Biomedical subjects
Publications and source records attributed to E Gagerman.
The dopaminergic drug bromocriptine inhibited the release of insulin from isolated mouse pancreatic islets. The effect was counteracted by haloperidol or pimozide. It is suggested that insulin release may be inhibited through activation of D-2 dopaminergic receptors in the pancreatic beta-cells.
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1. Acetylcholine potentiated glucose-stimulated insulin release from ob/ob-mouse islets in salt-balanced bicarbonate buffer and to a lesser extent in Tris buffer; basal insulin release at 3 mM-D-glucose was not affected. Potentiation required the presence of Ca(2+).2. In bicarbonate buffer, ACh stimulated the islet uptake of (45)Ca(2+) at 3 mM-glucose but not significantly at 11 mM; no effect was seen in Tris buffer.3. At 11 mM-glucose, ACh increased the fluorescence from Ca(2+)-chlorotetracycline in dispersed islet cells; the effect was inhibited by atropine.4. At both 3 and 11 mM-glucose, ACh stimulated the islet uptake of (22)Na(+) in 60 min. At 11 mM-glucose, (22)Na(+) uptake in 5 min was also enhanced significantly, and this effect was inhibited by atropine.5. At 3 mM-glucose, ACh probably stimulated the islet uptake of (86)Rb(+) in 10 min.6. ACh had no effect on (36)Cl(-) retention at 3 or 11 mM-glucose, or on the oxidation of D-[U-(14)C]glucose (11 mM).7. The insulin secretory potentiator, ACh, does not act by accelerating glucose oxidation and does not induce the same ionic effects as the secretory initiator, D-glucose. Increased Na(+) permeability and altered interaction of Ca(2+) with the plasma membrane may play roles in the cholinergic depolarization of beta-cells and potentiation of insulin release.
Isolated pancreatic islets of noninbred ob/ob mice were used to test the hypothesis that adenylate cyclase responds to changes of the transmembrane milieu or electric field in intact beta-cells. In the presence of a phosphodiesterase inhibitor, ouabainstimulated both the release of insulin and the islet content of cAMP. Ouabain had no noticeable effect on the islet content of cGMP. These results support the hypothesis at test. However, because ouabain also had some stimulatory effect on cAMP in islet homogenates, a direct action of ouabain on adenylate cyclase cannot be ruled out.
To elucidate the importance of cholinergic innervation for pancreatic beta-cells in vivo, atropine sulphate (0.2 mg/kg body weight) was subcutaneously injected into mice 4 times a day for 10 days. Control animals received 0.9% NaCl. Paraffin sections of the pancreas were stained for beta-cells with aldehyde fuchsin and for alpha-cells (glucagon cells) with silver according to Grimelius. Endocrine and exocrine cell nuclei were measured with an ocular screw micrometer. The light absorbance at 550 nm wave-length of aldehyde-fuchsin-stained islet sections was measured with a microscope photometer. Atropine caused no loss of body weight or apparent food consumption. The nuclei of beta-cells shrank significantly in response to atropine; A550 of islet surfaces showed a significant negative correlation to beta-cell nuclear size. Acinar cell nuclei near islets also became smaller after atropine treatment but to a lesser extent. No such change was observed in the alpha-cells. A trophic influence of the vagal nerve may be important for the long-term control of beta-cell function.
Acetylcholine potentiated the glucose-induced insulin release from microdissected mouse islets of Langerhans but had no effect on basal insulin release. Significant potentiation was obtained with 0.1 micron acetylcholine in the presence of 10 micron eserine and with 1 micron or more acetylcholine in the absence of a choline esterase inhibitor. Carbamylcholine, too, potentiated insulin release. Potentiation was blocked by methylatropine, whereas methylatropine alone had no effect on insulin release. Acetylcholine or carbamylcholine (5-500 micron) had no obvious effect on cyclic GMP or cyclic AMP in the islets. In the presence of 11.1 mM D-glucose, the membrane potential of beta-cells oscillated slowly between a polarized silent state of -50 to -55 mV and a depolarized active state of -33 to -39 mV, at which a fast spike activity occurred. Acetylcholine made the potential stay at the plateau and induced a continuous spike activity pattern. Atropine inhibited the electrical effects of acetylcholine but not those of glucose alone. It is suggested that cholinergic potentiation of insulin release is mediated by changes of transmembrane ionic fluxes, probably without the intervention of cyclic GMP or cyclic AMP.
The sensitivity of the radioimmunoassay for cGMP was considerably increased by previous 2'-O-succinylation of the nucleotide. The basal content of cGMP in beta-cell-rich pancreatic islets isolated from ob/ob-mice was similar to that of cAMP, i.e. about 3 mumoles per kg dry weight. Extra-cellular Ca2+ was a prerequisite for maintaining this amount of cGMP. The islet cGMP differed from cAMP in being only slightly enhanced or not affected at all when the islets were exposed to high concentrations of glucose, the sulphydryl reagents chloromercuribenzene-p-sulphonic acid and iodoacetamide, or the potent phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine. The data obtained suggest that the turnover rate for cGMP is much slower than that for cAMP in the pancreatic beta-cells. The interrelationships between the two cyclic nucleotides do not seem to fit into a simple pattern of antagonism.