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6.1. It is known from the literature that in diabetes mellitus there is an increased tendency for the thrombocytes to aggregate. This fact represents a risk of thrombosis supplementary to the vascular wall lesions which develop in the course of this disease. An inhibition of platelet aggregation such as has recently been obse3rved in vitro under the influence of beta-cytotropic sulphonylureas (tolbutamide, glicalazide), must therefore be regarded as an additional, desired quality of action of these agents. 6.2. In an attempt to throw more light on this subject studies were conducted to discover whether an inhibition of platelet aggregation can be regarded as a basic property of all beta-cytotropic antidiabetic agents and whether dissociation exists between this property and the hypoglycemic effect. The possible existence of evidence for identical or similar sites of action of sulphonylureas on the control system of the thrombocytes, beta-cells and the liver was also investigated, the main point of interest being whether sulphonylurea derivatives exert their effects via the adenylate cyclase -cAMP-system. The thrombocytes were also used to discover whteher ss-cytotropic antidiabetic agents, such as non-steroidal antiphlogistic compounds, inhibit the synthesis of aggregation-promoting prostaglandins (PGE2). 6.3. The influence on adenosine diphosphate (ADP)-induced thrombocyte aggregation has been dtudied in vitro with platelet rich rat plasma (PRP) using a turbidimetric method. Preliminary studies have also been conducted with PRP obtained after previous treatment of the donor animals...
In 53 sulphonylurea-treated diabetic patients, the activity of glypentide and the patients' general tolerance of the drug were studied. The results show that the new oral hypoglycemic drug has a similar, and superior in many instances, activity to other similar drugs such as glybenclamide and glypizide, and to the activity of the classical sulphonylureas (chlorpropamide and carbutamide). The patients' tolerance of the drug was excellent. No digestive disorders, undesirable side effects or hypoglycemias were seen in the patients. Analysis of lipid levels showed that glypentide induces a significant decrease in total lipid and cholesterol values, being this action more marked in patients with normal body weight non-treated with a hypocaloric diet.
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The study examines the effects of sulfonylurea compounds on the histo- and ultracytochemical calcium distribution within the B-cells of mice using the glyoxal-bis-(2-hydroxyanil) (GBHA) and the pyroantimonate method combined with X-ray microanalysis. Treatment with tolbutamide (200 mg/kg), glibenclamide (2 mg/kg) and glisoxepide (2 mg/kg), causing moderate hypoglycemia and B-cell degranulation, was associated with an unchanged (30, 90 min) or slightly increased (180, 360 min, 4, 42d) GGHA staining intensity of the islet cells compared with controls. Ultra-cytochemically sulfonylureas provoked, compared with controls, a redistribution of calcium-rich, electron dense pyroantimonate precipitates (EDPP). Precipitation predominantly occurred along the inner surface of the plasma membranes and within the granule halos. In contrast, the cytoplasmic matrix, the Golgi complexes and the rough endoplasmic reticulum contained only few fine precipitates. The sulfonylureas investigated exerted identical effects on the histo- and ultracytochemical calcium distribution in B-cells. The results indicate that sulfonylurea-induced insulin secretion is associated with an accumulation and redistribution of calcium within the B-cells. This supports the hypothesis that an altered calcium handling by the B-cell mainly accounts for the insulinotropic effect of sulfonylureas.
Chlorpropamide is known to enhance the water permeability response of the toad urinary bladder to vasopressin and to theophylline. In other studies, we have shown that prostaglandin E synthesis by the toad bladder inhibits the water permeability response to arginine vasopressin and to theophylline. In this study, the effect of chlorpropamide on vasopressin-, theophylline-, and cyclic AMP-stimulated water flow and on prostaglandin E biosynthesis was investigated in the toad urinary bladder in vitro. Chlorpropamide inhibited prostaglandin E biosynthesis during vasopressin-, theophylline- and cyclic AMP-stimulated water flow. Tolbutamide and glyburide, two other sulfonylurea compounds, also enhanced vasopressin-stimulated water flow and inhibited vasopressin-stimulated prostaglandin E biosynthesis. We conclude that the mechanism of enhancement on vasopressin-stimulated water flow by the sulfonylureas is the inhibition of prostaglandin E biosynthesis.
The role of cyclic adenosine-3',5'-monophosphate (cAMP) for insulin secretion has been investigated. In isolated islets of Langerhans from the rat, glucose increases cAMP concomitant with insulin secretion. Stimulation of these two parameters is likewise reversible in parallel. The minimal and maximal concentrations of glucose eliciting cAMP and insulin responses are similar. Isomers and epimers of glucose influence insulin and cAMP in a parallel fashion as do sulfonylurea compounds (tolbutamide and glibenclamide). On the contrary, the time-dependent potentiation of glucose-induced insulin secretion is not accompanied by gross changes in cAMP. Reciprocally, in the absence of glucose islet cAMP can be markedly elevated by other agents (methyl xanthines, cholera toxin) without major insulin responses. The results indicate that metabolism of cAMP in the beta-cell is intimately linked to the glucose (and sulfonylurea) action on insulin secretion, although other factors influenced by the hexose are also necessary for the release process. The finding that the cAMP response is impaired in fasting, during the neonatal period and in diabetes mellitus (in the Chinese hamster) suggests an important role for the nucleotide in physiological and pathophysiological states characterized by decreased insulin release.
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Pancreatic islets rich in beta-cells were isolated from non-inbred ob/ob-mice and used for studying various aspects of the function of the plasma membrane. A review is given of the authors' work along the following lines: the role of transmembrane transport or membrane binding in the recognition of insulin-releasing sugars, amino acids, sulfonylureas, and sulphydryl-blocking agents; the role of cyclic 3',5'-AMP and cations in the coupling of stimulus recognition to insulin discharge; alloxan beta-cytotoxicity in vitro and its prevention by sugars; the isolation of a subcellular fraction enriched by plasma membranes. 1. It is suggested that D-glucose is recognized as an insulin secretagogue by being metabolized in the beta-cells; the teleological purpose of the transmembrane transport system being to allow fluctuations of the extracellular glucose concentration to be rapidly transmitted to the cell interior. Insulin-releasing sulfonyluraes and sulphydryl reagents are thought to act directly on the beta-cell plasma membrane, however. 2. Although cyclic 3',5'-AMP may amplify the expression of a secretory signal induced by D-glucose, studies with cholera toxin suggest that activation of the adenylate cyclase does not per se elicit secretion. The increase of islet cyclic 3',5'-AMP observed in response to several secretagogues, including D-glucose, may be secondary to membrane depolarization. 3. The possible role of an electrodiffusional mechanism in controlling the electrical potential is emphasized; a decrease of K+ permeability, rather than an increase of Na+ permeability, is suggested to be involved in the depolarizing action of D-glucose. Studies with the lanthanum-wash technique indicated that D-glucose causes a net flux of Ca2+ from the outside to the inside of the beta-cells. Although this uptake may relate to the enhancement of insulin secretion, the detailed mechanisms are unclear. 4. Inhibition of the Na+/K+ pump may be one of the earliest events in damage to the beta-cell by alloxan, on the basis of Rb+ studies. Protective effects of glucose against alloxan toxicity appear to be close related. 5. Studies of enzyme markers, the binding of wheat germ agglutinin, and electron microscopy indicate the presence of plasma membranes in a smooth-membrane fraction obtained by fractionating islet homogenates at consecutive sucrose gradients.