Tatsuya Suzuki

A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia

The effectiveness and safety of yokukansan (TJ-54), a traditional Japanese medicine (kampo) for the treatment of the behavioural and psychological symptoms of dementia (BPSD), were evaluated in 106 patients diagnosed as having Alzheimers disease (AD) (including mixed-type dementia) or dementia with Lewy bodies. Patients were randomly assigned to group A (TJ-54 treatment in period I and no treatment in period II; each period lasting 4 wk) or group B (no treatment in period I and TJ-54 treatment in period II). BPSD and cognitive functions were evaluated using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE), respectively. Activities of daily living (ADL) were evaluated using Instrumental Activities of Daily Living (IADL) in outpatients and the Barthel Index in in-patients. For the safety evaluation, adverse events were investigated. Significant improvements in mean total NPI score associated with TJ-54 treatment were observed in both periods (Wilcoxon test, p=0.040 in period I and p=0.048 in period II). The mean NPI scores significantly improved during TJ-54 treatment in groups A and B (p=0.002 and p=0.007, respectively) but not during periods of no treatment. Among the NPI subscales, significant improvements were observed in delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability. The effects of TJ-54 persisted for 1 month without any psychological withdrawal symptoms in group A. TJ-54 did not show any effect on either cognitive function or ADL. No serious adverse reactions were observed. The present study suggests that TJ-54 is an effective and well-tolerated treatment for patients with BPSD.

Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure

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.

Oral glucose loading attenuates endothelial function in normal individual.

Eur J Clin Invest 2011; 41 (5): 465–473

A CHINESE HERBAL MEDICINE, CHOTO‐SAN, IMPROVES COGNITIVE FUNCTION AND ACTIVITIES OF DAILY LIVING OF PATIENTS WITH DEMENTIA: A DOUBLE‐BLIND, RANDOMIZED, PLACEBO‐CONTROLLED STUDY

CASE REPORT This 81-year-old man presented in January 2004 at the emergency department for a first episode of acute abdominal distension. He had been hospitalized 8 years earlier for a myocardial infarction and atrial fibrillation. He lived at home with his wife. His treatment included aspirin (75 mg/d), an angiotensin-converting enzyme inhibitor, and digoxin. Initial electrolyte analysis showed severe hypokalemia, at 2.0 mmol/L. Natremia, urea nitrogen, and creatinemia were in the normal range. The electrocardiogram showed atrial fibrillation, with a ventricular rate of 92 beats per minute. A plain abdominal ray showed a gaseous distension of the right colon and of the rectum without sigmoid volvulus or fecal impaction. The diagnosis of acute colonic pseudoobstruction was made, and a colonoscopic exsufflation was performed. Kaliuresis was low (18 mmol/L). The patient was given 40 mEq potassium chloride intravenously. Because of the atrial fibrillation, thyroid function tests were performed, which showed latent hyperthyroidism with low thyroid-stimulating hormone (0.015 mUI/mL (normal range 0–15.4)) and normal peripheral hormones (T4, 19.4 pmol/L (normal range 10–25); T3, 5.23 pmol/L (normal range 4.5–9.2)). Clinically, the thyroid was normal. A second exsufflation was performed the day after admission. Kalemia was measured at 2.9 mm/L. The patient was given potassium supplementation orally (20 mEq/d). He was discharged on the tenth day. Kaliemia was 3.9 mmol/L. The abdomen was normal. A beta-blocker was added to his treatment because of the history of myocardial infarction, and potassium supplementation was stopped. The patient was rehospitalized 3 months later, in April 2004, with the same presentation: acute colonic pseudoobstruction and hypokalemia (1.9 mmol/L) with a low kaliuresis (11 mmol/L). Potassium supplementation was given intravenously initially and then orally. Two colonic exsufflations were necessary. The patient was discharged 10 days after admission. Kalemia was measured at 4.9 mmol/L. A third attack of acute colonic pseudoobstruction occurred 1.5 months later, in May 2004. Kalemia was measured at 2.5 mmol/L. The hypothesis of a relationship between hypokalemia and hyperthyroidism was formulated. Thyroid-stimulating hormone was undetectable (0.005 mUI/L (normal range 0.15–4), and free T4 was elevated (33 pmol/L (normal range 10–25)). Treatment with NeoMercazole (40 mg/d) was initiated. Radioactive iodine uptake was 30% at 4 hours, and the patient was treated with 7 milli Curie of 131 Iodine at the beginning of June 2004. Three months later, kalemia remained in the normal range, no colonic pseudoobstruction occurred, and thyroid function had normalized. DISCUSSION This observation of TPP is unusual in two aspects: the age of the patient and the type of paralysis. TPP usually occurs in young Asian men. To our knowledge, it has never been described in an elderly person. The most frequent clinical presentation is recurrent attacks of flaccid weakness, predominantly involving the lower limbs. Bulbar, ocular, cardiac, and respiratory muscles are rarely involved. Smooth-muscle paralysis has never been described. The cardinal biochemical abnormality during an attack is hypokalemia, which is the result of an intracellular shift of potassium, the total body potassium store being normal. The relationship between thyrotoxicosis and hypokalemia is based on the fact that thyroid hormone has been shown to increase sodium/potassium ATPase activity in skeletal muscle, the liver, and the kidneys, resulting in increased intracellular transport of potassium in the setting of hyperthyroidism, but the pathogenic mechanisms of TPP are not totally explained. A defect in the neuromuscular junction, classically suggested, may explain the colonic paralysis observed. As in classical TPP, recurrent attacks of colonic pseudoobstruction occurred until correction of the hyperthyroid status. Hyperthyroidism must be excluded in older people who present with a hypokalemic colonic pseudoobstruction.

Relationship between daily and day-to-day glycemic variability and increased oxidative stress in type 2 diabetes

AIMSnTo determine the association of daily and day-to-day glucose variability with oxidative stress.nnnMETHODSnThis was a cross-sectional analysis of 68 patients with type 2 diabetes mellitus (T2DM) over 72h of continuous glucose monitoring. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were measured before breakfast on day 1. Glucose variability, mean glucose level (MGL), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD) in glucose levels and area under the postprandial plasma glucose curve (AUCPP) were measured on days 2 and 3. Plasma oxidant capacity against N,N-diethylparaphenylenediamine was measured with the diacron-reactive oxygen metabolites (d-ROMs) test on day 1.nnnRESULTSnOverall, 66.2% males with the mean age of 63.2±12.6years, diabetes duration of 12.9±10.4years, and HbA1c level of 8.1±1.6% (65±17mmol/mol) were included. MGL (r=0.330), HbA1c (r=0.326), MAGE (r=0.565), MODD (r=0.488), and AUCPP (r=0.254) exhibited significant correlations with d-ROMs and not FPG; these correlations remained significant after adjustment for clinical factors (sex, age, duration of diabetes, smoking habit, insulin use, statin use, angiotensin II receptor blocker use, BMI, LDL-C, HDL-C, TG, eGFR, and systolic blood pressure) (R2=0.268, R2=0.268, R2=0.417, R2=0.314, and R2=0.347, respectively). MAGE was significantly correlated with MODD (r=0.708) and MAGE and MODD were independently correlated with d-ROMs by multivariate analysis.nnnCONCLUSIONSnTherefore, oxidative stress is associated with daily and day-to-day glucose variability in patients with T2DM.

The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance

BackgroundPrevious studies have demonstrated that postprandial hyperglycemia attenuates brachial artery flow-mediated dilation (FMD) in prediabetic patients, in diabetic patients, and even in normal subjects. We have previously reported that postprandial hyperinsulinemia also attenuates FMD. In the present study we evaluated the relationship between different degrees of postprandial attenuation of FMD induced by postprandial hyperglycemia and hyperinsulinemia and differences in ingested carbohydrate content in non-diabetic individuals.MethodsThirty-seven healthy subjects with no family history of diabetes were divided into 3 groups: a 75-g oral glucose loading group (OG group) (n =u200914), a test meal group (TM group) (nu2009=u200912; 400u2009kcal, carbohydrate content 40.7u2009g), and a control group (nu2009=u200911). The FMD was measured at preload (FMD0) and at 60u2009minutes (FMD60) and 120 (FMD120) minutes after loading. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were determined at preload (PG0, IRI0) and at 30 (PG30, IRI30), 60 (PG60, IRI60), and 120 (PG120, IRI120) minutes after loading.ResultPercentage decreases from FMD0 to FMD60 were significantly greater in the TM group (−21.19%u2009±u200917.90%; Pu2009<u20090.001) and the OG group (−17.59%u2009±u200926.64%) than in the control group (6.46%u2009±u20099.17%; Pu2009<u20090.01), whereas no significant difference was observed between the TM and OG groups. In contrast, the percentage decrease from FMD0 to FMD120 was significantly greater in the OG group (−18.91%u2009±u200916.58%) than in the control group (6.78%u2009±u200911.43%; Pu2009<u20090.001) or the TM group (5.22%u2009±u200937.22%; Pu2009<u20090.05), but no significant difference was observed between the control and TM groups. The FMD60 was significantly correlated with HOMA-IR (ru2009=u2009−0.389; Pu2009<u20090.05). In contrast, FMD120 was significantly correlated with IRI60 (ru2009=u2009−0.462; Pu2009<u20090.05) and the AUC of IRI (ru2009=u2009−0.468; Pu2009<u20090.05). Furthermore, the percentage change from FMD0 to FMD120 was significantly correlated with the CV of PG (ru2009=u20090.404; Pu2009<u20090.05), IRI60 (ru2009=u20090.401; pu2009<u20090.05) and the AUC of IRI (ru2009=u20090.427; Pu2009<u20090.05). No significant correlation was observed between any other FMDs and glucose metabolic variables.ConclusionDifferences in the attenuation of postprandial FMD induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.

Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study.

OBJECTIVEnThe objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients.nnnMETHODSnThis study was an open-label, randomized, case-control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA(1c)), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level.nnnRESULTSnSerum low-density lipoprotein cholesterol levels significantly decreased from 113±38 mg/dl at baseline to 90±20 mg/dl (P=.009) at week 12 of colestimide administration. HbA(1c) significantly decreased from 7.4%±0.9% at baseline to 6.9%±0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4±10.1 μg/ml to 12.4±9.5 μg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5-AG. However, ΔVFA was inversely correlated with Δcholic acid, and multivariate analysis revealed that ΔVFA was a significant explanatory variable.nnnCONCLUSIONSnColestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity.

Urinary N-acetyl-β-d-Glucosaminidase Levels are Positively Correlated With 2-Hr Plasma Glucose Levels During Oral Glucose Tolerance Testing in Prediabetes

Urinary N‐acetyl‐β‐D‐glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N‐acetyl‐β‐d‐glucosaminidase (NAG) levels in prediabetic subjects.

Postprandial Glycemic Control Conditions in Relation to Urinary N-Acetyl-β-d-Glucosaminidase in Patients with Type 2 Diabetes Mellitus Without Low Glomerular Filtration Rate

BACKGROUNDnThis study assessed the relationship between the serum level of 1,5-anhydroglucitol (1,5-AG), a marker of postprandial hyperglycemia, and the ratio of the urinary activity of N-acetyl-β-D-glucosaminidase (NAG) to creatinine (NAG index) in patients with type 2 diabetes mellitus.nnnSUBJECTS AND METHODSnThis was a cross-sectional study with 153 patients who had an estimated glomerular filtration rate of ≥60u2009mL/min/1.73u2009m(2) and no proteinuria and who had never been treated with oral hypoglycemic agents or insulin. On the basis of 1,5-AG levels, the patients were divided into a High 1,5-AG group (>14.0 μg/mL) and a Low 1,5-AG group (≤14.0 μg/mL).nnnRESULTSnThe logarithmically transformed NAG index was significantly higher in the Low 1,5-AG group than in the High 1,5-AG group when all glycated hemoglobin (HbA1c) levels were included. The logarithmically transformed NAG index was lowest in the High 1,5-AG group with an HbA1c level of ≤6.4% and was highest in the Low 1,5-AG group with an HbA1c level of ≥7.5%. Multivariate regression analysis showed that the NAG index had a higher independent association with 1,5-AG than with HbA1c or the fasting plasma glucose level. In all models, multivariate regression analyses showed that the NAG index was correlated with age.nnnCONCLUSIONSnThese results suggest that postprandial hyperglycemia correlates with early renal tubule injury in type 2 diabetes mellitus.

Low-molecular-weight lipoprotein (a) and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease in patients with type 2 diabetes mellitus: Lp(a) phenotype, lymphocyte, and coronary heart disease

BackgroundThe aim of the present prospective study was to examine whether lipoprotein (a) [Lp(a)] phenotypes and/or low relative lymphocyte concentration (LRLC) are independently associated with coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM).MethodsSerum Lp(a) concentration, Lp(a) phenotypes, and RLC were analyzed in 214 subjects. Lp(a) phenotypes were classified into 7 subtypes according to sodium dodecyl sulfate-agarose gel electrophoresis by Western blotting. Subjects were assigned to the low-molecular-weight (LMW (number of KIV repeats: 11–22) ) and high-molecular-weight (HMW( number of KIV repeats: >22 )) Lp(a) groups according to Lp(a) phenotype and to the LRLC (RLC: <20.3%) and normal RLC (NRLC; RLC: ≥20.3%) groups according to RLC. A CHD event was defined as the occurrence of angina pectoris or myocardial infarction during the follow-up period.ResultsDuring the follow-up period, 30 cases of CHD events were verified. Neutrophil count showed no correlation with CHD, while relative neutrophil concentration and RLC showed positive and negative correlations, respectively, with CHD. The Cox proportional hazard model analysis revealed the following hazard ratios adjusted for LMW Lp(a), LRLC, and LMW Lp(a)u2009+u2009LRLC: (4.31; 95% confidence interval [CI], 1.99-9.32; Pu2009<u20090.01, 3.621; 95% CI, 1.50-8.75; Pu2009<u20090.05, and 7.15; 95% CI, 2.17-23.56; Pu2009<u20090.01, respectively).ConclusionsOur results suggest that both LMW Lp(a) and LRLC are significant and independent risk factors for CHD and that the combination thereof more strongly predicts CHD in patients with T2DM.