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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of streptozotocin-induced diabetes on the beta-adrenergic receptor-coupled adenylate cyclase was studied in rat heart particulate fractions. Streptozotocin treatment decreased the number of myocardial beta-adrenergic receptors by 34% with no change in the apparent affinity of these receptors for [3H]dihydroalprenolol. The maximal isoproterenol-activated accumulation of cAMP in streptozotocin-treated rat hearts was decreased by only 10%. Insulin administration to streptozotocin-treated rats increased the number of myocardial beta-adrenergic receptors to near or above control levels. Administration of L-T4 to streptozotocin-treated rats had the same effect. Total T4, free T4, and total T3 levels were all significantly decreased in the diabetic animals. Administration of insulin to streptozotocin-treated rats increased the serum thyroid hormone levels toward or above the levels found in control animals. Streptozotocin-induced diabetes had no significant effect on cardiac beta-adrenergic receptor number in thyroidectomized rats. Insulin did not elevate cardiac beta-adrenergic receptor number in thyroidectomized diabetic rats. The decrease in the number of myocardial beta-adrenergic receptors occurring in diabetes mellitus is probably mediated through thyroid hormones.
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PMID:Decreased beta-adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. 632 44

Myocardial membranes from rats rendered diabetic with streptozotocin were used to determine muscarinic receptors with 3H-quinuclidinyl benzilate. In the acute state of diabetes, four days after induction, the density of receptors were equal in controls, insulin (glucosuria) and non insulin-treated (glucosuria and ketonuria) diabetic animals. In myocardial membranes from diabetic rats agonist binding to the muscarinic receptor was shifted to higher affinity than in controls. Computer modeling revealed that guanine nucleotides transformed agonist binding from two sites to a site of low affinity in controls. In membranes from insulin-treated diabetic animals the shift to lower affinity occurred but two receptor sites remained. In non insulin-treated membranes the nucleotides failed to exert any effect. Inhibition of adenylate cyclase by the muscarinic agonist oxotremorine was amplified in diabetic membranes. This indicates that the function of the inhibitory nucleotide binding protein (NI), as reflected by agonist binding to the receptor and adenylate cyclase inhibition, is sensitive to the hormonal status.
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PMID:Effects of acute ketotic and non-ketotic diabetes on the myocardial muscarinic receptors. 644 90

The effect of chronic experimental diabetes on the adenylate cyclase system (AC) in the rat heart was investigated. Rats were made diabetic by an intravenous injection of streptozotocin (65 mg/kg), hearts were removed 8 weeks later and washed cell particles were isolated. AC activity was measured in the absence and presence of different concentrations of forskolin, NaF, GTP analogue [Gpp(NH)p] or epinephrine. A significant depression in the epinephrine stimulated AC activity was observed in diabetic hearts. Basal AC activity and stimulation of AC with forskolin, NaF and Gpp(NH)p were not significantly different between control and diabetic preparations. These results indicate no apparent alterations in the regulatory or catalytic properties of AC in hearts from chronic diabetic rats. The observed depression in epinephrine stimulated AC activity may account for the depressed inotropic action of catecholamines in the diabetic cardiomyopathy.
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PMID:Alterations in adenylate cyclase activity due to streptozotocin-induced diabetic cardiomyopathy. 670 25

The effects of Ca2+-calmodulin on adenylate cyclase activity in EGTA-washed, 27000 g particulate fractions of mouse and rat pancreatic islets were studied. Ca2+ (10 microM)-calmodulin (1 microM) stimulated adenylate cyclase activity 53.1 +/- 5.2 (N = 6)% in the particulate fraction of rat islets. Trifluoperazine (50 microM), a specific inhibitor of calmodulin, inhibited the Ca2+-calmodulin activation of the adenylate cyclase activity of this fraction of rat islets. These results confirm previous reports dealing with Ca2+-Calmodulin and rat islet adenylate cyclase [Valverde, Vandermeers. Anjaneyulu & Malaisse (1979) Science 206, 225-227; Sharp, Wiedenkeller, Kaelin, Siegel & Wollheim (1980) Diabetes 29, 74-77]. In contrast, however, Ca2+ (1-100 microM)-calmodulin (1-10 microM) did not stimulate the adenylate cyclase activity in the EGTA-washed particulate fraction of mouse islets, and trifluoperazine (50 microM) did not inhibit the adenylate cyclase activity of this fraction of mouse islets, although some remaining calmodulin [0.18 +/- 0.05 (n = 3) microgram/mg of protein] could be demonstrated. GTP (10 microM) enhanced islet adenylate cyclase activity considerably, but did not confer any sensitivity towards Ca2+-calmodulin on mouse islet adenylate cyclase. The results question the role of calmodulin in the Ca2+-dependent rise in cyclic AMP evoked by glucose in pancreatic islets.
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PMID:Differential effects of Ca2+-calmodulin on adenylate cyclase activity cyclase activity in mouse and rat pancreatic islets. 675 27

Clonidine (0.08 to 80.0 ng/ml) caused a dose-related inhibition of glucose-stimulated insulin release, but failed to affect glucose oxidation, glucose-stimulated 45Ca net uptake, and adenylate cyclase activity in isolated rat islets. Phentolamine antagonized the effect of clonidine upon insulin release. Despite profound inhibition of insulin secretion, the drug failed to affect the time course for the changes evoked by glucose in either 45Ca fractional outflow rate from perfused islets or insulin release from the isolated perfused pancreas. The latter changes were multiphasic, revealing an initial secretory peak, a period of low secretory activity, and a second secretory elevation before establishing a period characterized by a steadily and slowly increasing insulin output. In the clonidine-treated islets, the secretory rate was not significantly different from the basal value during the period after the initial secretory response. Thus, despite continuous stimulation with glucose, insulin release appears as a discontinuous phenomenon, even when little insulin is secreted during the initial phase of stimulation.
Diabetes 1980 Mar
PMID:Mode of action of clonidine upon islet function: dissociated effects upon the time course and magnitude of insulin release. 699 21

Basal adenylate cyclase activity in rat lung alveolar tissue particulate fraction was depressed during streptozotocin-induced diabetes. However, the activation of the particulate adenylate cyclase by the cytoplasmic factor(s) was markedly increased in lungs from the diabetic rats. The increased activation of basal adenylate cyclase in the diabetic tissue appeared to be due to an increase in the activity of the cytoplasmic factor(s) and not due to an increase in the sensitivity of the particulate enzyme to the cytoplasmic factor(s). Insulin treatment of the diabetic animals restored the activation of adenylate cyclase by the supernatant activator to the control values. The cytoplasmic factor(s) did not appear to be related to the ubiquitous calcium-dependent regulator protein, calmodulin.
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PMID:Influence of streptozotocin-induced diabetes on the cytoplasmic factors modulating adenylate cyclase activity in rat lungs. 702 48

GLP-1 (glucagon-like peptide 1 (7-36) amide) plays an important role in the regulation of insulin secretion and proinsulin gene expression of pancreatic beta-cells. Patients with insulinoma tumors show uncontrolled insulin hypersecretion. This study demonstrates the molecular cloning of a cDNA for the GLP-1 receptor from a human insulinoma employing a lambda-gt11 cDNA library. The cloned cDNA encoded a seven transmembrane domain protein of 463 amino acids which showed high homology to the GLP-1 receptor in normal human pancreas. Four amino acid exchanges were found in comparison to a receptor sequence obtained from regular pancreatic islets. When transfected transiently into COS-7 or stably into fibroblast CHL cells a high affinity receptor was expressed which coupled to the adenylate cyclase with normal basal cAMP and increasing intracellular cAMP levels under GLP-1 stimulation. The receptor accepted GLP-1 and the non-mammalian agonist exendin-4 as high affinity ligands. In transfected COS-7 cells, GLP-1 did not influence intracellular calcium, whereas in the stably transfected fibroblasts GLP-1 transiently increased intracellular calcium to a small extent. The understanding of GLP-1 receptor regulation and signal transduction will aid in the discovery of compounds that act as agonists of the GLP-1 receptor for potential use in the treatment of diabetes and will facilitate the understanding of its expression under normal and pathophysiological conditions.
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PMID:Signal transduction of the GLP-1-receptor cloned from a human insulinoma. 751 95

Hyperthyroidism occurs in association with pregnancy or trophoblastic tumours. This is due to the secretion of thyroid stimulators by trophoblastic cells, most likely hCG or a variant form of hCG. In the present studies we sought to identify hCG variants with enhanced thyrotropic activity contained in crude hCG extract from pregnancy urine (hCGc). Such studies seem now feasible, because highly sensitive assays employing CHO cells transfected with the recombinant human TSH receptor recently became available. Initially, we found the activity of hCGc to both inhibit the binding of 125I-bTSH to CHO-TSHr cells and to stimulate the cAMP release by the cells to be increased, compared to highly purified hCG (hCGp), which was tested in comparable immunological concentrations. We then processed hCGc on a DEAE-52 anionexchange column to separate materials of interest, termed hCGv, from hCGp. HCGv was further purified by gel chromatography, and found to be enriched in terms of both, its holo-hCG immunoactivity and its TSH binding inhibiting activity, compared to hCGc where it was derived from. It also proved more potent than hCGp to bind to recombinant hTSH receptor and to stimulate adenylate cyclase activity in CHO-TSHr cells. Enzymatic desialylation was able to increase the potency of both hCGv and hCGp, and rendered the two desialylated hCG forms nearly equipotent. Isoelectric focusing and direct measurement of sialic acid contents revealed hCGv to be less sialylated than hCGp.(ABSTRACT TRUNCATED AT 250 WORDS)
Exp Clin Endocrinol Diabetes 1995
PMID:Crude urinary human chorionic gonadotropin contains variant forms of HCG with low sialic acid content that exhibit an increased thyrotropic activity in CHO cells expressing the human TSH receptor. 758 19

The arylpiperazine L-686,398 was described as an oral hypoglycemic agent and is shown to be an insulin secretagogue in vitro. The characteristics of its activity were similar to those of the incretin glucagon-like peptide I (GLP-I). We demonstrate that both the peptide and L-686,398 increase the accumulation of cAMP in isolated ob/ob mouse pancreatic islet cells, but by different mechanisms. Although GLP-I activates adenylate cyclase, the arylpiperazine has no effect on this enzyme or on the binding of 125I-labeled GLP-I to its receptor on RINm5F rat insulinoma cell membranes. However, L-686,398 inhibits the total cAMP phosphodiesterase (PDE) activity in homogenates of ob/ob mouse pancreatic islets with an EC50 of approximately 50 mumol/l. To determine the mechanism of PDE inhibition by the arylpiperazine and to examine its specificity, we studied the kinetics of arylpiperazine inhibition of two recombinant PDEs. The arylpiperazine is a competitive inhibitor of both a human heart type III PDE and a rat type IV-D PDE. Inhibition of the type III and IV isozymes are characterized by Ki values of 27 and 5 mumol/l, respectively. Although not extremely potent, the arylpiperazine does exhibit modest selectivity between these PDEs. The observation that L-686,398 acts as a PDE inhibitor suggests that exploration for beta-cell-specific PDE isoforms may reveal novel PDEs as targets for the development of therapeutically useful glucose-dependent insulin secretagogues.
Diabetes 1995 Jan
PMID:A novel insulin secretagogue is a phosphodiesterase inhibitor. 781 16

The goal of this study was to determine whether diabetes mellitus alters reactivity of the basilar artery in vivo to activation of beta-adrenergic receptors. We measured diameter of the basilar artery in non-diabetic and diabetic (streptozotocin 50-60 mg/kg i.p.) rats during superfusion with isoproterenol and norepinephrine, which dilate cerebral blood vessels via activation of beta-adrenergic receptors. Dilatation of the basilar artery in response to isoproterenol and norepinephrine was significantly less in diabetic compared to non-diabetic rats. To determine whether impaired dilatation of the basilar artery in diabetic rats in response to isoproterenol and norepinephrine was related to an alteration in catalytic activity of adenylate cyclase, we examined dilatation of the basilar artery in response to forskolin, a direct activator of adenylate cyclase. In contrast to that observed for isoproterenol and norepinephrine, forskolin produced similar dilatation of the basilar artery in non-diabetic and diabetic rats. Thus, the findings of the present study suggest that diabetes mellitus impairs dilatation of the basilar artery in vivo in response to activation of beta-adrenergic receptors. In addition, impairment of beta-adrenergic mediated dilatation of the basilar artery during diabetes mellitus does not appear to be related to an alteration in catalytic activity of adenylate cyclase.
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PMID:Effect of diabetes mellitus on responses of the rat basilar artery to activation of beta-adrenergic receptors. 782 Jun 63


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