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)

An AGE-modified form of LDL (AGE-LDL) circulates in patients with diabetes mellitus or renal insufficiency and shows impaired plasma clearance kinetics when injected into transgenic mice that express the human LDL receptor. The advanced glycosylation inhibitor aminoguanidine decreases plasma LDL in diabetic patients, further suggesting that the AGE modification of LDL contributes significantly to increased LDL in vivo. We utilized AGE-specific antibodies to identify the major site(s) of AGE modification within apolipoprotein B (apoB), which impairs the binding of AGE-LDL by human fibroblast LDL receptors. Despite the large size of apoB (4536 amino acid residues) and its high content of potentially reactive lysines, the predominant site of AGE-immunoreactivity was found to lie within a single 67 amino acid domain located 1791 residues N-terminal to the LDL receptor binding site. These data point to the high specificity and reactivity of this site toward AGE formation and to a significant structural interaction between this region of apoB and the LDL receptor binding domain. A low but detectable degree of AGE modification was found to affect this site in LDL which was isolated from normal, non-diabetic individuals, suggesting that advanced glycosylation may contribute to elevated LDL in the general population as well.
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PMID:Site-specific modification of apolipoprotein B by advanced glycosylation end-products: implications for lipoprotein clearance and atherogenesis. 904 1

To investigate the possible implication of non-enzymatic glycosylation in the etiopathogenesis of the diabetic retinopathy, we studied the effect of early and advanced glycation products on the growth of retinal microvascular cells. Glucose modified products were obtained by incubating bovine serum albumin or fetal bovine serum with 0.5 M glucose for 10 (early glycation products: EG-BSA and EG-FBS, respectively) or 60 days (advanced glycation end products: AGE-BSA and AGE-FBS, respectively). Cell growth was assessed by cell counting and DNA content determination. EG-BSA or AGE-BSA significantly decreased pericyte proliferation after 8 days of culture (33 and 13% inhibition, respectively). Concerning endothelial cells, EG-BSA reduced proliferation to 40% whereas AGE-BSA increased it to 156% after 4 days of culture. The glucose-treated sera didn't exhibit the same growth effects, neither the EG-FBS nor the AGE-FBS significantly affected endothelial cell proliferation. Only the AGE-FBS showed a significant inhibitory effect on pericyte proliferation (40% inhibition). We conclude that retinal microvascular cell growth in vitro could be differently modulated by early and advanced glycation products. The inhibitory effect of AGEs observed on pericyte growth, suggests that glycoxidation could be implicated in the pericyte loss observed in diabetic retinopathy.
Diabetes Res Clin Pract 1997 Jan
PMID:Growth modulation of retinal microvascular cells by early and advanced glycation products. 906 64

Receptors for advanced glycation end products (RAGE), which bind and internalize AGE-modified proteins formed from oxidation and other products of the nonenzymatic glycation reaction, have been mechanistically implicated in the development of the chronic complications of diabetes. In the present experiments, we sought evidence for the participation of RAGE in diabetic nephropathy by analysis of steady state levels of mRNA encoding RAGE in the renal cortex of a well-defined animal model (the db/db mouse) that develops renal pathology similar to that found in human diabetes. In these animals, increased AGE-product formation was confirmed by measurement of fluorescence in serum and renal cortex proteins. Renal involvement was confirmed by demonstration of increased urine albumin excretion and elevated serum creatinine concentrations relative to nondiabetic (db/m) littermate controls. Despite elevated concentrations of circulating and tissue AGE-modified proteins, the level of RAGE mRNA expression in renal cortex of diabetic mice did not significantly differ from that in nondiabetic littermate controls. The findings militate against changes in RAGE expression in the pathogenesis of renal abnormalities in this animal model.
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PMID:RAGE mRNA expression in the diabetic mouse kidney. 914 29

Glycation of proteins and their subsequent structural and functional modifications have been ascribed to play a prominent role in the pathogenesis of several secondary complications of diabetes, such as cataract and retinopathy. In addition, it plays a role in the generalized ageing process as well. Investigations have been conducted to explore the possibility of preventing the above process by use of pyruvate and alpha-keto glutarate as representatives of physiologically compatible keto acids. The results demonstrate that both these compounds are effective in preventing the initial glycation reaction as well as the formation of AGE products. Both these compounds also inhibit the generation of high molecular weight aggregates associated with cataract formation. Mechanistically, the preventive effects appear to be due to (1) competitive inhibition of glycation by the keto acids and (2) the antioxidant (radical scavenging) properties of these compounds. The results are hence considered useful from the point of view of developing these and other keto acid derivatives as pharmacological agents useful in preventing glycation related protein changes and consequent tissue pathological manifestations.
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PMID:Formation of advanced glycation end (AGE) products in diabetes: prevention by pyruvate and alpha-keto glutarate. 920 91

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of tumour necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro. Human serum albumin minimally-modified by glucose-derived advanced glycation endproducts (AGEmin-HSA) and human serum albumin highly-modified by glucose-derived advanced glycation endproducts (AGE-HSA) stimulated markedly lower synthesis and secretion of TNF-alpha from THP-1 cells than did MGmin-HSA. The median effective concentration EC50 value of MGmin-HSA for the secretion of TNF-alpha was 5.8 +/- 0.3 microM and the maximal secretion was 0.28 +/- 0.01 ng TNF-alpha/ml (n = 12) for incubations containing 5 x 10(5) cells/ml. MGmin-HSA (0.2-2.0 microM) also stimulated chemotaxis of THP-1 cells in vitro but AGE-HSA did not in this concentration range. The EC50 value of MGmin-HSA for the chemotactic response was 0.44 +/- 0.07 microM (n = 15). Similar induction of the synthesis and secretion of TNF-alpha and chemotaxis by monocytes in response to MGmin-HSA in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of chronic clinical complications of diabetes mellitus.
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PMID:Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 929 94

In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity. Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes.
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PMID:The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. 935 26

Diabetic mice (6 weeks duration) were studied to assess the interaction of advanced glycation endproduct-modified albumin (AGE-Alb) with micro- and macrovascular endothelium, and to evaluate the alterations induced in the ultrastructure of the lung, kidney, and aorta. [125I]-AGE-Alb and AGE-Alb-Au were perfused in situ in the vasculature; the total uptake was quantitated by spectrometry, and the endothelial pathways of AGE-Alb-Au and the morphological alterations of the vascular beds were examined by electron microscopy. The results showed that [125I]-AGE-Alb (0.567 microM) was taken up specifically and saturably by all organs studied, and particularly by the lung. AGE-Alb-Au endocytosis and transcytosis occurred in the pulmonary and aortic endothelia, and were enhanced in diabetic animals. Also in diabetic animals, AGE-Alb-Au was detected throughout the kidney glomerular basement membrane (GBM) and within open filtration slits of podocytes, suggesting altered barrier function. The structural modifications progressed, and at the end of the experimental period, in the lung approximately 28% of the capillaries and approximately 25% of the alveoli became compressed or even collapsed, due to the hyperplasia of extracellular matrix and interstitial connective tissue. The presence of adherent intravascular macrophages suggests the development of an inflammatory immune process. The structural modifications observed in kidney glomeruli included thickening (approximately 30%) of the GBM and the disappearance of diaphragms between the cellular processes of podocytes. The aortic endothelium displayed luminal foldings, increased number (2.8-fold) of Weibel-Palade bodies, and proliferation of basal lamina. Together, the results show that in diabetes there is enhanced vascular uptake of AGE-Alb and significant pathomorphological changes of micro- and macrovessels.
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PMID:Capillary and aortic endothelia interact in situ with nonenzymatically glycated albumin and develop specific alterations in early experimental diabetes. 945 74

Advanced glycation end-product(s) (AGE) are formed in biological systems when reducing sugars react with amino groups on proteins. Long-lived proteins such as collagen and lens crystallins are known to be susceptible to AGE modification and may play a major role in the development of diabetes and other age-related pathologies. It has been previously suggested that AGE formation might affect the lifespan of experimental animals. Our study is the first to examine the effect of AGE accumulation on the life span of an organism, Drosophila melanogaster. We found that Drosophila melanogaster maintained at 24 degrees C accumulate significant AGE over their lifespan. Young flies (10 days old) had 44% less AGE than senescent flies (75 days old). We were able to reduce AGE accumulation in Drosophila melanogaster by raising the flies on a medium containing a known AGE inhibitor, aminoguanidine HCl. Reduction of AGE in flies failed to increase their mean lifespan, and high concentrations (40 mM) reduced the mean life span, which suggests that aminoguanidine is toxic at levels near those required for inhibition of AGE formation. However, the common fruit fly, Drosophila melanogaster, provides a simple model system to study the age-dependent accumulation of glycated proteins and their inhibition by novel compounds.
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PMID:Age-dependent accumulation of advanced glycation end-products in adult Drosophila melanogaster. 957 11

The prevalence and severity of periodontal disease is increased in patients with both insulin-deficient and insulin-resistant forms of diabetes. While a number of underlying factors likely contribute to enhanced periodontal inflammation and alveolar bone loss in diabetes, a common characteristic of these disorders, regardless of etiology, is the presence of hyperglycemia. A critical consequence of hyperglycemia is non-enzymatic glycation and oxidation of proteins and lipids. After a series of reversible reactions which lead to the generation of Schiff bases/Amadori products, a further series of complex molecular rearrangements ensues which results in the formation of the irreversible advanced glycation end products, or AGEs. AGEs accumulate during the process of normal aging in the plasma and tissues, but to an accelerated degree in patients with diabetes. A central means by which AGEs are believed to impart their pathogenic effects is via interaction with specific cellular receptors; the best-characterized of these is receptor for AGE, or RAGE. RAGE, a member of the immunoglobulin superfamily of cell surface molecules, is present in increased levels on target cells in diabetes, such as endothelial cells and monocytes. One consequence of AGE-RAGE interaction is the generation of enhanced cellular oxidant stress, a means by which cell signaling pathways may be activated, thereby resulting in altered cellular phenotype and cellular dysfunction. In this report, we will review our studies to date on AGEs and RAGE and consider the implications of their enhanced interaction in the pathogenesis of accelerated periodontal disease in diabetes.
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PMID:Enhanced interaction of advanced glycation end products with their cellular receptor RAGE: implications for the pathogenesis of accelerated periodontal disease in diabetes. 972 86

Diabetes is a risk factor for periodontal disease in humans. In hyperglycemia, glycoxidation of proteins and lipids results in the formation of advanced glycation endproducts, or AGEs. The accumulation of AGEs in the plasma and tissues, and their interaction with their cellular receptor for AGE (RAGE), has been implicated in diabetic complications. In order to establish a model with which to delineate the specific host response factors that underlie the development of periodontal disease in diabetes, male C57BL/6J mice were rendered diabetic with streptozotocin. One month after documentation of diabetes or control state, mice were inoculated with the human periodontal pathogen Porphyromonas gingivalis, strain 381 (P. gingivalis) or treated with vehicle. Infection with P. gingivalis was achieved, as demonstrated by infiltration of gingival tissue with granulocytes, presence of DNA specific for P. gingivalis as well as increased serum antibody titer to P. gingivalis. At 2 and 3 months after infection, increased alveolar bone loss was demonstrated in P. gingivalis-inoculated diabetic vs. non-diabetic mice, along with enhanced tissue-destructive capacity, as demonstrated by increased collagenolytic activity in gingival extracts. Consistent with an important role for AGE-RAGE interaction, increased AGE deposition and expression of vascular and monocyte RAGE were demonstrated in diabetic gingiva compared with non-diabetic controls. Taken together, these data indicate that we have established a murine model of enhanced periodontal disease in diabetes. This model will serve to delineate molecular mechanisms which account for the increased susceptibility of diabetic patients to periodontal disease.
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PMID:A murine model of accelerated periodontal disease in diabetes. 984 4


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