研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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L-Carnitine improves gastrointestinal disorders and altered the intestinal microbiota in hemodialysis patients

Irie, J., Kanno, Y., Kikuchi, R., Yoshida, T., Murai, S., Watanabe, M., Itoh, H. and Hayashi, M.

Biosci Microbiota Food Health 36 （ 1 ） 11 - 16 2017年

ISSN 2186-6953

Patients receiving hemodialysis also manifest gastrointestinal symptoms, such as constipation, caused by restriction of water intake and the loss of body water balance. Because dietary carnitine deficiency is considered to cause smooth muscle dysmotility of the gastrointestinal tract similarly to that in skeletal muscles, carnitine deficiency in hemodialysis patients may be one cause of gastrointestinal discomfort and dysfunctions. We performed a multicenter nonrandomized single-arm prospective clinical trial. Fifteen Japanese patients receiving hemodialysis were administered L-carnitine tablets (900 mg) for 3 months, and clinical and biochemical analyses were performed before and after treatment. The serum total carnitine level was increased significantly by supplementation with L-carnitine for 3 months (from 40.9 +/- 2.6 mumol/l to 172.3 +/- 19.0 mumol/l, p<0.05). The myasthenia score was decreased significantly by the supplementation (from 1.3 +/- 0.3 to 0.8 +/- 0.2, p<0.05). The frequency of passing stool tended to increase with the treatment for 3 months (from 4.2 +/- 0.5 times/week to 4.8 +/- 0.5 times/week). A phyla-level analysis of the microbiota showed that the composition of the individual microbiota was not different between before and after supplementation. A genus-level analysis, however, revealed that the relative abundance of genus Clostridium subcluster 4 was significantly decreased by the supplementation (from 7.7 +/- 1.9% to 4.7 +/- 1.3%, p<0.05). Oral supplementation of L-carnitine to the patients receiving hemodialysis improved not only their muscle discomfort but also their gastrointestinal disorders and microbiota, although its effect on the prognosis of hemodialysis patients should be further investigated.

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[Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).]

Irie, J. and Itoh, H.

Clin Calcium 27 （ 7 ） 983 - 990 2017年

ISSN 0917-5857

Sirtuins are NAD+-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD+ decline during the aging process, the approach to regulating aging using NAD+ precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD+ through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed.

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Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese

Fujii, C., Kawai, T., Azuma, K., Oguma, Y., Katsukawa, F., Hirose, H., Tanaka, K., Meguro, S., Matsumoto, H. and Itoh, H.

J Diabetes Res 2017 1567467 2017年

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

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One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes.

Nojima J, Meguro S, Ohkawa N, Furukoshi M, Kawai T, Itoh H

Proceedings of the Japan Academy. Series B, Physical and biological sciences 93 （ 9 ） 746 - 754 2017年

ISSN 0386-2208

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Generation of kidney tubular organoids from human pluripotent stem cells

Yamaguchi, S., Morizane, R., Homma, K., Monkawa, T., Suzuki, S., Fujii, S., Koda, M., Hiratsuka, K., Yamashita, M., Yoshida, T., Wakino, S., Hayashi, K., Sasaki, J., Hori, S. and Itoh, H.

Sci Rep 6 38353 2016年12月

ISSN 2045-2322

Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3beta inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.

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Nonalbuminuric Renal Insufficiency: Can It Be a Novel Category of Diabetic Nephropathy?

Tanaka, M. and Itoh, H.

Endocrinol Metab (Seoul) 31 （ 4 ） 533 - 534 2016年12月

ISSN 2093-596X

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Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

Futatsugi, K., Tokuyama, H., Shibata, S., Naitoh, M., Kanda, T., Minakuchi, H., Yamaguchi, S., Hayashi, K., Minamishima, Y. A., Yanagita, M., Wakino, S. and Itoh, H.

Sci Rep 6 36533 2016年11月

ISSN 2045-2322

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

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Corrigendum to "Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia" [YPLAC 37C (2016) 72-78]

Nartita, T., Ichihara, A., Matsuoka, K., Takai, Y., Bokuda, K., Morimoto, S., Itoh, H. and Seki, H.

Placenta 47 130 2016年11月

ISSN 0143-4004

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The role of short-chain fatty acid on blood pressure regulation

Miyamoto, J., Kasubuchi, M., Nakajima, A., Irie, J., Itoh, H. and Kimura, I.

Curr Opin Nephrol Hypertens 25 （ 5 ） 379 - 83 2016年09月

ISSN 1062-4821

PURPOSE OF REVIEW: The gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. RECENT FINDINGS: Olfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein-coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SUMMARY: The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases.

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Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner

Kawano, Y., Nakae, J., Watanabe, N., Kikuchi, T., Tateya, S., Tamori, Y., Kaneko, M., Abe, T., Onodera, M. and Itoh, H.

Cell Metab 24 （ 2 ） 295 - 310 2016年08月

ISSN 1550-4131

High-fat diet (HFD) induces low-grade chronic inflammation and insulin resistance. However, little is known about the mechanism underlying HFD-induced chronic inflammation in peripheral insulin-responsive tissues. Here, we show that colonic pro-inflammatory macrophages regulate insulin sensitivity under HFD conditions. To investigate the pathophysiological role of colonic macrophages, we generated macrophage-specific chemokine (C-C Motif) receptor 2 (Ccr2) knockout (M-Ccr2KO) and intestinal epithelial cell-specific tamoxifen-inducible Ccl2 knockout (Vil-Ccl2KO) mice. Both strains exhibited similar body weight to control under HFD. However, they exhibited decreased infiltration of colonic pro-inflammatory macrophages, decreased intestinal permeability, and inactivation of the colonic inflammasome. Interestingly, they showed significantly improved glucose tolerance and insulin sensitivity with decreased chronic inflammation of adipose tissue. Therefore, inhibition of pro-inflammatory macrophage infiltration prevents HFD-induced insulin resistance and could be a novel therapeutic approach for type 2 diabetes.

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Dysbiosis in the Pathophysiology of Coronary Artery Disease

Irie, J. and Itoh, H.

J Atheroscler Thromb 23 （ 8 ） 901 - 2 2016年08月

ISSN 1340-3478

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Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial

Ueshima, K., Itoh, H., Kanazawa, N., Komuro, I., Nagai, R., Takeuchi, M. and Yamazaki, T.

J Atheroscler Thromb 23 （ 8 ） 976 - 90 2016年08月

ISSN 1340-3478

AIM: Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease (CVD). The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examines whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy, but without a history of coronary artery disease. METHODS: Patients who had elevated low-density lipoprotein cholesterol (LDL-C) and diabetic retinopathy without a history of coronary artery disease were eligible for the study. Patients were randomly assigned in a 1:1 ratio to receive intensive or standard therapy. Patients are being treated with monotherapy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) for a maximum of 5.5 years to achieve the following LDL-C target: 70 mg/dL for the intensive therapy group or >/=100 and 120 mg/dL for the standard therapy group. The primary endpoint is a composite of incidence of CVD and death from CVD. RESULTS: Between May 2010 and October 2013, 5,995 patients were assessed for eligibility, and 5,144 were assigned to the study treatment (2,571 and 2,573 in the intensive and standard therapy groups, respectively), and baseline data were analyzed from 5,107 (2,550 in the intensive therapy group and 2,557 in the standard therapy group). CONCLUSIONS: This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. Furthermore, this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003486.

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Effects of Obesity and Diabetes on alpha- and beta-Cell Mass in Surgically Resected Human Pancreas

Inaishi, J., Saisho, Y., Sato, S., Kou, K., Murakami, R., Watanabe, Y., Kitago, M., Kitagawa, Y., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 101 （ 7 ） 2874 - 82 2016年07月

ISSN 0021-972

CONTEXT: The ethnic difference in beta-cell regenerative capacity in response to obesity may be attributable to different phenotypes of type 2 diabetes among ethnicities. OBJECTIVE: This study aimed to clarify the effects of diabetes and obesity on beta- (BCM) and alpha-cell mass (ACM) in the Japanese population. DESIGN, SETTING, AND PARTICIPANTS: We obtained the pancreases of 99 individuals who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis. Questionnaires on a family history of diabetes and history of obesity were conducted in 59 patients. Pancreatic sections were stained for insulin or glucagon, and fractional beta- and alpha-cell area were measured. Islet size and density as well as beta-cell turnover were also quantified. RESULTS: In patients with diabetes, BCM was decreased by 46% compared with age- and body mass index-matched nondiabetic patients (1.48% +/- 1.08% vs 0.80% +/- 0.54%, P < .001), whereas there was no difference in ACM between the groups. There was no effect of obesity or history of obesity on BCM and ACM irrespective of the presence or absence of diabetes. There was a negative correlation between BCM, but not ACM, and glycated hemoglobin before and after pancreatic surgery. In addition, reduced BCM was observed in patients with pancreatic cancer compared with those with other pancreatic tumors. CONCLUSIONS: These findings suggest that the increase in BCM in the face of insulin resistance is extremely limited in the Japanese, and BCM rather than ACM has a major role in regulating blood glucose level in humans.

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Combination of 5-aminolevulinic acid and ferrous ion reduces plasma glucose and hemoglobin A1c levels in Zucker diabetic fatty rats

Hara, T., Koda, A., Nozawa, N., Ota, U., Kondo, H., Nakagawa, H., Kamiya, A., Miyashita, K., Itoh, H., Nakajima, M. and Tanaka, T.

FEBS Open Bio 6 （ 6 ） 515 - 28 2016年06月

ISSN 2211-5463

Mitochondrial dysfunction is associated with type 2 diabetes mellitus (T2DM). 5-Aminolevulinic acid (ALA), a natural amino acid produced only in the mitochondria, is a precursor of heme. Cytochromes that contain heme play an important role in aerobic energy metabolism. Thus, ALA may help reduce T2DM-associated hyperglycemia. In this study, we investigated the effect of ALA combined with sodium ferrous citrate (SFC) on hyperglycemia in Zucker diabetic fatty (ZDF) rats. We found that the gavage administration of ALA combined with SFC (ALA/SFC) for 6 weeks reduced plasma glucose and hemoglobin A1c (HbA1c) levels in rats without affecting plasma insulin levels. The glucose-lowering effect depended on the amount of ALA/SFC administered per day. Furthermore, the glucose tolerance was also significantly improved by ALA/SFC administration. Although food intake was slightly reduced in the rats administered ALA/SFC, there was no effect on their body weight. Importantly, ALA/SFC administration induced heme oxygenase-1 (HO-1) expression in white adipose tissue and liver, and the induced expression levels of HO-1 correlated with the glucose-lowering effects of ALA/SFC. Taken together, these results suggest that ALA combined with ferrous ion is effective in reducing hyperglycemia of T2DM without affecting plasma insulin levels. HO-1 induction may be involved in the mechanisms underlying the glucose-lowering effect of ALA/SFC.

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miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype

Morizane, R., Fujii, S., Monkawa, T., Hiratsuka, K., Yamaguchi, S., Homma, K. and Itoh, H.

Clin Exp Nephrol 20 （ 3 ） 394 - 401 2016年06月

ISSN 1342-1751

BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

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The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats

Minakuchi, H., Wakino, S., Hosoya, K., Sueyasu, K., Hasegawa, K., Shinozuka, K., Yoshifuji, A., Futatsugi, K., Komatsu, M., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 31 （ 3 ） 413 - 23 2016年03月

ISSN 0931-0509

BACKGROUND: The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS). METHODS: Six-week-old Sprague-Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham-operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated. RESULTS: In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed. CONCLUSIONS: In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions.

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Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats

Yoshifuji, A., Wakino, S., Irie, J., Tajima, T., Hasegawa, K., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 31 （ 3 ） 401 - 12 2016年03月

ISSN 0931-0509

BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 x 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.

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Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice

Morimoto, K., Watanabe, M., Sugizaki, T., Irie, J. and Itoh, H.

Endocrinology 157 （ 3 ） 1071 - 81 2016年03月

ISSN 0013-7227

Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

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Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia

Nartita, T., Ichihara, A., Matsuoka, K., Takai, Y., Bokuda, K., Morimoto, S., Itoh, H. and Seki, H.

Placenta 37 72 - 8 2016年01月

ISSN 0143-4004

INTRODUCTION: The prorenin receptor ((P)RR) contributes to the regulation of the tissue renin-angiotensin system (RAS) and the function of V-ATPase, which are essential for Wnt signaling. Thus, (P)RRs may be involved in the control both of feto-placental and maternal circulation during pregnancy. This study was conducted to clarify how placental (P)RR expression and plasma soluble (P)RR [s(P)RR] levels are associated with blood pressure elevations and renal function during pregnancy. METHODS: We conducted a cross-sectional study, conducted at Saitama medical center in 2010-2013. Preeclamptic women (n = 16) diagnosed according to the criteria of Japan Society of Obstetrics and Gynecology and normotensive pregnant women (n = 15) participated in the study. We measured the expression of (P)RR in the placenta, plasma s(P)RR levels, systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR). RESULTS: Placental expression of (P)RR was significantly higher in preeclamptic women than in normotensive pregnant women. The plasma s(P)RR levels were significantly higher in preeclamptic women than in normotensive pregnant women. Systolic blood pressure (SBP) was positively correlated with placental (P)RR levels (P = 0.0001) and plasma s(P)RR levels (P = 0.005) in all pregnant women. In preeclamptic women, SBP was positively correlated with placental (P)RR levels (P = 0.004), but not with plasma s(P)RR levels (P = 0.15). The eGFR was negatively correlated with placental (P)RR levels (P = 0.02) and plasma s(P)RR levels (P = 0.0002) in all pregnant women. In preeclamptic women, eGFR was negatively correlated with plasma s(P)RR levels (P = 0.006), but not with placental (P)RR levels (P = 0.93). DISCUSSION: Placental (P)RR can be involved in blood pressure regulation via the tissue RAS. On the other hand, plasma s(P)RR may be involved in the pathogenesis of decreased renal function in preeclampsia.

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Time-dependent changes in insulin requirement for maternal glycemic control during antenatal corticosteroid therapy in women with gestational diabetes: a retrospective study

Itoh, A., Saisho, Y., Miyakoshi, K., Fukutake, M., Kasuga, Y., Ochiai, D., Matsumoto, T., Tanaka, M. and Itoh, H.

Endocr J 63 （ 1 ） 101 - 4 2016年

ISSN 0918-8959

Though recommended for pregnant women at risk of preterm birth to improve perinatal outcomes, antenatal corticosteroid (ACS) treatment can cause maternal hyperglycemia, especially in cases of glucose intolerance. A standardized protocol for preventing hyperglycemia during ACS treatment remains to be established. We herein retrospectively investigated the time-dependent changes in insulin dose required for maternal glycemic control during ACS treatment in gestational diabetes (GDM). Twelve singleton pregnant women with GDM who received 12 mg of betamethasone intramuscularly twice 24 hours apart were included in this analysis. Of those, eight also received ritodrine hydrochloride for preterm labor. The blood glucose levels were maintained at 70-120 mg/dL with continuous intravenous infusion of insulin and nothing by mouth for 48 hours after the first betamethasone administration. After the first dose of betamethasone, the insulin dosage needed for glycemic control gradually increased and reached a maximum (6.6 +/- 5.8 units/hr) at 10 hours, then, decreased to 4.1 +/- 1.5 units/hr at 24 hours. Similar changes in the insulin requirement were found after the second betamethasone dose (the maximum insulin dosage: 5.5 +/- 1.6 units/hr at 9 hours following the second administration). Women treated with ritodrine hydrochloride needed more insulin, than those without ritodrine hydrochloride treatment (130.8 +/- 15.0 vs. 76.8 +/- 15.2 units/day, respectively, p < 0.05). Our data indicated that the requirement for insulin is highest 9-10 hours after each dose of betamethasone. When GDM is treated with ACS, levels of blood glucose should be carefully monitored, especially in patients treated with ritodrine hydrochloride.

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