Search

Obesity has become a public global health problem. More than 13% of the world’s 7.8 billion people (11% of men and 15% of women) are obese, defined as having a body mass index above 30 kg/m2. In North America and several Middle Eastern Countries, more than 30% of adults are obese. The alarming problem is that children as young as twelve years of age are now becoming obese. Obesity with high-fat and high-sugar diets is a risk factor for type 2 diabetes mellitus (T2DM), hypertension and early-onset heart failure (HF) with preserved ejection fraction (HFpEF) that leads to frequent hospitalizations. It is possible that diet, inactivity and other modern lifestyle factors may have an important role in the development of heart failure, either with or without decrease in ejection fraction [1]. This mini review discusses whether circadian oscillations in metabolism and inflammation could be responsible for the time-of-day-dependence of adverse cardio-vascular events in patients with HFpEF by increasing production of cytotoxic a-dicarbonyl species methylglyoxal (MG) and by decreasing expression of the primary MG-degrading enzyme glyoxalase-1 (Glo1), respectively.

Background and Purpose\ud Endothelial cell-mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia-reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs).\ud \ud Experimental Approach\ud Endothelial cell-mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia-reperfusion injury were assessed in brains of male Sprague-Dawley rats with streptozotocin-induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal-degrading enzyme glyoxalase-I (Glo-I) in cSMCs.\ud \ud \ud Key Results\ud After 7–8 weeks of T1D, endothelial cell-mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF-κB activity and TNF-α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid-cerebral artery exacerbated ischaemia-reperfusion injury. In cSMCs, Glo-I protein was decreased, and the methylglyoxal-synthesizing enzyme, vascular adhesion protein 1 (VAP-1) and methylglyoxal were increased. Restoring Glo-I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP-1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia-reperfusion injury and increased microvessel perfusion.\ud \ud Conclusions and Implications\ud Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia-reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D.

Heart failure and arrhythmias occur at rates 3-5 times higher in individuals with diabetes mellitus compared with age-matched, healthy individuals. Studies attribute these defects in part to alterations in function of cardiac ryanodine receptors (RyR2), the principal Ca2+ release channel on the internal sarcoplasmic reticulum (SR). To date, mechanisms underlying RyR2 dysregulation during diabetes remain poorly defined. A rat model of type 1 diabetes, in combination with echocardiography, in vivo and ex vivo hemodynamics, video edge-detection, confocal microscopy, Western blots, mass spectrometry, site-directed mutagenesis, [3H]ryanodine binding, lipid bilayer and transfection assays were used to ascertain if post-translational modifications by reactive carbonyl species (RCS) are a contributing cause. After 8 weeks of diabetes, spontaneous Ca2+ release in ventricular myocytes increased ~5-fold. Evoked Ca2+ release from the SR was also non-uniformed (dyssynchronous). Total RyR2 protein remained unchanged, but its ability to bind the Ca2+-dependent ligand [3H]ryanodine was significantly reduced. Western blots and mass spectrometry revealed RCS adducts on select basic residues. Mutating residues to delineate the physiochemical impact of carbonylation yielded channels with enhanced and reduced cytoplasmic Ca2+-responsiveness. The prototype RCS methylglyoxal (MGO) increased then decreased the open probability (Po) of RyR2. MGO also increased spontaneous Ca2+ release and induced Ca2+ waves in healthy myocytes. Treating diabetic rats with RCS scavengers normalized spontaneous and evoked Ca2+ release from the SR, reduced carbonylation of RyR2, and increased binding of [3H]ryanodine to RyR2. From these data we conclude that posttranslational modification by RCS is a contributing cause for heterogeneity in RyR2 activity seen during experimental diabetes.

Whole exome sequencing has provided significant opportunities to discover novel candidate genes for intellectual disability and autism spectrum disorders. Variants in the spectrin genes SPTAN1, SPTBN1, SPTBN2, and SPTBN4 have been associated with neurological disorders; however, SPTBN5 gene-variants have not been associated with any human disorder. This is the first report that associates SPTBN5 gene variants (ENSG00000137877: c.266A>C; p.His89Pro, c.9784G>A; p.Glu3262Lys, c.933C>G; p.Tyr311Ter, and c.8809A>T; p.Asn2937Tyr) causing neurodevelopmental phenotypes in four different families. The SPTBN5-associated clinical traits in our patients include intellectual disability (mild to severe), aggressive tendencies, accompanied by variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux. We also provide a review of the existing literature related to other spectrin genes, which highlights clinical features partially overlapping with SPTBN5.