinct phenotypes have emerged through the repetitive selection. Using C57BL/6, C3H, and AKR as background strains, mice showing inferior and superior glucose tolerance after HFD feeding were selected and bred repetitively over 20 generations to produce SDG-P and SDG-R, respectively. In addition to the blood glucose levels, HFD intake and body weight were also measured over the selective breeding period. As the generations proceeded, SDG-P mice became more susceptible to HFD-induced glucose intolerance and body weight gain, whereas SDG-R mice had gradually reduced HFD intake. The differences in fasting and post-glucose challenge blood glucose levels, body weight, and HFD intake became more evident between the 2 colonies through the selective breeding, mainly due to the HFD-induced glucose metabolism impairment and body weight gain in SDG-P mice and the reduction of HFD intake in SDG-R mice. These transgenerational changes in the metabolic phenotypes suggest that the genetic loci associated with the quantitative traits have been selectively enriched in SDG-P and SDG-R.

DOI： 10.1507/endocrj.EJ14-0241

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 66-year-old man with type 2 diabetes on hemodialysis treatment was admitted due to poor glycemic control. His serum insulin level and the (125)I-insulin binding rate were extremely high with an increased eosinophil count, although he did not have an allergic reaction to insulin or an elevation of specific IgE for human insulin. A Scatchard analysis revealed that the patient's insulin antibodies had a low affinity constant and a high binding capacity. Prednisolone administration decreased the eosinophil count and (125)I-insulin binding rate; accordingly, the glycemic control improved. Corticosteroid therapy may be a potent therapeutic strategy for insulin antibody-induced severe insulin resistance with eosinophilia.

DOI： 10.2169/internalmedicine.54.4022

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ENDOCRINE SOC  

The increase in the number of patients with diabetes has become a worldwide healthcare issue, with numbers predicted to reach approximately 600 million by 2035. In Asia-Pacific region, the prevalence of type 2 diabetes has increased dramatically in recent decades, of which the major causes are believed to be modern lifestyle changes, e.g., Western dietary pattern and reduced physical activity, on their genetic basis of lower insulin secretory capacity. Particularly, in East Asian countries, the amount of fat intake has increased nearly three-fold over this half of century; dietary fat appears to be the major culprit of type 2 diabetes pandemic in East Asia. However, convincing evidence has not yet been provided as to whether high-fat diet causes type 2 diabetes in epidemiological cohort studies. Here, we summarize clinical studies regarding fat intake and type 2 diabetes, and animal studies on high-fat diet-induced diabetes including our recent works on the novel mouse lines (selectively bred diet-induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R]) to address the etiology of high-fat diet-induced diabetes. These epidemiological and experimental findings would provide further insight into the etiology of type 2 diabetes under the modern nutritional environment, namely in the context of increased fat intake.

DOI： 10.1507/endocrj.EJ15-0055

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

BACKGROUND: A number of epidemiological studies demonstrated that postprandial hyperglycemia is a risk factor for cardiovascular disease in individuals with impaired glucose tolerance. Although several laboratory studies have addressed the plausible causal role of postprandial acute hyperglycemia (glucose spikes) in the development of atherosclerosis, there is little convincing evidence in vivo whether the atherosclerotic lesion formation can be accelerated solely by glucose spikes. Here, we assessed the effect of repetitive glucose spikes on atherosclerotic lesion formation in mice. METHODS: Female C57BL/6 mice were fed an atherogenic diet from 8 to 28 weeks of age. During the atherogenic diet feeding period, the mice orally received a glucose solution (50 mg glucose/mouse; G group) or water (W group) twice daily, 6 days a week. Atherosclerotic lesion formation in the aortic sinus was quantitatively analyzed in serial cross-sections by oil red O staining. RESULTS: G group mice showed transient increases in blood glucose level (~5 mmol/L above W group), and the levels returned to levels similar to those in W group mice within 60 min. No significant differences in glucose tolerance, insulin sensitivity, and plasma lipid profiles were observed after the 20-week repetitive administration between the 2 groups. G group mice showed an approximately 4-fold greater atherosclerotic lesion size in the aortic sinus than W group mice. Gene expression levels of Cd68 and Icam1 in the thoracic aorta were higher in G group mice than in W group mice. CONCLUSIONS: These results indicate that glucose spikes can accelerate atherosclerotic lesion formation, with little influence on other metabolic disorders. Repetitive glucose administration in wild-type mice may serve as a simple and useful approach to better understanding the causal role of glycemic spikes in the development of atherosclerosis.

DOI： 10.1371/journal.pone.0136840

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記述言語：英語   出版者・発行元：SPRINGER  

IF3.057

DOI： 10.1371/journal.pone.0084725

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jdi.12135

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Hereditary predisposition to diet-induced type 2 diabetes has not yet been fully elucidated. We recently established 2 mouse lines with different susceptibilities (resistant and prone) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-resistant [SDG-R] and -prone [SDG-P], respectively). To investigate the predisposition to HFD-induced glucose intolerance in pancreatic islets, we examined the islet morphological features and functions in these novel mouse lines. Male SDG-P and SDG-R mice were fed a HFD for 5 weeks. Before and after HFD feeding, glucose tolerance was evaluated by oral glucose tolerance test (OGTT). Morphometry and functional analyses of the pancreatic islets were also performed before and after the feeding period. Before HFD feeding, SDG-P mice showed modestly higher postchallenge blood glucose levels and lower insulin increments in OGTT than SDG-R mice. Although SDG-P mice showed greater β cell proliferation than SDG-R mice under HFD feeding, SDG-P mice developed overt glucose intolerance, whereas SDG-R mice maintained normal glucose tolerance. Regardless of whether it was before or after HFD feeding, the isolated islets from SDG-P mice showed impaired glucose- and KCl-stimulated insulin secretion relative to those from SDG-R mice; accordingly, the expression levels of the insulin secretion-related genes in SDG-P islets were significantly lower than those in SDG-R islets. These findings suggest that the innate predispositions in pancreatic islets may determine the susceptibility to diet-induced diabetes. SDG-R and SDG-P mice may therefore be useful polygenic animal models to study the gene-environment interactions in the development of type 2 diabetes.

DOI： 10.1371/journal.pone.0084725

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

OBJECTIVE: Impaired glucose tolerance (IGT) is an independent risk factor for atherosclerotic cardiovascular disease. However, due to the lack of appropriate animal models, the underlying mechanisms for IGT-induced atherosclerosis remain to be elucidated in vivo. We recently used selective breeding to establish 2 mouse lines with distinctively different susceptibilities to diet-induced glucose intolerance, designated selectively bred diet-induced glucose intolerance-resistant (SDG-R) and SDG-prone (SDG-P), respectively. Here, we assessed atherosclerotic lesion formation in these mice. METHODS: Female SDG-R and SDG-P mice were fed an atherogenic diet (AD; 1.25% cholesterol, 0.5% sodium cholate, and 36% energy as fat) for 20 weeks (8-28 weeks of age). Oral glucose tolerance tests were performed during the AD-feeding period. Atherosclerotic lesion formation was quantitatively analyzed in serial aortic sinus sections by oil red O staining. Plasma lipids were measured after the AD-feeding period. RESULTS: Glucose tolerance was impaired in SDG-P mice as compared to SDG-R mice over the 20-week AD-feeding period. No significant differences were observed in any plasma lipid measurement between the 2 mouse lines. Aortic sinus atherosclerotic lesion formation in SDG-P mice was approximately 4-fold greater than that in SDG-R mice. CONCLUSION: In 2 mouse lines with different susceptibilities to diet-induced glucose intolerance, IGT accelerated atherosclerotic lesion formation. These mice may therefore serve as useful in vivo models for investigating the causal role of IGT in the pathogenesis of atherosclerosis.

DOI： 10.1016/j.atherosclerosis.2013.10.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AIMS/INTRODUCTION: Postprandial hyperglycemia is a potent risk factor for cardiovascular disease. Serum glycated albumin (GA) has been reported to reflect postprandial blood glucose fluctuations. In the present study, we assessed the possible correlation of GA with the presence of carotid plaque to evaluate the potential clinical usefulness of GA for predicting atherosclerotic cardiovascular complications in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes (n = 236) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control (aged 19-86 years, 81 females and 155 males) were examined. Clinical measurements were taken on admission. The presence of carotid plaque was assessed by ultrasonography. RESULTS: In patients with carotid plaque (n = 154), GA (P = 0.023) was higher than those without carotid plaque (n = 82). In contrast, neither fasting plasma glucose (P = 0.48) nor glycated hemoglobin (P = 0.41) was significantly different between the groups. The results of logistic regression analysis showed that GA (age- and sex-adjusted odds ratio [95% confidence interval], 1.05 [1.01-1.09]; P = 0.017) and glycated hemoglobin (1.17 [1.01-1.37]; P = 0.036) were significantly associated with the presence of carotid plaque. CONCLUSIONS: The positive correlation of serum GA with the presence of carotid plaque in type 2 diabetes suggests that GA will serve as a useful clinical marker for predicting diabetic cardiovascular complications.

DOI： 10.1111/jdi.12085

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記述言語：英語   出版者・発行元：SPRINGER  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1111/jdi.12022

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

UNLABELLED: Aims/Introduction:  The development of type 2 diabetes is primarily due to lifestyle and environmental factors, as well as genetics, as shown by familial clustering. To establish mouse lines for evaluating heritable factors determining susceptibility to diet-induced diabetes, we performed selective breeding for differences in high fat diet (HFD)-induced glucose intolerance. MATERIALS AND METHODS:   Selective breeding was performed using hybrid mice of C57BL/6J, C3H/HeJ and AKR/N backgrounds. After 5-week HFD feeding, mice showing high and low 2-h blood glucose levels in an oral glucose tolerance test (OGTT) were selected and bred over 14 generations to produce lines prone and resistant to diet-induced glucose intolerance (designated Selectively bred Diet-induced Glucose intolerance-Prone [SDG-P] and -Resistant [SDG-R]). RESULTS:   At 5 weeks of age (pre HFD feeding), SDG-P mice showed higher blood glucose levels both in the OGTT and insulin tolerance test as compared to SDG-R mice. After receiving HFD, the glucose intolerance of SDG-P mice became more evident without hyper insulin secretion. In addition, SDG-P mice had greater body weight gain and lower HDL-cholesterol levels as compared to SDG-R mice. In comparison with C57BL/6J, a well-known strain prone to HFD-induced glucose intolerance, SDG-P mice showed significantly higher glucose levels in OGTT after the 5-week HFD feeding. CONCLUSIONS:   Susceptibility to HFD-induced glucose intolerance was transmitted over generations and was intensified by selective breeding. The newly established mouse lines, SDG-P and SDG-R, may be useful in investigating the pathophysiology of type 2 diabetes through elucidating the crucial factors for determining the susceptibility to HFD-induced glucose intolerance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00175.x, 2011).

DOI： 10.1111/j.2040-1124.2011.00175.x

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記述言語：英語   出版者・発行元：SPRINGER  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Increasing evidence indicates that phospholipid oxidation plays important roles in atherosclerosis. Here, we investigated the involvement of Rho-family GTPases inphosphatidylcholine hydroperoxide (PCOOH)-induced THP-1 cell adhesion to ICAM-1. Isoprenoid depletion by fluvastatin and geranylgeranyltransferase inhibition by GGTI-286 suppressed PCOOH-induced cell adhesion to ICAM-1 and F-actin-rich membrane protrusion formation. Pull-down assays demonstrated the activation of Rac1 and Rac2 in PCOOH-treated cells. Pan-Rho-family GTPase inhibitor Clostridium difficile toxin B, Rac-specific inhibitor NSC23776, and RNA interference of the Rac isoforms suppressed the cell adhesion. These findings indicate the involvement of Rac GTPase activation in PCOOH-induced cell adhesion to ICAM-1 via actin reorganization.

DOI： 10.1016/j.bbrc.2011.02.032

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

AIM: We investigated how dietary management affected body weight (BW) reduction and energy expenditure in obese and normal-weight type 2 diabetic patients. METHODS: Type 2 diabetic patients who were hospitalized for diabetic control (93 men and 51 women) were checked for resting energy expenditure (REE). Subjects were divided into the two groups according to body mass index (BMI): obese (BMI > or = 25), and normal-weight (BMI <25). Following the recommendations by JDS, JAS and JASSO, ideal body weight was calculated as [IBW=height (m) x height (m) x 22 (kg/m(2))], and dietary calorie (kcal/day) was determined as 25 kcal/kg IBW. RESULTS: Dietary calorie intake during hospitalization was similar in both groups. REE was greater in obese than in normal-weight patients. The difference between the calorie intake and energy expenditure (Deltacalorie) was -222+/-26 kcal in obese patients and 69+/-27 kcal in normal-weight patients. Obese patients therefore had larger BW decreases than normal-weight patients (-171+/-12 vs. -92+/-11 g/day, p<0.005). In the obese group, a positive correlation was found between the change of BW and Deltacalorie. This correlation remained after adjusting for age, BMI, gender, and respiratory quotient. Serum lipid profiles were significantly improved in both groups. CONCLUSION: These diet instructions showed the appropriate calorie restriction depending on the BMI and induced reasonable BW reduction in both obese and normal-weight subjects. The dietary program recommended by JDS, JAS and JASSO is practically useful for BW control and for improving lipid metabolism in type 2 diabetic patients.

DOI： 10.5551/jat.3806

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Insulin tolerance test (ITT) is the gold standard for assessing the hypothalamic-pituitary-adrenal (HPA) function. GH-releasing peptide (GHRP)-2, which has a strong GH-stimulating activity, is useful for diagnosing GH deficiency as well as ITT. Additionally, GHRP-2 is also known to activate HPA axis. There have been no comparative studies of pituitary-adrenal responsiveness between GHRP-2 test and ITT in patients with hypothalamic/pituitary disease. To assess whether GHRP-2 test could be an alternative to ITT for diagnosing HPA axis failure, both ITT and GHRP-2 test were performed in 15 patients suspected of hypopituitarism. A 100mug dose of GHRP-2 was administered intravenously and plasma ACTH and serum cortisol concentrations were measured. In ITT, a peak cortisol value over 18mug/dl is considered normal. Nine patients were diagnosed as HPA axis failure by ITT. Their median peak cortisol in GHRP-2 test was 11.4mug/ml. In 6 patients diagnosed as normal HPA axis status by ITT, their median peak cortisol in response to GHRP-2 test was 21.4mug/dl, significantly higher (p=0.0032) than seen in patients diagnosed as HPA axis failure. There was a strong correlation between the peak cortisol in GHRP-2 test and ITT (r=0.817; p<0.0001). When the cut-off value for the peak cortisol in GHRP-2 test was set to 13-14mug/dl for diagnosing HPA axis failure, the specificity and sensitivity were 100% and 88.9%, respectively. Although further studies that include normal subjects are needed, these preliminary results suggest the possibility that GHRP-2 test may be an alternative to ITT for assessing HPA axis function.

DOI： 10.1016/j.peptides.2009.12.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The accumulation of phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine (PC), in blood plasma and tissues has been observed in various pathological conditions, including atherosclerosis. However, the biological roles of PCOOH in these conditions remain unknown. To estimate the atherogenicity of PCOOH, we evaluated the effect of PCOOH on THP-1 monocytic cell adherence to immobilized vascular endothelial cell adhesion molecules. THP-1 cell adhesion to intracellular adhesion molecule-1 (ICAM-1) was dose-dependently increased by addition of PCOOH. Phosphatidylcholine hydroxide (a hydroxyl analog of PCOOH) also induced THP-1 cell adhesion to ICAM-1, whereas nonoxidized PC, sn-2 truncated PCs, and other hydroperoxide compounds did not affect the adhesion. In the PCOOH-treated cells, obvious protruding F-actin-rich membrane structures were formed, and lymphocyte function-associated antigen-1 (LFA-1) was localized to the protruding structures. Cytochalasin D, an actin polymerization inhibitor, suppressed the PCOOH-induced cell adhesion to ICAM-1 and the membrane protrusions. These results indicate that PCOOH evokes LFA-1-mediated cell adhesion to ICAM-1 via actin cytoskeletal organization, and the mechanism may participate in monocyte adherence to the arterial wall in the initiation of atherosclerosis.

DOI： 10.1194/jlr.M800582-JLR200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Aims: The atherogenicity of chylomicron remnants has been discussed. We examined whether serum apoB48 level is associated with the presence of carotid plaque in type 2 diabetic patients.
Method: Forty type 2 diabetic patients (21 males and 19 females, 52.8 +/- 11.8 years old; mean +/- S.D.) were divided into two groups by the presence or absence of carotid plaque. The diurnal change of serum apoB48 level was measured by enzyme-linked immunosorbent assay.
Results: Fasting serum apoB48 level was higher in the subjects with carotid plaque than those without (6.5 +/- 3.8 vs. 4.1 +/- 1.9 mu g/ml, p = 0.01). Age- and gender-adjusted analysis showed that the presence of carotid plaque was associated with fasting apoB48 (OR 1.43; 95% CI, 1.07-2.09, p = 0.04) and triglyceride (OR 1.14; 95% CI, 1.02-1.32, p = 0.04) levels. In normal LDL-cholesterol (&lt;140 mg/dl) subjects, the presence of carotid plaque was associated with fasting apoB48 level (OR 2.16; 95% CI, 1.22-5.32, p = 0.04), but not associated with fasting triglyceride level (OR 1.11; 95% CI, 0.99-1.30, p = 0.13).
Conclusions: Serum apoB48 level was strongly associated with the presence of carotid plaque in type 2 diabetic patients. (C) 2008 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.diabres.2008.04.028

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公社)日本医師会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞Point ◎低血糖を契機に発見される内分泌疾患には,インスリノーマ,下垂体機能低下症,副腎皮質機能低下症などがある.◎上記が否定された場合には,大分子量IGF-IIを産生する膵外腫瘍などの非膵島細胞腫瘍性低血糖症(NICTH)の可能性もある.◎専門医への紹介を検討する際には,低血糖発作時に採血した血液中でのインスリンやその拮抗ホルモンの測定結果があることが望ましい.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01440&link_issn=&doc_id=20210804040009&doc_link_id=10.11477%2Fmf.1402227751&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1402227751&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)医学出版  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公社)日本栄養・食糧学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(公社)日本ビタミン学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(公社)日本栄養・食糧学会  

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記述言語：日本語   出版者・発行元：(公社)日本栄養・食糧学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（その他）  

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記述言語：日本語   出版者・発行元：日本肥満症治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

ミトコンドリア遺伝子3243A-G変異を呈するミトコンドリア糖尿病は遺伝子異常が同定された糖尿病の中では最も頻度が高い。低身長、やせの体型を呈し、糖尿病診断時年齢が比較的若年であり、糖尿病の母系遺伝を認め、感音性難聴等が合併する頻度が高いと言われているが、日常診療で見過ごされている例も少なくない。今回我々はミトコンドリア遺伝子3243A-G変異を呈したミトコンドリア糖尿病の3症例を経験した。その3症例は全て軽度〜高度の感音性難聴の合併を認めたが、肥満の症例や糖尿病の母系遺伝が明らかではない症例があり、その臨床像は陽性、陰性所見が混在していた。ミトコンドリア糖尿病の臨床像は多彩ではあるが、糖尿病に加えて感音性難聴や難聴の家族歴を有している症例には、ミトコンドリア遺伝子変異の検査等の積極的な検索を行う事が望ましいと思われた。(著者抄録)

DOI： 10.11213/tonyobyo.59.421

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00926&link_issn=&doc_id=20160824280004&doc_link_id=10.11213%2Ftonyobyo.59.421&url=https%3A%2F%2Fdoi.org%2F10.11213%2Ftonyobyo.59.421&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：日本語   出版者・発行元：(公社)日本栄養・食糧学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公社)日本栄養・食糧学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公社)日本油化学会  

糖尿病患者数の増加は世界的な問題となっており、2035年にはおよそ6億人に到達すると予想されている。特にアジア太平洋地域での2型糖尿病患者数の増加は顕著であり、アジア人特有の低インスリン分泌能という遺伝的背景に加えて、食習慣の欧米化や身体活動量の低下といった生活環境の変化がその主因と考えられている。本邦を含む、東アジア諸国では脂肪摂取量が半世紀で約3倍に増加しているが、脂肪摂取量の増加が2型糖尿病の発症を増加させるか否かについては現在も一定した見解は得られていない。本稿では、脂肪摂取と2型糖尿病発症に関する臨床的・基礎的な知見を整理すると共に、筆者らが選抜交配により作出した高脂肪食投与時の耐糖能が異なる新規モデルマウスの解析結果を紹介し、脂肪摂取量の増加という現代の食環境下での2型糖尿病発症を決定する要因について考察したい。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J03681&link_issn=&doc_id=20150202450003&doc_link_id=10.5650%2Foleoscience.15.69&url=https%3A%2F%2Fdoi.org%2F10.5650%2Foleoscience.15.69&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：日本医科大学医学会  

DOI： 10.1272/manms.10.210

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

DOI： 10.1272/manms.10.162

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J04260&link_issn=&doc_id=20141024470001&doc_link_id=%2Fcw1nimed%2F2014%2F001004%2F002%2F0162-0163%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw1nimed%2F2014%2F001004%2F002%2F0162-0163%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(株)北隆館  

グリコアルブミン(GA)は本邦で測定法が開発された血糖変動指標であり、過去2〜3週間の平均血糖値を反映する。GAは糖尿病診療で広く用いられているグリコヘモグロビン(HbA1c)に比べて、より短期の血糖変動や食後高血糖を反映することから、介入早期や治療薬変更後の効果判定に利用されると共に、HbA1cが不正確となる貧血、腎不全、妊娠といった病態においても、GAを血糖管理指標として代用することが可能である。また最近の研究から、GAやGA/HbA1c比を用いた糖尿病の病型推定や大血管障害のサロゲートマーカーとしての活用も注目されている。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ENDOCRINE SOC  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

内臓脂肪の蓄積に伴いインスリン抵抗性が惹起され耐糖能異常をもたらす.中高年女性の耐糖能異常にはエストロゲンの作用が関与している可能性が示唆されている.女性は閉経後に心血管疾患発症リスクが上昇し,特に糖尿病罹患者ではリスクが高くなるといわれている.(著者抄録)

DOI： 10.11477/mf.1409103634

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J01564&link_issn=&doc_id=20140416260005&doc_link_id=10.11477%2Fmf.1409103634&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1409103634&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：社団法人日本循環器学会  

CiNii Books

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本臨床生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01759&link_issn=&doc_id=20130806180008&doc_link_id=issn%3D0289-8020%26volume%3D34%26issue%3D7%26spage%3D931&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0289-8020%26volume%3D34%26issue%3D7%26spage%3D931&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

脂質異常症の診断は血清脂質の測定に始まる.健診や日常診療において簡便に測定できる血清脂質検査は総コレステロール(TC),HDLコレステロール(HDL-C)および中性脂肪[トリグリセリド(TG)]である.本稿ではこれら3種類の脂質を「一般脂質」と定義した.TCはすべてのリポ蛋白^注1)に含まれるコレステロールの総量である.これらの濃度変化は,リポ蛋白の合成と異化・分解のバランスの結果である.臨床の場でリポ蛋白分析やアポ蛋白測定を頻繁に行うのは現実的ではない.基本的なリポ蛋白代謝の流れ(図1)を正しく理解したうえで,一般脂質の異常からリポ蛋白代謝異常症の実態を考えて診療することが重要である.この理解は治療薬の選択に通じる.本稿では一般脂質の測定について概説し,その結果から考えられる病態の鑑別方法について解説する.(著者抄録)

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

症例は76歳男性。20年前に糖尿病と診断され経口血糖降下薬で加療されていたが、2009年7月に血糖コントロール不良のため前医へ入院しインスリンアナログ製剤による治療が開始された。退院後から低血糖が頻回となり、総インスリン値11000μU/ml、125Iインスリン結合率89.5%とインスリン抗体による低血糖が疑われた。Scatchard解析の結果はhigh-affinity siteの親和性が低く、結合能が高い、インスリン自己免疫症候群(IAS)に類似した抗体であった。持続血糖モニター(CGM)にて早朝と昼食後に再現性のある血糖低下を認めたため、その結果に基づいてインスリン調節や療養指導を行ったところ血糖変動パターンは改善した。インスリン抗体によって血糖コントロールが不安定化した糖尿病ではインスリン作用時間の予測がつきにくく治療に難渋することが多いが、CGMによる介入が血糖コントロールの安定化に有用であることを示唆する貴重な1例と考えられたため報告する。(著者抄録)

DOI： 10.11213/tonyobyo.55.874

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00926&link_issn=&doc_id=20121210370008&doc_link_id=10.11213%2Ftonyobyo.55.874&url=https%3A%2F%2Fdoi.org%2F10.11213%2Ftonyobyo.55.874&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床栄養協会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

DOI： 10.2169/naika.101.2180

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01159&link_issn=&doc_id=20120815100003&doc_link_id=10031130597&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F10031130597&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)総合医学社  

＜point＞●インスリン抗体陽性の糖尿病では、出現したインスリン抗体の性質によって、インスリン抵抗性をきたす場合と頻回な低血糖を起こす場合がある。●頻回な低血糖を起こすインスリン抗体は、インスリン自己免疫症候群と類似した性質をもつことが知られており、血糖変動は、夜間から早朝にかけての血糖の低下と日中の高血糖が特徴とされている。●インスリン抗体陽性の糖尿病では、投与したインスリンが抗体に干渉されて作用時間の予測がつきにくく、CGMによる血糖変動パターンの把握が大変有用だと考えられる。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

本研究ではマウスを用いて高脂肪食で誘発される耐糖能異常を指標として高血糖値を示す個体の選抜交配を繰り返し、高脂肪食により糖代謝異常を惹起する因子が継代によって濃縮され、病態の出現が促進される系統の樹立を目標とした。その結果、高脂肪食負荷後の血糖値を指標とした選抜交配により、次世代の糖代謝異常出現率が増加しており、高脂肪食に対する反応性が形質として濃縮され次世代に伝播したと考えられた。更に高脂肪食負荷前の5週齢で既に耐糖能異常を呈していることから、選抜交配による糖代謝異常が系統的に確立されたと考えられた。また高脂肪食負荷前の5週齢雄では体重に差がみられないことから、糖代謝異常は肥満に先行して出現していると考えられた。以上より、今後、高血糖コロニーと正常血糖コロニーの差を更に検討することにより高脂肪食が肥満・糖尿病の発症に影響する遺伝子を解明できると考えられた。

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)ライフ・サイエンス  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本肥満症治療学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：日本肥満症治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

63歳女性。患者は数ヵ月前より肝機能障害で経口グリチルリチン酸製剤が開始された。しかし、その後、心拍動を強く感じるようになり、全身倦怠感をはじめ、脱力感の増強で自宅にて転倒、5時間後に発見され、著者らの施設へ救急搬送された。心電図では心拍数82回/分、不整、心室性期外収縮、QT延長、T波平低化、U波を認め、血清カリウムの著明低化と尿中カリウムの上昇を認めた。また、内分泌検査ではレニン活性、アルドステロンとも測定感度以下であった。以上より、低カリウム血症の原因はグリチルリチン酸による偽性アルドステロン症と診断されたが、その一方でCKおよびミオグロビンの著明上昇が認められ、甲状腺機能検査によりTSHの上昇が確認され、本症例は甲状腺機能低下症と診断された。治療としてグリチルリチン酸製剤の中止、カリウム製剤投与、更にカリウム保持性利尿薬の併用で脱力発作は軽快し、あわせて血清カリウム値、TSHは徐々に正常化した。

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(株)メジカルビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：毎日新聞出版(株)  

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