People in developing countries have faced multigenerational undernutrition and are currently undergoing major lifestyle changes, contributing to an epidemic of metabolic diseases, though the ...underlying mechanisms remain unclear. Using a Wistar rat model of undernutrition over 50 generations, we show that Undernourished rats exhibit low birth-weight, high visceral adiposity (DXA/MRI), and insulin resistance (hyperinsulinemic-euglycemic clamps), compared to age-/gender-matched control rats. Undernourished rats also have higher circulating insulin, homocysteine, endotoxin and leptin levels, lower adiponectin, vitamin B12 and folate levels, and an 8-fold increased susceptibility to Streptozotocin-induced diabetes compared to control rats. Importantly, these metabolic abnormalities are not reversed after two generations of unrestricted access to commercial chow (nutrient recuperation). Altered epigenetic signatures in insulin-2 gene promoter region of Undernourished rats are not reversed by nutrient recuperation, and may contribute to the persistent detrimental metabolic profiles in similar multigenerational undernourished human populations.
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•Undernourished rats are protein / calorie-restricted for 50 generations•Recuperation rats are generated by feeding normal chow for two more generations•Undernourished and Recuperation rats show multiple markers of metabolic disease•Metabolic / epigenetic alterations are not reversed following nutrient recuperation
In a rat model of undernutrition over 50 generations, closely mimicking human populations in developing countries, Hardikar et al. show that undernourished rats display metabolic abnormalities associated with epigenetic changes, which are not reversed following unrestricted access to normal chow in two subsequent generations.
We assessed the impact of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, ...and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD).
In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio HR 0.81 95% confidence interval 0.74-0.88; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 0.75-0.91), cerebrovascular (HR 0.77 0.65-0.92), and peripheral vascular (HR 0.58 0.38-0.88) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 0.69-0.85). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 0.75-0.95) in the first year followed by a 24% reduction (HR 0.76 0.67-0.85) thereafter.
The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.
ObjectivesTo identify and review evaluations of strategies to recruit men aged 50 years and over to randomised controlled trials (RCTs).DesignSystematic review and narrative synthesis.Data ...sourcesMEDLINE, EMBASE, CINAHL and ORRCA databases were searched to 1 December 2017.Eligibility criteriaStudies using quantitative methods to evaluate recruitment strategies to RCTs of men aged 50 years and older.Data extraction and synthesisA single reviewer extracted data (for each strategy, number of participants approached, screened and randomised, and cost). Study quality was assessed using National Heart, Lung and Blood Institute Quality Assessment Tools and considered study design, description of interventions, description and measurement of outcomes, completeness of outcome reporting, performance of statistical testing and consideration of confounders. Recruitment strategies were categorised by the recruitment stage they addressed.ResultsSixteen studies (n >14 000) were included: one good quality, ten fair quality and five poor quality. Studies evaluated strategies to identify prospective participants, and to improve the processes for assessing participant eligibility, providing participant information and seeking consent. In good and fair quality studies, the most effective strategies for identifying participants were referral from an affiliated health service provider (two studies), mass mailing (five studies) and media coverage (two studies). Community outreach activities such as displaying posters and attending local community events were not effective (two studies). Trial-specific training of site recruitment staff, developed using qualitative analysis of recruitment visits (two studies), and provision of study information to prospective participants at a multidisciplinary, group information session (one study) both improved recruitment.ConclusionImproved engagement of men aged 50 years and older in RCTs is needed. A gender-sensitised approach to RCT recruitment may help to address this need. We have identified several promising recruitment strategies that merit further evaluation.PROSPERO registration numberCRD42017060301.
HDL as a Target for Glycemic Control Waldman, Boris; Jenkins, Alicia J; Sullivan, David ...
Current drug targets,
05/2017, Letnik:
18, Številka:
6
Journal Article
Recenzirano
HDL has long been known for its role in reverse cholesterol transport, thought in part to explain the well-recognized links between low levels of HDL-C and cardiovascular disease. The past decade has ...seen increasing evidence from epidemiological, basic science and early human intervention studies that HDL biology is more complex and may influence the onset and progression of type 2 diabetes. Research has identified multiple potential pathways by which higher HDL particle concentrations or functional improvements may ameliorate the development and progression of the disease. These include promotion of insulin secretion and pancreatic islet beta-cell survival, promotion of peripheral glucose uptake, and suppression of inflammation. The relationships between HDL-C levels, commonly used in clinical practice, and HDL particle number, size and various HDL functions is complex, and is intimately linked with triglyceride metabolism. The complexity of these relationships is amplified in diabetes, which negatively impacts multiple aspects of lipoprotein biology. This article reviews the rationale for, and potential of, HDL-based anti-diabetic pharmacotherapy, with an emphasis on the particular challenges posed by diabetes-related HDL dysfunction, and on the difficulties of selecting appropriate targets and HDL-related biomarkers for research and for clinical practice. We discuss aspects of HDL metabolism that are known to be altered in type 2 diabetes, potentially useful measures of HDL-targeted therapy in diabetes, and review early intervention studies in humans. These areas provide a firm foundation for further research and knowledge expansion in this intriguing area of human health and disease.
Triglyceride-lowering trials Keech, Anthony C; Jenkins, Alicia J
Current opinion in lipidology
28, Številka:
6
Journal Article
Recenzirano
We provide an overview of current evidence about the independent role of high triglyceride levels for cardiovascular risk and for acute pancreatitis.
Natural experiments of Mendelian randomization ...have given us a deeper understanding about the molecular pathways involved in triglyceride metabolism. Individuals with low-triglyceride levels generally have lower rates of cardiovascular disease (CVD). There has been a significant growth in the development of new agents that modulate enzymes involved in a variety of aspects of triglyceride packaging into VLDL or chylomicron particles, and triglyceride catabolism. Antisense inhibitors of apolipoprotein CIII are being tested, as are a variety of agents designed to increase lipoprotein lipase activity. Large-scale trials are underway with purified fatty acid (FA) formulations in over 20 000 individuals in aggregate. A large study of a new fibrate is underway.
A focus on patients with elevated triglyceride levels is a new paradigm not previously the focus of large trials. Clinical outcome data on cardiovascular risk reductions remains sparse. Some drugs are already approved for use in rare inherited disorders predisposing to severe hypertriglyceridaemia and acute pancreatitis. Safety and costs issues are critical.
Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and ...the risk of glycemic progression in patients with type 2 diabetes.
In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin.
The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio 95% CI for each unit decrease to ∼0.2 kilobases: 1.10 1.06-1.14), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = -0.05 -0.06 to -0.04). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35-2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12-1.70).
Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.
Abstract
The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical ...factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10–20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes,
p
< 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group median lower quartile (LQ)–upper quartile (UQ) 5.0 (2.6–28.7) versus 650.9 (401.2–732.4) pmol/L respectively,
p
< 0.0001 and lower in childhood versus adult-onset diabetes median (LQ–UQ) 4.2 (2.6–12.2) pmol/L vs. 8.0 (2.3–80.5) pmol/L,
p
= 0.02, respectively. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%,
p
for trend < 0.05).
Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.
Biomarkers in Diabetic Retinopathy Jenkins, Alicia J; Joglekar, Mugdha V; Hardikar, Anandwardhan A ...
The review of diabetic studies,
2015 Spring-Summer, 2015-00-00, 20150101, Letnik:
12, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in ...the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.
The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR) and other diabetes-induced microvascular complications. This interest stems from two ...recent large, well-designed clinical trials that demonstrated large reductions in the progression of DR and the need for laser intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes. In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline. Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell apoptosis. These factors are believed to be important in the development of DR regardless of the underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further, fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given the results of these preclinical studies, further clinical trials are needed to establish the benefits of fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation into clinical practice should be continually revised as more information becomes available.
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