Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles

Six-year time-trend analysis of dyslipidemia among adults in Newfoundland and Labrador: findings from the laboratory information system between 2009 and 2014

Background: Dyslipidemia, an increased level of total cholesterol (TC), triglycerides (TG), low-density-lipoprotein cholesterol (LDL-C) and decreased level of high-density-lipoprotein cholesterol (HDL-C), is one of the most important risk factors for cardiovascular disease. We examined the six-year trend of dyslipidemia in Newfoundland and Labrador (NL), a Canadian province with a historically high prevalence of dyslipidemia. Methods: A serial cross-sectional study on all of the laboratory lipid tests available from 2009 to 2014 was performed. Dyslipidemia for every lipid component was defined using the Canadian Guidelines for the Diagnosis and Treatment of Dyslipidemia. The annual dyslipidemia rates for each component of serum lipid was examined. A fixed and random effect model was applied to adjust for confounding variables (sex and age) and random effects (residual variation in dyslipidemia over the years and redundancies caused by individuals being tested multiple times during the study period). Results: Between 2009 and 2014, a total of 875,208 records (mean age: 56.9 ± 14.1, 47.6% males) containing a lipid profile were identified. The prevalence of HDL-C and LDL-C dyslipidemia significantly decreased during this period (HDL-C: 35.8% in 2009 [95% CI 35.5-36.1], to 29.0% in 2014 [95% CI: 28.8-29.2], P = 0.03, and LDL-C: 35.2% in 2009 [95% CI: 34.9-35.4] to 32.1% in 2014 [95% CI: 31.9-32.3], P = 0.02). A stratification by sex, revealed no significant trend for any lipid element in females; however, in men, the previously observed trends were intensified and a new decreasing trend in dyslipidemia of TC was appeared (TC: 34.1% [95% CI 33.7-34.5] to 32.3% [95%CI: 32.0-32.6], p < 0.02, HDL-C: 33.8% (95%CI: 33.3-34.2) to 24.0% (95% CI: 23.7-24.3)], P < 0.01, LDL-C: 32.9% (95%CI:32.5-33.3) to 28.6 (95%CI: 28.3-28.9), P < 0.001). Adjustment for confounding factors and removing the residual noise by modeling the random effects did not change the significance. Conclusion: This study demonstrates a significant downward trend in the prevalence of LDL-C, HDL-C, and TC dyslipidemia, exclusively in men. These trends could be the result of males being the primary target for cardiovascular risk management

GIV as a Regulator of GLUT4 Trafficking : : A Novel Target for Modulating Insulin Resistance in Diabetes

Insulin resistance (IR) and Diabetes are well known risk factors for many cardiovascular diseases. IR is a result of dysregulated signaling downstream of the insulin receptor (InsR). Binding of insulin to its receptor triggers the activation of IRS1, which in turn activates the PI3K-Akt pathway and trimeric G protein, Gi, both prerequisites for the translocation of glucose transporters, GLUT4, to the plasma membrane (PM) and glucose uptake. In IR, circulating fatty acids activate PKC[theta], which phosphorylates and antagonizes IRS1- mediated responses. Efforts at reinstating sensitivity in IR simply by targeting the known players within the insulin signaling pathway have failed, and thus, the search for new targets continues. GIV (a.k.a. Girdin) has recently been identified as a multimodular signal transducer and a guanine nucleotide exchange factor (GEF) for Galphai, which enhances the PI3K-Akt pathway downstream of the InsR. Here we show that activation of Gi and PI3K-Akt signals via GIV's GEF function is critical for enhancing IRS1 activation and GLUT4 translocation to the PM. Phosphoinhibition of GIV's GEF function by PKC[theta] antagonized GIV-dependent IRS1 and Akt activation and translocation of GLUT4 to the PM. We conclude that GIV is one of the key mediators of insulin response that activates PI3K-Akt and Gi to maintain insulin sensitivity, and that its phosphoinhibition by the fatty-acid-PKC[theta] pathway contributes significantly to the development of IR. Future work unraveling how GIV-GEF mediates insulin response, and how its inhibition can trigger IR will offer a new target to combat IR and reverse/halt the progression of cardiovascular disease

GIV/girdin binds exocyst subunit-Exo70 and regulates exocytosis of GLUT4 storage vesicles

Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Gαi, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1-Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCθ pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response

Cardiac MRI in a Patient with Coincident Left Ventricular Non-Compaction and Hypertrophic Cardiomyopathy

Left ventricular non-compaction cardiomyopathy is a rare congenital cardiomyopathy that affects both children and adults. Since the clinical manifestations are not sufficient to establish diagnosis, echocardiography is the diagnostic tool that makes it possible to document ventricular non-compaction and establish prognostic factors. We report a 47-year-old woman with a history of dilated cardiomyopathy with unknown etiology. Echocardiography showed mild left ventricular enlargement with severe systolic dysfunction (EF = 20-25%). According to cardiac magnetic resonance imaging findings non-compaction left ventricle with hypertrophic cardiomyopathy was considered, and right ventricular septal biopsy was recommended. Right ventricular endomyocardial biopsy showed moderate hypertrophy of cardiac myocytes with foci of myocytolysis and moderate interstitial fibrosis. No evidence of infiltrative deposition was seen

Iranian Hepatitis C, chronic Transforming Growth Factor Beta1

Background: Chronic hepatitis C infection is caused by the hepatitis C virus (HCV), and its clinical complications include liver cirrhosis, liver failure, and hepatocellular carcinoma. Transforming growth factor-β1 (TGF-β1) is an important cytokine in cell growth and differentiation, angiogenesis, extracellular matrix formation, immune response regulation, and cancer development and progression. Objectives: The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in TGF-β1 and chronic HCV infection among patients referred to the Taleghani Hospital, Tehran, Iran between 2008 and 2010. Patients and Methods: In this case-control study, samples were collected using a convenience sampling method. We genotyped 164 HCV patients and 169 healthy controls for 3 SNPs in the TGF-β1 gene (-509 promoter, codon 10, and codon 25). We determined the SNP genotypes by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. To confirm the PCR-RFLP genotyping results, 10 % of the samples were re-genotyped using a direct sequencing method

Study of Parvovirus 4 Infection in HCV Infected Patients and Healthy Individuals Referred to Taleghani Hospital, Tehran.

Abstract Background: Parvovirus 4 (PARV4) was first discovered in 2005, in a hepatitis B virus–infected injecting drug user (IDU). To date, the best evidence about PARV4 transmission is parenteral roots and comes from IDU individuals. It seems that the prevalence of the virus in the normal population is very low. In this study, we investigated the prevalence of PARV4 virus among patients with chronic HCV infection compared with healthy controls and related risk factors among these groups. Materials and Methods: A total of 206 patients, including 103 patients with chronic HCV infection and 103 healthy controls, were studied by use of nested-PCR and also real-time PCR techniques. Results: AST enzyme levels with a mean of 40.45+34.84 and 18.58+5.9 in patients and healthy group respectively and the amount of enzyme ALT among patients with a mean of 40.45+35.75 and 21.50+11.35 in patients and healthy group respectively, were reported. Finally, after screening all DNA samples from patients and controls, we discovered that none of these people are infected with the PARV4 virus. Conclusion: This study is the first to investigate the occurrence of PARV4 among HCV patients in Iran. The results show that, the virus is not important in Iranian population, even in patients with blood born infections such as HCV and further studies in other areas and various groups are required