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)

RT6 is an unusual cell membrane protein that is expressed exclusively by postthymic T cells. The inherent defect in its expression has been correlated to lymphopenia and genetically determined susceptibility for insulin-dependent diabetes mellitus in the rat. We report here the primary structure of the RT6.2 alloantigen as deduced from the cDNA sequence. The predicted amino acid sequence of RT6.2 begins with a conventional leader of 20 amino acids and ends in a hydrophobic C-terminal extension peptide of 29 amino acids as is common for phosphatidylinositol-anchored proteins. Native RT6.2 is predicted to comprise 226 amino acids, with a calculated Mr of 26,036. Four cysteine residues account for two intrachain disulfide bonds. The sequence lacks potential N-glycosylation sites and contains an excess of positively charged residues. Homology searches in protein sequence data banks suggest that RT6.2 is not encoded by a member of the immunoglobulin supergene family. Moreover, these analyses did not reveal any close homologies of RT6.2 to known proteins: the highest homology found was 21.2% identity in a 52-amino acid overlap to the torpedo acetylcholinesterase precursor. Southern blot analyses indicate that RT6.2 is the product of a single-copy gene and provide evidence for closely related genes in the mouse and other species. The corresponding gene products remain to be identified.
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PMID:Primary structure of rat RT6.2, a nonglycosylated phosphatidylinositol-linked surface marker of postthymic T cells. 230 May 88

Longitudinal muscles from the ileum of rats rendered diabetic for 10 to 12 weeks by injection of streptozotocin (STZ) developed greater contractile force in response to muscarinic agonists, (acetylcholine, carbamylcholine and bethanechol) than muscles from age-matched control rats. There was no change, however, in the sensitivity of longitudinal smooth muscles to muscarinic agonists as reflected by the EC50 values for stimulation of muscle contraction. This increased responsiveness of the muscles was accompanied by a 32% reduction in the density of muscarinic receptors (381 +/- 93 vs. 560 +/- 74 fmol/mg of membrane protein) in muscles from STZ-diabetic rats. There was no change in agonist or antagonist binding affinities in muscles from diabetic rats, and there was no alteration in the distribution of receptors between the states characterized by high and low affinity agonist binding. There was also no change in acetylcholinesterase activity in muscle membranes isolated from STZ-diabetic rats. The origin of the increased responsiveness of ileal smooth muscles in this model of diabetes is not clear, but may involve changes in the muscarinic signal transduction pathway beyond the receptor level, or in the contractile apparatus itself.
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PMID:Increased muscarinic responsiveness and decreased muscarinic receptor content in ileal smooth muscle in diabetes. 238 82

Although prostaglandin E2 (PGE2) is known to inhibit glucose-induced insulin secretion, it is uncertain whether PGE2 actions on the beta-cell are direct, whether they are equipotent for both phases of hormone secretion, and whether the same mechanism of action prevails throughout. Study of the HIT cell, a clonal line of pancreatic beta-cells, provides answers to these questions because perifusion with glucose and 3-isobutyl-1-methylxanthine stimulates biphasic insulin secretion. Perifusion with PGE2 decreased both the first and second phases of glucose-induced insulin release to 47 +/- 4% of controls. Pretreatment with pertussis toxin partly prevented PGE2 inhibition to 80 +/- 4% of controls for first phase and 79 +/- 4% of controls for second phase. To evaluate whether the partial prevention of PGE2 inhibition seen with pertussis toxin pretreatment was caused by Gi heterotrimer association between the preincubation period and the end of perifusion, PGE2 actions were also examined during continuous treatment with pertussis toxin. Under these conditions, PGE2 inhibition of both phases was totally prevented. However, no difference was observed in membrane protein ADP ribosylation when cells were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis after pretreatment or continuous treatment with pertussis toxin. Cyclic AMP (cAMP) accumulation was inhibited by PGE2 (from 3263 +/- 153 to 1549 +/- 158 fmol/10(6) cells) but less so after pretreatment with pertussis toxin (correlation between insulin release and cAMP accumulation during perifusion; n = 18, r = .85, P less than .001). Thus, PGE2 equally inhibits both phases of glucose-induced insulin secretion and cAMP generation through a pertussis toxin-sensitive G protein-mediated direct effect on the pancreatic beta-cell.
Diabetes 1989 Nov
PMID:Pertussis toxin-sensitive G protein mediation of PGE2 inhibition of cAMP metabolism and phasic glucose-induced insulin secretion in HIT cells. 248 18

Brief exposure of hepatocytes to glucagon, angiotensin or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate) caused the inactivation of the inhibitory guanine nucleotide regulatory protein Gi. Glucagon-mediated desensitization of glucagon-stimulated adenylate cyclase activity was seen in hepatocytes from both normal rats and those made diabetic with streptozotocin, where Gi is not functionally expressed. Normal glucagon desensitization was seen in hepatocytes from young animals, 6 weeks of age, which had amounts of Gi in their hepatocyte membranes which were some 45% of that seen in mature animals (3.4 pmol/mg of plasma-membrane protein). Streptozotocin-induced diabetes in young animals abolished the appearance of functional Gi in hepatocyte plasma membranes. Pertussis-toxin treatment of hepatocytes from both normal mature animals and those made diabetic, with streptozotocin, blocked the ability of glucagon or angiotensin or TPA to elicit desensitization of adenylate cyclase. The isolated B (binding)-subunit of pertussis toxin was ineffective in blocking desensitization. Neither induction of diabetes nor treatment of hepatocytes with pertussis toxin inhibited the ability of glucagon and angiotensin to stimulate the production of inositol phosphates in intact hepatocytes. Thus (i) Gi does not appear to play a role in the molecular mechanism of glucagon desensitization in hepatocytes, (ii) the G-protein concerned with receptor-stimulated inositol phospholipid metabolism in hepatocytes appears not to be a substrate for the action of pertussis toxin, (iii) in intact hepatocytes, treatment with glucagon and/or angiotensin can elicit the inactivation of the inhibitory G-protein Gi, and (iv) pertussis toxin blocks desensitization by a process which does not involve Gi.
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PMID:Glucagon desensitization of adenylate cyclase and stimulation of inositol phospholipid metabolism does not involve the inhibitory guanine nucleotide regulatory protein Gi, which is inactivated upon challenge of hepatocytes with glucagon. 249 30

Diabetes is associated with a decrease in glucose uptake into muscle, the primary tissue responsible for whole body glucose uptake in the fed state. To study the basis of such a decrease we estimated the number of glucose transporters in skeletal muscle membranes from control and streptozotocin (STZ)-treated rats. Animals were injected with 65 mg STZ/kg and were clearly diabetic (hyperglycemic and glycosuric) at 1 week. After an overnight fast, animals were killed, and skeletal muscle from hind limbs were removed and used to prepare plasma membranes and internal membranes. The number of glucose transporters was determined by D-glucose-protectable equilibrium binding of [3H]cytochalasin-B. STZ-treated rats showed a 37% decrease in the number of glucose transporters per mg protein in crude membranes. The decrease was more pronounced in plasma membranes (average 50% decrease) than in the intracellular membranes (32% decrease). The reduction in the number of glucose transporters was specific, since it was not paralleled by changes in other plasma membrane markers or in total protein, although plasma membrane protein decreased by 15% in STZ-treated rats. When total recoveries of transporters were calculated (i.e. picomoles of transporters recovered per g tissue), the number of transporters in the plasma membrane fraction from STZ-treated rats was decreased by 68% relative to that in control animals. In the intracellular membranes and in total crude membranes from diabetic rats the transporters were decreased by 45%. This suggests that in STZ-treated rats there is an overall decrease in the number of glucose transporters, and that the plasma membrane is further specifically depleted of transporters. The decrease in glucose transporter number in the plasma membrane could at least in part be the cause of the diminished glucose uptake in diabetic muscle and for overall drop in total body glucose utilization of this condition.
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PMID:Decrease in glucose transporter number in skeletal muscle of mildly diabetic (streptozotocin-treated) rats. 252 29

The actions of insulin are mediated by an integral plasma membrane protein, the insulin receptor. The processed receptor is a tetramer composed of two alpha-subunits that bind insulin and two beta-subunits that traverse the plasma membrane and are, in their cytosolic domains, protein tyrosine kinases. The insulin proreceptor cDNA has been cloned and its complete amino acid sequence deduced. The availability of cDNA permitted an analysis of both the role of protein tyrosine kinase activity in insulin action and the autophosphorylation sites that regulate kinase activity. The human cDNA probe has also been used to identify a putative Drosophila insulin receptor. This work is reviewed, and approaches that may be used to identify physiological substrates for the receptor kinase are suggested.
Diabetes 1989 Dec
PMID:Banting lecture 1989. Structure and function of insulin receptors. 255 39

Antibodies in serums from newly diagnosed insulin-dependent (type I) diabetes mellitus (IDDM) patients and individuals experiencing early phases of beta-cell destruction specifically immunoprecipitate a minor pancreatic islet cell membrane protein of 64,000 Mr (64K). In this report, we demonstrate the use of two-dimensional (2-D) gel electrophoresis to unambiguously identify the 64K antigen. By nonequilibrium pH-gradient gel electrophoresis in the first dimension and sodium dodecyl sulphate-polyacrylamide gel electrophoresis in the second dimension, the 64K protein separates into two components, designated alpha and beta, that differ in size but display identical charge heterogeneity. The high resolution of the 2-D method efficiently separates the 64K components from background proteins in immunoprecipitates from crude detergent lysates of islets. The background proteins were identified as major cellular proteins carried nonspecifically through the immunoprecipitation procedure. The high affinity and specificity of the 64K autoantibodies were demonstrated by the exclusive and greater than 1000-fold purification of this minor protein by immunoprecipitation with IDDM serums. The 2-D analyses did not reveal additional proteins specifically immunoprecipitated by IDDM serums, suggesting that the 64K protein is the only protein antigen specifically and consistently recognized by IDDM autoantibodies in the relatively stringent conditions of immunoprecipitation. Moreover, the 2-D analyses demonstrate that purification of membrane protein fractions from both human and rat islets before the immunoprecipitation efficiently removes background proteins and substantially increases the specificity of 64K autoantibody measurements by traditional methods.
Diabetes 1989 Sep
PMID:Revelation of specificity of 64K autoantibodies in IDDM serums by high-resolution 2-D gel electrophoresis. Unambiguous identification of 64K target antigen. 267 Jun 43

At clinically achievable concentrations (10(-9) to 5 X 10(-6) M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea IC50, 10(-7) M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported; in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 X 10(-6) M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5-40 ng/micrograms membrane protein) to myocardial membranes incubated with 10(-7) M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme. Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.
Diabetes 1986 Sep
PMID:Differential activities of tolbutamide, tolazamide, and glyburide in vitro on rabbit myocardial membrane Ca2+-transporting ATPase activity. 294 19

To characterize endogenous control mechanisms for human erythrocyte membrane Ca2+-ATPase ("calcium pump") activity, we studied the effect of changes in blood glucose concentration in vivo within the physiologic range on Ca2+-ATPase activity in red cells. Red cells obtained in the course of induced hyperglycemia were also studied to determine susceptibility of membrane Ca2+-ATPase to stimulation in vitro by thyroid hormone and calmodulin, both of which have been shown previously to enhance Ca2+-ATPase activity. Oral glucose administration (75 g) to eight healthy, adult subjects induced predictable increases in concentrations of blood glucose and immunoreactive insulin. Basal levels of activity of Ca2+-ATPase in red cells obtained after glucose ingestion fell 55% (P less than 0.025) by 30 min after glucose with recovery of enzyme activity to levels not significantly different from basal by 60 min. Activity of red cell Ca2+-ATPase at time zero was significantly stimulated in vitro by thyroxine (T4, 10(-10) M), triiodo-L-thyronine (T3, 10(-10) M), and calmodulin (100 ng/mg membrane protein). In vivo glucose administration led to depression of red cell enzyme responsiveness in vitro to T4 and T3; recovery from this effect did not occur by 120 min after oral administration of glucose. Calmodulin responsiveness of the enzyme in vitro was less significantly reduced in red cells obtained after glucose ingestion. Intravenous (i.v.) glucose administration (20 g) to five subjects also led to decreased basal enzyme activity (61% of fasting level at 20 min). A significant decrease in response of enzyme to T4 was achieved by 8 min after glucose administration (P less than 0.02), with recovery by 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Jul
PMID:The effect of in vivo glucose administration on human erythrocyte Ca2+-ATPase activity and on enzyme responsiveness in vitro to thyroid hormone and calmodulin. 298 51

To examine the role of glucose transport proteins in cellular insulin resistance, we studied subcutaneous adipocytes isolated from lean control, obese control (body mass index [BMI] 33.4 +/- 0.9), and untreated obese non-insulin-dependent diabetes mellitus (NIDDM) patients (BMI 35.2 +/- 2.1; fasting glucose 269 +/- 20 mg/dl). Glucose transporters were measured in plasma membrane (PM), low-density (LDM), and high-density (HDM) microsomal subfractions from basal and maximally insulin-stimulated cells using the cytochalasin B binding assay, and normalized per milligram of membrane protein. In all subgroups, insulin led to an increase in PM glucose transporters and a corresponding depletion of transporters in the LDM. Insulin recruited 20% fewer transporters to the PM in the obese subgroup when compared with lean controls, and this was associated with a decline in LDM transporters with enlarging cell size in the control subjects. In NIDDM, PM, and LDM, transporters were decreased 50% in both basal and stimulated cells when compared with obese controls having similar mean adipocyte size. Cellular depletion of glucose transporters was not the only cause of insulin resistance, because the decrease in rates of [14C]-D-glucose transport (basal and insulin-stimulated) was greater than could be explained by reduced numbers of PM transporters in both NIDDM and obesity. In HDM, the number of transporters was not influenced by insulin and was similar in all subgroups. We conclude that (a) in NIDDM and obesity, both reduced numbers and impaired activity of glucose transporters contribute to cellular insulin resistance, and (b) in NIDDM, more profound cellular insulin resistance is associated primarily with a further depletion of cellular transporters.
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PMID:Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. 336 6


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