Ping Li

Aldosterone perturbs adiponectin and PAI-1 expression and secretion in 3T3-L1 adipocytes.

Aldosterone is considered as a new cardiovascular risk factor that plays an important role in metabolic syndrome; however, the underlying mechanism of these effects is not clear. Hypoadiponectinemia and elevated circulating concentration of plasminogen activator inhibitor-1 (PAI-1) are causally associated with obesity-related insulin resistance and cardiovascular disease. The aim of the present study is to investigate the effect of aldosterone on the production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Northern and Western blot analyses revealed that aldosterone treatment inhibited adiponectin mRNA expression and secretion and simultaneously enhanced PAI-1 mRNA expression and secretion in a time- and dose-dependent manner. Rosiglitazone did not prevent aldosterones effect on adiponectin or PAI-1 expression. In contrast, tumor necrosis factor (TNF)-α produced dramatic synergistic effects on adiponectin and PAI-1 expression when added together with aldosterone. Furthermore, the effects of aldosterone on adiponectin and PAI-1 expression appear to be mediated through glucocorticoid receptor (GR) but not mineralocorticoid receptor (MR). These results suggest that the effects of aldosterone on adiponectin and PAI-1 production are one of the underlying mechanisms linking it to insulin resistance, metabolic syndrome and cardiovascular disease.

SGK1 is regulated by metabolic-related factors in 3T3-L1 adipocytes and overexpressed in the adipose tissue of subjects with obesity and diabetes

AIMS The present study aimed to investigate the pathophysiological role of SGK1 in the development of metabolic syndrome by investigating the expression and regulation of serum and glucocorticoid-inducible kinase 1 (SGK1) in adipose tissues in obesity and diabetes. METHODS SGK1 expression in adipose tissue was investigated using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. SGK1 regulation in differentiated 3T3-L1 adipocytes by metabolic-related factors was assessed using Northern blot analysis. Humans with obesity and type 2 diabetes and KKAy and db/db mice were used to evaluate SGK1 expression in the adipose tissue of subjects with obesity and diabetes using quantitative real-time PCR and Western blot analysis. RESULTS SGK1 was expressed in white adipose tissue as shown by mRNA and protein levels. Aldosterone and glucocorticoids stimulated SGK1 expression in a time- and dose-dependent manner, whereas PPAR-γ agonists inhibited SGK1 expression in differentiated 3T3-L1 adipocytes. Furthermore, SGK1 mRNA and protein were overexpressed in the adipose tissue of mice and humans with obesity and type 2 diabetes. CONCLUSION Aldosterone, glucocorticoids and other factors contribute to excessive SGK1 expression in adipose tissue. This excessive SGK1 expression may be related to adipose tissue dysfunction, which may contribute to the development of obesity, diabetes and metabolic syndrome.

Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease†

The aim of the present study was to compare the effects of gliclazide, liraglutide, and metformin in type 2 diabetes mellitus (T2DM) patients with non‐alcoholic fatty liver disease (NAFLD).

Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: A randomized trial

To compare the effects of gliclazide, liraglutide and metformin on body composition in patients with type 2 diabetes mellitus with non‐alcoholic fatty liver disease.

Cardiovascular Autonomic Neuropathy Is an Independent Risk Factor for Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes

Aim This study aimed to evaluate the association between cardiovascular autonomic neuropathy (CAN) and left ventricular diastolic dysfunction (LVDD) in type 2 diabetes patients. Methods 315 type 2 diabetes patients from inpatients of Drum Tower Hospital were included and classified into no CAN (NCAN), possible CAN (PCAN), and definite CAN (DCAN) based on cardiovascular autonomic reflex tests. The left ventricular diastolic function was assessed by tissue Doppler imaging echocardiography. Results The distribution of NCAN, PCAN, and DCAN was 11.4%, 51.1%, and 37.5%, respectively. The proportion of LVDD increased among the groups of NCAN, PCAN, and DCAN (39.4%, 45.3%, and 68.0%, P = 0.001). Patients with DCAN had higher filling pressure (E/e′ ratio) (10.9 ± 2.7 versus 9.4 ± 2.8, P = 0.013) and impaired diastolic performance (e′) (6.8 ± 1.7 versus 8.6 ± 2.4, P = 0.004) compared with NCAN. CAN was found to be an independent risk factor for LVDD from the multivariate regression analysis (OR = 1.628, P = 0.009, 95% CI 1.131–2.344). Conclusions Our results indicated that CAN was an independent risk marker for the presence of LVDD in patients with diabetes. Early diagnosis and treatment of CAN are advocated for preventing LVDD in type 2 diabetes.

Effects of Exenatide on Metabolic Changes, Sexual Hormones, Inflammatory Cytokines, Adipokines, and Weight Change in a DHEA-Treated Rat Model

Insulin resistance and hyperandrogenism are the main features of polycystic ovarian syndrome (PCOS). Low-grade inflammation is also involved in PCOS. This study was performed to evaluate the effect of exenatide on metabolic changes, sexual hormones, inflammatory cytokines, adipokines, and weight changes in a dehydroepiandrosterone (DHEA)-treated rat model. After the model was produced by daily subcutaneous injections of DHEA, rats were given metformin (265 mg/kg), exenatide (10 μg/kg), and saline (1 mL). One group served as a control group. Blood samples and ovarian tissues were removed and prepared for biochemical and hormonal analyses. Exenatide significantly reduced body weight and insulin, testosterone, interleukin 6 (IL-6), PEDF, and visfatin levels. Exenatide also ameliorated changes in ovarian morphology, as evidenced by decreased numbers of cystic follicles and various follicles and elevated numbers of granular cell layers. The effects observed with exenatide were comparable to those observed with metformin. This study has provided evidence that exenatide may be efficient in the treatment of PCOS.

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

This study investigates the effectiveness and mechanisms of a serum- and glucocorticoid-inducible kinase 1 (SGK1) inhibitor in counteracting hyperglycemia. In an in vivo experiment, we demonstrated that after an 8-week treatment with an SGK1 inhibitor, the fasting blood glucose and HbA1c level significantly decreased in db/db mice. RT-PCR and western blot analyses revealed that intestinal SGK1 and sodium glucose co-transporter 1 (SGLT1) expression were enhanced in db/db mice. Treatment with an SGK1 inhibitor decreased excessive SGLT1 expression in the intestine of db/db mice. In vitro experiments with intestinal IEC-6 cells showed that the co-administration of an SGK1 inhibitor partly reversed the SGLT1 expression and glucose absorption that were induced by dexamethasone. In conclusion, this study revealed that the favorable effect of an SGK1 inhibitor on hyperglycemia is partly due to decreased glucose absorption through SGLT1 in the small intestine. These data collectively suggest that SGK1 may be a potent target for the treatment of diabetes and other metabolic disorders.

Clinical and Pathological Characteristics of Hypertensive and Normotensive Adrenal Pheochromocytomas

INTRODUCTION Pheochromocytoma/Paraganglioma (PPGL) present with an extremely variable clinical picture which ranges from dramatic, to mild, to silent, depending on tumor attitude to release catecholamines. Hypertension is the hallmark of these tumors but is not always present. Distinct differences of clinical manifestations exist in hypertensive pheochromocytomas (HPs) and normotensive pheochromocytomas (NPs), however the comparative analysis is lacking. METHODS The objective was to assess the clinical symptoms, hemodynamics, metabolism, radiological and histological features of patients with HPs and NPs. This study included 104 pheochromocytoma patients who were categorized into HPs (n=69) and NPs (n=35) groups. All clinical records were reviewed. Tumor samples were examined to determine the Adrenal Gland Scale Score and were available for measurement of gene transcriptions. Biochemical examinations of 95 subjects with primary hypertension (PH) were recorded for comparative study. RESULTS Patients with NPs showed lower proportion of clinical triad, inapparent metabolic disorders and lower urinary catecholamine levels than HPs, but higher than PH. Tumor weight positively correlated with 24 h urinary norepinephrine level in patients with HPs (P=0.028), and tumor diameter negatively correlated with phenylethanolamine-N-methyltransferase (PNMT) immunohistochemistry (P=0.011) in NPs but not in HPs. The Adrenal Gland Scale Score of NPs group was similar to that of HPs group. The positive percentage of epinephrine type (E-type) of catecholamine in HPs group was higher than that in the NPs. The transcript gene levels of PNMT, secretogranin II (SGII) and neuropeptide Y (NPY) from tissue samples were significantly lower in NPs than in HPs (PPNMT=0.038, PSGII=0.040, PNPY=0.032), while vesicular monoamine transporter 1 (VMAT1) had no difference between HPs and NPs (PVMAT1=0.053). CONCLUSION HPs and NPs have distinct differences in clinical, biochemical and pathological phenotypes, which are closely related with productions involved in tumor occurrence and development.

Adrenal androgen measurement for assessing the selectivity of adrenal venous sampling in primary aldosteronism

HighlightsCompared to cortisol, the AV/PV ratios of androstenedione and DHEA in AV samples were larger in AVS.Compared to cortisol, the concentrations of androstenedione and DHEA in AV samples were less variable over time in AVS.An SI ≥ 3 for androstenedione or DHEA provided optimal sensitivity and specificity in AVS. &NA; Adrenal venous sampling (AVS) is the reference standard for primary aldosteronism (PA) subtyping. Cortisol is widely used to assess the success of selective AVS, but it is not always reliable. The aim of the present study was to investigate the usefulness of adrenal androgens, compared to cortisol, in assessing the selectivity of AVS. We consecutively recruited 37 patients with PA undergoing AVS. AVS procedures were performed with the bilateral simultaneous technique without cosyntropin stimulation. We collected two baseline blood samples from 10 patients with a 15‐min interval between time‐15 (t‐15) and time 0 (t0) to measure the variability in the levels of the tested hormones over time. Cortisol, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS) concentrations were measured in adrenal and peripheral venous (AV and PV, respectively) samples. The selectivity index (SI) values for androstenedione and DHEA were on average 3.0‐ and 2.0‐fold higher, respectively, than those for cortisol, respectively (P < 0.05). However, the SI for DHEAS was 5.0‐fold lower than the SI for cortisol (P < 0.05). Plasma androstenedione and DHEA concentrations positively correlated with cortisol and aldosterone concentrations in AV samples (P < 0.01). Compared to cortisol, the variation ratio of AV androstenedione and DHEA decreased from t‐15 to t0 (0.23 and 0.43 vs. 0.52; P = 0.001 and P = 0.061, respectively). Using receiver operating characteristic curves, an SI ≥ 3 for androstenedione or DHEA provided optimal sensitivity and specificity in AVS. Given the much larger AV/PV ratios and reduced variability compared to cortisol, the adrenal androgens androstenedione and DHEA are useful for assessing the selectivity of AVS without cosyntropin stimulation and may be superior analytes in conditions with marked variability of cortisol levels or with adrenocortical tumors cosecreting cortisol and aldosterone.

Expression and Histopathological Significance of Disabled-2 in Aldosterone-Producing Adenoma

The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the zona glomerulosa (ZG) in rodents. The aim of the present study was to investigate the significance of immunohistochemical staining to detect DAB2 in the adrenal tissue of patients with APA. We investigated the expression of DAB2 in 36 adrenal glands with APA, 23 adrenal glands with cortisol-producing adenoma (CPA), and 33 adrenal glands with non-functioning adenoma (NFA). Immunohistochemical staining was performed using anti-DAB2 antibodies on paraffin-embedded sections. We analysed the expression of DAB2 semi-quantitatively by scoring staining intensity, and assessed the correlation of this information with the clinical findings. DAB2 mRNA expression in adenoma tissues was evaluated by RT-PCR. DAB2 was highly expressed in the ZG in normal human adrenal glands. DAB2 expression was heterogeneous in APA, with spotted, strong staining noted in most samples (25 of 36 APA). CPA and NFA also exhibited extensive low or moderate DAB2 expression. DAB2 mRNA was significantly increased and positively correlated with CYP11B2 in APA (p<0.05). In APA, the DAB2 score adjusted for tumour volume was positively correlated with plasma aldosterone (p<0.05). Patients with low or moderate DAB2 staining more frequently exhibited high blood pressure and were diagnosed at a younger age compared with patients with high DAB2 staining. The present study clearly demonstrates that DAB2 is a specific marker of the ZG in normal human adrenal glands but that DAB2 immunostaining is not sufficiently powerful for histopathological diagnosis of APA. DAB2 might be involved in excessive aldosterone biosynthesis and correlate with specific clinical characteristics of APA patients.