Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that
) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and ...constitutes a vicious cycle;
) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and
) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation.
Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered ...classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.
The Maastricht Study is an extensive phenotyping study that focuses on the etiology of type 2 diabetes (T2DM), its classic complications, and its emerging comorbidities. The study uses ...state-of-the-art imaging techniques and extensive biobanking to determine health status in a population-based cohort of 10,000 individuals that is enriched with T2DM individuals. Enrollment started in November 2010 and is anticipated to last 5-7 years. The Maastricht Study is expected to become one of the most extensive phenotyping studies in both the general population and T2DM participants worldwide. The Maastricht study will specifically focus on possible mechanisms that may explain why T2DM accelerates the development and progression of classic complications, such as cardiovascular disease, retinopathy, neuropathy and nephropathy and of emerging comorbidities, such as cognitive decline, depression, and gastrointestinal, musculoskeletal and respiratory diseases. In addition, it will also examine the association of these variables with quality of life and use of health care resources. This paper describes the rationale, overall study design, recruitment strategy and methods of basic measurements, and gives an overview of all measurements that are performed within The Maastricht Study.
To investigate the impact of activities of daily living (ADL) versus moderate-intensity endurance-type exercise on 24-h glycemic control in patients with type 2 diabetes.
Twenty males with type 2 ...diabetes participated in a randomized crossover study consisting of three experimental periods of 3 days each. Subjects were studied under sedentary control conditions, and under conditions in which prolonged sedentary time was reduced either by three 15-min bouts of ADL (postmeal strolling, ∼3 METs) or by a single 45-min bout of moderate-intensity endurance-type exercise (∼6 METs). Blood glucose concentrations were assessed by continuous glucose monitoring, and plasma insulin concentrations were determined in frequently sampled venous blood samples.
Hyperglycemia (glucose >10 mmol/L) was experienced for 6 h 51 min ±1 h 4 min per day during the sedentary control condition and was significantly reduced by exercise (4 h 47 min ± 1 h 2 min; P < 0.001), but not by ADL (6 h 2 min ± 1 h 16 min; P = 0.67). The cumulative glucose incremental areas under the curve (AUCs) of breakfast, lunch, and dinner were, respectively, 35 ± 5% (P < 0.001) and 17 ± 6% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition. The insulin incremental AUCs were, respectively, 33 ± 4% (P < 0.001) and 17 ± 5% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition.
When matched for total duration, moderate-intensity endurance-type exercise represents a more effective strategy to improve daily blood glucose homeostasis than repeated bouts of ADL. Nevertheless, the introduction of repeated bouts of ADL during prolonged sedentary behavior forms a valuable strategy to improve postprandial glucose handling in patients with type 2 diabetes.
•We present a validated LC–MS/MS method to determine AGE concentration in foods.•Three major AGEs were determined; CML, CEL and MG-H1.•High-heat processed food items were high in AGE content.•Fruits, ...vegetables, butter and coffee had the lowest AGE content.•We present a 190-item AGE database that can be used to quantify dietary AGE intake.
The aim of this study was to validate an ultra-performance liquid chromatography tandem mass-spectrometry (UPLC–MS/MS) method for the determination of advanced glycation endproducts (AGEs) in food items and to analyze AGEs in a selection of food items commonly consumed in a Western diet. Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were quantified in the protein fractions of 190 food items using UPLC–MS/MS. Intra- and inter-day accuracy and precision were 2–29%. The calibration curves showed perfect linearity in water and food matrices. We found the highest AGE levels in high-heat processed nut or grain products, and canned meats. Fruits, vegetables, butter and coffee had the lowest AGE content. The described method proved to be suitable for the quantification of three major AGEs in food items. The presented dietary AGE database opens the possibility to further quantify actual dietary exposure to AGEs and to explore its physiological impact on human health.
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease ...(CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in
PNPLA3
,
TM6SF2
and
GCKR
as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in
PNPLA3
and
TM6SF2
were found to protect against CAD, whereas variants in
GCKR
were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for
PNPLA3
and
TM6SF2
, and lipid-raising for
GCKR
) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.
There have been increasing numbers of case reports and observational studies of adverse events in patients receiving long-term therapy with proton pump inhibitors (PPIs). The effects of PPI therapy ...on risks of fundic gland polyps (FGPs) and gastric cancer have received considerable attention. We performed a systematic review with a meta-analysis of randomized controlled trials and observational studies that assessed these risks.
We searched the PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials databases for relevant studies published through July 2015. We calculated pooled odds ratio for FGPs and the risk ratio for gastric cancer in PPI users compared with PPI nonusers using fixed- and random-effects models.
We analyzed data from 12 studies, comprising more than 87,324 patients: 1 randomized controlled trial reporting the effect of PPIs on gastric polyps (location not specified), 6 cohort and 1 case-control studies on FGPs, and 1 cohort and 3 case-control studies on gastric cancer. Pooled odds ratios for FGPs were 1.43 (95% confidence interval, 1.24-1.64) and 2.45 (95% confidence interval, 1.24-4.83) from fixed- and random-effects models, respectively. The pooled risk ratio for gastric cancer was 1.43 (95% confidence interval, 1.23-1.66) from each model. We observed significant heterogeneity among studies reporting on FGPs, but not among studies reporting on gastric cancer.
Based on a systematic review with meta-analysis, long-term use of PPIs (≥12 months) is associated with an increased risk of FGPs. PPI therapy might also increase the risk of gastric cancer, but this association could be biased, because of the limited number of studies and possible confounding factors.
The etiologic factors of late-life depression are still poorly understood. Recent evidence suggests that microvascular dysfunction is associated with depression, which may have implications for ...prevention and treatment. However, this association has not been systematically reviewed.
To examine the associations of peripheral and cerebral microvascular dysfunction with late-life depression.
A systematic literature search was conducted in MEDLINE and EMBASE for and longitudinal studies published since inception to October 16, 2016, that assessed the associations between microvascular dysfunction and depression.
Three independent researchers performed the study selection based on consensus. Inclusion criteria were a study population 40 years of age or older, a validated method of detecting depression, and validated measures of microvascular function.
This systematic review and meta-analysis has been registered at PROSPERO (CRD42016049158) and is reported in accordance with the PRISMA and MOOSE guidelines. Data extraction was performed by an independent researcher.
The following 5 estimates of microvascular dysfunction were considered in participants with or without depression: plasma markers of endothelial function, albuminuria, measurements of skin and muscle microcirculation, retinal arteriolar and venular diameter, and markers for cerebral small vessel disease. Data are reported as pooled odds ratios (ORs) by use of the generic inverse variance method with the use of random-effects models.
A total of 712 studies were identified; 48 were included in the meta-analysis, of which 8 described longitudinal data. Data from 43 600 participants, 9203 individuals with depression, and 72 441 person-years (mean follow-up, 3.7 years) were available. Higher levels of plasma endothelial biomarkers (soluble intercellular adhesion molecule-1: OR, 1.58; 95% CI, 1.28-1.96), white matter hyperintensities (OR, 1.29; 95% CI, 1.19-1.39), cerebral microbleeds (OR, 1.18; 95% CI, 1.03-1.34), and cerebral (micro)infarctions (OR, 1.30; 95% CI, 1.21-1.39) were associated with depression. Among the studies available, no significant associations of albuminuria and retinal vessel diameters with depression were reported. Longitudinal data showed a significant association of white matter hyperintensities with incident depression (OR, 1.19; 95% CI, 1.09-1.30).
This meta-analysis shows that both the peripheral and cerebral forms of microvascular dysfunction are associated with higher odds of (incident) late-life depression. This finding may have clinical implications because microvascular dysfunction might provide a potential target for the prevention and treatment of depression.
Obese individuals frequently develop hypertension, which is for an important part attributable to renin-angiotensin-aldosterone system (RAAS) overactivity. This review summarizes preclinical and ...clinical evidence on the involvement of dysfunctional adipose tissue in RAAS activation and on the renal, central, and vascular mechanisms linking RAAS components to obesity-associated hypertension.
•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.
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