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)

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

Proposed mechanisms by which insulin exerts its effects are discussed. Evidence for a role for the tyrosine kinase activity of the insulin receptor and of a phosphorylation/dephosphorylation cascade is presented. The possible roles of phospholipid breakdown, diacylglycerol, and protein kinase C are discussed. The hypothesis that insulin elicits the hydrolysis of a glycosyl phosphatidylinositol to form a mediator of certain of its actions is considered in detail. The evidence that a G protein is involved in insulin action is analyzed.
Diabetes 1991 May
PMID:Some thoughts on the mechanism of action of insulin. 190 25

The syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the beta-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 mumol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.
 ...
PMID:Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. 195 1

Diabetes mellitus is associated with high levels of adenosine 3',5'-cyclic monophosphate in tissue and plasma. Diabetes inhibits and insulin stimulates and restores low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase activity. We recently reported that phorbol ester, a tumor promoting agent known to act through protein kinase C also stimulates phosphodiesterase. Here, we address the issue of whether or not the activation of phosphodiesterase by insulin and phorbol ester is different in streptozotocin diabetic adipose tissue. Rat adipose tissue was incubated with insulin, phorbol ester or other known components or effectors of the protein kinase C pathway, i.e. 1,2 dioleoyl-glycerol, 1- oleoyl, 2- acetylglycerol, Ca(++)-Ionophore A 23187, and nifedipine. After incubation, preparation and assay of adenosine 3',5'-cyclic monophosphate phosphodiesterase was made. As in previous data streptozotocin-diabetes inhibits basal phosphodiesterase by about 50% (P less than .02); insulin and phorbol ester each stimulate phosphodiesterase, in streptozotocin-diabetes less than normal (P less than .025); nifedipine inhibits phorbol stimulated phosphodiesterase in streptozotocin-diabetes but not normal (P less than .001); and nifedipine inhibits insulin stimulated phosphodiesterase in normal (84%) and diabetic (97%) (P less than .005). In normal and diabetic tissue, diacyl glycerol and oleoyl-acyl glycerol stimulate phosphodiesterase, are augmented by ionophore and inhibited by nifedipine. In addition 32P incorporation studies and measurements of tyrosine kinase activity are presented which support these differences between normal and diabetic. In summary then, these data suggest common pathways of activation for low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase by insulin and phorbol ester; imply a relationship between two second messenger systems, phosphoinositides and adenosine 3',5'-cyclic monophosphate; and demonstrate a difference in activation of phosphodiesterase between normal and diabetic adipose tissue.
 ...
PMID:Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway: differences in normal and diabetic tissue. 196 4

Endothelial cells are likely to play an important role in the development of diabetic vascular diseases since they are exposed directly to the abnormal circulating metabolites of diabetes and may be easily damaged early in the natural course of vascular complications. Recently, we have demonstrated a decrease of insulin binding and autophosphorylation of the insulin receptor in cultured capillary endothelial cells of diabetic rats. In this study, similar defects in insulin receptor of aortic endothelial cells cultured from diabetic BB rats were found. The specific insulin binding was 45% lower in cells from diabetic than from non-diabetic rats (3.9 +/- 1.3 vs 7.3 +/- 1.2% per mg protein, p less than 0.05), which was due to a decrease of cell surface binding sites. In contrast to the decrease in insulin binding, insulin-like growth factor-I binding was higher in cells of diabetic than control rats (20.6 +/- 5.6 vs 13.7 +/- 4.6% per mg protein). The decrease in insulin binding could not be induced by the two-week treatment of endothelial cells from non-diabetic rats with medium containing high concentration of glucose (400 mg/dl). Insulin-induced tyrosine kinase activity of partially purified insulin receptor measured using poly-glutyr as substrate was also lower in cells from diabetic rats (normal:1.4 +/- 0.6-fold; diabetic 0.5 +/- 0.3-fold above baseline; (p less than 0.05). These data suggest that the diabetic milieu in vivo can induce persistent defects in insulin receptor of aortic endothelial cells. Further studies are warranted to understand the potential pathophysiological role of these defects.
Diabetes Res 1990 May
PMID:Changes of insulin receptor in aortic endothelial cells from diabetic rats. 196 86

Mutations in the insulin receptor gene can lead to in vivo and in vitro insulin resistance and can be the cause of diabetes mellitus in selected patients. We have studied a 22-year-old diabetic woman with Type A insulin resistance and acanthosis nigricans. Insulin binding to the patient's erythrocytes, monocytes, adipocytes, fibroblasts, and transformed lymphocytes was decreased. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's transformed lymphocytes. Determination of the nucleotide sequence of the patient's insulin receptor cDNA revealed that the subject was a compound heterozygote who inherited two different mutant insulin receptor gene alleles. The paternal allele contains a missense mutation encoding the substitution of glutamine for arginine at position 981 in the tyrosine kinase domain of the receptor. The maternal allele contains a nonsense mutation causing premature termination after amino acid 988 in the beta-subunit, thereby deleting most of the kinase domain. The mRNA encoded by the allele with the premature stop codon is likely to be unstable, since mRNA transcripts from this allele were decreased markedly compared with the other allele. The mother, who is heterozygous for the nonsense mutation, exhibited only mild insulin resistance, whereas the proband was severely insulin-resistant; this indicates that the missense mutation is biologically significant. In summary, (1) we have identified a patient and her family with a genetic form of insulin resistance and diabetes due to a defect at the level of the insulin receptor; (2) the proband is a compound heterozygote displaying a missense mutation (position 981) in one allele and a nonsense mutation (position 988) in the other insulin receptor gene allele; (3) the missense mutation is in the kinase domain and encodes a receptor with impaired in vitro kinase activity; and (4) based on the in vitro and in vivo phenotype, the kinase domain mutation at position 981 is biologically significant leading to insulin resistance.
 ...
PMID:Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles. 200 58

We used the recently described technique of single-stranded conformation-polymorphism (SSCP) analysis to examine the insulin-receptor locus. First, the ability of the method to detect known mutations and polymorphisms in the insulin-receptor coding sequence was assessed. Regions of the insulin-receptor sequence containing 16 different nucleotide changes, 9 in patient genomic DNA and 7 as cloned cDNA in plasmids, were analyzed. All 9 patient genomic DNA mutants and 5 of 7 plasmid mutants exhibited variant SSCP patterns. To investigate the potential of the technique for screening many patients, the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). Exons 17-21 were amplified from genomic DNA with polymerase chain reaction and subjected to SSCP analysis. Exons 19, 20, and 21 revealed no bands of aberrant migration, suggesting a high degree of conservation of these sequences. One diabetic subject had an SSCP variant in exon 18. Direct sequencing of this subject's genomic DNA revealed a heterozygous missense mutation (Lys1068----Glu1068). Five different SSCP patterns were detected in exon 17. Based on direct sequencing, these patterns were explained by combinations of three different nucleotide substitutions, two of which were common silent polymorphisms. One subject had a heterozygous missense mutation Val985---- Met985. Allele-specific oligonucleotide hybridization confirmed the presence of these mutations in the appropriate diabetic subjects and also detected the Val985 mutation in heterozygous form in 1 of 13 nondiabetic white subjects. SSCP analysis is a sensitive rapid method for screening for mutations in the insulin-receptor gene.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Jun
PMID:Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms. 204 Mar 94

Insulin regulates cellular metabolic reactions by its action on the plasma membrane, intracellular enzymes and the nucleus. The first stage in the propagation of the insulin signal is the coupling of insulin to specific receptors at the cell surface. The exact mechanism whereby the transmembrane signalling mechanism (s) results in different insulin-mediated cellular effects is not known. However, the insulin receptor tyrosine kinase, the expression of second messengers, and the action of protein kinase C may, either individually or in combination, mediate some of the insulin effects, such as translocation and activation of glucose transporter proteins. Insulin resistance in clinical conditions such as insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), hypertension and obesity may be acquired to a large extent, and is thus partially reversible. Regulatory factors in insulin sensitivity, such as free fatty acids, counterregulatory hormones and blood glucose level, play an important role in the metabolic control and pathogenesis of insulin resistance in man.
 ...
PMID:Regulation of insulin action at the cellular level. 204 21

Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of insulin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase alpha activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.
 ...
PMID:Effects of glyburide on carbohydrate metabolism and insulin action in the liver. 211 86

Protein tyrosine kinase activity found in the beta-subunit of the insulin receptor provides a mechanism by which insulin binding on the outside of the cell transmits its signal across the plasma membrane into the cytosol. The autophosphorylation of the insulin receptor on tyrosyl residues activates the intrinsic tyrosine kinase of the receptor, rendering its ligand independent. Evidence suggests that phosphorylation of tyrosyl residues 1146, 1150, and 1151 in the kinase domain of the beta-subunit play a role in activation. Point mutations in the cytoplasmic portion of the beta-subunit confirm the above suggestions and indicate that additional sites are important for receptor function. We present methodology for overproducing the cytoplasmic domain of the receptor in the Baculovirus expression system. The protein, produced in insect cells and larvae, is soluble and fully active on autophosphorylation. Like the intact receptor, its autophosphorylation is intramolecular. Because greater than or equal to 10 mg of pure protein can be isolated from 10(10) insect cells infected with the recombinant Baculovirus encoding the human insulin-receptor kinase domain, sufficient enzyme is available for various studies, including physicochemical analysis. Isolation of beta-subunit defects found in the receptors of patients with various forms of diabetes mellitus also implicates the insulin-receptor kinase in insulin action. Finally, a potential model system for the genetic analysis of the insulin-insulin-receptor system with Drosophila melanogaster is noted. Conservation of the deduced amino acid sequence for both alpha- and beta-subunit sequences between humans and insects highlights the significance of this manner of signal transduction throughout nearly 1 billion years of evolution.
Diabetes Care 1990 Mar
PMID:Insulin-receptor approaches to studying protein kinase domain. 215 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>