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Endocrinology AND Hyperlipidemia [keywords]
- The effect of insulin on circulating PCSK9 in postmenopausal obese women. [JOURNAL ARTICLE]
- Clin Biochem 2014 Apr 8.
PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.The purpose of this study was to investigate the effects of chronic and acute hyperinsulinemia on PCSK9 in a large cohort of human subjects as well as at a cellular level.The in vivo effect of hyperinsulinemia on plasma PCSK9 concentration was studied using euglycemic-hyperinsulinemic clamps in 82 non-diabetic post-menopausal obese patients. We studied the in vitro effects of insulin stimulation on PCSK9 mRNA as well as on protein expression and secretion in HepG2 and Huh7 cells.Analysis of the pre and post-clamp data revealed a 15.4% (p<0.001) lowering of plasma PCSK9 concentration after acute insulin induction. In vitro studies post-insulin stimulation showed that mRNA levels of PCSK9 reduced by 25% in HepG2 cells (p<0.027) and by 59% in Huh7 cells (p<0.01). Intracellular concentration of PCSK9 were 10% lower in HepG2 cells (p<0.05) and 35% lower in Huh7 cells (p<0.05).Our results show an inhibitory effect of acute hyperinsulinemia on PCSK9 in humans both in vitro and in vivo. This data may assist in evaluating PCSK9 levels in individuals on insulin therapy.
- Validation of a Novel Clinical Prediction Score for Severe Coronary Artery Diseases before Elective Coronary Angiography. [Journal Article]
- PLoS One 2014; 9(4):e94493.
Coronary artery disease (CAD) severity is associated with patient prognosis. However, few efficient scoring systems have been developed to screen severe CAD in patients with stable angina and suspected CAD before coronary angiography. Here, we present a novel scoring system for CAD severity before elective coronary angiography.Five hundred fifty-one patients with stable angina who were admitted for coronary angiography were enrolled in this study. Patients were divided into training (n = 347) and validation (n = 204) cohorts. Severe CAD was defined as having a Gensini score of 20 or more. All patients underwent echocardiography (ECG) to detect ejection fraction and aortic valve calcification (AVC). Multivariable analysis was applied to determine independent risk factors and develop the scoring system.In the training cohort, age, male sex, AVC, abnormal ECG, diabetes, hyperlipidemia, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as independent factors for severe CAD by multivariable analysis, and the Severe Prediction Scoring (SPS) system was developed. C-indices of receiver operating characteristic (ROC) curves for severe CAD were 0.744 and 0.710 in the training and validation groups, respectively. The SPS system also performed well during calibration, as demonstrated by Hosmer-Lemeshow analysis in the validation group. Compared with the Diamond-Forrester score, the SPS system performed better for severe CAD prediction before elective coronary angiography.Severe CAD prediction was achieved by analyzing age, sex, AVC, ECG, diabetes status, and lipid levels. Angina patients who achieve high scores using this predicting system should undergo early coronary angiography.
- The clinical and cardiometabolic effects of d3-growth hormone receptor polymorphism in acromegaly. [JOURNAL ARTICLE]
- Pituitary 2014 Apr 6.
Exon 3-deleted GH receptor variant (d3-GHR) is associated with increased responsiveness to exogenous GH. The aim of this study was to determine the effect of d3-GHR polymorphism on the GH/IGF-1 relationship, clinical parameters, and comorbidity in acromegalic patients.The study included 118 acromegalic patients (61 female and 57 male; mean age: 50.3 ± 12.2 years) and 108 healthy controls (94 female and 14 male: mean age: 41.1 ± 11.1 years). The prevalence of GHR genotypes was evaluated via PCR.In all, 71 (60.2 %) patients had the fl/fl-GHR genotype, 40 (33.9 %) were heterozygous for the fl/d3-GHR genotype, and 7 (5.9 %) were homozygous for the d3/d3-GHR genotype. The prevalence of fl/fl-GHR, fl/d3-GHR, and d3/d3-GHR genotypes in the control group was 57.4, 29.6, and 13.0 %, respectively-similar prevalences as in the patient group. Patients that were heterozygous and homozygous for the d3 allele were subgrouped (d3-GHR subgroup), and were compared to those with the fl/fl-GHR genotype (fl/fl-GHR subgroup). Anthropometric measures, features of pituitary adenoma, and baseline GH and IGF-1 levels were similar in both subgroups. The prevalence of coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes mellitus, and multinodular goiter did not differ between patient subgroups. In total, 24 (20.3 %) of the patients had cancer and the prevalence of cancer was similar in the d3-GHR (14.9 %) and fl/fl-GHR (23.9 %) subgroups (P = 0.23). More of the acromegalic patients that were d3 carriers had discordant GH and IGF-1 levels at baseline and post surgery, but the difference was not significant. A significant correlation between basal GH and IGF-1 levels was observed only in the patients with the fl/fl-GHR genotype (R(2) = 0.227, P < 0.001).The d3-GHR variant genotype did not have an effect on clinical features or comorbidity in acromegalic patients, but it might play a role in GH/IGF-1 level discordance in acromegaly.
- Akt-dependent phosphorylation of hepatic FoxO1 is compartmentalized on a WD40/Propeller/FYVE scaffold and is selectively inhibited atypical PKC in early phases of diet-induced obesity. A mechanism for impairing gluconeogenic but not lipogenic enzyme expression. [JOURNAL ARTICLE]
- Diabetes 2014 Apr 4.
Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical PKC (aPKC) in liver and muscle, and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF mice, resting/basal and insulin-stimulated Akt and atypical PKC (aPKC) activities were diminished in muscle, but, in liver, these activities were elevated basally and were increased by insulin to normal levels. Despite elevated hepatic Akt activity, FoxO1 phosphorylation, which diminishes gluconeogenesis, was impaired; in contrast, Akt-dependent phosphorylation of glycogenic GSK3β and lipogenic mTOR was elevated. Diminished Akt-dependent FoxO1 phosphorylation was associated with_reduced Akt activity associated with scaffold protein, WD40/Propeller/FYVE, which reportedly facilitates FoxO1 phosphorylation. In contrast, aPKC activity associated with WD40/Propeller/FYVE was increased. Moreover, inhibition of hepatic aPKC reduced its association with WD40/Propeller/FYVE, restored WD40/Propeller/FYVE-associated Akt activity, restored FoxO1 phosphorylation, and corrected excessive expression of hepatic gluconeogenic and lipogenic enzymes. Additionally, Akt and aPKC activities in muscle improved, as did glucose intolerance, weight gain, hepatosteatosis and hyperlipidemia. We conclude that Akt-dependent FoxO1 phosphorylation occurs on the WD/Propeller/FYVE scaffold in liver and is selectively inhibited in early DIO by diet-induced increases in activity of co-compartmentalized aPKC.
- Clinical challenges in the management of isolated GH deficiency type IA in adulthood. [Journal Article]
- Endocrinol Diabetes Metab Case Rep 2014.:130057.
Isolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet.Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.
- Application of the back-error propagation artificial neural network (BPANN) on genetic variants in the PPAR-γ and RXR-α gene and risk of metabolic syndrome in a Chinese Han population. [Journal Article]
- J Biomed Res 2014 Mar; 28(2):114-22.
This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propagation artificial neural network (BPANN). We established the model based on data gathered from metabolic syndrome patients (n = 1012) and normal controls (n = 1069) by BPANN. Mean impact value (MIV) for each input variable was calculated and the sequence of factors was sorted according to their absolute MIVs. Generalized multifactor dimensionality reduction (GMDR) confirmed a joint effect of PPAR-γ and RXR-α based on the results from BPANN. By BPANN analysis, the sequences according to the importance of metabolic syndrome risk factors were in the order of body mass index (BMI), serum adiponectin, rs4240711, gender, rs4842194, family history of type 2 diabetes, rs2920502, physical activity, alcohol drinking, rs3856806, family history of hypertension, rs1045570, rs6537944, age, rs17817276, family history of hyperlipidemia, smoking, rs1801282 and rs3132291. However, no polymorphism was statistically significant in multiple logistic regression analysis. After controlling for environmental factors, A1, A2, B1 and B2 (rs4240711, rs4842194, rs2920502 and rs3856806) models were the best models (cross-validation consistency 10/10, P = 0.0107) with the GMDR method. In conclusion, the interaction of the PPAR-γ and RXR-α gene could play a role in susceptibility to metabolic syndrome. A more realistic model is obtained by using BPANN to screen out determinants of diseases of multiple etiologies like metabolic syndrome.
- Prevalence and Correlates of Erectile Dysfunction in Type 2 Diabetes Mellitus: A Cross-Sectional Single-Center Study Among Turkish Patients. [JOURNAL ARTICLE]
- Metab Syndr Relat Disord 2014 Mar 25.
Abstract Objective: The aim of this study was to evaluate prevalence of erectile dysfunction (ED) in patients with type 2 diabetes mellitus (T2DM) in relation to vascular and neurogenic correlates. Methods: A total of 116 males including T2DM patients [n=68; mean age, 56.7 (5.8) years] and age-matched healthy controls [n=48; mean age, 57.0 (6.6) years] were included in this cross-sectional single-center study. Data on anthropometrics, blood biochemistry, concomitant hypertension, hyperlipidemia, and coronary artery disease (CAD) were recorded in each subject along with measurement of carotid artery intima media thickness (CIMT) and evaluation of erectile dysfunction (ED) via International Index of Erectile Function (IIEF-5) Questionnaire. A univariate analysis was performed to determine the relationship of cardiovascular risk factors and diabetes-related complications to ED. Results: Patient and control groups were similar in terms of percentage patients with hyperlipidemia (51.5% and 39.6%, respectively) and CAD (33.8% and 22.9%, respectively), whereas concomitant hypertension was more common (P=0.05) and CIMT values were significantly higher (P=0.020) in patients with T2DM compared with controls. Polyneuropathy was noted in 46.2% of patients, nephropathy in 30.8%, and retinopathy in 33.8%. ED scores were significantly lower in patients than controls [14.3 (7.3) vs. 18.2 (6.3), P=0.004] with a significantly higher percentage of patients than controls in the category of severe dysfunction (29.4 vs. 10.4%, P=0.014). Univariate analysis revealed that diabetic polyneuropathy was the only factor to be associated with higher likelihood (93.3% in the presence and 60.0% in the absence of neuropathy) and severity (43.3% in the presence and 14.3% in the absence of neuropathy) of ED (P=0.004). Conclusion: Findings from the present cross-sectional single-center study revealed the prevalence of ED to be considerably higher in patients with T2DM than age-matched healthy controls, with identification of diabetic polyneuropathy as the only risk factor associated with higher likelihood and more severe forms of ED.
- Increased depression, diabetes and diabetic complications in Graves' disease patients in Asia. [JOURNAL ARTICLE]
- QJM 2014 Apr 9.
This study aimed to evaluate the risk of depression and other cardiovascular comorbidities in Graves' disease (GD) patients in Asia.The study patients were all newly diagnosed with GD [International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) 242.0] from January 1998 to December 2008. Patients aged <20 years or those with preexisting mental disorder (ICD-9-CM 290-319) were excluded from analyses. Control patients were randomly selected for the non-GD cohort, 1:4 frequency matched to the GD cohort according to sex, age and index year. The same exclusion criteria applied to the GD cohort were applied to the non-GD cohort. The GD cohort contained 4195 patients and the non-GD cohort contained 16 780 patients.The GD patients were more likely to have diabetes (8.03% vs. 4.48%, P < 0.0001), hypertension (18.1% vs. 13.5%, P < 0.0001), hyperlipidemia (11.9% vs. 9.09%, P < 0.0001) and coronary artery disease (10.3% vs. 5.86%, P < 0.0001) than the control patients were. The GD patients were also associated with significantly higher risk of depression than the control patients were (hazard ratio = 1.69, 95% confidence interval = 1.45-1.96).GD and GD treatment are associated with increased risk of depression diabetes and diabetic complications in Asian patients.
- Plasminogen Activator Inhibitor-1 Deficiency Ameliorates Insulin Resistance and Hyperlipidemia but not Bone Loss in Obese Female Mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 28.:en20131888.
We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is involved in type 1 diabetic bone loss in female mice. PAI-1 is well known as an adipogenic factor induced by obesity. We therefore examined the effects of PAI-1 deficiency on bone, glucose and lipid metabolism in high fat and high sucrose diet (HF/HSD)-induced obese female mice. Female wild-type (WT) and PAI-1-deficient (KO) mice were fed with HF/HSD or normal diet for 20 weeks from 10 weeks of age. HF/HSD increased the levels of plasma PAI-1 in WT mice. PAI-1 deficiency suppressed the levels of blood glucose, plasma insulin and total cholesterol elevated by obesity. Moreover, PAI-1 deficiency improved glucose intolerance and insulin resistance induced by obesity. Bone mineral density (BMD) at trabecular bone as well as the levels of Osterix and alkaline phosphatase, and receptor activator of nuclear factor κB ligand mRNA in tibia were decreased by HF/HSD in WT mice, and those changes by HF/HSD were not affected by PAI-1 deficiency. HF/HSD increased the levels of plasma TNF-α both in WT and PAI-1 KO mice, and the levels of plasma TNF-α were negatively correlated with trabecular BMD in tibia of female mice. In conclusion, we revealed that PAI-1 deficiency does not affect the trabecular bone loss induced by obesity despite the amelioration of insulin resistance and hyperlipidemia in female mice. Our data suggest that the changes of BMD and bone metabolism by obesity might be independent of PAI-1 as well as glucose and lipid metabolism.