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Papers - ITOH Hiroshi

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Skew of plasma low- and high-density lipoprotein distributions to less dense subfractions in normotriglyceridemic chronic kidney disease patients on maintenance hemodialysis treatment

Homma, K., Homma, Y., Shiina, Y., Wakino, S., Suzuki, M., Fujishima, S., Hayashi, K., Hori, S. and Itoh, H.

Nephron Clin Pract 123 ( 1-2 ) 41 - 5 2013

ISSN 1660-2110

BACKGROUND: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. METHODS: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. RESULTS: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL2 in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL3 were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. CONCLUSION: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

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Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

Hirata, T., Tomita, K., Kawai, T., Yokoyama, H., Shimada, A., Kikuchi, M., Hirose, H., Ebinuma, H., Irie, J., Ojiro, K., Oikawa, Y., Saito, H., Itoh, H. and Hibi, T.

Int J Endocrinol 2013 587140 2013

ISSN 1687-8337

AIM: This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. METHODS: This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 40 mg once a day (n = 12) [DOSAGE ERROR CORRECTED] or losartan at a dose of 50 mg once a day (n = 7) for 12 months. RESULTS: The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 +/- 0.26 to 0.59 +/- 0.22 mEq/L (mean +/- SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. CONCLUSION: Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

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A large coronary aneurysm and its probable precursor lesions in a patient with autosomal dominant polycystic kidney disease: an implication for the process of aneurysmogenesis

Ohara, K., Kimura, T., Karasawa, T., Tokuyama, H., Wakino, S., Hayashi, K., Itoh, H. and Okada, Y.

Pathol Int 62 ( 11 ) 758 - 62 2012.11

ISSN 1320-5463

Coronary artery aneurysms are rare complications of autosomal dominant polycystic kidney disease (ADPKD), and their pathogenesis remains poorly understood. We report an autopsy case of a 64-year-old ADPKD patient with an asymptomatic, large (4 cm in diameter) saccular aneurysm arising from the left circumflex (LCX) branch of the coronary artery with only mild atherosclerotic changes. Autopsy also revealed small, focal defects of media with or without microaneurysm formation in the LCX, mesenteric and renal arteries, and a fibromuscular dysplasia-like lesion with microaneurysm in the common iliac artery. Since polycystin-1 and -2 are expressed in arterial smooth-muscle cells, these findings imply that abnormal polycystin expression in ADPKD initially causes the focal medial defects, some of which might later progress to microaneurysms and then overt aneurysms. To the best of our knowledge, this is the first description of the pathologic findings of an ADPKD-associated coronary aneurysm and its probable precursor lesions in arteries.

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[The ACE2/Ang(1-7)/Mas receptor axis in cardiovascular and renal diseases]

Kanda, T. and Itoh, H.

Nihon Rinsho 70 ( 9 ) 1487 - 91 2012.09

ISSN 0047-1852

The renin-angiotensin-aldosterone system(RAAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease and chronic renal failure. In this cascade, the ACE/Ang II/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation and fibrosis. Recently the ACE2/Ang(1-7)/Mas receptor axis has been recognized as a negative regulator of the RAAS. ACE2 metabolizes Ang II into Ang(1-7), which has opposite properties of Ang II through Mas receptor activation. Both animal and human studies provide strong evidence that the ACE2/Ang(1-7)/Mas receptor axis is protective for end-organ damage. Therefore, the ACE2/Ang(1-7)/Mas receptor axis could be a therapeutic target for coronary artery disease and chronic renal failure.

[Current status of vaccination therapy for hypertension]

Sasamura, H., Azegami, T. and Itoh, H.

Nihon Rinsho 70 ( 9 ) 1627 - 32 2012.09

ISSN 0047-1852

The renin-angiotensin system (RAS) plays a central role in the control of systemic blood pressure. Since the 1950s, both laboratory and clinical studies have been performed to test the efficacy of vaccines against the RAS for the management of hypertension. Although initial studies using renin vaccines and angiotensin I vaccines were unsuccessful, a recent phase IIa study has shown that vaccination against angiotensin II is effective for the treatment of patients with essential hypertension. Results from animal studies have also suggested that vaccination against the AT1 receptor may be effective not only for lowering blood pressure, but also for the prevention of hypertensive end-organ damage. In the future, the RAS may be an important target for the development of vaccines not only for the treatment, but also for the prevention of hypertension and hypertensive complications.

Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance

Kawano, Y., Nakae, J., Watanabe, N., Fujisaka, S., Iskandar, K., Sekioka, R., Hayashi, Y., Tobe, K., Kasuga, M., Noda, T., Yoshimura, A., Onodera, M. and Itoh, H.

Diabetes 61 ( 8 ) 1935 - 48 2012.08

ISSN 0012-1797

Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1(-/-)), a Pdk1 knockout with transactivation-defective Foxo1 (Delta256LysMPdk1(-/-)), a constitutively active nuclear (CN) Foxo1 (CNFoxo1(LysM)), or a transactivation-defective Foxo1 (Delta256Foxo1(LysM)). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1(-/-) mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1(LysM) promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1(LysM) mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.

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A case of hypoglycemic hemiparesis and literature review

Yoshino, T., Meguro, S., Soeda, Y., Itoh, A., Kawai, T. and Itoh, H.

Ups J Med Sci 117 ( 3 ) 347 - 51 2012.08

ISSN 0300-9734

An 89-year-old man with diabetes treated with metformin 500 mg/day and glimepiride 4 mg/day was hospitalized because of hypoglycemic right hemiparesis and dysarthria (casual glucose value 1.8 mmol/L), which resolved quickly following administration of 40 mL of 40% dextrose. Hemiparesis is a rare symptom (4.2%) of hypoglycemia. There are about 200 case reports of hypoglycemic hemiparesis. The average glucose level at which hemiparesis developed was 1.8 mmol/L. Right-sided hemiparesis predominated (R 66%; L 34%). On imaging studies, abnormal findings were frequently observed in the internal capsule or splenium of the corpus callosum. The mechanism of hemiparesis is not fully understood. The existence of cases in which hypoglycemia cannot be distinguished from stroke on imaging studies suggests the importance of measurement of the blood glucose level when the symptoms of stroke are first recognized.

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Coenzyme Q10 reverses mitochondrial dysfunction in atorvastatin-treated mice and increases exercise endurance

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

J Appl Physiol (1985) 113 ( 3 ) 479 - 86 2012.08

ISSN 0161-7567

Statins are cholesterol-lowering drugs widely used in the prevention of cardiovascular diseases; however, they are associated with various types of myopathies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and thus decrease biosynthesis of low-density lipoprotein cholesterol and may also reduce ubiquinones, essential coenzymes of a mitochondrial electron transport chain, which contain isoprenoid residues, synthesized through an HMG-CoA reductase-dependent pathway. Therefore, we hypothesized that statin treatment might influence physical performance through muscular mitochondrial dysfunction due to ubiquinone deficiency. The effect of two statins, atorvastatin and pravastatin, on ubiquinone content, mitochondrial function, and physical performance was examined by using statin-treated mice. Changes in energy metabolism in association with statin treatment were studied by using cultured myocytes. We found that atorvastatin-treated mice developed muscular mitochondrial dysfunction due to ubiquinone deficiency and a decrease in exercise endurance without affecting muscle mass and strength. Meanwhile, pravastatin at ten times higher dose of atorvastatin had no such effects. In cultured myocytes, atorvastatin-related decrease in mitochondrial activity led to a decrease in oxygen utilization and an increase in lactate production. Conversely, coenzyme Q(10) treatment in atorvastatin-treated mice reversed atorvastatin-related mitochondrial dysfunction and a decrease in oxygen utilization, and thus improved exercise endurance. Atorvastatin decreased exercise endurance in mice through mitochondrial dysfunction due to ubiquinone deficiency. Ubiquinone supplementation with coenzyme Q(10) could reverse atorvastatin-related mitochondrial dysfunction and decrease in exercise tolerance.

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MPO-ANCA associated crescentic glomerulonephritis with numerous immune complexes: case report

Morizane, R., Konishi, K., Hashiguchi, A., Tokuyama, H., Wakino, S., Kawabe, H., Hayashi, M., Hayashi, K. and Itoh, H.

BMC Nephrol 13 32 2012.06

ISSN 1471-2369

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) is a major cause of rapidly progressive glomerulonephritis (RPGN). ANCA-associated CGN is generally classified into pauci-immune RPGN, in which there are few or no immune complexes. CASE PRESENTATION: A 78-year-old man presented with RPGN after a 7-year course of chronic proteinuria and hematuria with stable renal function. A blood examination showed a high titer of myeloperoxidase (MPO)-ANCA. A renal biopsy showed crescentic glomerulonephritis with abundant subepithelial, intramenbranous and subendothelial deposits by electron microscopy, leading to the diagnosis of ANCA-associated CGN superimposed on type 3 membranoproliferative glomerulonephritis (MPGN). CONCLUSIONS: This case is unique in that type 3 MPGN and MPO-ANCA-associated CGN coexisted, and no similar case has been reported to date. Because ANCA-associated CGN has a predilection for elderly individuals and primary type 3 MPGN is rarely seen in this age group, coincidental existence appears less likely. This case may confer valuable information regarding the link between immune complex and ANCA-associated CGN.

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Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway

Ichikawa, R., Takayama, T., Yoneno, K., Kamada, N., Kitazume, M. T., Higuchi, H., Matsuoka, K., Watanabe, M., Itoh, H., Kanai, T., Hisamatsu, T. and Hibi, T.

Immunology 136 ( 2 ) 153 - 62 2012.06

ISSN 0019-2805

Dendritic cells (DCs) are known as antigen-presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non-lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin-12 (IL-12) and tumour necrosis factor-alpha in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL-12 hypo-producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down-regulated during monocyte differentiation to DCs. Stimulation with 8-bromoadenosine-cyclic AMP (8-Br-cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL-12 hypo-producing DCs. These results indicate that BAs induce the differentiation of IL-12 hypo-producing DCs from monocytes via the TGR5-cAMP pathway.

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Novel repressor regulates insulin sensitivity through interaction with Foxo1

Nakae, J., Cao, Y., Hakuno, F., Takemori, H., Kawano, Y., Sekioka, R., Abe, T., Kiyonari, H., Tanaka, T., Sakai, J., Takahashi, S. and Itoh, H.

Embo j 31 ( 10 ) 2275 - 95 2012.05

ISSN 0261-4189

Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Lepr(db/db) mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity.

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Vaccination against the angiotensin type 1 receptor for the prevention of L-NAME-induced nephropathy

Azegami, T., Sasamura, H., Hayashi, K. and Itoh, H.

Hypertens Res 35 ( 5 ) 492 - 9 2012.05

ISSN 0916-9636

Previous studies have shown that renin-angiotensin (Ang) system vaccines may be effective for the treatment of hypertension, but their efficacy for the prevention of renal disease is unclear. The aim of this study was to compare the effects of an Ang II type 1 (AT1) receptor vaccine with an Ang II receptor blocker (ARB) and a vasodilator on blood pressure (BP) and renal injury in the L-NAME nephropathy model. Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg kg(-1) per day) or hydralazine hydrochloride (5 mg kg(-1) per day), then administered NG-nitro-L-arginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. Vaccination against the AT1 receptor caused a significant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME treatment resulted in a marked increase in proteinuria in the control groups, which was completely suppressed in the AT1 vaccine-treated group, and glomerular injury scores were also significantly decreased. Real-time RT-PCR and immunofluorescence studies revealed increased renin mRNA, and increased glomerular expression of nephrin. Comparable results were seen in rats treated continuously with the ARB candesartan, but not with hydralazine. These results suggest that transient AT1 vaccination is as effective as continuous treatment with ARB, not only for the attenuation of hypertension, but also for the prevention of L-NAME-induced nephropathy in SHR.

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Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension

Shibata, H. and Itoh, H.

Am J Hypertens 25 ( 5 ) 514 - 23 2012.05

ISSN 0895-7061

The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent.

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[The 39th scientific meeting: perspectives of internal medicine; the cutting edge of treatment of medical disorders encountered in clinical practice; 10. Summary]

Itoh, H.

Nihon Naika Gakkai Zasshi 101 ( 3 ) 654 - 5 2012.03

ISSN 0021-5384

'Memory' and 'legacy' in hypertension and lifestyle-related diseases

Sasamura, H. and Itoh, H.

Hypertens Res 35 ( 3 ) 272 - 3 2012.03

ISSN 0916-9636

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Bile acid binding resin improves metabolic control through the induction of energy expenditure

Watanabe, M., Morimoto, K., Houten, S. M., Kaneko-Iwasaki, N., Sugizaki, T., Horai, Y., Mataki, C., Sato, H., Murahashi, K., Arita, E., Schoonjans, K., Suzuki, T., Itoh, H. and Auwerx, J.

PLoS One 7 ( 8 ) e38286 2012

ISSN 1932-6203

BACKGROUND: Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. METHODS AND FINDINGS: We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. CONCLUSION: Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistance.

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Effect of obesity on declining beta cell function after diagnosis of type 2 diabetes: a possible link suggested by cross-sectional analysis

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

Endocr J 59 ( 3 ) 187 - 95 2012

ISSN 0918-8959

It has been reported that beta cell function progressively declines in patients with type 2 diabetes. The objective of this study was to assess the effect of obesity on declining beta cell function after diagnosis of type 2 diabetes. We conducted a cross-sectional study of 689 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007. Fasting and postprandial serum C-peptide immunoreactivity (CPR) and urinary CPR levels had been measured during admission. The subjects were stratified according to BMI and time since diagnosis. CPR index was calculated as CPR (ng/mL) / plasma glucose (mg/dL) x 100. All CPR measurements were significantly higher in the 263 obese (BMI >/=25) subjects compared to the 426 lean subjects (BMI <25). There was a significant negative correlation between CPR indices and duration of diabetes, suggesting a progressive decline in beta cell function after diagnosis of type 2 diabetes. However, this decline was more apparent in obese subjects (postprandial CPR index 0.059/year) compared to lean subjects (0.025/year). The significant difference in serum CPR indices between the lean and obese subjects was lost in subjects more than 10 years after diagnosis. In conclusion, our observations suggest that beta cell function shows a greater progressive decline in obese subjects than in lean subjects with type 2 diabetes. Treatment of obesity may be an important strategy to preserve beta cell function in patients with type 2 diabetes.

Factors Associated with the Decline of Kidney Function Differ among eGFR Strata in Subjects with Type 2 Diabetes Mellitus

Meguro, S., Tomita, M., Kabeya, Y., Katsuki, T., Oikawa, Y., Shimada, A., Kawai, T., Itoh, H. and Atsumi, Y.

Int J Endocrinol 2012 687867 2012

ISSN 1687-8337

Introduction. There is no report about risk factors for renal deterioration according to the clinical stage, divided by the estimated glomerular filtration rate (eGFR) in type 2 diabetes. Materials and Methods. We evaluated the factors correlated with the annual eGFR decline in 1303 subjects with type 2 diabetes whose eGFR was >/=30 mL/min/1.73 m(2). eGFR strata were defined by baseline eGFR value as follows: stratum 1: >/=90, stratum 2: >/=60, <90, and stratum 3: >/=30, <60. Results. The annual eGFR decline was 2.3 +/- 5.4 mL/min/1.73 m(2) in overall subjects. Multiple linear regression analysis demonstrated that age, male sex, systolic blood pressure, logarithmically transformed albumin excretion rate (AER), eGFR strata, and hemoglobin concentration were significantly correlated with the annual eGFR decline. When stratified by eGFR, the factors that showed a significant correlation were different among eGFR strata. AER was significantly correlated with annual eGFR decline in all eGFR strata. Hemoglobin concentration showed a significant correlation only in the advanced eGFR stratum. Conclusion. The factors correlated with the annual eGFR decline were different among eGFR strata in type 2 diabetes mellitus, and hemoglobin concentration and AER were important factors for renal deterioration, especially in the advanced eGFR stratum.

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A new preventive strategy for hypoglycemia incorporating added food diet in patients with type 2 diabetes who received sitagliptin therapy

Meguro, S., Sano, M., Kawai, T., Matsuhashi, T., Mogi, S., Fukuda, K., Itoh, H. and Suzuki, Y.

Endocr Res 37 ( 4 ) 175 - 81 2012

ISSN 0743-5800

There has been concern as to whether dipeptidyl peptidase-4 (DPP-4) inhibitors can be used safely in patients with relatively good glycemic control. This study, approved by the institutional review board of Hanzoumon Diabetes City Atlas Clinic, examined whether DPP-4 inhibitor sitagliptin could safely achieve good glycemic control without severe hypoglycemia by employing the "added food" concept. The subjects were 60 patients (46 men and 14 women) with type 2 diabetes who started sitagliptin therapy during a 1-month period from December 15, 2009 to January 15, 2010. They were recommended to have added food between meals to prevent hypoglycemia, while maintaining the same daily calorie intake. HbA(1c) decreased from 7.1 +/- 1.2% to 6.5 +/- 0.6% after 6 months of sitagliptin treatment (p < 0.001). In patients with a baseline HbA(1c) <7%, it decreased from 6.5 +/- 0.3% to 6.1 +/- 0.4% (p < 0.001). Systolic blood pressure was significantly reduced from 127.7 +/- 17.0 to 122.7 +/- 17.9 mmHg in the patients with a baseline HbA(1c) < 7% (p = 0.018). However, body weight increased by approximately 900 g and high-density lipoprotein cholesterol decreased significantly from 1.57 +/- 0.46 to 1.43 +/- 0.35 mmol/L (p < 0.01) in the patients concomitantly receiving sulfonylureas with sitagliptin. Excellent glycemic control was achieved by sitagliptin treatment together with the added food concept. However, combined use of sitagliptin with sulfonylureas requires attention to weight gain and the lipid profile. Further clinical studies will elucidate whether sitagliptin can decrease cardiovascular events as well as normalizing blood glucose and lowering the blood pressure.

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Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan

Hayashi, K., Sasamura, H., Azegami, T. and Itoh, H.

J Atheroscler Thromb 19 ( 8 ) 736 - 46 2012

ISSN 1340-3478

AIM: Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. METHODS AND RESULTS: Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased. CONCLUSION: These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

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