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)

These studies were designed to investigate the cytologic localization and topographic distribution of insulin receptors in human placental villi. Biochemical studies showed placental villi to specifically bind 125I-insulin. Radioautographic studies showed the specific binding to be localized to the surface of the syncytial trophoblast. Topographic distribution of insulin binding was determined with ferritin-insulin. Initial studies using ferritin-insulin containing some oligomers of ferritin revealed the insulin receptors to be specifically associated with the glycocalyx region of the surface membranes of microvilli. No insulin receptors were detectable in association with the intermicrovillous plasma membrane even though its glycocalyx is in direct continuity with the glycocalyx of microvilli. Monomeric ferritin-insulin showed the same nonuniform distribution of the insulin receptor, which suggests that there is not complete freedom of lateral mobility of the insulin receptors in the surface membrane of this tissue. The insulin receptors were found to occur as singletons or in groups of two or more. Incubations with monomeric ferritin-insulin at 4 degrees or with tissue prefixed with formaldehyde showed that the groups of insulin receptors were naturally occurring, i.e., they are present prior to and independent of insulin binding and thus not secondary to ligand-induced aggregation. The physiologic meaning of the nonuniform distribution and the groups of insulin receptors is unclear at present.
Diabetes 1978 May
PMID:Nonuniform distribution and grouping of insulin receptors on the surface of human placental syncytial trophoblast. 64 42

We studied the effect of sera from two patients who had an unusual form of diabetic syndrome with extreme insulin resistance on the metabolism of human adipocytes in vitro. The IgG fractions from sera A and B, which were obtained from two patients (1 and 2) with insulin-resistant diabetes, inhibited [125I] insulin binding to human adipocytes and, at the same time, stimulated glucose oxidation and inhibited the lipolysis induced by levarterenol in human adipocytes. On the other hand, the IgG fraction from the C serum, which was obtained from patient 2 after her diabetic syndrome had completely disappeared as a result of immunosuppressive therapy, did not inhibit [125I] insulin binding to human adipocytes, stimulate glucose oxidation, or inhibit lipolysis in human adipocytes. These facts suggest that these IgG fractions bind to or near the insulin receptor of human adipocytes, that they exhibit their insulin-like effect by binding to the insulin receptor in vitro, and, furthermore, that they are responsible for the extremely insulin-resistant diabetes. However, the apparent discrepancy between the effects of these IgG fractions on man in vitro and in vivo is puzzling and needs to be explained.
Diabetes 1978 Sep
PMID:Effects of anti-insulin receptor autoantibodies on the metabolism of human adipocytes. 68 5

The relative importance of the insulin resistance, the decreased cellular insulin binding and the relative insulin deficiency in the pathogenesis of diabetes mellitus in obese subjects has been studied. Ten obese diabetics were studied before and during treatment for 1 year with a 1200-1500 kcal's diet. No change was found in the insulin response to iv injection of glucose during treatment (P greater than 0.1), whereas the insulin sensitivity was normalized after 1 year (P less than 0.01). In parallel to the clinical normalization and the improvement of the insulin sensitivity the insulin binding to monocytes was normalized (P less than 0.01). We conclude that both the insulin resistance and the relative insulin deficiency are of decisive importance in the pathogenesis of diabetes mellitus of the obese. The insulin receptor defect seems to be one of the major factors responsible for the insulin resistance.
 ...
PMID:Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese diabetics for one year. 76 Mar 52

Insulinopenic states in rodents are known to cause an increase in the number of hepatic insulin receptors. To determine if this change is related to an abnormality in insulin receptor gene expression, insulin receptor binding, insulin receptor mRNA levels, and insulin receptor gene transcription rates have been measured in livers from rats rendered hypoinsulinemic by STZ administration (65 mg/kg) or fasting. In the two groups of experimental rats, insulin binding to liver plasma membranes was increased (approximately 40 and 25%, respectively) relative to control, normoinsulinemic animals. Northern blot analysis of either total or poly (A)+ RNA from livers of hypo- and normoinsulinemic rats revealed two major insulin receptor mRNA species of 9.5 and 7.5 kbs. In hypoinsulinemic rats, insulin receptor mRNA levels were increased > or = 10-fold, with similar effects on the two mRNA species. The effects of STZ administration and fasting on insulin receptor binding and insulin receptor mRNA levels were fully reversed by insulin treatment or refeeding, respectively. Injection of ACT D, an inhibitor of gene transcription, decreased insulin receptor mRNA levels by > or = 80% in control and diabetic rats and suppressed the overexpression of mRNA seen in diabetic rats. In vitro nuclear transcription assays showed that the rate of transcription of the insulin receptor gene was increased 2-fold in STZ-induced diabetic rats and fasted rats relative to control animals. Taken together, these results suggest that the upregulation of the insulin receptor induced by chronic insulinopenia results, at least in part, from an increase in insulin receptor gene transcription.
Diabetes 1992 Dec
PMID:Effects of STZ-induced diabetes and fasting on insulin receptor mRNA expression and insulin receptor gene transcription in rat liver. 128 Feb 38

The application of molecular scanning techniques to the detection of potentially pathogenic mutations in candidate genes in patients with non-insulin-dependent diabetes has revealed a number of molecular variants of uncertain pathophysiologic significance. The determination of the significance of such variants requires large-scale population studies of the prevalence of the mutant in affected and control groups. Herein, we describe two adaptations of the technique of single nucleotide primer extension (SNuPE) which allow the simultaneous examination of large numbers of alleles at multiple loci. The usefulness of these adaptations is illustrated by their application to the simultaneous detection of three point mutations, two in the tyrosine kinase domain of the insulin receptor and one in the insulin-responsive glucose transporter (GLUT4) in a highly insulin-resistant NIDDM population. By pooling genomic or amplified DNA and performing the SNuPE reactions with three primers of different length we could readily examine 300 alleles on a single 20 lane gel. Using pooled SNuPE, we also examined a large British Caucasian control population for the prevalence of GLUT4 Ile383, a variant which has previously been reported only in NIDDM. GLUT4 Ile383 was detected in 2/42 of the highly insulin-resistant NIDDM subjects and 4/240 middle-aged blood donors. Family studies and examination of the expressed mutant transporter will be necessary to establish whether this mutation is of functional significance. Pooled and multiplex SNuPE are powerful techniques with wide applicability to population genetic studies of specific mutations.
 ...
PMID:Rapid and simultaneous detection of multiple mutations by pooled and multiplex single nucleotide primer extension: application to the study of insulin-responsive glucose transporter and insulin receptor mutations in non-insulin-dependent diabetes. 130 12

The recent application of recombinant DNA technology to clinical investigation now allows the identification of the molecular alterations responsible for insulin resistance. In this review, the recent knowledge concerning these investigations is reported. Genetic mutations of the insulin gene as the source of insulin resistance have been reported for a long time. More recently a series of mutations of the insulin receptor gene have been identified as the cause of the extreme insulin resistance, observed in rare syndromes, such as type A insulin resistance or leprechaunism. However, it is probable that the majority of the molecular defects causing insulin resistance occur at the postreceptor level. The key proteins involved in the different intracellular signalling pathways of insulin are only partly identified. A better understanding of the mechanisms of insulin action is essential for the identification of corresponding genetic alterations. The investigations concerning the glucose transporter GLUT4 and glucokinase genes are good examples of complex but promising research, which has recently started. Elucidation of the genetic and molecular basis of diseases such as type II diabetes or other states associated with insulin resistance, is the long-term goal.
 ...
PMID:Molecular basis of insulin resistance. 130 16

Aging is associated with a postbinding defect in insulin action, leading to increased glucose intolerance and occasional diabetes. To determine whether defects in insulin receptor kinase (IRK) activity or in the phosphorylation of its physiological substrates underlie this age-related phenomenon, young (2-3 months old) and old (24-27 months old) Wistar rats were studied. When assayed in vitro, the hepatic IRK activities of noninjected old and young rats were comparable. Thirty seconds after the injection of insulin, the hepatic IRK activity of young rats increased 7- to 10-fold in a dose-dependent manner, with maximal effects obtained in rats injected with 20 mg insulin. By contrast, old animals exhibited impaired in vivo activation, with a mean 50% reduction in maximal IRK activity. When the rats were grouped into animals with mild (20%), moderate (50%), and severe (80%) reductions in maximal IRK activity, it was found that the mild and moderate defects could be reversed once the receptors were subjected to extensive autophosphorylation in vitro. The severe form of the defect was essentially irreversible and could not be corrected by phosphorylation in vitro. Immunoblotting with anti P-Tyr antibodies revealed that the reduced IRK activity in the old animals correlated with reduced intrahepatic tyrosine phosphorylation of the beta-subunit of the insulin receptor and pp180, a putative substrate of IRK. We, therefore, conclude that glucose intolerance in aging could be attributed at least in part to acquired defects in the in vivo activation of the hepatic IRK, which results in reduced phosphorylation of its putative substrate pp180.
 ...
PMID:Defects of insulin's signal transduction in old rat livers. 131 Dec 43

Classical insulin and IGF-1 receptors are alpha 2 beta 2 heterotetrameric complexes synthesized from two identical alpha beta half-receptor precursors. Recent data strongly suggests, however, that nonidentical alpha beta half-receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and in vitro. This review focuses primarily on two types of hybrid receptors. The first type is an insulin/IGF-1 hybrid receptor generated by the association of an alpha beta insulin half-receptor with an alpha beta IGF-1 half-receptor. The second type is one formed from a wildtype (kinase-active) insulin or IGF-1 alpha beta half-receptor and a mutant (kinase-inactive) insulin alpha beta half-receptor. Although the functional properties of insulin/IGF-1 hybrid receptors have not yet been completely defined, wildtype/mutant hybrid receptors are essentially substrate kinase inactive. These data indicate that the mutant alpha beta half-receptor exerts a transdominant inhibition upon the wildtype alpha beta half-receptor within the alpha 2 beta 2 holoreceptor complex. This defect in substrate kinase activity may contribute to the molecular defect underlying some syndromes of severe insulin resistance and diabetes. Heterozygous individuals expressing both wildtype and mutant tyrosine kinase-defective insulin receptor precursors demonstrate varying degrees of insulin resistance and diabetes. In addition, cell lines which express both endogenous wildtype and transfected kinase-defective insulin receptors display markedly decreased insulin and IGF-1 sensitivity and responsiveness. Formation of hybrid receptors which results in premature termination of insulin signal transduction may be one mechanism underlying the observation that kinase-inactive receptors inhibit the function of native receptors.
 ...
PMID:Insulin/IGF-1 hybrid receptors: implications for the dominant-negative phenotype in syndromes of insulin resistance. 131 61

Insulin binding and the capacity of insulin to stimulate the conversion of glucose to carbon dioxide and lipid, and to activate the protein tyrosine kinase associated with the insulin receptor have been investigated in adipocytes isolated from pregnant and non-pregnant women. Insulin binding and the conversion of glucose to lipid were the same for both groups. However, conversion of glucose to CO2 was higher in the non-pregnant group due to an elevated basal activity, and the increase produced by insulin was similar in both groups. The tyrosine kinase activity of the isolated receptor preparations was higher in the pregnant group due to an increase in the basal non-insulin dependent activity, and the increase produced by insulin was similar in both groups. These findings show the in vitro insulin responsiveness of isolated adipocytes is similar for both groups, and suggests that the in vivo insulin resistance of late pregnancy, as far as adipose tissue is concerned, is not due to any inherent defect in insulin action at the receptor or post-receptor level. In vivo insulin resistance may result from an increased level of circulating insulin antagonists.
Diabetes Res Clin Pract 1992 May
PMID:Evidence that the insulin resistance of pregnancy may not involve a post-receptor defect in human adipocytes. 131 88

The involvement of tyrosine phosphorylation in insulin action led us to hypothesize that increased activity of protein tyrosine phosphatases (PTPases) might contribute to insulin resistance in alloxan diabetes in the rat. Hepatic PTPase activity was measured using two artificial substrates phosphorylated on tyrosine: reduced, carboxyamidomethylated, and maleylated lysozyme (P-Tyr-RCML) and myelin basic protein (P-Tyr-MBP), as well as an autophosphorylated 48-kD insulin receptor tyrosine kinase domain (P-Tyr-IRKD). Rats that were made alloxan diabetic exhibited a significant increase in hepatic membrane (detergent-soluble) PTPase activity measured with P-Tyr-MBP, without a change in activity measured with P-Tyr-RCML or the P-Tyr-IRKD. The PTPase active with P-Tyr-MBP behaved as a high molecular weight peak during gel filtration chromatography. Characterization of this enzyme indicated it shared properties with CD45, the prototype for a class of transmembrane, receptor-like PTPases. Our results indicate that alloxan diabetes in the rat is associated with an increase in the activity of a large, membrane-associated PTPase which accounts for only a small proportion of insulin receptor tyrosine dephosphorylation. Nonetheless, increased activity of this PTPase may oppose tyrosine kinase-mediated insulin signal transmission, thus contributing to insulin resistance.
 ...
PMID:Differential regulation of multiple hepatic protein tyrosine phosphatases in alloxan diabetic rats. 132 40


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