•Cerebral small vessel disease may lead to stroke, dementia, and depression.•We did a systematic review/meta-analysis of studies on these associations.•Strong and consistent associations were ...found.•In particular for combined MRI features of small vessel disease.•A substantial burden of disease is attributable to small vessel disease.
MRI features of cerebral small vessel disease (CSVD), i.e. white matter hyperintensities, lacunes, microbleeds, perivascular spaces, and cerebral atrophy, may be associated with clinical events, but the strength of these associations remains unclear. We conducted a systematic review and meta-analysis on the association between these features and incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. For the association with stroke, 36 studies were identified (number of individuals/events n = 38,432/4,136), for dementia 28 (n = 16,458/1,709), for depression nine (n = 9,538/1,746), and for mortality 28 (n = 23,031/2,558). Only two studies evaluated perivascular spaces; these results were not pooled. Pooled analyses showed that all other features were associated with all outcomes (hazard ratios ranged 1.22–2.72). Combinations of two features were more strongly associated with stroke than any individual feature. Individual features and combinations of CSVD features are strongly associated with incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. If these associations are causal, the strength of these associations suggests that a substantial burden of disease is attributable to CSVD.
The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the ...major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.
Type 2 diabetes is associated with cognitive dysfunction and structural brain changes. Abnormalities in glucose regulation are involved in several complications related to type 2 diabetes, but their ...role in these cerebral complications is unclear. We systematically reviewed studies of the association between glucose regulation (glycaemia, hypoglycaemic events, insulin concentration, insulin resistance, and glucose-lowering treatment) and cognitive function and brain abnormalities on MRI in people with type 2 diabetes. The 86 papers included showed that glycaemia, particularly high HbA1c concentration and glucose variability, are negatively associated with cognitive function in people with type 2 diabetes without dementia. However, the strength of this association is weak, and HbA1c generally accounted for less than 10% of the variance in cognition. Importantly, few studies have measured long-term cerebral outcomes, such as dementia and structural brain changes on MRI, and the effect of glucose-lowering treatment on these outcomes. More randomised controlled trials are needed to establish the effect of glucose-lowering treatment on long-term cognitive function in people with type 2 diabetes.
Aims/hypothesis
In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular ...complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes.
Methods
Wild-type and
Glo1
-overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques.
Results
Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by
Glo1
overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased podocyte number and diabetes-induced elevation of urinary markers albumin, osteopontin, kidney-inflammation-molecule-1 and nephrin) were attenuated by
Glo1
overexpression. In line with this, downregulation of
Glo1
in cultured endothelial cells resulted in increased expression of inflammation and endothelium dysfunction markers. In fully differentiated cultured podocytes incubation with MGO resulted in apoptosis.
Conclusions/interpretation
This study shows that effective regulation of the GLO-I enzyme is important in the prevention of vascular intracellular glycation, endothelial dysfunction and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes.
The endothelium is a complex organ with a multitude of properties essential for control of vascular functions. Dysfunction of the vascular endothelium is regarded as an important factor in the ...pathogenesis of diabetic micro- and macro-angiopathy. Endothelial dysfunction in Type I and II diabetes complicated by micro- or macro-albuminuria is generalized in that it affects many aspects of endothelial function and occurs not only in the kidney. The close linkage between microalbuminuria and endothelial dysfunction in diabetes is an attractive explanation for the fact that microalbuminuria is a risk marker for atherothrombosis. In Type I diabetes, endothelial dysfunction precedes and may cause diabetic microangiopathy, but it is not clear whether endothelial dysfunction is a feature of the diabetic state itself. In Type II diabetes, endothelial function is impaired from the onset of the disease and is strongly related to adverse outcomes. It is not clear whether impaired endothelial function is caused by hyperglycaemia or by other factors. Impaired endothelial function is closely associated with and may contribute to insulin resistance regardless of the presence of diabetes. Endothelial dysfunction in diabetes originates from three main sources. Hyperglycaemia and its immediate biochemical sequelae directly alter endothelial function or influence endothelial cell functioning indirectly by the synthesis of growth factors, cytokines and vasoactive agents in other cells. Finally, the components of the metabolic syndrome can impair endothelial function.
This study sought to investigate the association of local and segmental arterial stiffness with incident cardiovascular events and all-cause mortality.
The association of different stiffness indices, ...in particular of carotid, brachial, and femoral stiffness, with cardiovascular disease and mortality is currently unknown.
In a population-based cohort (n = 579, mean age 67 years, 50% women, 23% with type 2 diabetes by design), we assessed local stiffness of carotid, femoral, and brachial arteries (by ultrasonography), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index, and systemic arterial compliance.
After a median follow-up of 7.6 years, 130 participants had a cardiovascular event and 96 had died. The hazard ratios (HRs) (95% confidence intervals CIs) per 1 SD for cardiovascular events and all-cause mortality, respectively, were HR: 1.22 (95% CI: 0.95 to 1.56) and 1.51 (95% CI: 1.11 to 2.06) for lower carotid distensibility; HR: 1.19 (95% CI: 1.00 to 1.41) and 1.28 (95% CI: 1.07 to 1.53) for higher carotid elastic modulus; HR: 1.08 (95% CI: 0.88 to 1.31) and 1.43 (95% CI: 1.10 to 1.86) for lower carotid compliance; HR: 1.39 (95% CI: 1.06 to 1.83) and 1.27 (95% CI: 0.90 to 1.79) for lower femoral distensibility; HR: 1.25 (95% CI: 0.96 to 1.63) and 1.47 (95% CI: 1.01 to 2.13) for lower femoral compliance; and HR: 1.56 (95% CI: 1.23 to 1.98) and 1.13 (95% CI: 0.83 to 1.54) for higher cfPWV. These results were adjusted for age, sex, mean arterial pressure, and cardiovascular risk factors. Mutual adjustments for each of the other stiffness indices did not materially change these results. Brachial stiffness, augmentation index, and systemic arterial compliance were not associated with cardiovascular events or mortality.
Carotid and femoral stiffness indices are independently associated with incident cardiovascular events and all-cause mortality. The strength of these associations with events may differ per stiffness parameter.
Beyond antihyperglycemic effects, metformin may improve cardiovascular outcomes. Patients with type 2 diabetes often have an elevated plasma level of N-terminal pro B-type as a marker of (sub) ...clinical cardiovascular disease. We studied whether metformin was associated with a reduction in the serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) in these patients.
In the HOME trial 390 insulin-treated patients with type 2 diabetes were randomized to 850 mg metformin or placebo three times daily. Plasma samples were drawn at baseline, 4, 17, 30, 43 and 52 months. In a post-hoc analysis we analyzed the change in NT-proBNP in both groups. We used a longitudinal mixed model analysis adjusting for age, sex and prior cardiovascular disease. In a secondary analysis we assessed a possible immediate treatment effect post baseline.
Metformin did not affect NT-proBNP levels over time in the primary analysis (-1% 95%CI -4;3, p = 0.62). In the secondary analysis there was also no sustained time independent immediate treatment effect (initial increase of 17% 95%CI 4;30, p = 0.006 followed by yearly decrease of -4% 95%CI -7;0, p = 0.07).
Metformin as compared to placebo did not affect NT-proBNP plasma levels in this 4.3-year placebo-controlled trial. Potential cardioprotective effects of metformin cannot be explained by changes in cardiac pressures or volumes to the extent reflected by NT-proBNP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The gut microbiota evolves from birth and is in early life influenced by events such as birth mode, type of infant feeding, and maternal and infant antibiotics use. However, we still have a gap in ...our understanding of gut microbiota development in older children, and to what extent early events and pre-school lifestyle modulate the composition of the gut microbiota, and how this impinges on whole body metabolic regulation in school-age children.
Taking advantage of the KOALA Birth Cohort Study, a long-term prospective birth cohort in the Netherlands with extensive collection of high-quality host metadata, we applied shotgun metagenomics sequencing and systematically investigated the gut microbiota of children at 6-9 years of age. We demonstrated an overall adult-like gut microbiota in the 281 Dutch school-age children and identified 3 enterotypes dominated by the genera Bacteroides, Prevotella, and Bifidobacterium, respectively. Importantly, we found that breastfeeding duration in early life and pre-school dietary lifestyle correlated with the composition and functional competences of the gut microbiota in the children at school age. The correlations between pre-school dietary lifestyle and metabolic phenotypes exhibited a striking enterotype dependency. Thus, an inverse correlation between high dietary fiber consumption and low plasma insulin levels was only observed in individuals with the Bacteroides and Prevotella enterotypes, but not in Bifidobacterium enterotype individuals in whom the gut microbiota displayed overall lower microbial gene richness, alpha-diversity, functional potential for complex carbohydrate fermentation, and butyrate and succinate production. High total fat consumption and elevated plasma free fatty acid levels in the Bifidobacterium enterotype are associated with the co-occurrence of Streptococcus.
Our work highlights the persistent effects of breastfeeding duration and pre-school dietary lifestyle in affecting the gut microbiota in school-age children and reveals distinct compositional and functional potential in children according to enterotypes. The findings underscore enterotype-specific links between the host metabolic phenotypes and dietary patterns, emphasizing the importance of microbiome-based stratification when investigating metabolic responses to diets. Future diet intervention studies are clearly warranted to examine gut microbe-diet-host relationships to promote knowledge-based recommendations in relation to improving metabolic health in children.
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