26 research outputs found

    Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells

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    Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function

    Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

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    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

    Early discharge and return to work following myocardial infarction

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    Individuals who have experienced a myocardial infarction (MI) account for the largest component of all hospitalization costs and foregone earnings due to cardiac disease. Early return to full employment and premorbid activity level should be the focus of cost-effective rehabilitative programs. Yet the economic benefits of vocational rehabilitation have not been directly researched. Therefore, issues of import regarding activity after MI include the timing of ambulation, discharge and return to work. Studies of early mobilization and discharge are contrasted in terms of methodology and outcome. These cite economic, social and psychological advantages, yet these factors are examined in isolation of other variables. A review of the literature reveals that there is a reluctance by many health professionals to institute such practices based in part on the dilemma surrounding selection of specific indicators and risk factors. Yet analysis reveals that the contention surrounding these exclusion criteria is perhaps unfounded, as the variance is less than is commonly assumed. Recurrent themes likewise emerge regarding the multiplicity of variables associated with the timing of resumption of employment, which is considered to be the most precise index of recovery following an MI. Of these, only early intense rehabilitation, directed at attitudinal and behavioural change, is amenable to modification by health professionals. Related research endeavours have examined employment following aortocoronary bypass surgery, risk factors in the work environment and work stressors which occur following MI. Controversy arises regarding the correlation of age and personality factors with return to work. Discrepancies in research findings are attributed to the diverse approaches to data collection, obstacles encountered in measuring psychological states, lack of operational definitions, differences in degree of rehabilitation and length of follow-up and the absence of controlled trials. Clearly, experimental research focusing on the job-related economic and human cost impact of specific rehabilitation programs must be conducted. Three strategies are identified which should facilitate return to premorbid levels of activity, including (1) the definition, development and integration of roles of diverse professionals within the interdisciplinary health care team, (2) the early detection and modification of psychological problems, physical disability and inappropriate occupations which would prevent MI patients from returning to their former occupations and (3) prompt follow-up and comprehensive structured rehabilitation programs which incorporate education, exercise and emotional support at the individual, family and community level. This analytical survey supports the principle of early mobilization, discharge and return to employment or premorbid state, yet operational definitions and deadlines are only in the infancy stage. Multidisciplinary experimental efforts must be directed toward the detection of significant variables and generalizable rehabilitation mechanisms. The process of programs requires testing as do the emotional, physical and health outcomes.

    Dyadic social-support for cardiac surgery patients--A Canadian approach

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    Over the past 15 years there has been a substantial increase in the number of cardiac operations being performed. The role of the lay helper volunteer who has successfully recovered from cardiac surgery, offering support to individuals about to undergo similar surgery, is earning a legitimate place in cardiac rehabilitation. This 'living proof' model of support appears to have a significant buffering effect through increasing the cardiac patients' readiness for cardiac surgery and motivation for cardiac rehabilitation. Most literature focuses on individuals who have suffered a myocardial infarction rather than those who must undergo cardiac surgery. The focus of this article is lay volunteer dyadic social-support for open-heart surgery patients. The authors describe such a program operating in Halifax, Nova Scotia, designed to link volunteers who have successfully recovered from open-heart surgery with those individuals about to undergo similar surgery. Comparisons are also made with parallel support programs in Canada and the United States. Thus far, only crude measurements of the effectiveness of this particular social-support intervention are available. The dyadic social-support that volunteers offer cardiac surgery patients seems to be effective as evidenced by the information discussed in this paper.dyadic social support cardiac surgery Canada and United States

    Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

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    Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects

    Erratum: Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms(Genet Med (2021)23(103-110)(s41436020009394)(10.1038/s41436-020-00939-4))

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    Correction to: Genetics in Medicine 2021; https://doi.org/10.1038/s41436-020-00939-4 In the article “Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms” by van Walree ES et al (Genet Med 2021;23:103-110), there was an error in a sentence in the Methods section of the abstract. This sentence should read “To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 controls, and the other 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls.