The diterpene glycoside, rebaudioside A, does not improve glycemic control or affect blood pressure after eight weeks treatment in the Goto-Kakizaki rat

The plant, Stevia rebaudiana Bertoni (SrB), has been used for the treatment of diabetes in traditional medicine. Previously, we have demonstrated that long-term administration of the glycoside stevioside has insulinotropic, glucagonostatic, anti-hyperglycemic and blood pressure-lowering effects in type 2 diabetic animal models. The aim of this study was to elucidate if long-term administration of rebaudioside A, another glycoside isolated from the plant SrB, could improve glycemic control and lower blood pressure in an animal model of type 2 diabetes. We divided male Goto-Kakizaki (GK) rats into two groups which were fed a standard laboratory chow diet for eight weeks. The diet was supplemented with oral rebaudioside A (0.025 g/kg BW/day) in the experimental group. Blood glucose, weight, blood pressure and food intake were measured weekly. Animals were equipped with an intra-arterial catheter, and at week eight the conscious rats underwent an intra-arterial glucose tolerance test (IAGTT) (2.0 g/kg BW). During the IAGTT, the level of glucose, glucagon, and insulin responses did not differ significantly between the two groups. Fasting levels of glucose, glucagon, insulin or levels of blood lipids did not differ between the groups throughout the study period. We observed no effect on blood pressure or weight development. In conclusion, oral supplementation with rebaudioside A (0.025 g/kg BW/day) for eight weeks did not influence blood pressure or glycemic control in GK rats. Rebaudioside A failed to show the beneficial effects in diabetic animals previously demonstrated for stevioside.     

Different regulation of p27 and Akt during cardiomyocyte proliferation and hypertrophy

Postnatal cardiomyocytes normally grow by hypertrophy but show a limited proliferate response to certain stimuli. Although the proliferative capacity declines shortly after birth, neonatal cardiomyocytes can grow both by hypertrophy and by proliferation. Therefore, we have used neonatal cardiomyocytes to investigate the molecular differences between hypertrophic and proliferative growth of cardiomyocytes. Stimulation of neonatal cardiomyocytes with angiotensin II mainly induced hypertrophy, whereas PDGF only had a minor effect on the size of the myocytes. In contrast, PDGF induced significant proliferation in the cardiomyocyte cultures whereas angiotensin II treatment only resulted in a small increase in the number of cells. Measurement of cyclin D-dependent kinase specific phosphorylation of pRb by immunohistochemistry showed that, both stimuli activate the G1 phase of the cell cycle. By western blotting we found that PDGF-induced proliferation correlates with activation of Akt, inactivation of GSK-3β and downregulation of the cyclin-dependent kinase inhibitor p27, whereas angiotensin II only had a small effect on Akt, GSK-3β and p27. Our data support the hypothesis that, the hypertrophic and proliferative responses are both activated by G1 cell cycle molecules. The difference between the two responses appears to be that high amounts of p27 are present during hypertrophic growth, whereas proliferation involves downregulation of p27 and GSK-3β activity and upregulation of Akt.     

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.     

Islet transplantation to the renal subcapsular space in streptozotocin-diabetic rats: short-term effects on glucose-stimulated insulin secretion

The immediate and short-term effects of transplantation of freshly isolated islets on glucose-stimulated insulin secretion were studied in streptozotocin-diabetic rats. At 2 days after the intravenous injection of streptozotocin (70 mg/kg), either 400 or 1000 freshly isolated, hand-picked islets were transplanted to the left renal subcapsular space. Intravenous glucose infusion (10 mg/min) performed 1, 3, 6, and 10 days after transplantation revealed that already at day 3, rats transplanted with 1000 islets had a significant plasma insulin response to glucose, though the response was lower than in healthy controls. At 6 and 10 days after transplantation, the 1000 islet-transplanted group of rats had a near-normal plasma insulin response to glucose. Basal plasma glucose levels were, however, still slightly elevated. Rats transplanted with 400 islets had a significant plasma insulin response at 10 days after transplantation, though the response was lower than in those transplanted with 1000 islets. It is concluded that a near-normal in vivo insulin secretory response to glucose is already obtained 6 days after transplantation with 1000 freshly isolated islets to the left renal subcapsular space in streptozotocin-diabetic rats. However, a slight hyperglycemia persists.     

Atrial fibrillation: the role of common and rare genetic variants

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1–2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain- and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.