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 native or modified alpha-amylase inhibitor Hoe 467A - isolated from the culture medium of Streptomyces tendae 4158 - and overlapping peptides were degraded by the automatic Edman technique. The oxidized or aminoethylated or oxidized and maleoylated inhibitor was digested with trypsin and the native inhibitor with pepsin. Further digestion with Staphylococcus aureus proteinase was also carried out. After peptic digestion two cystin peptides were isolated, which allowed the establishment of the disulfide bonds. The alpha-amylase inhibitor is a polypeptid consisting of 74 amino-acid residues with a molecular mass of 7958 Da. The inhibitor is composed of all naturally occurring amino acids except methionine and phenylalanine and shows no sequence homology to known inhibitors. The clinical and pharmacological importance in respect to the inhibitors ability for inactivation of human salivary and pancreatic alpha-amylase is discussed. Especially the proteinase resistance of the inhibitor enables a clinical application in human (e.g. Diabetes mellitus) per os.
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PMID:[The primary structure of the alpha-amylase inhibitor Hoe 467A from Streptomyces tendae 4158. A new class of inhibitors]. 660 9

Collagen from human skin was fractionated into neutral salt-soluble, acid-soluble, pepsin-released, and insoluble fractions. No age-related changes were observed in the proportion of collagen extracted by neutral salt. A significant age-related decrease in the proportion of acid-soluble collagen was found. A highly significant (P less than 0.001) age-related decrease in the amount of collagen released by pepsin digestion was observed, with a concomitant age-related increase in the fraction of insoluble collagen. The amount of ketoamine-linked glucose bound to this insoluble collagen also increased significantly with age. Skin collagen from three juvenile onset diabetics (JOD) and one young maturity onset diabetic (MOD) appeared to have undergone accelerated aging. JOD and the young MOD had significantly less collagen released by pepsin digestion and significantly more insoluble collagen than would be predicted by their ages. The collagen released by pepsin digestion of the diabetic samples had more high molecular weight components than similar fractions obtained from age-matched nondiabetic controls. There was also more ketoamine-linked glucose bound to the insoluble collagen of JOD than to that fraction from comparably aged control subjects. The apparent acceleration of collagen aging in diabetes mellitus may play a role in complications of diabetes that occur in collagen-rich tissues.
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PMID:Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. 678 79

The biosynthesis of collagen and fibronectin molecules by cultivated glomerular epithelial or mesangial cells was studied at confluency using radioactive proline or lysine as precursors. Collagen represented 0.5% of the total protein synthesized by the glomerular epithelial cells. About 60% of this collagenous protein were associated to the cell layer, whereas about 40% were secreted into the culture medium. Two major collagenous polypeptides were observed with apparent molecular weights of 185K and 170K, and were identified as two gene products of type IV procollagen. They exhibited ratios of 3- to 4-hydroxyproline, of total hydroxyproline to proline, and of hydroxylysine to lysine characteristic of type IV procollagen. They were degraded by bacterial collagenase. The patterns of peptides obtained after digestion of the 185K and 170K chains of this type IV procollagen with pepsin and V8 protease were identical to those obtained after digestion of type IV procollagen chains purified from a murine tumor (EHS sarcoma). Finally. a purified antibody to type IV collagen specifically immunoprecipitated the collagenous protein produced by the glomerular epithelial cells. By contrast, the mesangial cells synthesized about 5% of collagenous protein. 90% of this collagen were secreted into the cultured medium, whereas about 10% remained associated to the cell layer. Type I, III and IV procollagens were synthesized by the mesangial cells. Fibronectin was found in the medium and cell layer of both epithelial and mesangial cells. Fibronectin molecules were identified by their resistance to bacterial collagenase, their susceptibility to pepsin digestion, and their specific adherence to collagen. It was composed of disulfide-linked peptides of 220K daltons. The data therefore demonstrate that: (a) the glomerular epithelial and mesangial cells synthesize fibronectin molecules and type IV procollagen in vitro; (b) the cultivated mesangial cells also synthesize type I and III collagens. The implications of these findings in certain pathological circumstances, such as diabetes mellitus, are now being investigated.
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PMID:Synthesis of collagen and fibronectin by glomerular cells in culture. 732 12

The relationship between the extractability of collagen by enzymatic digestion and the degree of nonenzymatic glycation of collagen was examined in the aorta and skin from 38 subjects without diabetes mellitus (mean age: 62.3 +/- 20.2 years). Samples were obtained from the aortic media (M), lesion-free intima (I), atherosclerotic intima (A) and dermis of the skin (S). Collagen was extracted first by incubation with 1/50 (enzyme/substrate weight ratio) pepsin at 4 degrees C for 24 h (P-fraction) and then by incubation with 1/10 (enzyme/substrate weight ratio) pepsin at room temperature for 24 h (EP-fraction). The pepsin-insoluble precipitates were digested by incubation with 270 units of bacterial collagenase at 37 degrees C for 24 h (PIS-fraction). Collagen contents, ketoamines and collagen-linked fluorescence (CLF) were measured in each fraction. The amount of ketoamines and the level of CLF correlated inversely with the susceptibility of collagen to pepsin digestion in various tissues, including M, I, A and S. These values were highest in both the P- and EP-fractions of M, which contained the least amount of collagen extracted by pepsin digestion. In contrast, they were lowest in S, where the concentration of collagen extracted by pepsin digestion was greatest among all of the tissue samples. Atherosclerotic intima (A) and aortic media (M) showed an age-related increase in the total amount of collagen digested with pepsin and collagenase, which depended mainly on an increase in the content of pepsin-insoluble collagen. Although the total amount of collagen did not increase with advancing age in I or S, collagen in I and S became progressingly resistant to pepsin digestion. These results suggest that the age-related decrease in the susceptibility of collagen to pepsin digestion may be due to nonenzymatic glycation in atherosclerotic lesions as well as normal tissues, including the aortic media, lesion-free intima and skin. The level of CLF significantly increased with age in the P-fraction and/or EP fraction of M, I and S. However, there was no relationship between the level of CLF and the subject's age in A. Thus, the accumulation of advanced glycation endproducts (AGEs) on collagen fibers may be partially responsible for the increase in collagen matrix in atherosclerotic lesions of subjects without diabetes mellitus.
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PMID:Nonenzymatic glycation and extractability of collagen in human atherosclerotic plaques. 748 34

The Maillard or browning reaction between sugar and protein contributes to the increased chemical modification and cross-linking of long-lived tissue proteins in diabetes. To evaluate the role of glycation and oxidation in these reactions, we have studied the effects of oxidative and antioxidative conditions and various types of inhibitors on the reaction of glucose with rat tail tendon collagen in phosphate buffer at physiological pH and temperature. The chemical modifications of collagen that were measured included fructoselysine, the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine and fluorescence. Collagen cross-linking was evaluated by analysis of cyanogen bromide peptides using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by changes in collagen solubilization on treatment with pepsin or sodium dodecylsulfate. Although glycation was unaffected, formation of glycoxidation products and cross-linking of collagen were inhibited by antioxidative conditions. The kinetics of formation of glycoxidation products proceeded with a short lag phase and were independent of the amount of Amadori adduct on the protein, suggesting that autoxidative degradation of glucose was a major contributor to glycoxidation and cross-linking reactions. Chelators, sulfhydryl compounds, antioxidants, and aminoguanidine also inhibited formation of glycoxidation products, generation of fluorescence, and cross-linking of collagen without significant effect on the extent of glycation of the protein. We conclude that autoxidation of glucose or Amadori compounds on protein plays a major role in the formation of glycoxidation products and cross-liking of collagen by glucose in vitro and that chelators, sulfhydryl compounds, antioxidants, and aminoguanidine act as uncouplers of glycation from subsequent glycoxidation and cross-linking reactions.
Diabetes 1994 May
PMID:Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. 816 45

The relationship between long-term glycemic control and the advanced Maillard reaction was investigated in dura mater collagen and lens proteins from dogs that were diabetic for 5 years. Diabetic dogs were assigned prospectively to good, moderate, and poor glycemic control and maintained by insulin. Biochemical changes were determined at study exit. Mean levels of collagen digestibility by pepsin decreased (NS) whereas collagen glycation (P < 0.001), pentosidine cross-links (P < 0.001), and collagen fluorescence (P = 0.02) increased with increasing mean HbA1 values. Similarly, mean levels of lens crystallin glycation (P < 0.001), fluorescence (P < 0.001), and the specific advanced lens Maillard product 1 (LM-1) (P < 0.001) and pentosidine (P < 0.005) increased significantly with poorer glycemic control. Statistical analysis revealed very high Spearman correlation coefficients between collagen and lens changes. Whereas pentosidine cross-links were significantly elevated in collagen from diabetic dogs with moderate levels of HbA1 (i.e., 8.0 +/- 0.4%), lens pentosidine levels were normal in this group and were elevated (P < 0.001) only in the animals with poor glycemic control (HbA1 = 9.7 +/- 0.6%). Thus, whereas protein glycation and advanced glycation in the extracellular matrix and in the lens are generally related to the level of glycemic control, there is evidence for a tissue-specific glycemic threshold for pentosidine formation, i.e., glycoxidation, in the lens. This threshold may be in part linked to a dramatic acceleration in crystallin glycation with HbA1 values of > 8.0% and/or a loss of lens membrane permeability. This study provides support at the molecular level for the growing concept that glycemic thresholds may be involved in the development of some of the complications in diabetes.
Diabetes 1996 May
PMID:Evidence of a glycemic threshold for the formation of pentosidine in diabetic dog lens but not in collagen. 862 Oct 8

Recent immunohistological studies using antibodies against advanced glycation end products (AGEs) have demonstrated the presence of AGEs in several tissues. By an enzyme-linked immunosorbent assay using the monoclonal anti-AGE antibody, the present study aimed to determine AGEs in pepsin-insoluble collagen (PIC) as well as in pepsin-soluble collagen (PSC) from the aortas of streptozotocin (STZ)-induced diabetic rats (at 4, 16, and 28 weeks after STZ injection) and those of age-matched control rats. Addition of EDTA to the immunoassay buffer has led us to successful determination of AGEs in the aortic PIC samples with following results: 1) in diabetic rats, there was a time-related increase in the AGE contents at 28 weeks (n = 9, 226.4 +/- 13.5 ng/mg collagen [mean +/- SE]), compared with that at 4 and 16 weeks (n = 6, 79.6 +/- 9.5 ng/mg collagen, and n = 8, 149.4 +/- 30.9 ng/mg collagen at 4 and 16 weeks, respectively; both P < 0.05, between 4 and 16 weeks and 28 weeks); 2) after 28 weeks of diabetes, the AGE contents in PIC of aortas were significantly higher in diabetic rats than in controls (n = 9, 226.4 +/- 13.5 ng/mg collagen vs. n = 8, 129.6 +/- 14.9 ng/mg collagen, P < 0.01, diabetic vs. control); and 3) the level of the AGE content was strongly correlated with the PIC/total collagen (TC) ratio (n = 45, r = 0.698, P = 0.0001). By treating the samples of PSC with alkaline solution, the AGE content of PSC was also determined. In the PSC fraction, the AGE levels in the diabetic rats tended to increase with time and to be higher than those of control rats at 28 weeks although these changes were not statistically significant (diabetic: n = 4, 19.4 +/- 9.7; n = 6, 22.3 +/- 6.2; n = 6, 39.6 +/- 10.8; control: n = 4, 19.7 +/- 9.8; n = 6, 22.9 +/- 7.3; n = 7, 30.7 +/- 7.2; at 4, 16, and 28 weeks, respectively). Compared with the AGE levels of PSC, those of PIC were about four to seven times and four to five times higher in diabetic and control rats, respectively (PIC versus PSC in diabetic or control rats, all P < 0.001, at 4, 16, and 28 weeks, respectively). These findings provide the first immunochemical evidence that AGE adducts are present in the materials extracted sequentially by pepsin and collagenase and that these adducts in PIC accumulated as a function of the increase in the aortic PIC/TC ratio.
Diabetes 1996 Aug
PMID:Advanced glycation end products of the Maillard reaction in aortic pepsin-insoluble and pepsin-soluble collagen from diabetic rats. 869 Jan 49

Aminoguanidine (AG) is a nucleophilic compound that inhibits nonenzymatic, glucose-derived collagen cross-linking in animal tissues. Whether AG can attenuate the accumulation of collagen cross-links in the Biceps femoris muscle of 64-wk-old broiler breeder hens as well as improve meat quality, was investigated. Eighty-four broiler breeder hens (30-wk-old) were divided into four equal groups. Each group was assigned randomly to diets supplemented with 0. 200, 400, or 800 ppm AG, respectively. Birds were fed individually, 150 g diet/d. After feeding AG for 34 wk, six birds from each group were killed and samples from the leg muscle were analyzed for changes in collagen content. Aminoguanidine decreased (P < 0.05) glucose-derived collagen cross-links in skeletal muscle as measured by fluorescence and collagen solubility. Insoluble collagen fraction decreased with increasing AG dosage, whereas acid-soluble and pepsin-soluble fractions increased with increasing AG dosage. Aminoguanidine did not affect shear force. In agreement with studies on animals with diabetes, AG is a potent inhibitor of glucose-derived cross-linking in chickens although the results from the measurements of shear force do not support its used for improving carcass quality in spent hens.
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PMID:Inhibition by aminoguanidine of glucose-derived collagen cross-linking in skeletal muscle of broiler breeder hens. 877 39

Solubility of tail tendon collagen from normal, streptozotocin-induced diabetic Lewis rats, and diabetic animals treated with aminoguanidine and two novel advanced glycosylation end products (AGE)-formation inhibitors was investigated by limited pepsin digestion under acidic conditions. Assays were conducted using tail tendon collagen from Lewis rats obtained from two different vendors, Harlan and Charles River Laboratories. Collagen solubility was assessed by following the kinetics of pepsin digestion. The data revealed that the rate of digestion for diabetic animals is markedly slow relative to that of normals. More strikingly, the kinetics of the diabetic animals showed the feature of a lag in digestion regardless of the animal source. Experiments designed to optimize the difference in solubility between normal and diabetic animals demonstrated that Charles River animals exhibit a greater window of solubility than the Harlan animals. More importantly, a pronounced effect of aminoguanidine, an AGE-formation inhibitor, was observed in Charles River animals, but not in the Harlan animals, presumably because of the larger window of solubility between the normal and the diabetic animals in the former. These data indicated that the Charles River Lewis rats are an animal model that demonstrates greater efficacy in this assay. Analysis of in vivo screens designed to test efficacy of aminoguanidine and two novel AGE-formation inhibitors, ALT 462 and ALT 486, demonstrated that monitoring an in vivo dose response is highly dependent on the enzyme concentration as well as the time of digestion, and that 1.5 h of digestion and 10 microg/ml pepsin (5 pg pepsin/mg collagen) appeared optimal. Under these conditions, a 29% normalization of solubility was observed with aminoguanidine at 100 mg/kg body wt, whereas a similar normalization was observed at 10 mg/kg body wt for both ALT 462 and ALT 486. Thus, on a molar basis, ALT 462 and ALT 486 are at least 20 times more potent than aminoguanidine. This is the first demonstration of dose-dependent efficacy for AGE-formation inhibitors in animal models, and as such, this assay provides a method with which to assess the in vivo efficacy of other such inhibitors.
Diabetes 1996 Dec
PMID:Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formation inhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats. 892 53

Nonenzymatic glycosylation (glycation) of proteins, often referred to as the Maillard reaction, has been proposed to play a role in age and diabetes-related processes by forming protein and DNA adducts and cross-links. These cross-links may contribute to erectile dysfunction by scavenging nitric oxide, which is needed for erection. As the basis for a possible role of the advanced Maillard reaction in age-related erectile dysfunction, we investigated the presence of the specific advanced glycation endproduct (AGE) pentosidine in penile corpus cavernosum tissue and penile tunica albuginea tissue as a function of age. A total of 23 penile tissue specimens were obtained at autopsy, from which 19 samples of tunica albuginea and 21 samples of corpus cavernosum were derived. In addition, 13 penile corporal and tunical specimens were procured at the time of insertion of a penile prosthesis, from which 12 tunica albugineal specimens and 10 samples of corpus cavernosum were derived. Collagen was extracted with acetic acid and pepsin digestion, and the final insoluble collagen product was acid-hydrolyzed with 6 N HCL for 24 h at 110 degrees C. Pentosidine was quantified by high-performance liquid chromatography using a reverse-phase column. The level of pentosidine (expressed in picomoles per milligram of insoluble collagen) was found to increase with age in cadaver as well as living penile corporal and tunical albugineal tissues. Best-fit analysis revealed an exponential increase in both types of cadaver penile tissue, with regression equations of y = 15.29 x 10(9.9e-3x), R2 = 0.79, being obtained in the tunica and y = 13.2 x 10(7.63e-3x), R2 = 0.56, in the corpora. These correspond to 6- and 4-fold increases in pentosidine levels from puberty to the age of 100 years (P < 0.05), respectively. Mean pentosidine levels were higher in the tunica than in the corpora. Comparison of pentosidine levels in the tunica versus the corpora revealed a weakly linear correlation (y = 24.88 + 1.08x, R2 = 0.32). Levels in the tunical and corporal specimens from the living human specimens fell with the predicted confidence intervals of the cadaveric tissue. Tunical specimens from patients who underwent repair or revision of a previously inserted penile prosthesis had very low levels of pentosidine. The exponential age-related increase in pentosidine observed in both types of penile tissue suggests an impairment of collagen turnover, which could be related to the advanced glycation reaction in aging. It is not known whether pentosidine itself is directly associated with erectile dysfunction, but its formation is usually accompanied by extensive tissue modification. Formation of advanced Maillard reaction products, which is greatly accelerated in aging, diabetes, and uremia, could contribute to erectile dysfunction in these syndromes.
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PMID:Age-related increase in an advanced glycation end product in penile tissue. 911 57


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