PubMed Health⌕ Search

Biomedical subjects

A Hasselblatt

Publications and source records attributed to A Hasselblatt.

11 recordsLinked to original sources
PubMed1989

An insulin-releasing property of imidazoline derivatives is not limited to compounds that block alpha-adrenoceptors.

As we have demonstrated previously phentolamine stimulates the release of additional insulin from isolated mouse islets and raises plasma insulin levels in the whole rat. This effect was independent of the well known property of phentolamine to block alpha-adrenoceptors. In experiments on isolated pancreatic islets from mice we now demonstrate that tolazoline and antazoline which are chemically closely related to phentolamine, share its ability to potentiate insulin release. The following results were taken as evidence that this effect does not result from an alpha-adrenoceptor blocking action of imidazoline compounds. More than 10 times higher concentrations of phentolamine were required to liberate additional insulin from isolated islets than were effective in counteracting the inhibitory effect of clonidine on insulin release. The newly introduced alpha 2-adrenoceptor antagonist BDF 8933, which is an imidazoline derivative, stimulates insulin release as well, while the irreversible alpha-adrenoceptor blocking agent benextramine of different structure failed to do so, even when being present in concentrations blocking the alpha 2-adrenoceptor-mediated effects of clonidine. Antazoline shared the ability of phentolamine to stimulate insulin release despite having no or only very little alpha-adrenoceptor blocking activity. When used under our conditions, it almost entirely failed to alleviate the inhibition of insulin release induced by clonidine. We conclude that the response of the islet cells to imidazoline derivatives is not limited to those capable of blocking alpha-adrenoceptors. On the other hand, alpha-adrenoceptor blocking agents of different chemical structure fail to induce the release of additional insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1989

Dual action of clonidine on insulin release: suppression, but stimulation when alpha 2-adrenoceptors are blocked.

As shown previously clonidine reduces glucose-stimulated insulin release and this effect is mediated by inhibitory postsynaptic alpha 2-adrenoceptors. The present experiments demonstrate that clonidine has the additional property to also stimulate insulin release. This became evident when the alpha 2-adrenoceptors of isolated islets were blocked by benextramine, and thus protected from being stimulated by clonidine. In the presence of benextramine, clonidine no longer reduced, but on the contrary enhanced, the release of insulin in response to glucose. In control experiments benextramine by itself failed to affect insulin release from isolated islets. These results show that the imidazoline derivative clonidine shares the property of other imidazoline compounds to enhance the insulin response to glucose. All of these agents may stimulate insulin by binding to "imidazoline-preferring" sites, that clearly differ from alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1979

Insulin release by tolbutamide and glibenclamide. A comparative study on the perfused rat pancreas.

Glibenclamide, a "second generation" sulfonylurea, produced the same pattern of insulin release from the perfused rat pancreas as did tolbutamide. The stimulatory effect was closely dependent on the glucose concentration present. Both agents enhanced insulin secretion at 5--10 mM glucose, whereas no additional insulin was released when maximally stimulating levels of glucose (20 and 30 mM) were present. The concentrations of glibenclamide stimulating insulin release were 100--400 times lower than equieffective levels of tolbutamide. At glucose levels of 3 or 8 mM, however, glibenclamide did not liberate significantly more insulin from the pancreas than did tolbutamide. Thus the differences of tolbutamide and glibenclamide were quantitative rather than qualitative. Although the active concentrations differed the effects produced were comparable.

Animals↗
PubMed1977

Effects of polymer-linked sulfonylurea derivatives on insulin release.

In order to elucidate whether polymerlinked sulfonylurea derivatives may serve as tools to locate the sulfonylurea receptor site, an easily detectable sulfonylurea was synthetized and coupled to cyanogen-bromide activated dextran. The conjugate proved to be unstable and to release sufficient amounts of free agent to explain its insulinotropic activity. Based on these findings previous results claiming that dextran-linked sulfonylureas retain biological activity may be questioned. A stable conjugate was obtained when the acrylyl derivative of the sulfonylurea was co-polymerized with acrylamide. Both a high (greater than 50000) and a low (1500) molecular weight fraction of this conjugate failed to stimulate insulin release from the perfused rat pancreas, questioning the ability of macromolecular conjugates to combine with the sulfonylurea receptor site.

Acrylamides↗
PubMed1976

Inhibition of insulin and glucagon release from the perfused rat pancreas by cyproheptadine (Periactinol, Nuran).

The tricyclic compound cyproheptadine (Periactinol, Nuran) inhibited glucose-induced insulin release from the perfused rat pancreas. Tolbutamide-stimulated insulin release was significantly reduced in the presence and completely suppressed in the absence of a substimulatory glucose concentration (5 mM). Arginine produced a slow rise of insulin release, which was completely abolished by cyproheptadine. Furthermore the biphasic glucagon release due to the stimulus was inhibited. Oxidation of 14C-glucose in isolated islets was unaltered in the presence of cyproheptadine, and pyruvate added to the perfusion medium failed to reverse the inhibitory effect on glucose induced insulin release, indicating that impaired glucose metabolism is not responsible for the inhibition. In addition, the inhibition remained unchanged when phentolamine was present, suggesting that the effect is not mediated by inhibitory adrenergic alpha receptors. Theophylline, in contrast, partly overcame the inhibition. When the calcium concentration of the medium was enhanced, the inhibitory effect of cyproheptadine was still visible, although the relative inhibition had become smaller. The results suggest that cyproheptadine blocks insulin release by affecting a fundamental step of the stimulus-secretion coupling common to peptide hormones. A participation of a calcium-antagonizing effect in the inhibition is discussed.

Animals↗
PubMed1976

The inhibition of insulin secretion from the perfused rat pancreas after thyroxine treatment.

Thyroxine treatment did not significantly affect the immediate insulin secretory response of the perfused rat pancreas, but it inhibited the late phase of D-glucose-induced insulin secretion. Thyroxine treatment did not inhibit D-glyceraldehyde-, D-mannose-, and tolbutamide-induced insulin release from the perfused pancreas. An increase in the D-glucose concentration of the perfusion medium as well as feeding of the rats did not restore insulin secretion after thyroxine treatment. The inhibition of D-glucose-induced insulin release in response to thyroxine treatment was reversed after addition of either D-glyceraldehyde, dihydroxyacetone, DL-glyceric acid, pyruvate, or alpha-ketobutyrate to the perfusion medium. Tolbutamide, L-glucose, D-fructose, D-mannose, L-lactate, and propionic acid were not able to overcome the inhibition of D-glucose-induced insulin secretion. Except for alpha-ketobutyrate all substances which were effective in reversing the inhibition of D-glucose-induced insulin release were glycolytic intermediates. Comparing the glycolytic alpha-ketoacid pyruvate and the non-glycolytic ketoacid alpha-ketobutyrate, the only part common to both substances was the ketoacid moiety. It is concluded from these findings that the ketoacid moiety of the alpha-ketoacids plays an important role in reversing the effect of thyroxine on D-glucose-induced insulin release.

Animals↗
PubMed1976

Thyroid function and insulin secretion from the perfused pancreas in the rat.

The influence of thyroid function on the kinetics of glucose-induced insulin secretion from the isolated perfused rat pancreas has been studied. L-Thyroxine (L-T4) administration did not modify the immediate insulin secretory response of the perfused pancreas to glucose. L-Triiodothyronine (L-T3) treatment as well as propylthiouracil (PTU) treatment decreased the immediate insulin secretory response of the pancreas slightly. Only thyroidectomy (Tx) reduced the immediate secretory response of the pancreas significantly. L-T4 and L-T3 treatment inhibited the late phase of glucose-induced insulin secretion from the isolated perfused rat pancreas, whereas TX and PTU treatment resulted in increased insulin secretion. D-Thyroxine (D-T4) did not affect glucose-induced insulin release from the pancreas. Concomitantly, several parameters indicative of thyroid function were determined in these animals. When changes in body weight, rectal temperature, plasma glucose, plasma cholesterol, and plasma butanol-extractable iodine (BEI) in these rats were compared with the insulin secretory responses, it was evident that experimental hyperthyroidism results in decreased insulin release, whereas experimental hypothyroidism induces increased insulin secretion from the pancreas. The transitions from hypothyroid to euthyroid to hyperthyroid states are accompanied by a steady decrease in glucose-induced insulin release from the rat pancreas. Inhibition of glucose-induced insulin secretion from the pancreas is therefore a specific effect of thyroid hormones.

Animals↗
PubMed1976

Inhibition o'f insulin release by cyproheptadine: effects on 3',5'-cyclic-AMP-content and 45Ca-accumulation of incubated mouse islets.

Cyproheptadine (1, 10 and 100 muM) significantly reduced insulin release from isolated mouse islets in response to glucose. In contrast, 1 mM cyproheptadine induced a large release of insulin into the incubation medium probably due to islet cell damage, since the islets had lost a considerable amount of their protein content. 3',5'-cyclic-AMP-levels of the islets were not significantly affected by 10 muM cyproheptadine in the presence as well as in the absence of theophylline (10 mM). As the inhibitory effect of cyproheptadine on insulin release was correlated with reduced accumulation of calcium-45, the agent may inhibit insulin release by interfering with the calcium handling of the beta-cell.

Animals↗
PubMed1975

Thyroxine treatment and insulin secretion in the rat.

Thyroxine treatment increases blood glucose and plasma insulin levels in the rat. The hypoglycemic effect of tolbutamide is more pronounced in treated animals. The immediate insulin secretory response of the isolated perfused pancreas to maximal, but not to submaximal, glucose stimuli was increased after thyroxine treatment, especially in the lower dose range. However, as thyroxine treatment reduces insulin release during the prolonged late phase, the total amount of insulin released from the pancreas is reduced. Both the early response to tolbutamide and the subsequent basal secretion were increased after thyroxine treatment. When the pancreas of treated rats was exposed to glucose plus pyruvate the inhibition of the late phase was reversed. Isoprenaline did not overcome the inhibitory effect of thyroxine treatment on the late phase of glucose-induced insulin release. Thyroxine induces a selective inhibition of glucose induced insulin release which is reversed by pyruvate; this indicates that thyroxine interferes with the glycolysis in the beta cell.

Animals↗