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Papers - ITOH Hiroshi

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Rho-kinase contributes to pressure-induced constriction of renal microvessels

Homma, K., Hayashi, K., Wakino, S., Tokuyama, H., Kanda, T., Tatematsu, S., Hasegawa, K., Fujishima, S., Hori, S., Saruta, T. and Itoh, H.

Keio J Med 63 ( 1 ) 1 - 12 2014

ISSN 0022-9717

Renal afferent arterioles (AFF) regulate glomerular capillary pressure through two main mechanisms: the myogenic response (MYO) and tubuloglomerular feedback (TGF). Because Rho-kinase and nitric oxide synthase (NOS) are established factors that modulate vascular tone, we examined the role of these factors in pressure-induced AFF tone in Wistar-Kyoto rats and in spontaneously hypertensive rats (SHR) using an intravital CCD camera. Elevated renal perfusion pressure elicited marked AFF constriction that was partially inhibited by gadolinium, furosemide and fasudil, which inhibit MYO, TGF and Rho-kinase, respectively; however, this AFF constriction was completely blocked by combined treatment with fasudil+gadolinium or fasudil+furosemide. S-methyl-L-thiocitrulline (SMTC) partially reversed the fasudil-induced inhibition of TGF-mediated, but not that of MYO-mediated, AFF constriction. In SHR, the pressure-induced AFF response was enhanced, and MYO- and TGF-induced constriction were exaggerated. In the presence of gadolinium, SMTC partially mitigated the fasudil-induced inhibition of TGF-mediated AFF constriction. Immunoblot analyses demonstrated that both Rho-kinase activity and neuronal NOS were augmented in SHR kidneys. In conclusion, Rho-kinase contributes to MYO- and TGF-mediated AFF responses, and these responses are enhanced in SHR. Furthermore, neuronal NOS-induced nitric oxide modulates the TGF mechanism. This mechanism constitutes a target for Rho-kinase in TGF-mediated AFF constriction.

Ghrelin protects against renal damages induced by angiotensin-II via an antioxidative stress mechanism in mice

Fujimura, K., Wakino, S., Minakuchi, H., Hasegawa, K., Hosoya, K., Komatsu, M., Kaneko, Y., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

PLoS One 9 ( 4 ) e94373 2014

ISSN 1932-6203

We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1alpha. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-beta and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney.

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Postprandial serum C-peptide to plasma glucose ratio predicts future insulin therapy in Japanese patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Acta Diabetol 50 ( 6 ) 987 - 8 2013.12

ISSN 0940-5429

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Feasibility of regression of hypertension using contemporary antihypertensive agents

Sasamura, H., Nakaya, H., Julius, S., Tomotsugu, N., Sato, Y., Takahashi, F., Takeuchi, M., Murakami, M., Ryuzaki, M. and Itoh, H.

Am J Hypertens 26 ( 12 ) 1381 - 8 2013.12

ISSN 0895-7061

BACKGROUND: Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. METHODS: Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. RESULTS: In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. CONCLUSIONS: One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

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Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Hasegawa, K., Wakino, S., Simic, P., Sakamaki, Y., Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Kubota, E., Tokuyama, H., Hayashi, K., Guarente, L. and Itoh, H.

Nat Med 19 ( 11 ) 1496 - 504 2013.11

ISSN 1078-8956

Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.

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Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

Mitsuishi, M., Miyashita, K., Muraki, A., Tamaki, M., Tanaka, K. and Itoh, H.

Am J Physiol Endocrinol Metab 305 ( 7 ) E776 - 84 2013.10

ISSN 0193-1849

Loss of physical performance is linked not only to decreased activity in daily life but also to increased onset of cardiovascular diseases and mortality. A high-protein diet is recommended for aged individuals in order to preserve muscle mass; however, the regulation of muscle mitochondria by dietary protein has not been clarified. We investigated the long-term effects of a high-protein diet on muscle properties, focusing especially on muscle mitochondria. Mice were fed a high-protein diet from the age of 8 wk and examined for mitochondrial properties and exercise endurance at the ages of 20 and 50 wk. Compared with normal chow, a high-protein diet significantly decreased the amount of muscle mitochondria, mitochondrial activity, and running distance at 50 wk, although it increased muscle mass and grip power. Inhibition of TORC1-dependent signal pathways by rapamycin from 8 wk suppressed the decline in mitochondria and exercise endurance observed when mice were fed the high-protein diet in association with preserved AMPK activity. Collectively, these findings suggest a role for dietary protein as a suppressor of muscle mitochondria and indicate that the age-associated decline in exercise endurance might be accelerated by excessive dietary protein through rapamycin-sensitive suppression of muscle mitochondria.

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Change in beta-cell mass in Japanese nondiabetic obese individuals

Kou, K., Saisho, Y., Satoh, S., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 98 ( 9 ) 3724 - 30 2013.09

ISSN 0021-972

AIM: The aim of this study was to clarify the change in beta-cell mass in Japanese obese individuals. METHODS: We obtained the pancreas at autopsy from 39 lean and 33 obese Japanese nondiabetic individuals (aged 47 +/- 13 vs 47 +/- 12 y, P = .83, body mass index 20.4 +/- 1.6 vs 28.5 +/- 3.9 kg/m(2), P < .01). Pancreatic sections were stained for insulin, and beta-cell area (%BCA) was measured as the fraction of the beta-cell area to the total pancreas area. beta-Cell mass was then calculated as the product of %BCA and estimated pancreas weight. beta-Cell replication and apoptosis were assessed by double staining for insulin and Ki67 and insulin and single-stranded DNA, respectively. The frequencies of insulin-positive duct cells and scattered beta-cells were assessed as the surrogate markers of beta-cell neogenesis. The alpha-cell area (%ACA) was also measured, and the %ACA to %BCA ratio was determined. RESULTS: There was no increase in beta-cell mass in obese individuals compared with lean individuals (0.6 +/- 0.4 vs 0.7 +/- 0.4 g, P = .12). beta-Cell replication, beta-cell neogenesis, and beta-cell apoptosis were not significantly increased in the presence of obesity. There was no significant difference in %ACA to %BCA ratio between obese and lean individuals (0.91 +/- 1.09 vs 0.75 +/- 0.51, P = .47). CONCLUSION: There was no increase in beta-cell mass and no detectable change in beta-cell turnover in Japanese obese individuals.

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Renal microcirculation and calcium channel subtypes

Homma, K., Hayashi, K., Yamaguchi, S., Fujishima, S., Hori, S. and Itoh, H.

Curr Hypertens Rev 9 ( 3 ) 182 - 6 2013.08

ISSN 1573-4021

It has recently been reported that voltage-dependent Ca channel subtypes, e.g., L-, T-, N-, and P/Q-type, are expressed in renal arterioles and renal tubules, and the inhibition of these channels exerts various effects on renal microcirculation. For example, selective blockade of L-type Ca channels with nifedipine preferentially dilates the afferent arteriole and potentially induces glomerular hypertension. On the other hand, recently developed Ca channel blockers (CCBs) such as mibefradil and efonidipine block both T-type and L-type Ca channels and consequently dilate both afferent and efferent arterioles, leading to lowering of intraglomerular pressure. Interestingly, aldosterone has recently been recognized as a factor exacerbating renal diseases, and its secretion from adrenal gland is mediated by T-type Ca channels. Furthermore, T-type CCBs were shown to ameliorate renal dysfunction by suppressing inflammatory processes and renin secretion. On the basis of histological evaluations, N-type Ca channels are present in peripheral nerve terminals innervating both afferent and efferent arterioles. Further, it was suggested that N-type CCBs such as cilnidipine suppress renal arteriolar constriction induced by enhanced sympathetic nerve activity, thereby lowering intraglomerular pressure. Taken together, various Ca channel subtypes are present in the kidney and blockade of selective channels with distinct CCBs exerts diverse effects on renal microcirculation. Inhibition of T-type and N-type Ca channels with CCBs is anticipated to exert pleiotropic effects that would retard the progression of chronic kidney disease through modulation of renal hemodynamic and non-hemodynamic processes.

Effects of mitiglinide, a short-acting insulin secretagogue, on daily glycemic variability and oxidative stress markers in Japanese patients with type 2 diabetes mellitus

Kodani, N., Saisho, Y., Tanaka, K., Kawai, T. and Itoh, H.

Clin Drug Investig 33 ( 8 ) 563 - 70 2013.08

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues. METHODS: We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) >/= 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8-hydroxydeoxy guanosine. RESULTS: After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean +/- SD,7.4 +/- 0.7 to 6.8 +/- 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers. CONCLUSIONS: The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation.

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The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice

Hasegawa, K., Wakino, S., Kimoto, M., Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Faseb j 27 ( 6 ) 2301 - 15 2013.06

ISSN 0892-6638

The role of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in glucose metabolism is unknown. Here, we generated DDAH2 transgenic (Tg) mice. These mice had lower plasma glucose levels (60 min: 298+/-32 vs. 418+/-35 mg/dl; 120 min: 205+/-15 vs. 284+/-20 mg/dl) and higher insulin levels (15 min: 2.1+/-0.2 vs. 1.5+/-0.1 ng/ml; 30 min: 1.8+/-0.1 vs. 1.5+/-0.1 ng/ml) during intraperitoneal glucose tolerance tests when fed a high-fat diet (HFD) compared with HFD-fed wild-type (WT) mice. Glucose-stimulated insulin secretion (GSIS) was increased in Tg islets by 33%. Pancreatic asymmetrical dimethylarginine, nitric oxide, and oxidative stress levels were not correlated with improvements in insulin secretion in Tg mice. Secretagogin, an insulin vesicle docking protein, was up-regulated by 2.7-fold in Tg mice and in pancreatic MIN-6 cells overexpressing DDAH2. GSIS in MIN-6 cells was dependent on DDAH2-induced secretagogin expression. Pancreatic Sirt1, DDAH2, and secretagogin were down-regulated in HFD-fed WT mice by 70, 75, and 85%, respectively. Overexpression of Sirt1 overexpression by 3.9-fold increased DDAH2 and secretagogin expression in MIN-6 cells by 3.2- and 2.5-fold, respectively. DDAH2 overexpression improved GSIS in pancreas-specific Sirt1-deficient mice. In summary, the Sirt1/DDAH2/secretagogin pathway is a novel regulator of GSIS.

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Sema3A regulates bone-mass accrual through sensory innervations

Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., Ma, C., Xu, C., Bando, W., Fujita, K., Shinomiya, K., Hirai, T., Asou, Y., Enomoto, M., Okano, H., Okawa, A. and Itoh, H.

Nature 497 ( 7450 ) 490 - 3 2013.05

ISSN 0028-0836

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura, Y., Kanai, T., Saeki, K., Takabe, M., Irie, J., Miyoshi, J., Mikami, Y., Teratani, T., Suzuki, T., Miyata, N., Hisamatsu, T., Nakamoto, N., Yamagishi, Y., Higuchi, H., Ebinuma, H., Hozawa, S., Saito, H., Itoh, H. and Hibi, T.

Am J Physiol Gastrointest Liver Physiol 304 ( 8 ) G700 - 7 2013.04

ISSN 0193-1857

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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[Diabetes mellitus related common medical disorders : recent progress in diagnosis and treatment. Topics: I. Pathophysiology, diagnosis and treatment: 3. Primary aldosteronism, resistant hypertension and diabetes mellitus]

Shibata, H. and Itoh, H.

Nihon Naika Gakkai Zasshi 102 ( 4 ) 850 - 5 2013.04

ISSN 0021-5384

Relationship between Stage of Diabetic Retinopathy and Pulse Wave Velocity in Japanese Patients with Type 2 Diabetes

Tanaka, K., Kawai, T., Saisho, Y., Meguro, S., Harada, K., Satoh, Y., Kobayashi, K., Mizushima, K., Abe, T. and Itoh, H.

J Diabetes Res 2013 193514 2013

ISSN 2314-6745

Objectives. We investigated the relationship between the stage of diabetic retinopathy and pulse wave velocity (PWV). Methods. This was a cross-sectional study of 689 patients (406 men and 283 women) with type 2 diabetes who were admitted to our hospital from 2004 to 2007. Brachial-ankle pulse wave velocity (baPWV) was measured by an arterial pressure measurement device as PWV/ABI. Diagnosis of diabetic retinopathy was made by ophthalmologists based on the Davis classification: no diabetic retinopathy (NDR), simple retinopathy (SDR), pre-proliferative retinopathy (pre-PDR), and proliferative retinopathy (PDR). Results. There was a significant difference in PWV between patients without diabetic retinopathy (1657.0 +/- 417.9 m/s (mean +/- SD)) and with diabetic retinopathy (1847.1 +/- 423.9 m/s) (P < 0.001). In addition, the stage of diabetic retinopathy was associated with aortic PWV (1657.0 +/- 417.9 m/s in NDR (n = 420), 1819.4 +/- 430.3 m/s in SDR (n = 152), 1862.1 +/- 394.0 m/s in pre-PDR (n = 54), and 1901.1 +/- 433.5 m/s in PDR (n = 63) (P < 0.001)). Conclusions. In patients with diabetic retinopathy, even in those with SDR, PWV was higher than that in patients without diabetic retinopathy. Physicians should therefore pay attention to the value of PWV and macroangiopathy regardless of the stage of diabetic retinopathy.

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Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women

Saisho, Y., Miyakoshi, K., Ikenoue, S., Kasuga, Y., Matsumoto, T., Minegishi, K., Yoshimura, Y. and Itoh, H.

Endocr J 60 ( 4 ) 533 - 9 2013

ISSN 0918-8959

The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT). In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [IS(OGTT)] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUC(ins/glu)] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM.

Association between beta cell function and future glycemic control in patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Endocr J 60 ( 4 ) 517 - 23 2013

ISSN 0918-8959

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

C-reactive protein, high-molecular-weight adiponectin and development of metabolic syndrome in the Japanese general population: a longitudinal cohort study

Saisho, Y., Hirose, H., Roberts, R., Abe, T., Kawabe, H. and Itoh, H.

PLoS One 8 ( 9 ) e73430 2013

ISSN 1932-6203

AIMS: To clarify predictive values of C-reactive protein (CRP) and high-molecular-weight (HMW) adiponectin for development of metabolic syndrome. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46+/-8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis. RESULTS: Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome. CONCLUSION: Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population.

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Past Obesity as well as Present Body Weight Status Is a Risk Factor for Diabetic Nephropathy

Meguro, S., Kabeya, Y., Tanaka, K., Kawai, T., Tomita, M., Katsuki, T., Oikawa, Y., Atsumi, Y., Shimada, A., Tanaka, M., Irie, J., Saisho, Y. and Itoh, H.

Int J Endocrinol 2013 590569 2013

ISSN 1687-8337

Aims. We analyzed the prevalence of nephropathy according to past body weight status in Japanese subjects with type 2 diabetes because the influence of past obesity on diabetic complications is not certain. Methods. We examined the prevalence of nephropathy in 2927 subjects with type 2 diabetes mellitus according to current BMI and maximum BMI in the past. We defined "current obesity" as BMI on hospitalization of 25 or more, "previous obesity" as BMI on hospitalization of less than 25 and self-reported maximum BMI in the past of 25 or more, and "continuously lean" as maximum BMI of less than 25. Results. The prevalence of nephropathy was significantly higher in subjects with current obesity (40.6%) or previous obesity (35.6%) than in those who were continuously lean (24.3%) (P < 0.017). In logistic regression analysis, previous obesity, as well as current obesity, was a significant risk factor for nephropathy, independent of sex, age, disease duration, hypertension, dyslipidemia, HbA1c, and diabetic retinopathy. Conclusions. Obesity in the past, as well as the present body weight status, was a risk factor for diabetic nephropathy.

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The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H(+)-ATPase biogenesis

Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Ochi, H., Fukuda, T., Bokuda, K., Kurosawa, H., Yoshida, N., Takeda, S., Fukuda, K. and Itoh, H.

PLoS One 8 ( 11 ) e78603 2013

ISSN 1932-6203

The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H(+)-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the N-terminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Delta4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.

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Effects of adding ezetimibe to fluvastatin on kidney function in patients with hypercholesterolemia: a randomized control trial

Kinouchi, K., Ichihara, A., Bokuda, K., Morimoto, S. and Itoh, H.

J Atheroscler Thromb 20 ( 3 ) 245 - 56 2013

ISSN 1340-3478

AIMS: Statins not only reduce low-density lipoprotein (LDL) cholesterol, but also prevent the progression of kidney dysfunction. Ezetimibe, a cholesterol-absorption inhibitor, also lowers LDL cholesterol levels when added to statins; however, the effect of add-on ezetimibe on kidney function has had conflicting results. METHODS: We conducted an open-labeled, randomized, 12-month trial, comparing the effects of daily therapy with 20 mg fluvastatin either with or without 10 mg ezetimibe in 54 patients with dyslipidemia. The prespecified primary outcome was the percent change from baseline in kidney function, which was defined by the estimated glomerular filtration rate. The secondary outcomes were the changes in surrogate atherosclerotic markers. All analyses were by intention to treat. RESULTS: The primary outcome, the percent change from baseline (+/-SE) of the estimated glomerular filtration rate, was -5.5+/-1.9% in the fluvastatin-only group and 6.6+/-1.9% in the fluvastatin-plus-ezetimibe (combined-therapy) group (p=0.0002). Secondary outcomes, consisting of the cardioankle vascular index, augmentation index, ankle-brachial index, and maximum intima-media thickness of the carotid arteries, did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol was 122+/-23 mg per deciliter in the fluvastatin group and 111+/-29 mg per deciliter in the combined-therapy group (a between-group difference of 9.2%, p= 0.036). Side-effect and safety profiles were similar in the two groups. CONCLUSION: Combined therapy with fluvastatin 20 mg plus ezetimibe 10 mg daily resulted in a significant improvement in changes in the estimated glomerular filtration rate.

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