BackgroundFamilial Mediterranean Fever (FMF) is an autoinflammatory disorder caused by mutations in the MEFV gene. These mutations appear in different populations with different frequencies and their caused symptom severities vary from mild to moderate to severe depending on the mutation type.MethodsIn this study, we analyzed the mutations that have been reported in the MEFV gene from symptomatic FMF patients and compared their frequencies in different populations from the 1000 Genome and the Exome databases, using statistical clustering. We also analyzed the nucleotide and amino acid substitution patterns across the MEFV gene.ResultsWe found 16 (8%) nonsynonymous mutations outside exon 10 that did not cluster with known disease‐causing mutations (DCMs), due to their high frequencies in other populations. We also studied the substitution patterns for nucleotides and amino acids to determine the conserved and variable regions in the MEFV gene. In general more nonsynonymous substitutions were reported in exons 2, 3, and 10 from the FMF database (symptomatic FMF patients) compared to the 1000 Genome and the Exome databases. The same was true for amino acid (AA) substitutions where there were 1.5 times more radical (RAD) to conservative (CON) changes. However, when it came to AA substitutions exon 10 was quite conserved with a RAD/CON ratio of 0.9. In fact, we report that the most severe FMF symptoms are caused by conservative mutations in two highly conserved exon 10 regions.ConclusionWe found presumptive FMF‐causing mutations that did not cluster with DCMs based on their allele frequencies. We also observed that the type of mutation is less likely to determine the severity of the FMF symptoms; rather it was the location of the mutations that was the determining factor.
While current thinking posits that insulin signaling to GLUT4 exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle causes a complete loss of insulinstimulated glucose uptake. Similarly, brief (i.e. 1 h) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulates this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects are due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurs downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.
Introduction: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. Methods: We used Cre-LoxP methodology to generate mice with a tamoxifen-inducible, conditional knock out of Ep300 and/or Crebbp in skeletal muscle. At 13-15 weeks of age, the knockout was induced via oral gavage of tamoxifen and oral glucose tolerance, ex vivo skeletal muscle insulin sensitivity, and microarray and proteomics analysis were done. Results: Loss of both p300 and CBP in adult mouse skeletal muscle rapidly and severely impairs whole body glucose tolerance and skeletal muscle insulin sensitivity. Furthermore, giving back a single allele of either p300 or CBP rescues both phenotypes. Moreover, the severe insulin resistance in the p300/CBP double knockout mice is accompanied by significant changes in both mRNA and protein expression of transcript/protein networks critical for insulin signaling, GLUT4 trafficking, and metabolism. Lastly, in human skeletal muscle samples, p300 and CBP protein levels correlate significantly and negatively with markers of insulin resistance. Conclusions: p300 and CBP are jointly required for maintaining whole body glucose tolerance and insulin sensitivity in skeletal muscle.
Introduction: Heart failure is one of the leading causes of morbidity and mortality globally. The use of beta blockers (BB) in patients with chronic heart failure is the cornerstone of guideline directed medical therapy and is recommended by national guidelines. However, BB are often discontinued when a patient is admitted to the hospital with ADHF, especially when inotropic support is needed. Little is known about the effects of continuing BB therapy in patients with ADHF requiring inotropes. This study sought to compare the effect of BB continuation vs discontinuation on in-hospital mortality among patients admitted to the hospital in ADHF requiring inotropic therapy. Methods: A single center, retrospective, non-blinded study was conducted in patients hospitalized with ADHF requiring inotropes over a three-year period. Inclusion criteria were patients ≥ 18 years of age admitted with ADHF and treated with inotropes (milrinone, dobutamine) from 1/1/2017-1/1/2020 at Wake Forest Baptist Medical Center. We assessed BB continuation and discontinuation on admission. Continuation of BB was defined as BB given at least 50% of patient’s hospitalization time. A time to event analysis framework was implemented using Cox proportional hazards models to analyze the effect of BB use on in-hospital mortality. Results: A total of 449 patients were admitted with ADHF requiring inotropes who met study criteria. Of those patients, 206 (45.9%) were admitted and continued on BB therapy. Continuation of BB therapy was associated with significant improvements in survival compared with patients whose BB was discontinued. Compared with the BB discontinuation group, a 70% reduction in the likelihood of in-hospital mortality was observed among individuals that continued BB therapy [HR 0.30, 95% Cl: 0.18-0.61, p<0.002]. Conclusion: In our study, among patients admitted with ADHF requiring inotropes, those continued on BB therapy were 70% less likely to die during their hospitalization.
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