scholarly journals Global metabolic consequences of the chromogranin A-null model of hypertension: transcriptomic detection, pathway identification, and experimental verification

2010 ◽  
Vol 40 (3) ◽  
pp. 195-207 ◽  
Author(s):  
Ryan S. Friese ◽  
Jiaur R. Gayen ◽  
Nitish R. Mahapatra ◽  
Geert W. Schmid-Schönbein ◽  
Daniel T. O'Connor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Chromogranin A ◽  
Secretory Granules ◽  
Cholesterol Biosynthesis ◽  
Hepatic Cholesterol ◽  
The Metabolic Syndrome ◽  
Insight Into

Chromogranin A (CHGA) has a crucial role in formation of regulated secretory granules in neuroendocrine tissues and is also a prohormone that is proteolytically processed into peptides with diverse and complex actions. CHGA and several of its peptide products, including catestatin and pancreastatin, are implicated in pathogenesis of essential hypertension, insulin resistance, and the metabolic syndrome. The Chga knockout mouse (Chga KO) displays severe hypertension coupled with reduction in size, number, and density of regulated secretory granules. We performed genome-wide transcriptome profiling in Chga KO adrenal gland and liver for insight into biochemical and physiological systems altered in this monogenic mouse model of hypertension. Adrenal gene expression pathway prediction of enhanced insulin sensitivity ( P = 0.03) in Chga KO was confirmed with glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) measurements: blood glucose was normal in Chga KO, blood insulin was reduced 4.5-fold ( P < 0.0001), and HOMA-IR was decreased 3.8-fold ( P < 0.002). Remarkably, such observations conclusively dissociate fundamental features of the metabolic syndrome in this monogenic hypertension model. Exogenous pancreastatin treatment restored insulin sensitivity in the Chga KO to near-normal levels. Gene expression predictions of decreased adrenal cholesterol biosynthesis ( P < 0.001) and increased hepatic cholesterol biosynthesis ( P < 0.001) were verified with tissue total cholesterol assays: Chga KO adrenal cholesterol decreased 1.8-fold ( P = 0.039) and hepatic cholesterol increased 1.8-fold ( P = 0.018). Transcriptional regulatory network prediction identified sets of transcription factors that may provide insight into the unclear mechanistic links among CHGA, cholesterol, insulin sensitivity, and the metabolic syndrome. These experiments demonstrate, for the first time, that genetic variation at the CHGA locus impacts insulin sensitivity and tissue cholesterol levels in an intact, living organism. The Chga KO may constitute a unique model for studying the relationship between the CHGA locus and disease phenotypes of the metabolic syndrome.

Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension

Physiology ◽  
2007 ◽  
Vol 22 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Amy M. Jonk ◽  
Alfons J. H. M. Houben ◽  
Renate T. de Jongh ◽  
Erik H. Serné ◽  
Nicoloaas C. Schaper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Risk Factor ◽  
Microvascular Dysfunction ◽  
Important Risk Factor ◽  
Potential Mechanism ◽  
The Metabolic Syndrome ◽  
New Treatments ◽  
Insight Into

Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension.

scholarly journals Adiponectin Gene Expression and Plasma Values in Obese Women during Very-Low-Calorie Diet. Relationship with Cardiovascular Risk Factors and Insulin Resistance

2004 ◽  
Vol 89 (2) ◽  
pp. 756-760 ◽  
Author(s):  
Marta Garaulet ◽  
Nathalie Viguerie ◽  
Stefan Porubsky ◽  
Eva Klimcakova ◽  
Karine Clement ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Obese Women ◽  
Adiponectin Gene ◽  
Very Low Calorie Diet ◽  
Plasma Adiponectin ◽  
The Metabolic Syndrome ◽  
Low Calorie Diet ◽  
Calorie Diet

Adiponectin, a newly discovered adipose-tissue-specific protein, is thought to be involved in the regulation of insulin action. The aim of the present study was to determine whether adiponectin contributes to the improvement in insulin sensitivity during very-low-calorie diet (VLCD). Biopsies of sc abdominal adipose tissue and blood sampling for analysis of plasma adiponectin and related hormones and metabolites were performed before and at the end of a 4-wk VLCD in 33 nonmorbidly obese women (body mass index, 34.4 ± 4.1 kg/m2). VLCD produced a decrease in weight (7.1 ± 0.4 kg) and in insulin and leptin levels and led to an improvement in insulin sensitivity. Adiponectin gene expression and plasma levels were not modified during calorie restriction. Before VLCD, we found negative correlations between plasma adiponectin and variables related to the metabolic syndrome. Adiponectin mRNA levels showed a negative correlation with lipoprotein a plasma values. The correlations observed before VLCD were not found after VLCD. The data suggest that adiponectin is related to the protection against the metabolic syndrome but is not involved in the regulation of VLCD-induced improvement of insulin sensitivity.

IGF-I/IGFBP-3 ratio: a mechanistic insight into the metabolic syndrome

2009 ◽  
Vol 116 (6) ◽  
pp. 507-512 ◽  
Author(s):  
Justo Sierra-Johnson ◽  
Abel Romero-Corral ◽  
Virend K. Somers ◽  
Francisco Lopez-Jimenez ◽  
Anders Mälarstig ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Characteristic Curve ◽  
Model Assessment ◽  
Linear Regression Models ◽  
The Metabolic Syndrome ◽  
Igf I ◽  
Definition Of ◽  
Insight Into ◽  
Igfbp 3

Recent reports suggest that IGF (insulin-like growth factor)-I and IGFBP-3 (IGF-binding protein-3) have independent and opposing mechanistic effects on insulin. The aim of the present study was to assess the relationship between the IGF-I/IGFBP-3 ratio and the metabolic syndrome. We examined 3281 subjects (1463 men and 1818 women, aged 20–49 years), otherwise healthy adults, who participated in NHANES III (Third National Health and Nutrition Examination Survey), which has released measurements of IGF-I and IGFBP-3. Insulin resistance was estimated using the computer HOMA2 (homoeostatic model assessment 2) model. The updated ATP-III (Adult Treatment Panel III) definition of the metabolic syndrome was used. We applied adjusted logistic and linear regression models. After adjusting for age and race, men and women in the lowest quartile of the IGF-I/IGFBP-3 ratio were 3-fold more likely to meet the ATP-III definition of the metabolic syndrome and twice as likely to be insulin-resistant. Mean values of the IGF-I/IGFBP-3 ratio decreased significantly as the number of metabolic syndrome components increased (P<0.0001, as determined by ANOVA). The area under the ROC (receiver operating characteristic) curve for detecting insulin resistance using the IGF-I/IGFBP-3 ratio was 0.760, significantly improving upon either protein alone (P=0.01). In conclusion, the IGF-I/IGFBP-3 ratio is significantly associated with the metabolic syndrome. Calculating the ratio of these two proteins may provide insight into the metabolic syndrome clustering phenomenon.

scholarly journals Decreased insulin sensitivity in small for gestational age males treated with GH and preterm untreated males: a study in young adults.

2008 ◽  
Vol 158 (6) ◽  
pp. 899-904 ◽  
Author(s):  
J Rotteveel ◽  
M M van Weissenbruch ◽  
H A Delemarre-Van de Waal
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Birth Weight ◽  
Insulin Sensitivity ◽  
Low Birth Weight ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Gh Therapy ◽  
The Metabolic Syndrome ◽  
Preterm Born

BackgroundLow birth weight and preterm birth are associated with growth delay as well as the development of insulin resistance. Insulin resistance is especially seen in subjects with catch-up growth. GH therapy induces growth in short subjects with low birth weight at term, but little is known about the long-term effects on insulin sensitivity. GH therapy is now also proposed for preterms that remain short.MethodsWe investigated insulin sensitivity using the gold standard hyperinsulinemic-euglycemic clamp technique in 10 young adult males born small for gestational age (SGA) who had been treated with GH during childhood (GH) in comparison with 15 males born preterm AGA (premAGA), 13 males born preterm SGA (premSGA), and 15 males born at term with normal birth weight (CON). Furthermore, we investigated the presence of the metabolic syndrome.ResultsInsulin sensitivity was decreased in premAGA, premSGA, and GH subjects compared with CON males. The metabolic syndrome was not present in any of the groups.ConclusionInsulin sensitivity is decreased in GH-treated SGA born males as well as in preterm born males. With respect to the SGA subjects, whether the difference results from perinatal-, postnatal-, or GH therapy-related factors are not known. With respect to the preterm born subjects, close surveillance is needed when commencing GH therapy.

Sodium/lithium countertransport, insulin resistance, insulin peptides and microalbuminuria in clinically healthy 58-year-old men

2001 ◽  
Vol 100 (4) ◽  
pp. 443-449 ◽  
Author(s):  
Hans HERLITZ ◽  
Lena BOKEMARK ◽  
Eva-Lena ALENHAG ◽  
John WIKSTRAND ◽  
Björn FAGERBERG
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Univariate Analysis ◽  
Serum Triglycerides ◽  
The Metabolic Syndrome ◽  
Significant Difference ◽  
N 93 ◽  
Old Men

The activity of the erythrocyte transport system, sodium/lithium countertransport (SLC), has been linked to the metabolic syndrome characterized by insulin resistance and compensatory hyperinsulinaemia. We measured SLC and insulin sensitivity with the euglycaemic hyperinsulinaemic clamp method in a patient sample (n = 93) randomly selected from a large clinically healthy group of 58-year-old men (n = 818). The lipid profile, blood pressure, body mass index (BMI) and insulin were also analysed. There was a significant difference (P < 0.001) in SLC between subjects with the metabolic syndrome (n = 19) and subjects without any components of this syndrome (n = 20). There was a highly significant correlation between SLC and BMI, waist/hip ratio, total body fat mass, serum triglycerides, plasma insulin, proinsulin split products and C-peptide in a univariate analysis. There was also a significant correlation between SLC and insulin sensitivity measured as insulin-mediated glucose uptake (P < 0.01). In multiple regression analysis, only two of the variables showing univariate significance were independently correlated to SLC, i.e. serum triglycerides (P < 0.001) and BMI (P < 0.01). The subjects with a SLC value in the highest tertile had a 6-fold higher prevalence of insulin resistance (low-insulin-mediated glucose uptake) as compared with those with a SLC value in the lowest tertile. We conclude that, in clinically healthy 58-year-old men from the general population, erythrocyte SLC is closely linked to metabolic syndrome, in particular to obesity, triglycerides and insulin resistance.

Abstract 296: Decreased Hepatic Avpr1a Gene Expression and Elevated Serum Bile Acid in Mouse Model of Metabolic Syndrome

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Xiaoya Ma ◽  
Peter F Bodary
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Bile Acid ◽  
Bile Acids ◽  
Serum Bile Acid ◽  
Hepatic Gene Expression ◽  
Serum Bile Acids ◽  
Kk Mice ◽  
The Metabolic Syndrome

The KK/HIJ mouse has been demonstrated to have polygenic obesity and insulin resistance and serve as a model of metabolic syndrome. From microarray studies in this mouse strain, we observed hepatic gene expression of arginine vasopressin receptor 1A (Avpr1a) as the most differentially elevated gene in the liver following 3-week of voluntary wheel running activity. Subsequent studies validated that hepatic Avpr1a gene expression is significantly upregulated following voluntary activity and also highly suppressed (4 to 8-fold) in 2 independent models of insulin resistance (including obesity and lipoatrophic models). Although Avpr1a is highly abundant in the liver, its physiologic role is not well described. One proposed role for hepatic Avpr1a is mediation of vasopressin-induced bile acid secretion. To further evaluate the relationship between hepatic Avpr1a and bile acid homeostasis, we determined the age-related change in these variables in female KK mice. To investigate, adipose tissue, liver and serum were collected from female KK mice from before sexual maturity (PRE: 4.5 weeks old, n=9) and after sexual maturation (POST: 6 to 30 weeks old, n=12). Consistent with previous studies using this obesity-prone strain, we observed a robust increase in adiposity with age despite a standard rodent chow diet. RT-PCR studies of hepatic gene expression revealed a 53% lower Avpr1a in POST compared to PRE mice (p<0.00001). In parallel with the drop in hepatic Avpr1a gene expression was an increase in serum bile acids (PRE: 26.56± 9.98μmol/L; POST: 39.40± 9.63μmol/L; p<0.01). A negative correlation was evident between hepatic Avpr1a gene expression and serum bile acid level (R= -0.51). The change in Avpr1a and bile acids was pronounced at the age of onset of estrous cycling. In conclusion, female KK mice have a significant increase in fat mass with age in parallel with an elevation of serum bile acids and downregulation of hepatic Avpr1a gene expression. We propose that suppression of hepatic Avpr1a increases hydrophobic bile acids in the liver and serum and promotes hepatic inflammation, contributing to symptoms of the metabolic syndrome.

scholarly journals Surrogate Measures of Insulin Resistance in Middle-aged Non-diabetic Subjects

2013 ◽  
Vol 59 (6) ◽  
pp. 279-284
Author(s):  
Csép Katalin
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Fasting Insulin ◽  
Middle Aged ◽  
Insulin Levels ◽  
The Metabolic Syndrome ◽  
Sensitivity Indices ◽  
Increased Risk ◽  
Surrogate Measures

Abstract Objective: Insulin resistance has been shown to be a risk factor for type 2 diabetes and cardiovascular disease. The assessment of insulin sensitivity in the clinical practice, however, faces several difficulties. The study proposes to analyze surrogate measures of insulin resistance based on fasting insulin levels in central Romania, and check whether the diagnosis of the metabolic syndrome is an adequate strategy to identify middle-aged persons with reduced insulin sensitivity. Methods: Anthropometric measurements, metabolic profile, and surrogates measures of insulin sensitivity (GIR, HOMA, QUICKI, FIRI, Belfiore, Bennett, Raynaud, McAuley index) based on fasting insulin levels were assessed in 233 non-diabetic middle aged subjects. Results: Cutoff values, determined as the lowest quartile of insulin sensitivity for fasting insulin, HOMA, IRI (1/QUICKI), FIRI and Belfiore's, Bennett's, Raynaud's and McAuley's insulin sensitivity indices were 10.49 mU/L, 2.1, 3.01, 2.32, and 0.03, 1.34, 3.81, 6.29, 5.82. Components of the metabolic syndrome showed moderate but significant correlations with the surrogate measures of insulin resistance (r = 0.22-0.56, p <0.05). HOMA-IR and McAuley indices were the best predictors of clustered cardiometabolic risk factors (AUC - 0.83, 0.81 and 0.82). The metabolic syndrome diagnosis performed well in identifying patients with reduced insulin sensitivity (McAuley 2: sensitivity - 0.78, specificity - 0.84). Conclusion: Fasting insulin derived insulin sensitivity indices may help the recognittion of insulin resistant states predicting cardiometabolic disorders. Actively looking for insulin resistance by these simple indices, or by diagnosing the metabolic syndrome, those at increased risk can be recognized

scholarly journals Fasting insulin has a stronger association with an adverse cardiometabolic risk profile than insulin resistance: the RISC study

2009 ◽  
Vol 161 (2) ◽  
pp. 223-230 ◽  
Author(s):  
Susanne R de Rooij ◽  
Jacqueline M Dekker ◽  
Michaela Kozakova ◽  
Asimina Mitrakou ◽  
Olle Melander ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Odds Ratio ◽  
Cardiometabolic Risk ◽  
Oral Glucose ◽  
Fasting Insulin ◽  
Men And Women ◽  
The Metabolic Syndrome ◽  
Preclinical Atherosclerosis

ObjectiveFasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis.Design and methodsThe Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort consists of 1326 European non-diabetic, overall healthy men and women aged 30–60 years. We performed standard oral glucose tolerance tests and hyperinsulinemic euglycemic clamps. As a general measure of cardiovascular risk, we assessed the prevalence of the metabolic syndrome in 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis.ResultsFasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity (M/I) was correlated with most elements. The odds ratio for the metabolic syndrome of those in the highest quartile of fasting insulin compared with those in the lower quartiles was 5.4 (95% confidence interval (CI) 2.8–10.3, adjusted for insulin sensitivity) in men and 5.1 (2.6–9.9) in women. The odds ratio for metabolic syndrome of those with insulin sensitivity in the lowest quartile of the cohort compared with those in the higher quartiles was 2.4 (95% CI 1.3–4.7, adjusted for fasting insulin) in men and 1.6 (0.8–3.1) in women. Carotid IMT was only statistically significantly associated with fasting insulin in both men and women.ConclusionsFasting insulin, a simple and practical measure, may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy population than hyperinsulinemic euglycemic clamp-derived insulin sensitivity.

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