Hajime Izumiyama

Multi-center intervention study on glycohemoglobin (HbA1c) and serum, high-sensitivity CRP (hs-CRP) after local anti-infectious periodontal treatment in type 2 diabetic patients with periodontal disease

The purpose of this study was to examine whether periodontal treatment incorporating topical antibiotic therapy affects on levels of glycohemoglobin (HbA1c) and serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetic patients with periodontal disease, and to explore the relationship between CRP and glycemic control. The whole intervention group (n=32), which underwent anti-infectious periodontal treatment, showed only transient reduction in HbA1c levels without any change in hs-CRP, while the control group (n=17) did not show any changes in HbA1c or hs-CRP. Multiple regression analysis of all subjects revealed that BMI and change in hs-CRP correlated significantly with the reduction of HbA1c at 6 months after the periodontal treatment. Based on the results of multiple regression analysis, the intervention group was subdivided into two groups: those in which hs-CRP levels decreased (CRP-D group), and those in which hs-CRP levels unchanged or increased (CRP-N group) (n=16, respectively), and re-analysis was conducted based upon these subgroups. In the CRP-D subgroup, HbA1c was significantly reduced at the end of the study, but it did not decrease in the CRP-N subgroup. The decrease of HbA1c in the CRP-D subgroup following periodontal treatment was significantly greater than that in the CRP-N subgroup. BMI of each group remained unchanged in this study at the end of the study. Thus, the results suggested that periodontal treatment with topical antibiotics improves HbA1c through reduction of CRP, which may relate to amelioration of insulin resistance, in type 2 diabetic patients with periodontal disease.

Synthetic Salusins as Cardiac Depressors in Rat

Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-&bgr; being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-&bgr; administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-&bgr;–induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-&bgr; significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-&bgr; promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-&bgr; is also mediated via a direct myotropic effect.

Clinical outcome of subclinical Cushing's syndrome after surgical and conservative treatment

Subclinical Cushings syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS.

Periodontal treatment with topical antibiotics improves glycemic control in association with elevated serum adiponectin in patients with type 2 diabetes mellitus.

OBJECTIVES Chronic inflammation of periodontitis aggravates glycemic control in type 2 diabetic patients through aggravation of insulin resistance. Increased or decreased release of various inflammatory mediators, such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and adipokines, such as adiponectin, leptin, and resistin, are presumed to be responsible for developing and progressing insulin resistance. The purpose of this study was to examine the effects of periodontal treatment on glycemic control, serum inflammatory mediators and adipokines in type 2 diabetes patients with periodontitis. METHODS Twenty-one type 2 diabetic patients with periodontitis received periodontal treatment with topical antibiotics (intervention group) and 8 patients did not receive periodontal treatment (control group). Periodontal examination, including probing pocket depth (PPD) and bleeding on probing (BOP), and blood sampling were performed at baseline, 2 and 6 months after periodontal treatments. Glycated hemoglobin (HbA1c), hs-CRP, TNF-α, IL-6, adiponectin, leptin, and resistin were analyzed. RESULTS In the intervention group, improvements of PPD and BOP, decrease in HbA1c and elevation of serum adiponectin were observed, while in the control group, all parameters were not changed. Generalized linear model revealed that changes of serum adiponectin and TNF-α and change of BOP correlated significantly with the reduction of HbA1c at 6 months after periodontal treatments. CONCLUSION The results demonstrated that periodontal treatment improves periodontal status and glycemic control with elevation of serum adiponectin in type 2 diabetic patients. The results suggest that HbA1c is reduced by amelioration of insulin resistance due to elevated serum adiponectin after periodontal treatments.

Improvement of endothelial function in patients with hypertension and type 2 diabetes after treatment with telmisartan

Telmisartan, a selective antagonist for angiotensin type1 receptor and a partial agonist for peroxisome proliferator-activated receptor-γ, decreases blood pressure and has been shown to improve glucose and lipid metabolism, suggesting potential cardiovascular protective effects. In this study, we investigated whether long-term treatment with telmisartan improved endothelial function in 35 hypertensive patients with type 2 diabetes mellitus (T2DM). Office and home early morning blood pressure levels and flow-mediated vasodilation (FMD) were evaluated before and after 12 months of treatment with telmisartan. Blood samples were also obtained for measurement of several biochemical parameters and of adiponectin (AN) and highly sensitive C-reactive protein (hs-CRP) before and after treatment. After 12 months of treatment, office and morning blood pressure levels had significantly decreased, and levels of plasma glucose, glycosylated hemoglobin, total cholesterol, triglyceride and low-density lipoprotein cholesterol had also significantly decreased. Plasma AN and high-density lipoprotein cholesterol levels increased, but hs-CRP levels decreased. Furthermore, FMD significantly increased; changes in percent FMD showed a significant negative correlation with changes in systolic and diastolic blood pressure and a significant positive correlation with changes in AN. Stepwise multivariate regression analysis revealed that changes in plasma AN and office systolic blood pressure were both independent determinants for endothelial function after telmisartan treatment. In conclusion, this study shows that long-term treatment with telmisartan improves not only blood pressure and glucose and lipid metabolism but also endothelial function in hypertensive patients with T2DM, possibly by increased circulating AN and decreased blood pressure.

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

OBJECTIVE The pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA. METHODS We conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues. RESULTS Methylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone production, and five genes (PRRX1, RAB38, FAP, GCNT2, and ASB4) are potentially involved in tumorigenesis. CONCLUSION The present study is the first methylome analysis to compare APA with AAG in the same patients. Our integrated analysis of transcriptome and methylome revealed DNA hypomethylation in APA and identified several up-regulated genes with DNA hypomethylation that may be involved in aldosterone production and tumorigenesis.

Characteristics of neuropsychological functions in inpatients with poorly-controlled type 2 diabetes mellitus.

Aims/Introduction:  It has been suggested that type 2 diabetes is associated with cognitive impairment. We investigated the neuropsychological profile of inpatients with poorly controlled type 2 diabetes and assessed the effects of clinical factors on neuropsychological functions.

Improvement of glycemic control after periodontal treatment by resolving gingival inflammation in type 2 diabetic patients with periodontal disease.

Aims/Introduction:  Chronic inflammation aggravates glycemic control in patients with type 2 diabetes mellitus. An increase or decrease in the release and activities of various inflammatory mediators, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and C‐reactive protein (CRP), are presumed to be responsible for inducing insulin resistance. The purpose of the present study was to examine the effects of non‐surgical periodontal treatment incorporating topical antibiotics on glycemic control and serum inflammatory mediators in patients with type 2 diabetes mellitus with periodontitis.

Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial

Liraglutide, an analogue of human glucagon-like peptide 1, reduces cardiovascular events in patients with type 2 diabetes; however, it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events. Type 2 diabetic patients with insulin treatment were enrolled in this randomized, open-label, comparative study. Participants were randomly assigned to liraglutide plus insulin (liraglutide group) and insulin treatment (control group) at 1:1 allocation. Primary endpoint was the change in viscera fat are (VFA, cm2) at 24 weeks. Liver attenuation index (LAI) measured by abdominal computed tomography, urinary albumin-to-creatinine ratio (ACR, mg/g), and C-reactive protein (CRP) levels, skeletal muscle index (SMI), and quality of life (QOL) related to diabetes treatment were also determined. Seventeen patients (8; liraglutide group, 9; control group, mean age 59 ± 13 years; 53% female) completed this study. Liraglutide treatment significantly reduced VFA at 24 weeks; whereas, SFA was unchanged. ACR, LAI, and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups. Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI, albuminuria, and HbA1c. Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment. No severe adverse events were observed in both groups. Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation, albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes.

Indirect measure of visceral adiposity ‘A Body Shape Index’ (ABSI) is associated with arterial stiffness in patients with type 2 diabetes

Objective Among indirect measures of visceral adiposity, A Body Shape Index (ABSI), which is defined as waist circumference (WC)/(body mass index (BMI)2/3×height1/2), is unique in that ABSI is positively correlated with visceral adiposity and is supposed to be independent of BMI. ABSI has been also shown to be linearly and positively associated with visceral fat mass and all-cause and cardiovascular disease (CVD) in the general population. It is, however, uncertain whether ABSI could be associated with arterial stiffness in patients with diabetes. Methods This is a cross-sectional study of 607 patients with type 2 diabetes (mean age 64±12 years; 40.0% female). Visceral fat area (VFA, cm2) and subcutaneous fat area (SFA, cm2) were assessed with a dual-impedance analyzer. In order to estimate the risk for CVD, brachial-ankle pulse wave velocity (baPWV, cm) was used for the assessment of arterial stiffness. Results ABSI was significantly and positively correlated with VFA (r=0.138, p=0.001) and negatively associated with BMI (r=−0.085, p=0.037). The correlation of z-score for ABSI with VFA remained significant (r=0.170, p<0.001) but not with BMI (r=0.009, p=0.820). ABSI (standardized β 0.095, p=0.043) but not WC (standardized β −0.060, p=0.200) was significantly and positively correlated with baPWV in the multivariate model including BMI as a covariate. Conclusions ABSI appears to reflect visceral adiposity independently of BMI and to be a substantial marker of arterial stiffening in patients with type 2 diabetes.