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 protein anabolic effect of branched chain amino acids was studied in isolated quarter diaphragms of rats. Protein synthesis was estimated by measuring tyrosine incorporation into muscle proteins in vitro. Tyrosine release during incubation with cycloheximide served as an index of protein degradation. In muscles from normal rats the addition of 0.5 mM leucine stimulated protein synthesis 36--38% (P less than 0.01), while equimolar isoleucine or valine, singly or in combination were ineffective. The three branched chain amino acids together stimulated no more than leucine alone. The product of leucine transamination, alpha-keto-isocaproate, did not stmino norborane-2-carboxylic acid (a leucine analogue) were ineffective. Leucine and isoleucine stimulated protein synthesis in muscles from diabetic rats.Leucine, isoleucine, valine and the norbornane amino acid but not alpha-ketoisocaproate or beta-hydroxybutyrate decreased the concentration of free tyrosine in tissues during incubation with cycloheximide; tyrosine release into the medium did not decrease significantly. Leucine caused a small decrease in total tyrosine release, (measured as the sum of free tyrosine in tissues and media), suggesting inhibition of protein degradation. The data suggest that leucine may be rate limiting for protein synthesis in muscles. The branched chain amino acids may exert a restraining effect on muscle protein catabolism during prolonged fasting and diabetes.
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PMID:Studies concerning the specificity of the effect of leucine on the turnover of proteins in muscles of control and diabetic rats. 13 65

The effects of experimental diabetes on in vivo tyrosine phosphorylation of the insulin receptor (IR) and non-receptor proteins were investigated in rat skeletal muscle. Diabetes was induced in male Sprague-Dawley rats (200 g) by streptozotocin administration (100 mg/kg, ip). Diabetic animals were subsequently anesthetized, insulin was injected via cardiac puncture, and hindlimb skeletal muscles were removed, frozen in liquid N2, and homogenized in sodium dodecyl sulfate. Tyrosine phosphoproteins were first immunoprecipitated and then identified by immunoblotting with antiphosphotyrosine antibodies. In both control and diabetic rats, insulin stimulated tyrosine phosphorylation of the IR beta-subunit and a major nonreceptor 170,000 mol wt (Mr) endogenous protein (pp170) in a dose- and time-dependent manner. Total IR number (determined by immunoprecipitation and immunoblotting with an anti-IR antibody) increased 2.4-fold in diabetic muscle, but there was little change in phosphorylated insulin receptor beta-subunit (157 +/- 12% of control value; P less than 0.001). In contrast, pp170 phosphorylation increased markedly in diabetes (500 +/- 119% of control value; P less than 0.005), and the time course of its disappearance was delayed compared to that in control rats. These changes were reversed by insulin therapy (5 U, sc, twice daily), but not by correction of hyperglycemia with phlorizin (0.4 g/kg.day, sc). In conclusion, in rat skeletal muscle in vivo, streptozotocin-diabetes results in 1) increased total IR number, 2) reduced efficiency of IR phosphorylation, and 3) markedly enhanced tyrosine phosphorylation of a 170,000 Mr putative IR substrate. Hypoinsulinemia, but not hyperglycemia, appears to increase the level of the phophorylated 170,000 Mr protein in streptozotocin-diabetes.
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PMID:Changes in tyrosine phosphorylation of insulin receptors and a 170,000 molecular weight nonreceptor protein in vivo in skeletal muscle of streptozotocin-induced diabetic rats: effects of insulin and glucose. 153 27

Tyrosine-phosphorylated proteins in Triton X-100-solubilized fractions of rat livers were examined by immunoblotting with anti-phosphotyrosine antibodies. After 2 min of insulin injection via the portal vein into livers, three major bands of 170,000, 140,000, and 95,000 Mr were stimulated. Because the incubation of nitrocellulose membrane with anti-phosphotyrosine antibodies in the presence of 40 mM phosphotyrosine completely abolished these bands, the anti-phosphotyrosine antibodies appear to recognize the phosphotyrosine residues of these proteins. Insulin injection (2-2000 micrograms) very quickly stimulated the tyrosine phosphorylation of these proteins in a dose-dependent fashion. In contrast, insulinlike growth factor I or epidermal growth factor injection had little effect in stimulating the tyrosine phosphorylation of these proteins. Because anti-insulin-receptor antibodies immunoprecipitated a tyrosine-phosphorylated 95,000-Mr protein, this protein must be the beta-subunit of the insulin receptor; i.e., the beta-subunit of the insulin receptor and two other proteins were phosphorylated at tyrosine residues in vivo by insulin injection. These data suggest that the tyrosine phosphorylation and tyrosine kinase activity of the insulin receptor may have important roles in in vivo insulin action.
Diabetes 1990 May
PMID:Immunological detection of phosphotyrosine-containing proteins in rat livers after insulin injection. 169 94

Insulin action in skeletal muscle is markedly depressed at late pregnancy. The purpose of this study was to investigate whether insulin resistance of skeletal muscle during pregnancy is associated to intrinsic alterations in the biological activities of insulin receptor. To that end, insulin receptors from mixed, red and white skeletal muscle from control and 19-20 days pregnant rats were partially purified and insulin binding and tyrosine kinase activities were evaluated. Muscle insulin receptors from diabetic rats were also studied provided that changes in receptor number and tyrosine kinase activities had been clearly substantiated. Total high affinity insulin binding sites expressed either per gram of tissue or per milligram of protein were similar in muscles from control and pregnant rats, in contrast to diabetic rats in which an increased high affinity receptor number was observed. No differences in affinity were detected for high affinity binding sites in any of the groups investigated. The integrity of the partially purified insulin receptors from control and pregnant groups was identical as determined by affinity cross-linking of [125I-TyrB26]insulin to the receptor and by beta-subunit phosphorylation. Autophosphorylation of the beta-subunit and the pattern of phosphopeptides obtained after digestion of phosphorylated beta-subunit with trypsin, elastase, and staphylococcal V8 protease were indistinguishable in control and pregnant groups. Tyrosine receptor kinase was also similar in receptor preparations from control and pregnant muscle. This is in contrast to diabetes in which a defective tyrosine kinase was confirmed. In order to detect possible differences due to the fiber type, further sets of experiments were performed in receptor preparations from red and white muscle. In keeping with previous data, tyrosine kinase activity of the insulin receptor was 2.5-fold greater in red muscle than white muscle; however, under these conditions, receptor kinase activity was unmodified in preparations from pregnant rats in red and white muscle fibers. Recent evidence has revealed the existence of an insulin binding inhibitor in muscle extracts. We detected the presence of such an inhibitor in the flow-through fraction after WGA chromatography. This inhibitory activity was found to be greater in muscle extracts obtained from pregnant rats as compared to fractions from control rats. We conclude that insulin resistance of skeletal muscle at late pregnancy is not explained by intrinsic modifications of insulin receptor binding or kinase activities.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin resistance of skeletal muscle during pregnancy is not a consequence of intrinsic modifications of insulin receptor binding or kinase activities. 217 19

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1987 Jan
PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

Flux through, and maximal activities of, key enzymes of phenylalanine and tyrosine degradation were measured in liver cells prepared from adrenalectomized rats and from streptozotocin-diabetic rats. Adrenalectomy decreased the phenylalanine hydroxylase flux/activity ratio; this was restored by steroid treatment in vivo. Changes in the phosphorylation state of the hydroxylase may mediate these effects; there was no significant change in the maximal activity of the hydroxylase. Tyrosine metabolism was enhanced by adrenalectomy; this was not related to any change in maximal activity of the aminotransferase. Steroid treatment increased the maximal activity of the aminotransferase. Both acute (3 days) and chronic (10 days) diabetes were associated with increased metabolism of phenylalanine; insulin treatment in vivo did not reverse these changes. Although elevated hydroxylase protein concentration was a major factor, changes in the enzyme phosphorylation state may contribute to differences in phenylalanine degradation in the acute and chronic diabetic states. Tyrosine metabolism, increased by diabetes, was partially restored to normal by insulin treatment in vivo. These changes can, to a large extent, be interpreted in terms of changes in the maximal activity of the aminotransferase.
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PMID:The metabolism of L-phenylalanine and L-tyrosine by liver cells isolated from adrenalectomized rats and from streptozotocin-diabetic rats. 400 13

Insulin signaling is known to proceed through the insulin receptor to the insulin receptor substrate-1 (IRS-1). Tyrosine-phosphorylation of IRS-1 causes it to associate with the src-homology-2 (SH2) domains of at least four other proteins: phosphatidylinositol 3'-kinase (PI3K), growth factor receptor-bound protein-2 (GRB2), Nck, and Syp. In order to understand the cellular derangements associated with type I diabetes, the levels of these four SH2-containing proteins was determined in streptozotocin-induced diabetic rats. In liver tissue of diabetic rats, the levels of Nck and Syp were significantly decreased to 71 +/- 6% and 61 +/- 4% control, respectively, while in fat tissue only the Syp levels were significantly reduced to 72 +/- 9% control. PI3K levels were higher in livers of diabetic rats than controls, but unchanged in fat. The insulin-deficient diabetic condition was thus associated with altered levels of insulin signaling components.
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PMID:Altered expression of insulin signaling components in streptozotocin-treated rats. 762 33

The insulin receptor tyrosine kinase is required for insulin to elicit subsequent biological signalling. Recent studies have identified several endogenous substrates of the insulin receptor kinase, including one called insulin receptor substrate 1 (IRS-1). Tyrosine phosphorylation of this substrate results in its being bound by various proteins containing src homology 2 (SH2) sites, including a phosphatidylinositol 3-kinase and a ras activator complex containing GRB2 and son of sevenless (SOS) 1. Decreases in the insulin receptor tyrosine kinase activity have been observed in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. A model of insulin resistance has recently been described in which the insulin receptor is expressed in Chinese hamster ovary cells along with the phospholipid- and calcium-activated serine/threonine kinase called protein kinase C. In this model system, activation of protein kinase C is shown to interfere with insulin receptor signalling by inhibiting tyrosine phosphorylation of IRS-1 and its subsequent binding by phosphatidylinositol 3-kinase. Such a model system may be further utilized to determine the detailed biochemical basis for insulin resistance.
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PMID:Biochemical mechanisms of insulin resistance. 808 4

Our aim was to study the relationship between jejunal mucosal activity of ornithine decarboxylase and tyrosine kinase during proliferation in adolescent rats in vivo. Their relationship in the proliferating intestinal mucosa under in vivo conditions has not been reported before. From the results of in vitro studies, it was speculated that tyrosine kinase activity modulated ornithine decarboxylase activity during colonic mucosal proliferation (Majumdar AP. Am J Physiol 259:G626-G630, 1990). Jejunal mucosal hyperplasia was induced by Type 1 diabetes and suppressed in both control and diabetic rats by administration of difluoromethylornithine. Jejunal mucosal weight and enzyme activity were determined after 3, 6, and 10 days, and tyrosine-specific phosphorylated proteins after 10 days of induction of diabetes. Difluoromethylornithine suppressed jejunal mucosal proliferation and tyrosine kinase activity after the 6- and 10- day study periods. After the 3-day study period although jejunal mucosal growth was suppressed, tyrosine kinase activity was not. Activity of tyrosine kinase and ornithine decarboxylase were highly significantly correlated at all time periods in both control and diabetic rats. Tyrosine-specific phosphorylated proteins of 34, 54, 80, and 200 kDa proteins were observed in jejunal mucosa of both control and diabetic rats. In the difluoromethylornithine-treated rats, phosphorylation of the above proteins was negligible while the phosphorylation of a 14-kDa protein was prominent. We speculate that in vivo ornithine decarboxylase activity may be modulating tyrosine kinase activity and that phosphorylation of a 14-kDa protein was associated with suppressed mucosal growth in difluoromethylornithine-treated rats.
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PMID:Relation of ornithine decarboxylase and tyrosine kinase activity in the jejunal mucosa in vivo. 861 39

Focal adhesion kinase (p125FAK) is a novel non-receptor cytosolic tyrosine kinase which is activated through the phosphorylation of its tyrosine residue by ligands that bind to integrins and ligands that activate protein kinase C (PKC). In diabetic glomeruli, extracellular matrix proteins such as fibronectin, laminin and type IV collagen, which bind to integrins, were found to be increased in the mesangial area. Furthermore, PKC was shown to be activated in diabetic glomeruli. These changes might be able to cause the activation of p125FAK in diabetic glomeruli. To test this hypothesis, we examined tyrosine phosphorylation of p125FAK and paxillin, a proposed substrate of p125FAK, in glomeruli isolated from streptozotocin (STZ)-induced diabetic rats. Tyrosine phosphorylation of p125FAK or paxillin was evaluated by immunoblot analysis using anti-phosphotyrosine antibody after immunoprecipitation with anti-p125FAK or anti-paxillin antibody. Three and seven weeks after STZ injection, tyrosine phosphorylation of both p125FAK and paxillin was increased in diabetic glomeruli. The increase in tyrosine phosphorylation of p125FAK and paxillin was not observed in glomeruli from diabetic rats treated with insulin. To investigate the mechanism of increase in tyrosine phosphorylation of p125FAK, we examined tyrosine phosphorylation of p125FAK in mesangial cells plated on a fibronectin-coated dish or cultured under conditions of high glucose concentration (conditions under which PKC can be activated). Attachment of the cells to fibronectin induced tyrosine phosphorylation of p125FAK, while a high glucose concentration did not modulate tyrosine phosphorylation of p125FAK. In conclusion, tyrosine phosphorylation of p125FAK and paxillin was increased in diabetic glomeruli and these alternations may have been caused by changes in extracellular matrix proteins in diabetes.
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PMID:[Tyrosine phosphorylation of focal adhesion kinase (p125FAK) and paxillin in glomeruli from diabetic rats]. 871 7


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