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)

Apolipoprotein E polymorphisms are important determinants of blood lipid levels and have been associated with longevity and atherosclerosis. However, information is limited on the effects of apo E variation on the lipids of nonwhite and elderly individuals. We tested the hypothesis that apo E polymorphisms are associated with plasma lipid levels in an elderly, multiethnic population. Cross-sectional data from 1068 noninstitutionalized individuals from northern Manhattan over the age of 64 who were not on a lipid-lowering diet or drug were analyzed. The ethnic distribution was 34% African-Americans, 47% Hispanics, and 19% non-Hispanic Caucasians. In the entire group, the most prevalent apo E allele was epsilon 3 (76%), followed by epsilon 4 (16%) and epsilon 2 (8%); epsilon 4 was more prevalent in African-Americans (21%) than in non-Hispanic Caucasians (12%) or Hispanics (14%). The apo epsilon 2 allele was the most important correlate of plasma lipids, but association varied across ethnoracial groups. After being adjusted for age, sex, obesity, diabetes mellitus, and alcohol intake, LDL cholesterol levels declined with each apo epsilon 2 allele by 8.8 mg/dL in Hispanics and by 25.6 and 18.1 mg/dL in non-Hispanic Caucasians and African-Americans, respectively (P < .001). No significant independent effect was noted for any apo E genotype on HDL cholesterol. Overall, there was a reduction in the total/HDL cholesterol ratio, per apo epsilon 2 allele, of 0.82 in non-Hispanic Caucasians and 0.43 and 0.48 in African-American and Hispanic individuals, respectively (P < .05). In a multivariate model, apo epsilon 4 did not significantly affect plasma lipid levels. Plasma triglyceride levels were inversely correlated with the number of apo epsilon 4 alleles (175, 159, and 143 mg/dL with 0, 1, and 2 alleles, respectively; P =.002), and this effect increased with age. Thus, in an elderly, multiethnic population, apolipoprotein E polymorphisms were important determinants of blood lipids, with differing effects depending on ethnicity. The presence of apo epsilon 2 was associated with lower LDL cholesterol levels and total/HDL cholesterol ratio, although apo epsilon genotype did not influence HDL cholesterol levels. Prospective studies are needed to test whether apo epsilon 2 protects against incident cardiovascular disease in the elderly.
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PMID:Association of apo E polymorphism with plasma lipid levels in a multiethnic elderly population. 943 3

Hypercholesterolemia is a major determinant of the decline of renal function in patients with diabetes. Apolipoprotein E polymorphism may influence the metabolism of lipoprotein in diabetic patients. The purpose of this study was to investigate the association between genetic polymorphisms in apolipoprotein E and the progression of diabetic nephropathy in patients with non-insulin-dependent diabetes mellitus over a 10-year period (13 to 37 years; median, 20 years). Subjects with a stable renal function without overt proteinuria had a higher cholesterol level, lower incidences of hypertension and proliferative diabetic retinopathy, and a higher frequency of the E4 allele than subjects with a decline in renal function (end-stage renal failure requiring dialysis treatment). In the diabetic patients, the apolipoprotein E4 carriers had a higher cholesterol level than did the noncarriers. The survival rate from renal disease in the apolipoprotein E4 carriers was higher than in the noncarriers among the diabetic patients. Apolipoprotein E polymorphism and hypertension were identified as independent risk factors for the progression to renal failure. Results indicate that apolipoprotein E polymorphism is associated with the progression of diabetic nephropathy. Presence of the apolipoprotein E4 allele is a protective factor, and other alleles are risk factors.
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PMID:Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM. 953 Nov 84

Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.
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PMID:Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. 973 95

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.
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PMID:Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. 977 46

Diabetic nephropathy is the most serious complication of diabetes mellitus. Progression of the condition leads to end-stage renal failure, and other complications of diabetes are also common in this group of patients. The onset of overt albuminuria in a patient with diabetes heralds an increased risk of death, particularly from cardiovascular disease. There is considerable evidence to show that nephropathy is influenced by genetic factors. Epidemiological studies show that only a minority of patients with diabetes develop nephropathy irrespective of glycaemic control, suggesting that a subgroup of patients are at higher risk of nephropathy. Marked ethnic variation is observed, with nephropathy being more common in certain ethnic groups. Familial clustering of nephropathy is also observed. Parental history of hypertension, diabetes or cardiovascular disease appears to predispose to nephropathy in patients with diabetes. A number of methods are available to dissect polygenic disease: animal models, genetic association studies (case-control studies), affected sib-pair studies, discordant sib-pair studies and transmission distortion analysis. Most published work has been based on association studies. Association studies have shown conflicting results often due to small numbers of cases and controls, and poor phenotypic characterization. The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism has been studied in detail, but does not appear to be a strong risk marker for nephropathy. It does, however, appear to have a role in response to angiotensin-converting enzyme inhibition, with II homozygotes being the most responsive and DD homozygotes the least. A number of other genetic loci have also shown positive associations with nephropathy, including apolipoprotein E, heparan sulphate and aldose reductase. More recently, affected sib-pair analysis and discordant sib-pair analysis have suggested possible genetic loci on chromosomes 3, 7, 9, 12 and 20. These have yet to be reproduced in larger numbers of families, and the specific gene regions on these chromosomes remain elusive. The evidence presented in this review strongly supports the role of genetic factors in nephropathy. Detection of strong genetic risk markers for nephropathy will allow further insights into the pathogenesis of nephropathy, and possibly the development of novel therapeutic agents for its treatment. It will also allow preventive therapy to be directed at those patients with the greatest risk for development of diabetic nephropathy.
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PMID:Genetic determinants of diabetic nephropathy. 1002 57

Islet amyloid has been recognized as a pathological entity in type 2 diabetes since the turn of the century. It has as its unique component the islet beta-cell peptide islet amyloid polypeptide (IAPP), or amylin, which is cosecreted with insulin. In addition to this unique component, islet amyloid contains other proteins, such as apolipoprotein E and the heparan sulfate proteoglycan perlecan, which are typically observed in other forms of generalized and localized amyloid. Islet amyloid is observed at pathological examination in the vast majority of individuals with type 2 diabetes but is rarely observed in humans without disturbances of glucose metabolism. In contrast to IAPP from rodents, human IAPP has been shown to form amyloid fibrils in vitro. Because all human subjects produce and secrete the amyloidogenic form of IAPP, yet not all develop islet amyloid, some other factor(s) must be involved in islet amyloid formation. One hypothesis is that an alteration in beta-cell function resulting in a change in the production, processing, and/or secretion of IAPP is critical to the initial formation of islet amyloid fibrils in human diabetes. This nidus of amyloid fibrils then allows the progressive accumulation of IAPP-containing fibrils and the eventual replacement of beta-cell mass by amyloid and contributes to the development of hyperglycemia. One factor that may be involved in producing the changes in the beta-cell that result in the initiation of amyloid formation is the consumption of increased dietary fat. Dietary fat is known to alter islet beta-cell peptide production, processing, and secretion, and studies in transgenic mice expressing human IAPP support the operation of this mechanism. Further investigation using this and other models should provide insight into the mechanism(s) involved in islet amyloidogenesis and allow the development of therapeutic agents that inhibit or reverse amyloid fibril formation, with the goal being to preserve beta-cell function and improve glucose control in type 2 diabetes.
Diabetes 1999 Feb
PMID:Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. 1033 97

Type 2 diabetes is characterized by islet amyloid deposits, which are primarily composed of the amyloidogenic human form of islet amyloid polypeptide (IAPP, amylin). The mechanism of islet amyloido-genesis is not known, but other products (e.g., apolipoprotein E and perlecan) contained within islet amyloid may be necessary. Because rodent IAPP does not form islet amyloid, the currently available beta-cell lines are not useful for studying processes involved in amyloid formation. To develop a suitable in vitro cell system for the study of islet amyloid formation, we generated two new beta-cell lines that express the amyloidogenic human IAPP. We did this by crossbreeding human IAPP transgenic mice with RIP-Tag mice that develop islet tumors and then culturing one of these islet tumors from two separate offspring of this cross. The resultant 2350-2C0 and 2511 cell lines produce human as well as mouse IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI). Incubation of both these cell lines with 16.7 mmol/l glucose resulted in a two- to fourfold increase in human IAPP-LI, mouse IAPP-LI, and IRI secretion compared with 1.67 mmol/l glucose and the combination of 16.7 mmol/l glucose and 10 mmol/l arginine, 0.1 mmol/l 3-isobutyl-1-methylxanthine (IBMX), and 5 micromol/l carbachol induced a >50-fold increase in the release of these peptides. The omission of calcium from the above secretagogue cocktail reduced secretion of all three peptides to only two- to sixfold higher than the 16.7 mmol/l glucose condition. Perifusion with 16.7 mmol/l glucose plus 0.1 mmol/l IBMX caused a biphasic secretion of human IAPP-LI and mouse IAPP-LI, as well as IRI, in both cell lines, with the peak of the first phase being five- to sixfold higher than the prestimulated 1.67 mmol/l glucose condition. Immunoelectron microscopic inspection of both 2350-2C0 and 2511 cells after 7 days of culture did not reveal the presence of amyloid fibrils, suggesting the need for other critical components. We conclude that we have established two novel beta-cell lines that produce and secrete human IAPP in a regulated manner. These cell lines will be a useful tool to investigate the secretion of human IAPP as well as the necessity of other components for islet amyloid formation.
Diabetes 1999 Oct
PMID:Two novel immortal pancreatic beta-cell lines expressing and secreting human islet amyloid polypeptide do not spontaneously develop islet amyloid. 1051 60

Diabetic dyslipidemia is a major factor contributing to the accelerated atherosclerosis in type 2 diabetes mellitus. Although several mouse models are available, the plasma lipoproteins in response to diet have not been fully characterized in these animals. In this study, we have characterized the plasma lipoproteins and related apolipoproteins, as well as the vascular lipases, in diabetes (db/db) mice and their nondiabetic controls (+/?) in the C57BL/KsJ strain. Within 6 weeks of age, db/db mice developed significant obesity, fasting hyperglycemia, and hyperinsulinemia. By FPLC analysis, db/db mice showed a prominent peak in the low-density lipoprotein (LDL) range that was absent in +/? mice, although high-density lipoprotein (HDL) was the predominant species in both groups of animals. Postheparin lipoprotein lipase (LPL) activity in db/db mice was 28% of the level in +/? mice. Upon feeding a human-like 0.15% (wt/wt) cholesterol and 21% (wt/wt) fat "Western" diet, db/db mice developed elevated plasma cholesterol, accompanied by an exaggerated apolipoprotein E (apoE) response compared with +/? mice. FPLC analysis showed that the marked hypercholesterolemic response in db/db mice was the result of a massive increase in the LDL region, which overshadowed a moderate increase in HDL. We next isolated lipoproteins by ultracentrifugation and characterized them by nondenaturing gradient gel electrophoresis. With regular chow, db/db mice had almost exclusively small dense LDL with a peak size at 21.4 nm, as compared with 26.6 nm in nondiabetic controls. On the Western diet, the small dense LDLs persisted but larger particles also appeared in db/db mice, whereas the size distribution in +/? mice was unchanged by the diet. Our results suggest that db/db mice fed a Western diet have a plasma lipoprotein phenotype that shows some similarities to that in patients with type 2 diabetes mellitus, and that db/db mice are a useful model to study the pathogenesis and treatment of diabetic dyslipidemia.
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PMID:The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding. 1064 60

The pathology of Alzheimer's disease (AD) is not limited to amyloid plaques and neurofibrillary tangles. Recent evidence suggests that more than 30% of AD cases exhibit cerebrovascular pathology, which involves the cellular elements that represent the blood-brain barrier. Certain vascular lesions such as microvascular degeneration affecting the cerebral endothelium, cerebral amyloid angiopathy and periventricular white matter lesions are evident in virtually all cases of AD. Furthermore, clinical studies have demonstrated blood-brain barrier dysfunction in AD patients who exhibit peripheral vascular abnormalities such as hypertension, cardiovascular disease and diabetes. Whether these vascular lesions along with perivascular denervation are coincidental or causal in the pathogenetic processes of AD remains to be defined. In this chapter, I review biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described in AD. I also consider genetic influences such as apolipoprotein E in relation to cerebrovascular lesions that may shed light on the pathophysiology of the cerebral vasculature. The compelling vascular pathology associated with AD suggests that transient and focal breach of the blood-brain barrier occurs in late onset AD and may involve an interaction of several factors, which include perivascular mediators as well as peripheral circulation derived factors that perturb the endothelium. These vascular abnormalities are likely to worsen cognitive disability in AD.
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PMID:The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease. 1067 33

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.
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PMID:Are cerebrovascular factors involved in Alzheimer's disease? 1086 6


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