Effect of Exercise Therapy on Incident Admission in Patients with Type 2 Diabetes Mellitus Undergoing Inpatient Diabetes Self-management Education and Support Tokyo Metropolitan Toshima Hospital, Tokyo Metropolitan Hospital Organization, Japan.

BACKGROUND: Exercise therapy is the key to preventing admission of patients with type 2 diabetes mellitus (T2DM). However, a few studies have examined the effects of exercise therapy on patients with T2DM undergoing inpatient diabetes self-management education and support (IDSMES). OBJECTIVE: This study investigated whether exercise therapy influenced the incidence of admission after discharge in patients with T2DM undergoing IDSMES. METHODS: This retrospective cohort study included patients with T2DM who underwent IDSMES between June 2011 and May 2015. Overall, 258 patients were included in this study. The exercise therapy program was implemented in June 2013. Accordingly, patients diagnosed between June 2011 and May 2013 were categorized as the non-exercise therapy program group, while those diagnosed between June 2013 and May 2015 were categorized as the exercise therapy program group. Outcomes were incident diabetes-related and all-cause admissions within 1 year of discharge. Multiple logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the exercise therapy program's impact on the outcomes. RESULTS: Within 1 year of discharge, 27 (10.5%) patients underwent diabetes-related admissions and 62 (24.0%) underwent all-cause admissions. Multiple logistic regression analyses showed a significant association of the exercise therapy program with incident diabetes-related and allcause admissions [OR: 0.22 (95% CI: 0.08-0.59) and 0.44 (95% CI: 0.22-0.86), respectively]. CONCLUSION: Exercise therapy programs significantly lowered the incidences of diabetes-related and all-cause admissions. This indicates that implementing exercise therapy during hospitalization may be important for preventing admissions of patients with T2DM receiving IDSMES.

Relationship Between Long-Term Objectively Measured Physical Activity and Glycemic Control in Type 2 Diabetes Mellitus Patients: A Prospective Cohort Study.

INTRODUCTION: Increasing physical activity (PA) improves glycemic control in patients with type 2 diabetes mellitus (T2DM). However, whether long-term objectively measured PA is related to glycemic control remains unclear. The aim of this study was to investigate the relationship between long-term objectively measured PA and glycemic control in T2DM patients. RESEARCH DESIGN AND METHODS: This prospective cohort study recruited T2DM patients admitted to a hospital-based diabetes management and education program. The primary outcome was glycemic control by hemoglobin A1c at 6 months after discharge. We defined poor glycemic control according to the Japanese Clinical Practice Guidelines. The PA was objectively measured using a three-axis accelerometer during 6 months' period after discharge. The representative value of PA was the average daily steps during the measurement period and was divided into quartiles. To determine the relationship between the daily steps and poor glycemic control, we performed a multivariate logistic regression analysis. RESULTS: Ninety-four participants were enrolled in the study. Their median age was 59 years, and 38 (40.0%) of them showed poor glycemic control. Multivariate logistic regression analysis showed that the first (Q1, ≤ 6106 steps/day) and second quartiles (Q2, 6107-8258 steps/day) had significantly elevated risks of poor glycemic control compared to Q4 (≥ 10,542 steps/day), with odds ratios of 8.55 [95% confidence intervals (CI) =1.43-51.23] and 15.62 (95% CI 2.63-92.87), respectively. CONCLUSION: We found that lesser PA was significantly associated with poor glycemic control in T2DM patients. This finding may be beneficial for clinicians while providing long-term advice to diabetic patients.

Isolated adrenocorticotropin deficiency associated with delirium and takotsubo cardiomyopathy.

We report a 65-year-old woman with isolated adrenocorticotropic hormone (ACTH) deficiency. The patient was transported to the emergency outpatient department by ambulance complaining of malaise and nausea. Because her laboratory data revealed hyponatremia, we performed endocrinological examinations and diagnosed isolated ACTH deficiency. After admission, she went into a delirious state and suffered from takotsubo cardiomyopathy due to adrenal insufficiency. Replacement therapy with hydrocortisone sufficiently improved her delirium and cardiomyopathy. We conclude that her unstable mental state and myocardial dysfunction were closely related to adrenal insufficiency and suggest that adrenal crisis may cause delirium and Takotsubo cardiomyopathy.

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

Subclinical Cushing's 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.

Improvement of endothelial dysfunction in acromegaly after transsphenoidal surgery.

Flow-mediated vasodilatation (FMD) is a vascular functional test to detect endothelial dysfunction at the early stage of cardiovascular diseases. Patients with active acromegaly have higher morbidity and mortality due to cardiovascular events. To determine whether active acromegaly is associated with endothelial dysfunction, we studied 17 patients with active acromegaly for measurements of FMD, carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), and other biochemical parameters before and 3 months after transsphenoidal surgery (TSS). Baseline %FMD in patients with active acromegaly was significantly lower than that in age- and sex-matched control subjects. After TSS, the mean %FMD in acromegaly significantly increased from 5.3% to 7.4%; 12 patients had increased %FMD (responders), whereas 5 patients had decreased or unchanged %FMD (non-responders). However, neither carotid IMT nor baPWV changed after TSS. Serum levels of GH, insulin-like growth factor (IGF)-1, total cholesterol, low-density lipoprotein cholesterol (LDL-C), hemoglobin HA(1C), fasting plasma glucose and insulin levels, and homeostasis model assessment (HOMA)-R significantly decreased, whereas high-density lipoprotein cholesterol significantly increased. Responders had significantly lower baseline %FMD than did non-responders and both insulin levels and HOMA-R significantly decreased in responders, but not in non-responders after TSS. Simple regression analysis revealed that the change of %FMD showed a significant negative correlation with that of LDL-C, but not of IGF-1 or GH, in responders. In conclusion, it is suggested that endothelial dysfunction associated with active acromegaly improves soon after TSS, which is related to LDL-C and/or insulin resistance, but not to excess GH and/or IGF-1 itself.

Aldosterone induces superoxide generation via Rac1 activation in endothelial cells.

Currently, aldosterone is believed to be involved in the development of cardiovascular injury as a potential cardiovascular risk hormone. However, its exact cellular mechanisms remain obscure. This study was undertaken to examine the effect of aldosterone on superoxide production in cultured rat aortic endothelial cells with possible involvement of the small GTP-binding (G) protein Rac1. The aldosterone levels showed a time-dependent (6-24 h) and dose-dependent (10(-8) to 10(-6) m) increase in superoxide generation, whose effect was abolished by mineralocorticoid receptor antagonist (eplerenone), Src inhibitor (PP2), and reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitor (apocynin). Aldosterone activated NADP(H) oxidase and Rac1, whose effects were abolished by eplerenone. The aldosterone-induced superoxide generation was abolished either by nonselective small G protein inhibitor (Clostridium difficile toxin A) or dominant-negative Rac1. Dominant-negative Rac1 also inhibited aldosterone-induced ACE gene expression. Thus, the present study is the first to demonstrate that aldosterone induces superoxide generation via mineralocorticoid receptor-mediated activation of NAD(P)H-oxidase and Rac1 in endothelial cells, thereby contributing to the development of aldosterone-induced vascular injury.

Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice.

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg.d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.

Advanced endothelial dysfunction in diabetic patients with multiple risk factors; importance of insulin resistance.

AIM: Endothelial dysfunction is considered an early event in the development of atherosclerosis. The present study was undertaken to determine whether the accumulation of cardiovascular risk factors and insulin resistance are associated with endothelial function in diabetic patients. METHODS: 101 patients with type 2 diabetes without macroangiopathy stratified by the number of cardiovascular risk factors (dyslipidemia, hypertension, obesity) and 9 normal control subjects were studied for vascular endothelial functions by measuring flow-mediated vasodilation (FMD) using a high-resolution ultrasound method, brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (IMT), and the ankle-brachial index (ABI). RESULTS: FMD negatively correlated with baPWV and carotid IMT, and positively correlated with ABI. FMD was significantly lower in diabetic patients associated with 3 other risk factors than in those with diabetes alone. In subjects with fasting plasma glucose < or = 140mg/dL, FMD showed significant negative correlations with fasting insulin levels and homeostasis model assessment (HOMA)-R. Multivariate analysis revealed that insulin resistance as represented by HOMA-R and systolic blood pressure showed a significant association with impaired FMD. CONCLUSION: The present results suggest that the accumulation of cardiovascular risk factors is associated with endothelial dysfunction in diabetic patients, and that insulin resistance as well as high blood pressure could play a pathogenic role in the development of endothelial dysfunction.

Aldosterone increases osteopontin gene expression in rat endothelial cells.

Aldosterone is currently recognized as one of the important risk hormones for cardiovascular disease. However, the cellular mechanism by which aldosterone affects the process of cardiovascular injury has not been well understood. In the present study, we investigated whether aldosterone induces pro-inflammatory genes expression in rat aortic endothelial cells. Aldosterone significantly increased steady-state osteopontin mRNA and protein levels, but not those of adhesion molecules or chemokine. The stimulatory effect of aldosterone on osteopontin expression was time-dependent (3-24h) and dose-dependent (10(-10)-10(-6)M), and abolished by a mineralocorticoid receptor (MR) antagonist spironolactone, but not by a glucocorticoid receptor antagonist RU486. The aldosterone-induced osteopontin mRNA expression was completely blocked by a transcription inhibitor, actinomycin D, and a protein synthesis inhibitor, cycloheximide. Thus, the present study demonstrated for the first time that aldosterone directly acts on endothelial cells to induce osteopontin gene expression via MR-mediated genomic action, which may be responsible for the initiation of inflammation and fibrosis in cardiovascular tissue induced by aldosterone.