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

An insulin-degrading enzyme (IDE) was purified from the cytosol of human erythrocytes via the use of ammonium sulfate precipitation and chromatography on columns composed of DEAE-Sephadex, pentylagarose, hydroxylapatite, chromatofocusing resins, and Ultrogel AcA-34. The final preparation was purified greater than 50,000-fold and exhibited a single protein band of Mr = 110,000 on reduced sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Cross-linking of 125I-labeled insulin to the enzyme preparation labeled a protein of the same molecular weight, indicating that this band was in fact the enzyme. Intact insulin, insulin B chain, and glucagon inhibited this cross-linking half-maximally at concentrations of 0.1, 1, and 1.5 microM, respectively. Under nondenaturing conditions, the enzyme had an Mr = 300,000, suggesting that the enzyme may exist under physiological conditions as a dimer or timer. The purified enzyme was inhibited by both sulfhydrylmodifying reagents and chelating agents, indicating that a free thiol and metal were both required for the activity of the enzyme. The purified enzyme was found to degrade physiological concentrations of intact insulin more rapidly than insulin B chain, although at high substrate concentrations (greater than 1 microM) the enzyme degraded B chain to a greater extent. Additional characteristics of the enzyme were a pl of 5.2 and a pH optimum of 7.0. These properties of the red blood cell (RBC) enzyme were very similar to those reported for IDEs from other tissues. Moreover, a polyclonal antiserum to the IDE from skeletal muscle was found to recognize the RBC enzyme.
Diabetes 1986 Jun
PMID:Purification and characterization of insulin-degrading enzyme from human erythrocytes. 351 22

The activity of the insulin-degrading enzyme neutral cysteine proteinase (EC 3.4.22.11, insulinase) was studied in adipose tissue and in liver of nondiabetic, streptozotocin-diabetic, and insulin-treated diabetic rats. Proteinase activity was found to be significantly decreased during diabetes and was restored to near normal levels in both tissues following insulin treatment. The insulin-mediated increase of proteinase activity in both tissues was partially or completely blocked by actinomycin D (an inhibitor of RNA synthesis) and by cyclohexamide (an inhibitor of protein synthesis). Kinetic analysis showed that the changes in proteinase activity of both liver and adipose tissues were accompanied by a change in Vmax (i.e., maximal enzyme activity) without a change in Km (i.e., substrate affinity). These data indicate that insulin functions as an inducer for neutral cysteine proteinase in both tissues. These alterations in the proteinase activity paralleled the alterations in the activity of a second insulin-degrading enzyme, glutathione-insulin transhydrogenase in adipose tissue (this paper) and in liver (previously published papers) under the same physiological conditions.
 ...
PMID:Insulin-degrading neutral cysteine proteinase activity of adipose tissue and liver of nondiabetic, streptozotocin-diabetic, and insulin-treated diabetic rats. 355 42

A mathematical model of normal regulation of carbohydrate metabolism by the pancreas endocrine apparatus is presented. In a numerical experiment the model imitated changed levels of sucrose, insulin glucagon and gastrointestinal hormones in the blood in response to the ingested 50 g of glucose. The model of normal regulation was damaged in the way which theoretically should result in diabetes development. Then an estimation was made to what extent the disturbances of carbohydrate metabolism characteristic of diabetes were reproduced by the changed model. It has been shown that disturbances specific for diabetes appear when the sensitivity of beta-cells to glucose stimulus or hyperproduction of glucagon decreased. No changes in the behaviour of blood glucose typical of diabetes were obtained in the model when a decrease of the sensitivity of insulin receptors due to hyperinsulinemia in insulin-dependent tissues was imitated, as well as an increased activity of liver insulinase or hyposecretion of gastrointestinal hormones. These results point to the necessity of further development of these hypotheses.
 ...
PMID:[Checking of some hypotheses of the pathogenesis of diabetes mellitus by mathematical modeling]. 635 85

Insulin-degrading enzyme (IDE), which proteolytically degraded insulin with a high degree of specificity, was purified from pig skeletal muscle by ammonium sulfate precipitation, chromatography on Bio-Gel P-200 and DEAE-cellulose, and finally rechromatography on Sephadex G-200 (rechromatography fraction). The enzyme was also purified by affinity chromatography (affinity fraction). Both fractions migrated as a single component at the same position on polyacrylamidegel disc electrophoresis. Antiserum against pig muscle IDE was obtained by immunization of rabbits using the rechromatography fraction. By means of antiserum, it was shown that pig muscle IDE (affinity fraction), rat muscle cytosol-, and membrane-IDE gave a precipitin band of identity in Ouchterlony double-immunodiffusion systems. Quantitative immunoprecipitin data demonstrated that the antiserum inhibited the activities of the above three IDEs compared with normal rabbit serum. These data suggest that the insulin-degrading enzyme from porcine muscle and that from rat muscle have similar immunologic properties. The antiserum described here should be a useful tool for the examination of subcellular distribution and the quantitative analysis of insulin-degrading enzyme. It may also be helpful in determining the physiologic significance of IDE.
Diabetes 1980 Oct
PMID:Immunochemical studies on the insulin-degrading enzyme from pig and rat skeletal muscle. 677 21

The rate of binding and degradation of 125I insulin by red blood cell receptors was determined in children with insulin-dependent diabetes at rest and after physical exercise of moderate intensity (35% VO2max). Anthropometric values, duration of the disease, parameters of lipid and carbohydrate metabolism as well as blood serum levels of insulin and C-peptide were used as the features characterizing the studied children. The determination of the amount of bound and degraded 125I insulin by intact erythrocytes was carried out by the modified method of Gambhir. The method of Hildebrandt was used when the analogous measurements were carried out with hemolysate as a source of receptor. It was found that physical exercise of aerobic type resulted in an increase in the amount of 125I-insulin bound to the red blood cell receptors by about 30%. This value was not statistically significant. Statistically significant differences were, however, obtained for post-exercise concentrations of insulin and C-peptide in blood serum and for the amounts of 125I-insulin degraded by intact erythrocytes and by hemolysate. The observed increase in the amount of degraded insulin may reflect an increase in the activity of insulinase, an enzyme bound to the cell membrane and partly present in the cytoplasm.
 ...
PMID:[Binding and degradation of 125I insulin of erythrocyte receptors--effect of physical exertion]. 805 84

The signal transduction of the formyl-Met-Leu-Phe (FMLP) receptor in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes mellitus (NIDDM) was compared to that of PMNLs obtained from healthy volunteers. According to our previous studies in this group of patients neither the decrease in insulin binding capacity nor the enhanced insulin-degrading enzyme activity was involved. In control PMNLs, 10 nM FMLP induced a pertussis toxin-sensitive increase in phosphatidyl inositol (PI) cleavage and a subsequent Ca2+ signaling from the intracellular pools. On the other hand, the FMLP-induced protein kinase C (PKC) activation and translocation into the membrane could not be detected in these cells via the measurement of 32P incorporation into histone. In contrast, in PMNLs of this special group of patients suffering from NIDDM the FMLP stimulus produced a significantly low increase in PI cleavage and Ca2+ signaling from the intracellular pools. Moreover, in resting PMNLs of these patients with NIDDM, not only the [Ca2+]i but also the membrane-bound PKC activity was found to be significantly increased. In addition, PKC translocation into the cell membrane of diabetic PMNLs could be further triggered with FMLP as judged by the measurement of 32P incorporation into histone. Based on these results, it appears that the signaling of FMLP receptors in PMNLs of some NIDDM patients may have an alternative pathway through Ca2+ influx from extracellular medium, arachidonic acid cascade, and PKC activation.
 ...
PMID:Altered postreceptor signal transduction of formyl-Met-Leu-Phe receptors in polymorphonuclear leukocytes of patients with non-insulin-dependent diabetes mellitus. 943 1

Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci. Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene. Here we have mapped Niddm1b to 1 cM by genetic and pathophysiological characterization of new congenic substrains for the locus. The gene encoding insulin-degrading enzyme (IDE:) was located to this 1 cM region, and the two amino acid substitutions (H18R and A890V) identified in the GK allele reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, demonstrating a synergistic effect of the two variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, indicating that the effect is coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE: GK allele displayed post-prandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE: allele was unique to GK. These data point to an important role for IDE: in the diabetic phenotype in GK.
 ...
PMID:Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. 1095 57

A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.
 ...
PMID:Degradation of amylin by insulin-degrading enzyme. 1097 71

Insulin metabolism in erythrocytes and hepatocytes of normal and experimental diabetic rats was studied. Insulin-degrading complex of erythrocytes and hepatocytes was investigated at low insulin concentration in blood. Kinetic parameters of insulinase depend on insulin concentration in blood have shown. Thermo-acid resistant non-competitive endogenous inhibitors were purified from erythrocytes and hepatocytes. Increase of endogenous inhibitors influence insulin-degrading enzyme in diabetes. Synthesis of insulin-degrading enzyme in hepatocytes of diabetic rats was reduced. These results suggest that insulin-degrading activity in erythrocytes and hepatocytes is regulated by endogenous inhibitors, by synthesis of insulinase. This change of blood insulin concentration influences practically all the components of insulin-degrading complex.
 ...
PMID:[Insulin degradation in hepatocytes and erythrocytes of rats in normal condition and in experimental diabetes]. 1155 15

Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
 ...
PMID:Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. 1263 21


<< Previous 1 2 3 4 5 6 7 8 9 Next >>