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 insulin resistance seen in diabetes mellitus has been attributed partly to impaired autophosphorylation of the insulin receptor. It has been suggested that the phosphorylation of serine and/or threonine residues of the insulin receptor may reduce tyrosine autophosphorylation in streptozotocin-induced diabetic rats (STZ-D rats). To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1991 May
PMID:Dephosphorylation of the insulin receptor partially restores the decreased autophosphorylation in streptozotocin induced diabetic rats. 181 77

Mutations of the insulin receptor gene have been shown to cause insulin-resistant diabetes in patients with genetic forms of insulin resistance. We have previously reported that a mutation substituting valine for Phe382 in the alpha-subunit of the insulin receptor is associated with impaired transport of the mutant receptor to the plasma membrane (Accili, D., Frapier, C., Mosthaf, L., McKeon, C., Elbein, S. C., Permutt, M. A., Ramos, E., Lander, E. S., Ullrich, A., and Taylor, S. I. (1989) EMBO J. 8, 2509-2517). In this study, we demonstrate that the Val382 mutation impairs the ability of insulin to activate receptor autophosphorylation. Furthermore, the Val382 receptor has reduced activity to phosphorylate other peptide substrates in the presence of insulin. Nevertheless, when the Val382 mutant and wild-type receptors are mixed together, the wild-type human insulin receptor is able to phosphorylate the Val382 mutant receptor, thereby activating the tyrosine kinase activity of the mutant receptor. Thus, the conformational change caused by the Val382 mutation compromises the ability of the receptor to transmit a signal across the plasma membrane. Furthermore, our observations suggest that receptor phosphorylation by an intermolecular mechanism (i.e. transphosphorylation) may play a role in mediating the action of insulin upon the target cell.
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PMID:A mutation in the extracellular domain of the insulin receptor impairs the ability of insulin to stimulate receptor autophosphorylation. 184 71

Insulin receptor tyrosine kinase activity solubilized from liver of control and streptozotocin diabetic rats was studied using histone H2b and poly-Glu-Tyr (4:1) as phosphoacceptors. Both substrates inhibited autophosphorylation and exogenous kinase activity when added before, but not after, receptor activation with ATP. When H2b was added before ATP, insulin stimulated exogenous kinase activity of diabetic-derived receptors was significantly higher (approximately 50%) than control values at low H2b concentrations, but significantly lower (approximately 50%) than control values at high H2b concentrations, suggesting a decrease in the apparent Km and maximal velocity of the diabetic receptor tyrosine kinase toward H2b. When receptors were allowed to maximally autophosphorylate before the addition of H2b, the maximal H2b kinase activity of diabetic-derived receptors was only approximately 25% lower than that of controls. These effects were not attributable to altered ATP kinetics. Insulin receptor kinase activity toward the substrate poly-Glu-Tyr (4:1) was unaltered by insulinopenic diabetes. Insulin receptor alpha-beta dimers were not detectable in either control or diabetic-derived preparations. We conclude that the impairment of hepatic insulin receptor kinase activity associated with insulinopenic diabetes reflects a decreased ability to maximally activate, which is enhanced when the receptor is activated in the presence of some substrates, e.g. H2b. Impaired signalling by the diabetic-derived receptor appears to be dependent on the type of substrate and its concentration.
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PMID:Diabetes-associated impairment of hepatic insulin receptor tyrosine kinase activity: a study of mechanisms. 184 1

Mesangial cells are thought to play a central role in the renal complications of diabetes mellitus. Insulin-like growth factor I (IGF-I) has been found to promote mesangial cell proliferation and regulate normal mesangial cell function in an autocrine and/or paracrine fashion. To gain further insight into the potential regulatory role IGF-I may play in mesangial cell function in diabetes, IGF-I receptors were analyzed in mesangial cells isolated from diabetic mice (db/db) and their control littermates (db/m). Mesangial cells isolated from db/db mice exhibited higher levels of IGF-I receptors compared to cells from db/m mice. Insulin receptors were not detectable in either cell type by binding analyses; however, immunoblot analysis revealed insulin receptor alpha-subunits in wheat germ agglutinin-Sepharose-purified membranes from db/db cells. Northern blot analysis further indicated a lack of detectable insulin receptor mRNA in db/m cells, whereas db/db cells expressed multiple insulin receptor mRNA transcripts. Both IGF-I and insulin receptor mRNA levels were increased in db/db cells grown in the presence of high glucose (28 mM), whereas the receptor protein levels remained relatively constant or increased, respectively. This increased expression of IGF-I and insulin receptors in diabetic mesangial cells may have an important role in the development of diabetic nephropathy.
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PMID:Regulation of insulin-like growth factor I receptors in diabetic mesangial cells. 184 26

Although non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in insulin action, the molecular basis of this resistance is unknown. We studied fibroblasts from a markedly insulin-resistant patient with NIDDM but without acanthosis nigricans. Her fibroblasts were resistant to insulin when alpha-aminoisobutyric acid uptake was measured. Fibroblasts from this patient demonstrated normal insulin-receptor content as measured by both insulin-receptor radioimmunoassay and by Scatchard analysis. However, when compared with nondiabetic control subjects, insulin-receptor kinase assays of wheat-germ-purified receptors prepared from her fibroblasts showed very low basal and no insulin-stimulated tyrosine kinase activity. The insulin receptor was then removed from the wheat-germ fraction by monoclonal antibody affinity chromatography. This insulin-receptor-deficient fraction inhibited both basal and insulin-stimulated tyrosine kinase activity of highly purified insulin receptors. When the specificity of this inhibition was tested, less inhibition was seen with insulinlike growth factor I-receptor tyrosine kinase, and even less inhibition was seen with the proto-oncogene p60c-src tyrosine kinase. Thus, these studies indicate that fibroblasts from an insulin-resistant patient with NIDDM produce a relatively specific glycoprotein inhibitor of insulin-receptor tyrosine kinase. Therefore, these studies raise the possibility that this inhibitor may play an important role in the insulin resistance seen in this patient.
Diabetes 1991 Feb
PMID:Production of inhibitor of insulin-receptor tyrosine kinase in fibroblasts from patient with insulin resistance and NIDDM. 184 30

The effects of oral vanadyl sulfate administration for 9-12 days on carbohydrate and lipid metabolism in the basal state and on glucose dynamics during submaximal hyperinsulinemic clamps were investigated in nondiabetic and streptozocin-induced diabetic rats. Decreases in growth rate and water and food consumption were the only significant alterations noted in control animals receiving vanadyl. Administration of vanadyl to diabetic rats resulted in weight loss; a significant decrease in plasma glucose, triglyceride, and cholesterol levels; and decreases in food and water intake, without a concomitant change in plasma insulin concentrations. Vanadyl treatment did not modify either peripheral glucose utilization or hepatic glucose production in control rats during submaximal insulin clamps. In contrast, vanadyl therapy increased insulin-induced glucose utilization significantly and had a small but nonsignificant effect on insulin-mediated suppression of glucose production in diabetic rats. The tyrosine kinase activity of liver- and muscle-derived insulin receptors from diabetic rats that underwent clamp study, which reflected the in vivo phosphorylation state of insulin receptor, was not altered by vanadyl treatment. In conclusion, these results show that augmentation of peripheral glucose utilization is the major determinant of the antidiabetic action of vanadyl and support the notion that the action of vanadyl is independent of insulin-receptor kinase activity.
Diabetes 1991 Apr
PMID:Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity. 184 4

To investigate the early events in insulin signal transmission in liver, isolated rat hepatocytes were labeled with 32P, and proteins phosphorylated in response to insulin were detected by immunoprecipitation with anti-phosphotyrosine and anti-receptor antibodies and analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and autoradiography. In these cells, insulin rapidly stimulated tyrosine phosphorylation of the 95,000-Mr beta-subunit of the insulin receptor and a 175,000-Mr phosphoprotein (pp175). Both proteins were precipitated by anti-phosphotyrosine antibody, whereas only the insulin receptor was recognized with anti-insulin-receptor antibody. In the insulin-stimulated state, both pp175 and the receptor beta-subunit were found to be phosphorylated on tyrosine and serine residues. Based on precipitation by the two antibodies, receptor phosphorylation was biphasic with an initial increase in tyrosine phosphorylation followed by a more gradual increase in serine phosphorylation over the first 30 min of stimulation. The time course of phosphorylation of pp175 was rapid and paralleled that of the beta-subunit of the insulin receptor. The pp175 was clearly distinguished from the insulin receptor, because it was detected only when boiling SDS was used to extract cellular phosphoproteins, whereas the insulin receptor was extracted with either Triton X-100 or SDS. In addition, the tryptic peptide maps of the two proteins were distinct. The dose-response curve for insulin stimulation was shifted slightly to the left of the insulin receptor, suggesting some signal amplification at this step. These data suggest that pp175 is a major endogenous substrate of the insulin receptor in liver and may be a cytoskeletal-associated protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Jan
PMID:Coordinate phosphorylation of insulin-receptor kinase and its 175,000-Mr endogenous substrate in rat hepatocytes. 184 50

Genetic factors are essential to the occurrence of insulin-dependent diabetes (IDD) and non-insulin-dependent diabetes (NIDD), and all that environmental factors do is facilitate the development of diabetes in genetically predisposed subjects. Recent advances in molecular biology have improved our understanding of diabetic heredity. IDD is closely linked to the HLA region of chromosome 6. Ninety percent of IDD belong to the DR3 or DR4 group. The occurrence of IDD is facilitated by a peculiar conformation of the HLA DQ molecule which permits the presentation of antigens to the T-cells. Other genes still have to be discovered since IDD seems to be of polygenic origin. NIDD is even more "hereditary" than IDD, but owing to the lack of an unquestionable marker the responsible genes cannot be located with certainty. Several possible genes such as those of insulin, insulin receptor and glucose transporter, are suspected, at least in some forms of NIDD--a clinically and biologically highly heterogeneous disease. Widespread family studies should, in a not too distant future, locate the responsible gene thereby leading to early detection or even prevention of NIDD.
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PMID:[Diabetes and heredity]. 185 94

We previously showed that purified human IgG1 insulin autoantibody (IAA) from the serum of male patient T.H. with insulin autoimmune syndrome is directed at a determinant at the asparagine site on the human insulin B chain. An anti-idiotypic antibody (anti-TH) that inhibited TH-IAA binding to human insulin was obtained by immunizing BALB/c mice with TH-IAA. Anti-TH bound to viable IM-9 cells and the purified insulin receptor from IM-9 cells. Anti-TH binding to IM-9 cells and the insulin receptor was inhibited by TH-IAA but not by human IgG. Moreover, incubation of HepG2 cells with anti-TH had an inhibitory effect on insulin binding to HepG2 cells. Anti-TH, like insulin, stimulated amino acid uptake in HepG2 cells. These findings indicate that the conformation of TH-IAA idiotope is a mirror image of the determinant on the insulin B chain, the binding site for TH-IAA on anti-TH is also related to the insulin binding site on the insulin receptor, and anti-TH mimics insulin action on the insulin receptor.
Diabetes 1991 Aug
PMID:Inducement of antibody that mimics insulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain. 186 May 61

Since the beginning of the seventies, studies of the cellular mechanisms behind insulin resistance in man have included studies of insulin receptor binding and insulin action in isolated cells. In the first studies, only measurements of insulin binding to circulating blood cells (mononuclear cells and erythrocytes) were possible. In these studies it was thus necessary to anticipate that insulin binding to these cells was representative for binding to target cells for insulin (adipocytes, hepatocytes, muscle cells). Later, studies of the human adipocyte became available. In the isolated human adipocyte it was possible to measure both insulin binding and the action of insulin on glucose transport and on the intracellular glucose processing. Immediately, it was observed that receptor binding to the different cell types was not always comparable. Moreover, the relationship between fat cell insulin binding and action was not always straightforward. Because fat tissue is only responsible for a small fraction of total glucose uptake, it is not possible to know whether changes in insulin binding and action in this tissue is representative for changes in the total organism. In the present review these problems have been elucidated by studies of patients with insulin-dependent and non-insulin-dependent diabetes mellitus. In chapter one, the methods used in the clinical studies are reviewed. The precision (intraassay variability) and reproducibility (intraperson variability) has been measured for all insulin receptor assays. It was found that the earlier used assay for mononuclear cells was improved by using a pure monocyte assay, because precision as well as reproducibility was improved. On the other hand, these values were considerably poorer than those found for the other cell types. The precision was 0.09, 0.04, and 0.04 for monocytes, erythrocytes and adipocytes, respectively. The reproducibility was 0.19, 0.06 and 0.11. In order to be able to measure comparability between insulin binding to the above mentioned cell types and hepatocytes, methods for measurement of insulin binding to these cell types from swine have been developed. These studies showed that insulin binding to swine cells have many similarities to that of human cells whereas several dissimilarities were seen between insulin binding to rat and human cells. Thus, it is surmised that swine cells are more suitable than rat cells concerning insulin receptor binding and action studies.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin receptor binding and action in human adipocytes. A critical approach to methods, correlations with receptor binding to other cell types, and relations between insulin binding and action. 186 54


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