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)

The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.
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PMID:Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. 1243 93

The ABCA subfamily of ABC transporters includes ten members to date. In this study, we describe an additional gene, ABCA12. Four full-length cDNA sequences have been obtained from human placenta that contain two different polyadenylation sites and two splicing forms, coding for ABCA12 isoforms of 2,595 and 2,516 amino acid residues. Both isoforms are predicted to have two ATP-binding domains (nucleotide binding domain, NBD) and two transmembrane (TM) domains, features shared by all other ABCA subfamily proteins. ABCA12 is most closely related to ABCA1, with an amino acid similarity of 47%. Northern blot analysis demonstrates that a 9.5-kb transcript is mainly expressed in the stom- ach. ABCA12 was mapped to human chromosome 2q34. Two other genes from ABCA subfamily are associated with human inherited diseases, ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders. The ABCA12 gene is located in a region of chromosome 2q34 that harbors the genes for lamellar ichthyosis, polymorphic congenital cataract, and insulin-dependent diabetes mellitus (IDDM13), and therefore is a positional candidate for these pathologies.
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PMID:Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. 1269 99

Diflubenzuron (DIMILIN) is a powerful insecticidal chemical which has been known for many years to inhibit chitin synthesis in vivo in insects and related arthropod species. However, its action mechanism has remained unresolved partly because of its inaction on any of the enzymes involved in chitin synthesis in vitro. Based on our previous work (Diflubenzuron affects gamma-thioGTP stimulated Ca2+ transport in vitro in intracellular vesicles from the integument of the newly molted American cockroach, Periplaneta americana L. Insect Biochem. Mol. Biol. 24 (1994) 1009) showing that diflubenzuron inhibits Ca2+ uptake by vesicles obtained from the integument of American cockroach, Periplaneta americana (L.), in vitro, we tested the hypothesis that the action site of diflubenzuron is an ABC (ATP binding cassette) transporter, probably a sulfonylurea-sensitive transporter. Glibenclamide, one of the most commonly used sulfonylureas for type II diabetes treatment, was the positive control. When given to immature insects, glibenclamide clearly caused toxicity, with symptoms indicating molting abnormality comparable to diflubenzuron. Its LD50 (0.472 microg/nymph) was approximately 2.8 times the value obtained for diflubenzuron (0.17 microg/nymph, topical) in German cockroach, Blattella germanica (L.). However, in terms of the inhibitory activities on chitin synthesis, in isolated integuments glibenclamide showed an identical potency to diflubenzuron in B. germanica nymphs. A competitive binding assay with [3H]-glibenclamide and unlabeled diflubenzuron clearly established that the latter is capable of competitively displacing the former radioligand. The KD values observed for vesicles prepared from fruit fly larvae, Drosophila melanogaster M., were 44.9 nM for glibenclamide and 65.0 nM for diflubenzuron, respectively. Furthermore, glibenclamide was found to affect Ca2+ uptake by isolated cuticular vesicles from B. germanica in a manner very similar to diflubenzuron. These results support our conclusion that the sulfonylurea receptor (SUR) is the target of diflubenzuron in inhibition of chitin synthesis in these two insect species.
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PMID:Significance of the sulfonylurea receptor (SUR) as the target of diflubenzuron in chitin synthesis inhibition in Drosophila melanogaster and Blattella germanica. 1526 79

Little information is available on cholesterol absorption and synthesis in human type 1 diabetes. We studied these variables using serum cholesterol precursor sterol ratios to cholesterol as surrogate markers of cholesterol synthesis and those of cholestanol and plant sterols to reflect cholesterol absorption in seven type 1 diabetic subjects and in five age- and body weight-matched control subjects. Total and lipoprotein cholesterol levels were similar, but triglycerides in intermediate-density lipoprotein (IDL) and LDL were higher in type 1 diabetic than in control subjects. Most of the marker sterols were transported by LDL and HDL in both groups. The percentage of esterified cholesterol was lower in triglyceride-rich lipoproteins in diabetic patients than in control subjects. The ratios of the absorption marker sterols in serum were higher, and those of the synthesis markers were lower in type 1 diabetic than in control subjects. The increased cholestanol ratios were seen in all lipoproteins, and those of free and total plant sterols were mainly in LDL, whereas the decreased free and total synthesis markers were mainly in all lipoproteins. In conclusion, high absorption and low synthesis marker sterols seem to characterize human type 1 diabetes. These findings could be related to low expression of ABC G/5 G/8 genes, resulting in high absorption of cholesterol and sterols in general and low synthesis of cholesterol compared with type 2 diabetes.
Diabetes 2004 Sep
PMID:Cholesterol metabolism in type 1 diabetes. 1533 30

High glucose-induced endothelial cell dysfunction is considered to be the main cause of the development of vascular diabetes complications. Cultured endothelial cells exposed to high glucose in vitro demonstrate a variety of alterations, including extracellular matrix (ECM) deposition, growth inhibition, and changes in cell motility. Some of these effects were shown to be mediated by the up-regulation of endothelial transforming growth factor-beta1 (TGFbeta1) secretion and activation. We investigated the influence of high glucose on human immortalized endothelial cell line ECV304. According to our data, confluent cells exposed to 30 mM glucose for 48 h secrete the increased amount of total and active TGFbeta1 ( approximately 1.4-fold), and accumulate more chondroitin sulphate (CS) in their conditioned medium, pericellular matrix, and cell layer ( approximately 1.6- to 2.0-fold). By blocking the coupling of CS chains to the core protein with p-nitrophenyl-beta-D-xyloside and by chondroitinase ABC treatment, we demonstrated that the increased accumulation of pericellular CS is accompanied by increased cell attachment to immobilized hyaluronic acid (HA), while the expression of cell surface CD44 remains unaltered. Since the exogenous TGFbeta1 affects ECV304 cells in a similar manner, and anti-TGFbeta1-neutralizing antibody cancels the effect of high glucose, we suggest the involvement of TGFbeta1 in the development of endothelial cell response to high glucose in terms of CS accumulation and cell binding to HA.
J Diabetes Complications
PMID:TGFbeta1 is involved in high glucose-induced accumulation of pericellular chondroitin sulphate in human endothelial cells. 1533 4

During inflammation, several cell types synthesize and secrete phospholipase A2 that catalyses lipid oxidation in LDL. Myeloperoxidase, a haeme protein secreted by activated phagocytes, oxidizes L-tyrosine to a tyrosyl radical that is a physiological catalyst for the initiation of lipid oxidation in LDL. Lipid oxidation results in the generation of aldehydes that substitute lysine residues in the apolipoprotein B-100 moiety. Lipid together with protein oxidation in LDL results in the generation of oxidized LDL. We, among others, have demonstrated an association between coronary heart disease (CHD) and increased plasma levels of oxidized LDL. Recently, we have demonstrated a higher prevalence of elevated oxidized LDL in persons with high-calculated CHD risk prior to events. The odds of having elevated oxidized LDL for persons with high-calculated CHD risk prior to events were even higher than for persons with diagnosed CHD. A likely explanation is that once CHD has been diagnosed the patients are more treated with a statin that appears to decrease oxidized LDL even beyond its cholesterol-lowering effect. We have identified several metabolic syndrome components (high triglycerides, low HDL-cholesterol, glucose intolerance and diabetes) that independently of LDL-cholesterol, predicted high levels of oxidized LDL. Finally, elevated oxidized LDL predicted myocardial infarction in the Health ABC cohort consisting of well-functioning elderly people, even after adjusting for age, gender, race, smoking, and the metabolic syndrome.
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PMID:Oxidized LDL and coronary heart disease. 1552 50

Type 2 diabetes (T2DM) is one of the most costly and burdensome chronic diseases in Taiwan and is a condition increasing in epidemic proportions all over the world. The symptoms of T2DM, including hyperglycemia, hypertension, and hyperlipidemia are among the highest risk factors for the development of complications with the disease. Blood sugar control alone is not enough for T2DM management. Proper HbA1C, blood pressure, and cholesterol level have been proven by many researchers to decrease T2DM morbidity and mortality. Therefore, the public and health care providers should know this latest ABC management to decrease the complications in T2DM.
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PMID:[Risk factor management in respect of type 2 diabetic complications: ABC management]. 1622 43

Today we know there are four different types of ATPases that operate within biological membranes with the purpose of moving many different types of ions or molecules across these membranes. Some of these ions or molecules are transported into cells, some out of cells, and some in or out of organelles within cells. These ATPases span the biological world from bacteria to eukaryotic cells and have become most simply and commonly known as "transport ATPases." The price that each cell type pays for transport work is counted in molecules of hydrolyzed ATP, a metabolic currency that is itself regenerated by a transport ATPase working in reverse, i.e., the ATP synthase. Four major classes of transport ATPases, the P, V, F, and ABC types are now known. In addition to being involved in many different types of biological/physiological processes, mutations in these proteins also account for a large number of diseases. The purpose of this introductory article to a mini-review series on transport ATPases is to provide the reader with a very brief and focused look at this important area of research that has an interesting history and bears significance to cell physiology, biochemistry, immunology, nanotechnology, and medicine, including drug discovery. The latter involves potential applications to a whole host of diseases ranging from cancer to those that affect bones (osteoporosis), ears (hearing), eyes (macromolecular degeneration), the heart (hypercholesterolemia/cardiac arrest,), immune system (immune deficiency disease), kidney (nephrotoxicity), lungs (cystic fibrosis), pancreas (diabetes and cystic fibrosis), skin (Darier disease), and stomach (ulcers).
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PMID:Transport ATPases: structure, motors, mechanism and medicine: a brief overview. 1669 64

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3+/-15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-alpha SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin.
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PMID:Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study. 1739 Jan 49

The role of renin-angiotensin system (RAS) genes on the risk of lower extremity arterial disease (LEAD) in elderly people remains unclear. We assessed the relationship of genetic polymorphisms in RAS: G-6A, T174M and M235T of the angiotensinogen (AGT) gene, and the angiotensin-converting enzyme insertion/deletion (ACE_I/D) variant to the risk of LEAD in the Health, Aging and Body Composition (Health ABC) Study. This analysis included 1228 black and 1306 white men and women whose age ranged between 70 and 79 years at the study enrollment. LEAD was defined as ankle-arm index (AAI) <0.9. Genotype-phenotype associations were estimated by regression analyses with and without adjustment for established cardiovascular disease (CVD) risk factors. The proportion of LEAD was significantly higher in black (21.1%) than that in white elderly people (10.1%, P<0.0001). The distribution of AGT polymorphisms was also significantly different between black and white participants. There was no statistically significant association between the selected RAS genetic variants and LEAD after adjustment for age, antihypertensive medications, lipid-lowering medication, pack-year smoking, body mass index, low-density lipoprotein cholesterol, and prevalent diabetes and coronary heart disease. However, A-T haplotype of G-6A and M235T interacting with homozygous ACE_II (beta=-1.07, P=0.006) and with ACE inhibitors (beta=-1.03, P=0.01) significantly decreased the risk of LEAD in white but not in black participants after adjustment for the selected CVD risk factors. In conclusion, the study observed a gene-gene and gene-drug interaction for LEAD in the white elderly.
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PMID:Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study. 1742 48


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