[Cardiomyopathy induced by frequent premature ventricular complexes originating from the right ventricular outflow tract: left ventricular systolic function recovery after transcatheter ablation]. / Cardiomiopatia indotta da extrasistolia ventricolare frequente dal tratto di efflusso del ventricolo destro: recupero della funzione sistolica dopo ablazione transcatetere.

Left ventricular dysfunction due to frequent isolated premature ventricular complexes originating from the right ventricular outflow tract (RVOT) in patients without structural heart disease and in the absence of sustained ventricular tachycardia is a rare and poorly characterized entity. Successful identification and radiofrequency catheter ablation of the focal source of ventricular ectopy is the most effective treatment for these patients, leading to a complete normalization of ventricular dimensions and contractile function. In this article, we report two cases of left ventricular dysfunction resulting from frequent isolated premature ventricular complexes originating from the RVOT. After successful ablation of the ectopic focus, improvement of functional status and left ventricular function was observed in both patients, confirming the initial diagnostic hypothesis of a cardiomyopathy induced by repetitive ventricular ectopic beats from the RVOT.

High insulin levels impair intracellular receptor trafficking in human cultured myoblasts.

Chronic hyperinsulinemia is both a marker and a cause for insulin resistance. This study analyzes the effect of long-term exposure to high insulin levels on insulin-insulin receptor metabolism in human myoblasts. Cells were grown in the presence of low (107 pM, SkMC-L) or high (1430 pM, SkMC-H) insulin concentrations. Insulin receptor (IR) phosphorylation, IR internalization, dissociation and recycling, as well as insulin degradation have been investigated. Basal IR phosphorylation was higher in SkMC-H than in SkMC-L (P<0.01) but after acute insulin stimulation (10nM insulin for 10 min), IR phosphorylation increased (P<0.01) in SkMC-L, but not in SkMC-H. Chronic hyperinsulinism significantly decreased insulin-IR complex internalization (P<0.01). Nevertheless the t(1/2) value of receptor internalization was similar in both cells. Intracellular dissociation of insulin-IR complex was slightly but significantly lower in SkMC-H than in SkMC-L. Finally, SkMC-H showed a complete, but significantly delayed recycling of IR to plasma membrane (t(1/2)=20 min versus SkMC-L t(1/2)=7 min). The time course of intracellular degradation measured by HPLC, showed whenever studied, significantly (P<0.01) higher levels of intracellular intact insulin in cells exposed to high insulin concentrations. Nevertheless, the patterns of insulin degradation were over-imposable between SkMC-H and SkMC-L. In summary, continuous exposure of cultured myoblasts to high insulin levels induces subtle derangements of intracellular receptor trafficking and insulin degradation. These alterations may contribute to the insulin resistance of hyperinsulinemic states such as obesity and Type 2 Diabetes.

Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts.

Chronic hyperinsulinemia is both a marker and a cause for insulin resistance. This study analyzes the effect of long-term exposure to high insulin levels on the insulin-signaling pathway and glucose transport in cultured human myoblasts. Human myoblasts were grown in the presence of low (107 pmol/L, SkMC-L) or high (1430 pmol/L, SkMC-H) insulin concentrations for 3 weeks. Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. Basal glucose transport was similar in SkMC-L and SkMC-H, but after short-term insulin stimulation significantly increased (P < .01) only in SkMC-L. IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. Serine phosphorylation of IRS1 was similar in SkMC-L and SkMC-H. Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. These alterations may contribute to the derangement insulin-signaling pathway states of hyperinsulinemia such as obesity and type 2 diabetes.

Insulin permeability across an in vitro dynamic model of endothelium.

PURPOSE: Endothelium insulin permeability was investigated using in vitro, dynamic culture of endothelial cells. METHODS: Endothelial cells were cultured in a hollow fiber apparatus and continuously exposed to a flow. Transendothelial electrical resistance and permeability to [14C]sucrose and [14C]inulin were used to monitor the integrity of the endothelial monolayer. RESULTS: Under these experimental conditions, measurements of insulin permeability, investigated at increasing hormone concentrations, suggested that the predominant transendothelial insulin fluxes were attributable to bidirectional convective transport rather than to a saturable transport mechanism, in agreement with in vivo experiment results published earlier. Analytical determinations of insulin catabolism demonstrated a low percent of insulin degradation by the endothelium, leading to production of insulin metabolites qualitatively identical to those produced by human monocytes. CONCLUSIONS: The findings of this paper indicated that (a) insulin crosses the endothelial monolayer by paracellular "leak" and endothelial insulin receptors have a minor (if any) role in insulin transport; (b) degradation of the hormone by BAEC is minimal; (c) the in vitro, dynamic culture of endothelial cells presented here should represent a valuable transport model system to study permeability mechanisms of insulin and many other drugs.

Obesity modulates the expression of haptoglobin in the white adipose tissue via TNFalpha.

Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor alpha (TNFalpha) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) A(y), ob/ob and goldthioglucose-treated mice (10-, 8-, and 7-fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFalpha in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFalpha in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFalpha function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFalpha is an important signal for this regulation.