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

Prostaglandin E2 (PGE2) inhibits glucose-induced insulin secretion, and inhibitors of PGE2 synthesis augment this event. However, there has been confusion regarding prostaglandin regulation of insulin secretion, partly because no mechanism has been demonstrated for the inhibitory action of PGE2 on beta-cell function. These studies were performed with a clonal cell line of glucose-responsive beta-cells (HIT cells) to determine whether PGE2 effects on insulin secretion are receptor mediated and, if so, whether the postreceptor effects are mediated by inhibitory regulatory components (Ni) of adenylate cyclase. Saturable [3H]PGE2 binding to HIT cells was demonstrated. This binding was dissociable and specific for prostaglandins of the E series. Scatchard analyses of binding data indicated a single class of sites with a Kd of approximately 1 X 10(-9) M. Guinea pig islets were also demonstrated to have a single class of binding sites with a similar Kd but only 22% as many binding sites (0.060 vs. 0.013 pmol/mg protein, HIT cells vs. guinea pig islet). HIT cells were demonstrated to synthesize PGE2, and this synthesis was inhibitable by acetylsalicylic acid. Accumulation of cAMP by HIT cells was inhibited in a concentration-dependent manner by PGE2 with an IC50 of approximately 1 X 10(-9) M. Insulin secretion by HIT cells during static incubations with 11.1 mM glucose was also inhibited by PGE2 in a concentration-dependent manner with an IC50 of 1 X 10(-9) M. PGE2 was more potent than epinephrine but less potent than somatostatin in this regard. Maximum inhibition of glucose-induced insulin secretion was 26, 37, and 29% of control values for somatostatin, PGE2, and epinephrine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Sep
PMID:Receptor-mediated adenylate cyclase-coupled mechanism for PGE2 inhibition of insulin secretion in HIT cells. 288 85

Eicosanoids both negatively and positively modulate glucose-induced insulin secretion. Although the identity of the positive modulator is uncertain, the negative modulator appears to be prostaglandin E2 (PGE2), because 1) glucose stimulates PGE2 synthesis from islet cells; 2) exogenous PGE2 inhibits glucose-induced insulin secretion; 3) inhibition of beta-cell PGE2 synthesis increases glucose-induced insulin secretion, and this increase is reversed by exogenous PGE2; and 4) PGE2 binds to specific beta-cell receptors that are coupled to inhibitory regulatory components of adenylate cyclase whose activation decreases cAMP levels. Other possible regulatory effects of eicosanoids on islet function include modulation of islet blood flow and its immune responsiveness. From these considerations, the perspective is offered that eicosanoids are pluripotential modulators of islet function.
Diabetes 1988 Apr
PMID:Eicosanoids as pluripotential modulators of pancreatic islet function. 289 39

Rat insulinoma cells, which grow in culture and secrete insulin, were used to study the mechanism of stimulation of insulin release by glucagon. The parent cell line (RIN-m) and a clone that secretes high levels of insulin (5F) had been shown to possess specific receptors for glucagon. Glucagon (1 microM) stimulated a rapid increase in cyclic adenosine 3':5'-monophosphate (cAMP) that was followed by an increase in insulin secretion in both cell lines. The concentration of glucagon necessary for half-maximal stimulation of cAMP was 50 nM in parent and approximately 0.5 microM in 5F, whereas the concentration required to inhibit binding by 50% was 0.5 nM and 30 nM, respectively. In 5F, the dose-response relationships for cAMP and insulin secretion were superimposable. The glucagon effects on insulin secretion and cAMP did not require either glucose or amino acids in the incubation media. No refractoriness to glucagon stimulation of cAMP or insulin was noted. It may be concluded that there are significant differences between glucagon binding and glucagon responses in parent cells and clone 5F, there are glucagon receptors that are not coupled to adenylate cyclase, and cAMP mediates glucagon-stimulated insulin release.
Diabetes 1985 Aug
PMID:Characteristics of the interaction of the glucagon receptor, cAMP, and insulin secretion in parent cells and clone 5F of a cultured rat insulinoma. 299 Oct 48

Alloxan exerts a selective impairment of the insulin-producing B-cells of the islets of Langerhans, which may result in diabetes mellitus. The effects of alloxan on cyclic AMP metabolism in isolated mouse islets of Langerhans were investigated. Alloxan caused an immediate increase in islet content of cyclic AMP, whereas a subsequent glucose-stimulated increase of islet cyclic AMP content was inhibited in alloxan-exposed islets. No corresponding effects of the drug were, however, found on either islet adenylate cyclase or cyclic AMP phosphodiesterase activities in broken cell preparations. It appears unlikely that there is a direct interaction between alloxan and the enzyme molecules leading to irreversible changes. Alloxan may rather affect some metabolic factor essential for optimal enzyme function. The inhibition of glucose-stimulated increase in islet ATP content and adenylate energy charge in alloxan-treated islets suggests that such a factor might be dependent on intact ATP generation.
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PMID:Effects of alloxan on the islets of Langerhans: stimulation and inhibition of cyclic AMP production. 299 86

The objective of this study was to identify the biochemical mechanisms concerned with pulmonary growth and development. The data show that cyclic adenosine monophosphate (cAMP), adenylate cyclase, cAMP phosphodiesterase, and their regulation by intracellular modulators are important to the development of rat lungs. The presence in rat lung cytoplasm of factors modulating adenylate cyclase activity is described. These factors appear to be important physiologically as they are present in vivo, they appear in the cytoplasm at a specific age, and their activity is altered by diabetes and adrenalectomy and restored to original levels by administration of insulin and dexamethasone, respectively. The cytoplasmic activation of adenylate cyclase appears to be due to multiple proteins that can be resolved into less active components by DEAE-cellulose chromatography. Recombination of these proteins not only restored activity to the original level but actually resulted in more than additive activation, indicating some interdependence and positive cooperativity among the different components to maximally stimulate adenylate cyclase activity. The rat lung cytoplasmic activator protein regulates adenylate cyclase by a mechanism different from those reported for epinephrine, NaF, 5'-guanylimidophosphate, and calmodulin.
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PMID:Role of cyclic adenosine monophosphate in rat lung development. 299 86

The increased frequency of hypertension in diabetes and of abnormalities of carbohydrate metabolism in hypertension are now well established. It is conceivable that the high coincidence of the two diseases is based on a common metabolic defect. Studies of platelets permit the evaluation of the stimulatory, phosphoinositol-linked and the inhibitory, cyclic adenosine 3',5'-monophosphate-dependent pathways of cell activation. Furthermore, platelets may be relevant for the development of angiopathy through their contents of growth factors. Abnormalities of platelet aggregation have been demonstrated in hypertension and diabetes. They are accompanied by exaggerated stimulation of adenylate cyclase in hypertension and abnormal activity of cyclic guanosine 3',5'-monophosphate phosphodiesterase in diabetes. Defective function of platelets is also observed in patients and animals when the two diseases are present at the same time. Both increased and decreased aggregation have been described in these two diseases in the literature. The apparent discrepancies may be due to different types of platelet preparation, evaluation of aggregation, evolution of defect with age, and form of the disease. Integrated studies of biochemical mechanisms responsible for cell activation are needed to characterize the exact defect present in diabetes and hypertension in platelets.
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PMID:Abnormalities of platelet function in hypertension and diabetes. 300 Sep 39

Insulin acutely inhibits the catecholamine-stimulated rise in cAMP levels in fat, liver, and muscle primarily through stimulation of the enzyme cAMP phosphodiesterase (PDE). Adipocytes from rat epidydimal fat pads were exposed to insulin and fractionated by centrifugation. Whereas the cytosolic fraction contained a low-affinity cAMP PDE that was unaffected by insulin, the activity of a high-affinity enzyme residing in a particulate fraction was increased by insulin. This enzyme activity could be solubilized with nonionic detergent and chromatographed on ion exchange followed by chromatofocusing. The resulting enzyme preparation was subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Silver staining revealed a single band with a molecular weight of 60,000. This apparent molecular weight was verified by calculation of the hydrodynamic properties of the enzyme. Evaluation of its kinetic properties indicated that the enzyme activity residing in this solubilized 60,000-Mr protein exhibited lower affinity than the membrane-bound enzyme but was still specific for cAMP. Activation of this enzyme may be one of the primary mechanisms by which insulin counteracts the effects of adenylate cyclase-stimulating hormones.
Diabetes 1986 Jun
PMID:Purification of putative insulin-sensitive cAMP phosphodiesterase or its catalytic domain from rat adipocytes. 301 73

Our study describes the effect of norepinephrine on adenylate cyclase activity in adipocytes from control and diabetic rats. The results show that diabetes induced an increase in both basal and norepinephrine-stimulated adenylate cyclase activity. This higher activity was not suppressed when the animals were treated for 2 days with the beta-blocking agent propranolol. On the other hand, adipocytes from control animals treated with propranolol showed a higher adenylate cyclase activity (basal and in response to norepinephrine). beta-Adrenergic receptors were examined in adipocytes from control and diabetic rats with and without treatment with propranolol. The results show a higher beta-receptor density in adipocytes from diabetic animals. When the animals were treated with propranolol, the beta-blocker induced a higher receptor density in adipocytes from control animals without affecting the already increased receptor density in diabetic preparations. The data suggest that adenylate cyclase activity in response to norepinephrine in adipose tissue is increased during at least a certain period of the diabetic state. This increase in adenylate cyclase activity is accompanied with an increase in beta-receptor density, but in contrast to control animals, this receptor density is not further increased with propranolol treatment.
Diabetes 1986 Nov
PMID:Beta-adrenergic receptors and adenylate cyclase activity in diabetic rat fat cells. 301 7

The effect of streptozotocin-induced diabetes on cyclic AMP content, adenylate cyclase and cyclic-AMP phosphodiesterase activities in rat adipocytes was investigated. The results show that diabetes induced an increase in intracellular cyclic AMP. Basal adenylate cyclase activity and in response to norepinephrine were higher in fat cell membranes from diabetic rats. Adenylate cyclase activity stimulated by fluoride was the same in both normal and diabetic preparations. Low and high Km phosphodiesterase activities in adipocytes from diabetic rats were higher than the controls. The results suggest that the deficiency of insulin present in the diabetic state induces an increase in adenylate cyclase activity which increases the cyclic AMP production. This increase in cyclic AMP promotes a higher cyclic AMP-phosphodiesterase activity which is not sufficient to hydrolyze all the newly formed cyclic AMP.
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PMID:Cyclic AMP, adenylate cyclase and cyclic AMP-phosphodiesterase activities in diabetic rat adipocytes. 302 Aug 75

Cardiac beta-adrenergic receptors (beta AR) were studied in rats after 4 months of diabetes induced by streptozotocin (50 mg/kg, i.v.). Saturation binding studies performed using [125I]-iodocyanopindolol (ICYP) as an antagonist ligand showed that the number and affinity of beta AR were not significantly altered. Analysis of competition curves of ICYP binding by the agonist (-)-isoproterenol showed that diabetes induces an increase in the (-)-isoproterenol IC50 and a steepening of the curve ("pseudo-Hill" coefficient not significantly different from 1) in the absence of Gpp(NH)p, while these parameters were not significantly modified in the presence of Gpp(NH)p (10(-4) M). These results indicates that beta AR were not significantly reduced in number but altered in their capacity to efficiently couple with the GTP-binding protein of adenylate cyclase (AC). These data can be correlated to the alteration of beta-adrenergic stimulation of cardiac AC previously observed after 4 months of diabetes. The characteristics of beta AR alteration at this stage of the disease are similar to those of a first step of a beta AR desensitization process due to overstimulation.
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PMID:Cardiac beta-adrenergic receptors in diabetic rats: alteration of guanyl nucleotide regulation. 303 78


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