Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycation is responsible for disruption of lipoprotein functions leading to the development of atherosclerosis in diabetes. The effects of apolipoprotein E (apoE) glycation were investigated with respect to its interaction with receptors. The interaction of apoE with the low density lipoprotein receptor (LDL-R) and scavenger receptor A (SR-A) was measured by competition experiments performed using, respectively, on a human fibroblast cell line 125I-LDL, and on a murine macrophage cell line (J774) 125I-acetylated LDL, and unlabeled apoE/phospholipid complexes. Glycated apoE binding to heparin and heparan sulfates (HS) was assessed by surface plasmon resonance (SPR) technology. Site-directed mutagenesis was then performed on Lys-75, the major glycation site of the protein. The prepared mutant protein proved to be useful as a tool to study the role of Lys-75 in apoE glycation. The findings showed that, although glycation has no effect on apoE binding either to the LDL-R or to SR-A, it impairs its binding to immobilized heparin and HS. The glycation of Lys-75 was found to be proceed rapidly and contributed significantly to total protein glycation. We propose that, in the case of diabetes, glycation may lead to the atherogenicity of apoE-containing lipoproteins disturbing their uptake via the HS proteoglycan pathway.
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PMID:Early-glycation of apolipoprotein E: effect on its binding to LDL receptor, scavenger receptor A and heparan sulfates. 1206 54

Altered plasma levels of lipids and lipoproteins, obesity, hypertension, and diabetes are major risk factors for atherosclerotic cardiovascular disease. To identify genes that affect these traits and disorders, we looked for association between markers in candidate genes (apolipoprotein AII (apo AII), apolipoprotein AI-CIII-AIV gene cluster (apo AI-CIII-AIV), apolipoprotein E (apo E), cholesteryl ester transfer protein (CETP), cholesterol 7alpha-hydroxylase (CYP7a), hepatic lipase (HL), and microsomal triglyceride transfer protein (MTP)) and known risk factors (triglycerides (Tg), total cholesterol (TC), apolipoprotein AI (apo AI), apolipoprotein AII (apo AII), apolipoprotein B (apo B), body mass index (BMI), blood pressure (BP), leptin, and fasting blood sugar (FBS) levels.) A total of 1,102 individuals from the Pacific island of Kosrae were genotyped for the following markers: Apo AII/MspI, Apo CIII/SstI, Apo AI/XmnI, Apo E/HhaI, CETP/TaqIB, CYP7a/BsaI, HL/DraI, and MTP/HhpI. After testing for population stratification, family-based association analysis was carried out. Novel associations found were: 1) the apo AII/MspI with apo AI and BP levels, 2) the CYP7a/BsaI with apo AI and BMI levels. We also confirmed the following associations: 1) the apo AII/MspI with Tg level; 2) the apo CIII/SstI with Tg, TC, and apo B levels; 3) the Apo E/HhaI E2, E3, and E4 alleles with TC, apo AI, and apo B levels; and 4) the CETP/TaqIB with apo AI level. We further confirmed the connection between the apo AII gene and Tg level by a nonparametric linkage analysis. We therefore conclude that many of these candidate genes may play a significant role in susceptibility to heart disease.
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PMID:Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia. 1211 31

To elucidate risk factors for cerebral amyloid angiopathy (CAA) in the elderly, we have investigated 201 autopsy cases of elderly Japanese (ages: 62-104 years), including 82 patients with Alzheimer's disease (AD). Severity of CAA showed no relationship with the history of hypertension, hyperlipidemia, or diabetes mellitus, nor with severity of atherosclerosis of cerebral and systemic arteries, indicating that common vascular risk factors would not be related to CAA. Incidence and severity of CAA were significantly higher in the AD cases compared with the non-AD cases (p < 0.0001). Severity of CAA correlated with densities of senile plaques and neurofibrillary tangles in total and non-AD cases, although the correlations were not significant within the AD cases. Associations of genetic polymorphisms with CAA have been investigated for genes of apolipoprotein E (APOE), presenilin 1 (PS1), alpha1-antichymotrypsin (ACT), butyrylcholinesterase, alpha2-macroglobulin, and paraoxonase. Severity of CAA in APOE epsilon4 carriers is significantly higher than that in non-epsilon4 carriers in total cases, although no significant difference was found in the CAA severity between the epsilon4 carriers and non-epsilon4 carriers within the AD or non-AD group. An intronic polymorphism of PS1 was significantly associated with the severity of CAA, indicating that the PS1 2/2 genotype may be related to lower risk of CAA. A polymorphism in the signal peptide sequence of ACT was significantly associated with the CAA severity in the AD group. Our results suggest that CAA shares risk factors with AD and that multiple genetic factors would be associated with the risk of CAA in the elderly.
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PMID:Risk factors for cerebral amyloid angiopathy in the elderly. 1248 Jul 32

Cardiovascular, cerebrovascular and peripheral vascular diseases are the largest cause-specific reason for morbidity and mortality in end-stage renal disease (ESRD) patients. High prevalence of cardio- and cerebrovascular death may be explained by multiple factors present in patients with progressive renal disease, including hypertension, hyprelipidemia, hyperhomocysteinemia, diabetes mellitus, and hyperparathyroidism. Experimental studies have provided in vivo and in vitro data to support the notion that lipid abnormalities contribute to glomerular and interstitial injury of the renal parenchyma. Hypercholesterolemia and increased low-density lipoprotein (LDL) cholesterol are prevalent in patients with the nephrotic syndrome. Plasma high-density lipoprotein (HDL) cholesterol is decreased, and reverse cholesterol transport is impaired in hemodialysis (HD) and pre-ESRD patients. Chronic renal failure patients treated with HD have an increased prevalence of intermediate-density lipoprotein (IDL), and lipoprotein(a). The findings in the diabetic patients corresponded to those in non-diabetic patients with renal failure, but diabetic patients have higher apolipoprotein C-III and apolipoprotein E concentrations. Impaired lipid metabolism is common in patients receiving peritoneal dialysis (PD). In the most of the ESRD patients treated with peritoneal dialysis hypercholesterolemia and hypertriglyceridemia are found. Wide panels of therapeutic interventions aimed at correcting the lipid abnormalities that may develop in chronic renal patients, as well as in ESRD patients are currently available. Although some novel pharmacological agents are remarkably effective for returning the lipid abnormalities to normal, there is still no convincing evidence based on long-term prospective studies which clearly demonstrate a significant reduction in cardiovascular morbidity and mortality of ESRD patients. The therapeutic approaches, which may be considered, include mainly dietary and life-style modifications, selective use of some technical components of dialysis systems, and the judicious prescriptions of lipid-lowering drugs.
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PMID:[Lipoprotein disorders in chronic kidney failure, nephrotic syndrome and dialysis]. 1267 79

Islet amyloid is found in 90% of patients with Type 2 (non-insulin-dependent) diabetes at post-mortem. More extensive amyloidosis is associated with decreased islet function and requirement for insulin therapy. Severity of cerebral amyloidosis in Alzheimer's disease (AD) is increased in subjects with the apolipoprotein E (ApoE) epsilon 4 allele. To determine if ApoE genotype was associated with severity of islet amyloidosis and diabetes, samples were genotyped from 32 specimens of post-mortem pancreas and from patients classified by disease progression. DNA was extracted from blood samples from Caucasian patients diagnosed with Type 2 diabetes, at age >40 years, classified according to disease progression: group 1 on oral therapy for at least 10 years from diagnosis, (n=147) and group 2, requiring insulin within 6 years from diagnosis, (n=187). ApoE genotype was determined by restriction-fragment length polymorphism analysis. DNA in pancreatic extracts (23 diabetic; 9 non-diabetic subjects) showed no association of ApoE polymorphisms with either degree of islet amyloidosis or disease severity. The distributions of ApoE epsilon 2, epsilon 3 and epsilon 4 were similar in both clinical patient groups and in the non-diabetic group and unrelated to progression of disease. It is unlikely that the common polymorphisms for the ApoE gene are linked to amyloid formation or progression of islet dysfunction in Type 2 diabetes.
Diabetes Res Clin Pract 2003 May
PMID:Apolipoprotein E genotype, islet amyloid deposition and severity of Type 2 diabetes. 1270 18

Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.
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PMID:Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. 1280 3

Several predispocitional and genetic factors are thought to be involved in the etiology of Alzheimer s disease (AD). Except for age, there is no consensus among researchers about the factors that can best predict AD. Some studies have found that, older women, cerebrovascular risk factors (hypertension, ischemic heart disease, diabetes mellitus), and the presence of the apolipoprotein E (APOE) 4 allele to be associated with the development of dementia and AD. However, there are a few large scale studies that have entered magnetic resonance imaging (MRI) findings in the analysis of risk factors for AD. The Cardiovascular Health Study Cognition Study evaluated the determinants of the risk of dementia, diagnosed in 1998 99, among 3608 participants >65 years of age who had MRIof the brain in 1991 through 1994. In this cohort, there were 480 incident dementia cases, and 330 were diagnosed as AD. The CHS found that age, Modified Mini Mental State Examination scores, cerebral ventricular size, severity of white matter lesions, number of MRI identified infarcts, and the presence of the APOE 4 allele were predictors of dementia. This study showed the importance of controlling for neuroimaging findings the study of risk factors for dementia. Scores of global cognitive measures, the presence of the APOE 4 allele, and MRI of the brain were strong predictors of dementia and AD.
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PMID:[Risk factors for dementia in the Cardiovascular Health Study cognition study]. 1293 70

The literature on the association between apolipoprotein E (ApoE) and mortality across ethnic and age groups has been inconsistent. No studies have looked at this association in developing countries. We used data from the Indianapolis-Ibadan Dementia study to examine this association between APOE and mortality in 354 African-Americans from Indianapolis and 968 Yoruba from Ibadan, Nigeria. Participants were followed up to 9.5 years for Indianapolis and 8.7 years for Ibadan. Subjects from both sites were divided into 2 groups based upon age at baseline. A Cox proportional hazards regression model adjusting for age at baseline, education, hypertension, smoking history and gender in addition to time-dependent covariates of cancer, diabetes, heart disease, stroke, and dementia was fit for each cohort and age group. Having ApoE epsilon4 alleles significantly increased mortality risk in Indianapolis subjects under age 75 (hazard ratio: 2.00; 95% CI: 1.19-3.35; p = 0.0089). No association was found in Indianapolis subjects 75 and older (hazard ratio: 0.71; 95% CI: 0.45-1.10; p = 0.1238), Ibadan subjects under 75 (hazard ratio: 1.04; 95% CI: 0.78 to 1.40; p = 0.7782), or Ibadan subjects over 75 (hazard ratio: 1.21; 95% CI: 0.83 to 1.75; p = 0.3274).
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PMID:Apolipoprotein E and mortality in African-Americans and Yoruba. 1464 29

Ten healthy, non-smoking subjects without atopic constitution, (eight males and two females, mean age 67.3 +/- 2.5 years), participated in a study of vascular reactivity. The subjects were tested with respect to apolipoprotein E alleles. Three vasodilating substances were iontophoresed into the skin, acetylcholine chloride (ACh); isoprenaline sulfate (isoprenaline); and sodium nitroprusside (SNP). ACh and isoprenaline were delivered to the anode, while SNP was delivered to the cathode. Also, 0.9% sodium chloride (NaCl) was delivered to the cathode in order to assess the effect of the iontophoretic current itself. The resultant vasodilation was mapped by a newly developed laser Doppler perfusion imager (LDPI) and correlated with fasting concentrations of serum lipids and lipoproteins. Skin vessel reactivity test to ACh, isoprenaline and SNP, but not NaCl, showed statistically significant negative correlations to the ratio LDL cholesterol/HDL cholesterol (P<0.05). The skin vessel responses to endothelium-dependent and possibly also to endothelium-independent substances are correlated with serum lipids and lipoproteins. It might be feasible to follow the effect of lipid-lowering strategies non-invasively with the aid of iontophoresis and laser Doppler perfusion imaging. The response to NaCl at the cathode might be due to a direct depolarizating effect on perivascular nerves and might thus be of interest when evaluating small nerve fiber dysfunction, for instance in diabetes mellitus.
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PMID:Skin vessel reactivity tests in healthy middle-aged and elderly subjects: the influence of depolarizating current and serum lipids. 1476 17

Converging evidence has identified a potential association among Alzheimer's disease, glucose metabolism, insulin activity, and memory. Notably, type 2 diabetes, which is characterized by insulin resistance, may modulate the risk of Alzheimer's disease, and patients with Alzheimer's disease may have a greater risk for glucoregulatory impairments than do healthy older adults. In animal studies, it has been shown that raising blood glucose levels acutely can facilitate memory, in part, by increasing cholinergic activity, which is greatly diminished in patients with Alzheimer's disease. Other studies have confirmed that glucose administration can facilitate memory in healthy humans and in patients with Alzheimer's disease. Interestingly, glucose effects on memory appear to be modulated by insulin sensitivity (efficiency of insulin-mediated glucose disposal). Of course, the acute effects of glucose administration should be distinguished from the effects of chronic hyperglycemia (diabetes), which has been associated with cognitive impairments, at least in older adults. The relationship of insulin and memory has been more difficult to characterize. In animals, systemic insulin administration has been associated with memory deficits, likely due, in part, to hypoglycemia that occurs when exogenous insulin is not supplemented with glucose to maintain euglycemia. In healthy adults and patients with Alzheimer's disease, raising plasma insulin levels while maintaining euglycemia can improve memory; however, raising plasma glucose while suppressing endogenous insulin secretion may not improve memory, suggesting that adequate levels of insulin and glucose are necessary for memory facilitation. Clinical studies have corroborated findings that patients with Alzheimer's disease are more likely than healthy older adults to have reduced insulin sensitivity, and further suggest that apolipoprotein E genotype may modulate the effects of insulin on glucose disposal, memory facilitation, and amyloid precursor protein processing. Collectively, these findings support an association among Alzheimer's disease, impaired glucose metabolism, and reduced insulin sensitivity.
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PMID:Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. 1509 77


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