Cushing's syndrome (Cs) is caused by an autonomous and excessive secretion of glucocorticoids via ACTH-independent (adrenal cortisol-producing tumors) and ACTH-dependent (pituitary and ectopic ACTH-producing tumors) manner [1,2]. Chronic glucocorticoids excess causes central obesity, hypertension, insulin resistance and dyslipidemia, all of which are well-recognized cardiovascular risk factors [3,4]. In fact, it has been shown that CS patients have higher mortality rate of cardiovascular complications (myocardial infarction, congestive heart failure, stroke) than the age-and gender-matched normal population [5,6] Abstract. Cushing's syndrome (CS) as represented by chronic glucocorticoid excess is associated with increased rate of cardiovascular morbidity and mortality. because endothelial dysfunction is an early event of atherosclerosis, we investigated whether endothelial dysfunction is associated with CS and reversible. Twenty-one CS patients due to different causes were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), among whom 12 patients were re-evaluated after surgical and medical treatment; 12 age-and gender-matched subjects served as control. Percent (%) FMD in CS patients (5.8±1.9 %) was significantly (p =0.0014) lower than that in control subjects (8.1±1.7 %). In CS patients, %FMD showed significant (p <0.01) negative correlations with morning serum cortisol levels (r =-0.58) and 24-h urinary free cortisol excretion (r =-0.58). After surgical and medical treatment in CS patients, morning cortisol levels significantly (p =0.0025) decreased from 23.4 [15.6-37.3] to 10.2 [7.7-12.9] μg/dL, whereas %FMD significantly (p =0.0024) increased from 5.2±1.9 to 7.8±2.3 %; changes of %FMD after treatment significantly (p =0.0004) and inversely correlated with those of morning cortisol levels (r =-0.85), but not with those of body mass index, blood pressure, glycemic or lipid profiles. Taken together, the present study clearly revealed that endothelial dysfunction in CS patients is related to hypercortisolemia and reversible after treatment, suggesting the possible role of cortisol excess in the development of endothelial dysfunction, thereby possibly leading to increased cardiovascular complications.

Abstract. Endothelial dysfunction is considered to be an early event in the development of atherosclerosis. The present study was undertaken to evaluate endothelial function and biochemical markers in type 2 diabetes mellitus (T2dm) patients before and after treatment with or without pioglitazone (Pio). Forty-one T2dm patients without macroangiopathy were randomized to treatment with (n=20) or without (control, n=21) Pio for 12 weeks. Endothelial function was assessed by flow-mediated vasodilation (FMD) using a high-resolution ultrasound method before and after treatment. After treatment, HbA1c levels equally decreased in both groups, but PIO-treated group had significantly increased high-density lipoprotein cholesterol (hdL-c) levels, and decreased triglyceride, fasting insulin levels and homa-r. after treatment, increases in %FMD, plasma HDL-C and adiponectin (APN) levels were significantly greater in PIO-treated group than those in control group. Changes of %FMD showed significant positive correlations with those of plasma APN and HDL-C levels. In conclusion, the present study showed that treatment of T2dm improved endothelial function with greater increases in %FMD, APN and HDL-C levels in PIO-treated group than those in control group, suggesting the beneficial effect of PIO on endothelial function in T2dm.

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.

Telmisartan, a selective antagonist for angiotensin type1 receptor and a partial agonist for peroxisome proliferator-activated receptor-c, 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.

BackgroundIt remains unclear whether glycemic variability is related to diabetes microvascular disease, especially diabetes peripheral neuropathy (DPN). We investigated the association between glycemic variability and DPN with type 1 or 2 diabetes.MethodsForty patients (23 males and 17 females; aged 34–79 years) underwent continuous glucose monitoring (CGM) and a nerve conduction study (NCS). Glycemic variability was estimated by mean amplitude of glycemic excursions (MAGE) in CGM. DPN was quantitatively evaluated by NCS in the median, tibial, sural and medial plantar nerves.ResultsMAGE had a significantly positive correlation with disease duration and low-density lipoprotein cholesterol level (r = 0.462, p = 0.003; and r = 0.40, p = 0.011, respectively), and a significantly negative correlation with BMI and medial plantar compound nerve action potential amplitude (r = − 0.39, p = 0.012; and r = − 0.32, p = 0.042, respectively). Multivariate linear regression analysis with adjustment for clinical background showed that MAGE (β = − 0.49, p= 0.007) was independently associated with a higher risk of medial plantar neuropathy.ConclusionsGlycemic variability may be an independent risk factor for DPN.