scholarly journals SUR1-E1506K mutation impairs glucose tolerance and promotes vulnerable atherosclerotic plaque phenotype in hypercholesterolemic mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258408
Author(s):  
Erika Gurzeler ◽  
Anna-Kaisa Ruotsalainen ◽  
Anssi Laine ◽  
Teemu Valkama ◽  
Sanna Kettunen ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Atherosclerotic Plaque ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Positive Staining ◽  
Sulfonylurea Receptor ◽  
Vulnerable Atherosclerotic Plaque ◽  
Increased Risk ◽  
Plaque Phenotype

Background and aims Diabetes is a major risk factor of atherosclerosis and its complications. The loss-of-function mutation E1506K in the sulfonylurea receptor 1 (SUR1-E1506K) induces hyperinsulinemia in infancy, leading to impaired glucose tolerance and increased risk of type 2 diabetes. In this study, we investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice. Methods SUR1-E1506K mutated mice were cross-bred with LDLR-/- mice (SUR1Δ/LDLR-/-), 6 months old mice were fed a western-diet (WD) for 6 months to induce advanced atherosclerotic plaques. At the age of 12 months, atherosclerosis and plaque morphology were analyzed and mRNA gene expression were measured from aortic sections and macrophages. Glucose metabolism was characterized before and after WD. Results were compared to age-matched LDLR-/- mice. Results Advanced atherosclerotic plaques did not differ in size between the two strains. However, in SUR1Δ/LDLR-/- mice, plaque necrotic area was increased and smooth muscle cell number was reduced, resulting in higher plaque vulnerability index in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice. SUR1Δ/LDLR-/- mice exhibited impaired glucose tolerance and elevated fasting glucose after WD. The positive staining area of IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice, and IL-18 plasma level was elevated in SUR1Δ/LDLR-/- mice. Finally, the mRNA expression of IL-1β and IL-18 were increased in SUR1Δ/LDLR-/- bone marrow derived macrophages in comparison to LDLR-/- macrophages in response to LPS. Conclusions SUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.

scholarly journals Carotid Plaque Morphology is Similar in Patients with Reduced and Normal Renal Function

2020 ◽  
Vol 14 ◽  
pp. 117954682095179
Author(s):  
Caroline Heijl ◽  
Fredrik Kahn ◽  
Andreas Edsfeldt ◽  
Christoffer Tengryd ◽  
Jan Nilsson ◽  
...  
Keyword(s):  
Renal Function ◽  
Carotid Plaque ◽  
Continuous Variable ◽  
Intraplaque Hemorrhage ◽  
Plaque Morphology ◽  
Plaque Vulnerability ◽  
Vulnerable Atherosclerotic Plaque ◽  
Increased Risk ◽  
Plaque Phenotype ◽  
Tissue Calcium

Background: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). Methods: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. Results: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). Conclusions: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.

Abstract 511: Mrp8 And Mrp14,Endogenous Activators of Toll-lLke Receptor4, are Associated with Rupture-Prone Human Atherosclerotic Plaques

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mihaela G Ionita ◽  
Gerard Pasterkamp ◽  
Dominique deKleijn
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Inflammatory Status ◽  
Potential Marker ◽  
Plaque Phenotype ◽  
Histological Characteristics ◽  
Unstable Plaques ◽  
Human Carotid

Objectives : Atherosclerosis is a chronic, complex inflammatory process and is the underlying cause of stroke and myocardial infarction due to rupture of the atherosclerotic plaque leading to acute occlusion of the artery in the brain or heart. Macrophages, infiltrating atherosclerotic lesions, abundantly express Mrp8 and Mrp14. Recently Mrp8, Mrp14 and the complex Mrp8/14 have been identified as endogenous ligands of Tlr-4.The role of Tlr-4 in the development and progression of the atherosclerotic plaque is well recognized and it is associated with a rupture-prone plaque phenotype. Expression of Mrps in human plaques and its relation to plaque phenotype is unknown. For this, we investigated the levels of Mrp8, Mrp14 and Mrp8/14 complex in a large number of human atherosclerotic plaques. Methods and results : Mrp8, Mrp14 and Mrp8/14 were quantified by ELISAs in human carotid endarterectomy specimens (186 patients) and plaque phenotype was determined by immunohistochemistry. Mrp levels were higher in the unstable (58 fibro-atheromatous, 64 atheromatous) compared to the stable (64 fibrous) plaques: Mrp8 p = 0.001 ; Mrp14 p = 0.001 ; Mrp8/14 p = 0.01 . Concomitantly, Mrp8, Mrp14 and Mrp8/14 were associated with characteristics of unstable plaques: more macrophages ( p = 0.024; p = 0.002; p = 0.076 ), less smooth muscle cells ( p = 0.041; p = 0.001; p = 0.074 ), larger lipid core ( p = 0.001; p = 0.001; p=0.004 ), less collagen ( p = 0.440; p = 0.011; p = 0.372 ). Furthermore, Mrp plaque levels were positively correlated with the pro-inflammatory cytokines (IL-6 and IL-8) and matrix metalloproteinsases (MMP2, MMP8 and MMP9) plaque levels. EDA, marker of stable plaques, was negatively associated with Mrps plaque levels. Histological analysis revealed that Mrps are expressed by a subgroup of plaque macrophages localized in the plaque cap and shoulder, the most rupture-prone sites of an atherosclerotic plaque. Conclusions: We show that Mrp8, Mrp14 and Mrp8/14 are strongly associated with the histological characteristics and inflammatory status of human rupture-prone plaques and identify Mrps as a potential marker for rupture-prone plaques.

Abstract P339: Association Between Cardiometabolic Syndrome And Cancer: Systematic Review

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Anshul Saxena ◽  
Muni Rubens ◽  
Venkataraghavan Ramamoorthy ◽  
Sankalp Das ◽  
Chintan B Bhatt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Systematic Review ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cardiometabolic Risk ◽  
Cardiometabolic Risk Factors ◽  
Central Adiposity ◽  
Cardiometabolic Syndrome ◽  
Increased Risk

Introduction: Cardiometabolic syndrome consists of a cluster of metabolic dysfunctions such as impaired glucose tolerance, insulin resistance, dyslipidemia, central adiposity, and hypertension. According to the latest estimates, globally, nearly 25% of all adults have cardiometabolic syndrome. Both cardiometabolic syndrome and cancer pathophysiology commonly involve inflammation and oxidative stress. The objective of this systematic review was to evaluate existing evidences that support the association between cardiometabolic syndrome and risk of developing cancer. Methods: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Scopus for relevant articles published from the database inception until October 2019. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for this review. Using the Oxford Center for Evidence-Based Medicine guidelines individual studies were evaluated. A total of 59 articles were included in this study. Results: Our review showed that cardiometabolic syndrome was associated with increased risk for colorectal, hepatic, endometrial, breast, and bladder cancers. These associations showed variations for sex and geographical locations. For example, the associations were stronger for pancreatic and rectal cancers among women. The strength of these associations was also stronger for sex specific cancers such as breast and endometrial cancers. Studies on European populations showed that these associations were stronger for colorectal cancer among women. However, one study showed that presence of cardiometabolic syndrome contributed protective effects to prostate cancer among American men. In general, strongest associations were found for colorectal cancer among both men and women and hepatic cancer among men. Among cardiometabolic factors, impaired glucose tolerance and central adiposity were the greatest contributors towards increased risk for cancers. Conclusion: Given these results, there should be greater focus on primary prevention to identify and treat cardiometabolic risk factors. In addition, patients with greater cardiometabolic risk factors should be screened earlier and more frequently for cancers. A number of gender and geographical gaps identified in this review could be targeted for improvements as per the goals of 2030 sustainable development initiatives. Future studies should consider cardiometabolic syndrome and cancer together and develop effective interventions for decreasing the incidence and morbidity associated with both the conditions.

scholarly journals Anti-Thyroid Peroxidase Antibodies and Male Gender Are Associated with Diabetes Occurrence in Patients with Beta-Thalassemia Major

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Giovanni M. Pes ◽  
Francesco Tolu ◽  
Maria P. Dore
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Multiple Logistic Regression Analysis ◽  
Thalassemia Major ◽  
Male Gender ◽  
Beta Thalassemia ◽  
Thyroid Peroxidase ◽  
Glucose Metabolism Disorders ◽  
Increased Risk

Background. Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients withβ-thalassemia (β-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients withβ-T major.Methods. 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed.Results. Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36;p=0.008) and male gender (OR = 1.98;p=0.025) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665μg/L versus 2922 ± 2773μg/L;p<0.0001).Conclusions. In patients withβ-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients.

scholarly journals Uncoupling Protein 2 and Peroxisome Proliferator-Activated Receptor γ Gene Polymorphisms in Association with Diabetes Susceptibility in Chinese Han Population with Variant Glucose Tolerance

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Meicen Zhou ◽  
Shuli He ◽  
Fan Ping ◽  
Wei Li ◽  
Lixin Zhu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Peroxisome Proliferator ◽  
Chinese Han ◽  
Peroxisome Proliferator Activated Receptor ◽  
Han Population ◽  
Increased Risk

Objective. To investigate the association of polymorphisms in uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor (PPARγ) with glucolipid metabolism in Chinese Han population. Methods. Five hundred eighty-nine subjects were divided into normal glucose tolerance (NGT) group (n=198) and abnormal glucose tolerance group (n=358). HbA1c, blood lipid profile, plasma glucose, and insulin were determined. Insulin sensitivity (HOMA-IR and Matsuda index (ISIM)) and insulin secretion indexes (HOMA-β, early and total phase disposition index) were evaluated. Eight potential functional SNPs in UCP2 and 7 in PPARγ were selected. SNPs were genotyped on Sequenom MassARRAY platform. Results. The GG genotype of rs2920502 in PPARγ was associated with decreased risk of impaired glucose tolerance (G allele: OR: 0.818, 95%CI: 0.526–0.969, P=0.042; GG: OR: 0.715, 95%CI: 0.527–0.97, P=0.031). The TT genotype of rs3856806 in PPARγ was associated with increased risk of impaired glucose tolerance (T allele: OR: 1.46, 95%CI: 1.055–2.017, P=0.022; TT: OR: 1.58, 95%CI: 1.104–2.761, P=0.032). The GG genotype of rs2920502 in PPARγ had better blood glucose and increased insulin secretion and had lower HOMA-IR than GC/CC genotypes. Conclusion. It probably could prevent insulin resistance in early stage by classifying the genotype of rs649446 and rs7109266 in UCP2. The GG genotype of rs2920502 in PPARγ had a decreased risk for diabetes. The TT genotype of rs3856806 in PPARγ had an increased risk for diabetes.

scholarly journals Prevalence of diabetes and impaired glucose tolerance in patients with schizophrenia

2004 ◽  
Vol 184 (S47) ◽  
pp. s67-s71 ◽  
Author(s):  
Chris Bushe ◽  
Richard Holt
Keyword(s):  
Diabetes Mellitus ◽  
Mental Illness ◽  
Risk Factor ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Independent Risk Factor ◽  
Current Data ◽  
Increased Risk ◽  
General Populations ◽  
Prevalence Of Diabetes Mellitus

BackgroundA number of studies have examined the prevalence of diabetes mellitus and impaired glucose tolerance in general populations and in those with schizophrenia and other forms of serious mental illness.AimsTo establish whether it is possible to describe accurately comparative rates of diabetes mellitus and impaired glucose tolerance in populations of people with schizophrenia and those without mental illness.MethodReview of current literature.ResultsResearch published in the pre-neuroleptic era suggested that people with severe mental illness were at increased risk of developing glycaemic abnormalities. Recent studies appear to confirm that the prevalence of diabetes and impaired glucose tolerance may be higher in people with schizophrenia than in the general population, and suggest that patients with schizophrenia have impaired glucose tolerance even before they begin treatment.ConclusionsSchizophrenia may be a significant and independent risk factor for both diabetes and impaired glucose tolerance. Current data preclude precise estimates of the prevalence of these conditions among people with schizophrenia.

scholarly journals Glucocorticoid-Induced Preterm Birth and Neonatal Hyperglycemia Alter Ovine β-Cell Development

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3763-3776 ◽  
Author(s):  
Amita Bansal ◽  
Frank H. Bloomfield ◽  
Kristin L. Connor ◽  
Mike Dragunow ◽  
Eric B. Thorstensen ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Preterm Birth ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Cell Mass ◽  
Β Cell ◽  
High Blood Glucose ◽  
Increased Risk

Adults born preterm are at increased risk of impaired glucose tolerance and diabetes. Late gestation fetuses exposed to high blood glucose concentration also are at increased risk of impaired glucose tolerance as adults. Preterm babies commonly become hyperglycemic and are thus exposed to high blood glucose concentration at an equivalent stage of pancreatic maturation. It is not known whether preterm birth itself, or complications of prematurity, such as hyperglycemia, alter later pancreatic function. To distinguish these, we made singleton preterm lambs hyperglycemic (HYPER) for 12 days after birth with a dextrose infusion and compared them with vehicle-treated preterm and term controls and with HYPER lambs made normoglycemic with an insulin infusion. Preterm birth reduced β-cell mass, apparent by 4 weeks after term and persisting to adulthood (12 mo), and was associated with reduced insulin secretion at 4 months (juvenile) and reduced insulin mRNA expression in adulthood. Hyperglycemia in preterm lambs further down-regulated key pancreatic gene expression in adulthood. These findings indicate that reduced β-cell mass after preterm birth may be an important factor in increased risk of diabetes after preterm birth and may be exacerbated by postnatal hyperglycemia.

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