Glibenclamide induces glucokinase in rat pancreatic islets and liver.
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Animals↗
Biomedical subjects
S Lenzen
Publications and source records attributed to S Lenzen.
Regulation of energy metabolism in pancreatic islets by glucose and tolbutamide.
The kinetics of insulin secretion and oxygen uptake in response to D-glucose and tolbutamide were compared in mouse pancreatic islets. In addition, the role of decreased ATP as a driving force for secretagogue-induced oxygen consumption was examined. D-glucose (10-30 mmol/l) triggered a biphasic insulin release which always coincided with a monophasic increase in islet oxygen uptake. In the presence of D-glucose (5-30 mmol/l), tolbutamide (3-500 mumol/l) consistently elicited an initial peak of insulin secretion which was followed by a continued decline. Tolbutamide-induced secretory profiles were accompanied by similar respiratory profiles. Oxygen consumption per ng of insulin released during the test phase was higher after elevation of the glucose concentration than after addition of tolbutamide. In conjunction with 5 or 10 mmol/l D-glucose, but not with 15 or 30 mmol/l D-glucose, tolbutamide (30-100 mumol/l) lowered islet ATP content significantly (p less than 0.02). Phosphocreatine was not found in isolated islets, although they contained substantial creatine kinase activity. It is concluded that the driving force for tolbutamide-induced oxygen uptake is a decrease in the phosphorylation potential caused by the work load imposed by stimulation of the secretion process. However, a major proportion of the respiratory response to glucose also results from enhancement of biosynthesis.
Animals↗
2-ketoglutarate generation in pancreatic B-cell mitochondria regulates insulin secretory action of amino acids and 2-keto acids.
The various neutral amino acids and aliphatic 2-keto acids exhibit differential effects on insulin secretion. The common denominator for all these effects is the 2-ketoglutarate generation in the pancreatic B-cell mitochondria. The neutral amino acids L-leucine and L-norvaline and the aliphatic ketomonocarboxylic acids 2-ketoisocaproate, 2-ketocaproate, 2-ketovalerate, and 2-keto-3-methylvalerate all stimulate insulin secretion and increase 2-ketoglutarate generation in pancreatic B-cell mitochondria through activation of glutamate dehydrogenase and transamination with L-glutamate and L-glutamine, respectively. The neutral amino acids L-valine, L-norleucine, and L-alanine and the aliphatic 2-keto acids 2-ketoisovalerate and pyruvate do not stimulate insulin secretion and do not increase 2-ketoglutarate generation in pancreatic B-cell mitochondria. Inhibition of 2-keto acid induced insulin secretion by L-valine and L-isoleucine is accompanied by reduced 2-ketoglutarate generation in pancreatic B-cell mitochondria. Thus intramitochondrial 2-ketoglutarate generation in pancreatic B-cells may regulate the insulin secretory potency of amino acids and 2-keto acids.
Amino Acids↗
Transamination of neutral amino acids and 2-keto acids in pancreatic B-cell mitochondria.
High aminotransferase activities catalyzing the reactions between L-glutamate and L-glutamine and the aliphatic ketomonocarboxylic acids 2-ketoisocaproate, 2-ketocaproate, and 2-ketoisovalerate were observed in pancreatic B-cell mitochondria. While maximal rates of transamination with L-glutamate were observed in the presence of micromolar concentrations of keto acid, maximal rates of transamination with L-glutamine were recorded only in the presence of millimolar concentrations of keto acid. The insulin secretagogue 2-ketoisocaproate was the most effective transamination partner for L-glutamate, while the insulin secretagogue 2-ketocaproate was the most effective transamination partner for L-glutamine. Since B-cell mitochondria are well supplied with L-glutamate and L-glutamine, 2-ketoglutarate generation in the presence of these two neutral 2-keto acids may be an important prerequisite for their insulin secretory potency. High rates of transamination of 2-ketoglutarate were observed in the pancreatic B-cell mitochondria with the branched-chain amino acids L-leucine and L-valine, but not with L-norleucine. In connection with the ability of L-leucine to activate glutamate dehydrogenase, this high activity of the branched-chain amino acid aminotransferase in pancreatic B-cell mitochondria may provide an explanation for the insulin secretory potency of this amino acid.
Animals↗
Effects of isoprenaline and glucagon on insulin secretion from pancreatic islets.
The effects of isoprenaline and glucagon on insulin secretion from pancreatic islets were investigated. In the presence of high concentrations of isoprenaline (10-50 mumol/l), glucose-induced (20 mmol/l) insulin secretion from isolated perifused mouse islets was inhibited. This inhibition was apparently mediated by alpha 2-adrenoceptors, as it was antagonized by rauwolscine. At low concentrations isoprenaline (0.1 or 1 mumol/l) did not affect glucose-induced (2.5; 10 or 20 mmol/l) insulin secretion from perifused mouse or rat islets, even if alpha 2-adrenoceptors were blocked by rauwolscine. A stimulatory effect of isoprenaline on insulin secretion was also not observed in the perfused rat pancreas. However, when incubated mouse islets were exposed to glucose (10 mmol/l), insulin secretion was further enhanced by isoprenaline (0.5 mumol/l). To elucidate the underlying mechanism, the effects of glucagon on insulin secretion were investigated, because glucagon is released from the pancreatic A-cells during stimulation with isoprenaline and is accumulated in the islets and the surrounding medium during incubations of pancreatic islets. Indeed, glucagon stimulated insulin secretion from perifused mouse islets in the presence of high glucose (10 or 15 mmol/l) concentrations but not of low glucose (5 mmol/l) concentrations. Thus it is concluded that direct beta-adrenergic stimulation of pancreatic B-cells does not occur in mouse or rat pancreatic islets. Augmentation of glucose-induced insulin secretion by isoprenaline observed in incubation systems can be explained as a result of stimulation by glucagon, which is released from pancreatic A-cells by isoprenaline.
Animals↗
The dihydropyridine derivative, Bay K 8644, enhances insulin secretion by isolated pancreatic islets.
The effects of the dihydropyridine derivative Bay K 8644 upon insulin secretion by perifused isolated mouse pancreatic islets were examined. At a non-stimulatory glucose concentration (5 mmol/l) Bay K 8644 (1 mumol/l) did not stimulate insulin release. However, the same drug concentration enhanced the insulin secretory responses to an intermediate (15 mmol/l) or high (30 mmol/l) glucose concentration by 80 or 90%, respectively. Bay K 8644 was half maximally effective at 0.1 mumol/l and maximally effective at 1 mumol/l. The results are compatible with the view that voltage-dependent calcium channels are essential for stimulus-secretion coupling in pancreatic B-cells.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
A versatile Ca2+ ion-sensitive minielectrode with a microincubation chamber.
A new, versatile Ca2+ ion-sensitive minielectrode with a microincubation chamber was designed for the direct, continuous monitoring of changes in Ca2+ ion activity in microgram tissue samples. The sample can be stirred in the microincubation chamber and kept at a constant temperature through thermostatisation. Samples with a protein content ranging from 10 to 40 micrograms are required for the measurement. This is two to three orders of magnitude less than necessary for measurement of Ca2+ ion activity with conventional, commercially available Ca2+ ion-sensitive electrodes. The device should be useful for a variety of applications in many research areas where sample volumes are small. Some examples are presented in this communication using mitochondria and microsomes from nine different rat tissues. In these experiments it is shown that with mitochondria from all tissues a steady-state ambient free Ca2+ concentration between 0.6 and 0.8 microM is reached, though the Na+ sensitivity of ruthenium red-induced Ca2+ efflux from these mitochondria varies considerably in dependence on the tissue. The additional presence of microsomes resulted in a steady-state Ca2+ concentration between 0.1 and 0.2 microM.
Adrenal Glands↗
Secretory, enzymatic, and morphological characterization of rat pancreatic endocrine tumours induced by streptozotocin and nicotinamide.
Rat pancreatic endocrine tumours were induced by administration of streptozotocin plus nicotinamide. Fifteen to eighteen months later tumours with wet weights of 0.1 to 224 mg were isolated. These tumours were compared with normal rat pancreatic islets. Insulin release from perifused tumours was stimulated by D-glucose, L-leucine, 2-ketoisocaproate, and D-glyceraldehyde, potentiated by theophylline and inhibited by norepinephrine. Compared with isolated rat pancreatic islets, however, insulin secretory responsiveness to glucose stimulation and insulin content were reduced in tumour tissue. Hypoglycaemia in tumour bearing rats and impaired diffusion of insulin out of the tumours may explain this difference. The pattern of enzyme activities observed in tumour tissue was typical for pancreatic endocrine tissue. The activities of succinate dehydrogenase, the two types of the monoamine oxidase, and alpha-glucosidase were in the normal range in tumour tissue. Only the activities of 5'nucleotidase and glutamate dehydrogenase were decreased. Immunocytochemical analysis of the tumours revealed that they contained an average of 91% B-cells. In addition 8% of D-cells were encountered. Proportions of A-cells and PP-cells ranged below 1%. Thus this endocrine tumour of the pancreas with a high proportion of functionally intact B-cells is an interesting model for studying regulation of secretion and endocrine tumour development.
Adenoma, Islet Cell↗
Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue.
In mouse pancreatic islets the kinetics of insulin secretion and O2 uptake in response to the non-metabolizable leucine analogue (+/-)-BCH (2-endo- aminonorbornane -2-carboxylic acid) were compared. In addition, the fuel-mobilizing effect of (+/-)-BCH was studied with a mitochondrial fraction from islets. (1) Within 2 min 20 mM-(+/-)-BCH markedly enhanced insulin release or O2 consumption by islets respiring in the absence of exogenous fuels. During prolonged exposure to 20 mM-(+/-)-BCH secretion declined more rapidly than O2 uptake. (2) L-Glutamine (10 mM) prevented the decrease of both insulin release and O2 uptake of islets exposed to 20mM-(+/-)-BCH. During the second phase of insulin release in response to 20 mM-(+/-)-BCH + 10 mM-L-glutamine, kinetics of secretion and respiration correlated closely. (3) Initial peaks were consistently seen in the (+/-)-BCH-induced secretory profiles, but never in the respiratory profiles. (4) In contrast with L-glycerol 3-phosphate, L-malate or pyruvate, L-glutamine or L-glutamate maintained low rates of oxidative phosphorylation in B-cell mitochondria. The effects of L-glutamine or L-glutamate were potentiated severalfold by (+/-)-BCH. (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity. (6) The results support the view that (+/-)-BCH stimulates insulin secretion via a primary enhancement of hydrogen supply to the respiratory chain of B-cell mitochondria.
Adenosine Triphosphate↗
Transamination of 3-phenylpyruvate in pancreatic B-cell mitochondria.
High aminotransferase activities catalyzing the reaction between L-glutamate and the aromatic ketomonocarboxylic acid, 3-phenylpyruvate, were observed in the mitochondria from pancreatic B-cells. At very low concentrations of 3-phenylpyruvate, L-glutamine was an effective amino group donor. The aminotransferase activities for the aliphatic ketomonocarboxylic acids, pyruvate and 2-ketoisovalerate, were lower in B-cell mitochondria. High rates of transamination of 2-ketoisocaproate with L-glutamine were observed and may be an important prerequisite for the insulin secretory potency of this 2-keto acid. Since B-cell mitochondria are well supplied with L-glutamine and L-glutamate, 3-phenylpyruvate-induced 2-ketoglutarate production may explain the insulin secretory potency of 3-phenylpyruvate which is not a fuel for pancreatic islet cells.
Animals↗
Thyroid hormones, gonadal and adrenocortical steroids and the function of the islets of Langerhans.
Thyroid hormones, gonadal and adrenocortical steroids, are glucoregulatory hormones. Thyroid hormones increase the provision of glucose to meet the enhanced energy demands which they impose. Glucose tolerance is decreased, associated with increased hepatic glucose production, although the glucose-raising effects of thyroid hormones are partially offset by an increased rate of glucose utilization especially in the postabsorptive state. The insulin secretory capacity of the pancreatic B cells is reduced by an excess of thyroid hormones, and the onset of diabetes may be hastened as pancreatic insulin reserves are depleted. Natural estrogens can improve glucose tolerance through a beta-cytotropic effect and enhanced insulin sensitivity. Progesterone may produce similar effects in the absence of estrogens, but progestins appear to antagonize the effects of estrogens. Testosterone exerts only marginal effects on glucose tolerance. Glucocorticoids decrease glucose tolerance by increased hepatic glucose production and impaired peripheral glucose utilization. Glucocorticoids reduce insulin sensitivity and responsiveness in peripheral tissues. However, the diabetogenic influence of glucocorticoid excess is partly compensated by a beta-cytotropic effect and a condition of diabetes develops when the functional reserve of the endocrine pancreas becomes limiting.
Adrenal Cortex Hormones↗
Intracellular localization of calcium in pancreatic B-cells in relation to insulin secretion by the perfused ob/ob mouse pancreas.
Changes in the distribution of intracellular calcium in B-cells from the perfused ob/ob mouse pancreas in relation to the secretory state of the B-cell were followed using the pyroantimonate technique for calcium precipitation. At the internal surface of the B-cell membrane a highly mobile reservoir of calcium was mobilized during the first 1-3 min of stimulation of the B-cells by glucose as well as by tolbutamide resulting in an increased calcium precipitation in the cytoplasma. During prolonged stimulation of insulin secretion by glucose the calcium precipitation along the internal surface of the B-cell membrane was restored. Concomitantly calcium deposits in the secretory granules and to a lesser extend in the mitochondria increased. Tolbutamide neither restored the membrane-bound pool nor increased the calcium uptake of the secretory granules but decreased mitochondrial calcium. It suggests that this cytoplasmic increase of calcium primarily results from intracellular redistribution.
Animals↗
A versatile microfiltration device.
A versatile vacuum microfiltration device was designed for separation of small volumes of liquid from samples of cells or subcellular organelles through membrane filters. It is especially useful for separation of small samples from radioactive tracer when low blank values are mandatory for the performance of the measurement. In the present communication the microfiltration device was used for the separation of organelles from incubation medium labeled with 45Ca2+ for measurement of uptake of 45Ca2+ by small samples of liver or pancreatic islet mitochondria or of pancreatic islet secretory granules. Measurement of 45Ca2+ uptake was possible in samples containing less than 1 microgram of protein even if the sample was incubated with only 10,000 cpm of 45CaCl2. Blank values ranged only between 2.6 and 4.7% of the test values. The device should be useful for a variety of applications in many research areas where sample volumes are small.
Animals↗
[Caries prevention is also treated with fluoride preparations].
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Calcium↗
Monoamine oxidase in pancreatic islets, exocrine pancreas, and liver from rats. Characterization with clorgyline, deprenyl, pargyline, tranylcypromine, and amezinium.
Monoamine oxidase (MAO) was characterized in tissue homogenates from pancreatic islets, exocrine pancreas, and liver from rats. Phenylethylamine was preferentially deaminated by pancreatic islet MAO while 5-hydroxytryptamine was preferentially deaminated by MAO from exocrine pancreas, and tyramine was a good substrate for both tissues. All three substrates were well deaminated by liver tissue. Clorgyline, a selective inhibitor of MAO-A, preferentially inhibited deamination of 5-hydroxytryptamine by all three tissue homogenates, while deprenyl, a selective inhibitor of MAO-B, preferentially inhibited deamination of phenylethylamine. In the case of pargyline, a less selective MAO-B inhibitor, the preference in favour of phenylethylamine was less pronounced. According to these results, MAO in pancreatic islets can be classified as predominantly type B enzyme species and MAO in exocrine pancreas as predominantly type A enzyme species while both types of the enzyme are present in the liver. Using the same three MAO substrates and compared with the effects of the selective enzyme inhibitors, clorgyline and deprenyl, tranylcypromine can be classified as a potent nonselective inhibitor of MAO in homogenates of all three tissues investigated with a slight preference in favour of the inhibition of the B-form of the enzyme, while in contrast amezinium can be classified as a weak nonselective inhibitor of MAO with a slight preference in favour of the inhibition of the A-form of the enzyme. All MAO inhibitors tested also inhibited insulin secretion by isolated incubated rat pancreatic islets, however only at IC50 which were two to three decimal powers higher than those necessary for the inhibition of the MAO activity, thus indicating that inhibition of MAO activity and inhibition of insulin secretion are apparently not closely related.
Animals↗
Characterization of succinate dehydrogenase and alpha-glycerophosphate dehydrogenase in pancreatic islets.
Succinate dehydrogenase activities in homogenates of rat and ob/ob mouse pancreatic islets were only 13% of the activities in homogenates of liver and were also several times lower than in homogenates of pancreatic acinar tissue. This indicates that the content of mitochondria in pancreatic islet cells is very low. The very low activity of succinate dehydrogenase is in agreement with the low mitochondrial volume in the cytoplasmic ground substance of pancreatic islet cells as observed in morphometric studies. This may represent the poor equipment of pancreatic islet cells with electron transport chains and thus provide a regulatory role for the generation of reducing equivalents and chemical energy for the regulation of insulin secretion. The activities of succinate dehydrogenase in tissue homogenates of pancreatic islets, pancreatic acinar tissue, and liver were significantly inhibited by malonate and diazoxide but not by glucose, mannoheptulose, streptozotocin, or verapamil. Tolbutamide inhibited only pancreatic islet succinate dehydrogenase significantly, providing evidence for a different behavior of pancreatic islet cell mitochondria. Therefore diazoxide and tolbutamide may affect pancreatic islet function through their effects on succinate dehydrogenase activity. The activities of alpha-glycerophosphate dehydrogenase in homogenates of pancreatic islets and liver from rats and ob/ob mice were in the same range, while activities in homogenates of pancreatic acinar tissue were lower. None of the test agents affected alpha-glycerophosphate dehydrogenase activity. Thus the results provide no support for the recent contention that alpha-glycerophosphate dehydrogenase activity may be critical for the regulation of insulin secretion.
Animals↗
[Fluoride preparations in caries prevention].
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Calcium Fluoride↗
Effects of 4-methyl-2-methylenevalerate, a non-metabolizable analogue of 2-ketoisocaproate, on insulin secretion and metabolism in ob/ob mouse pancreatic islets.
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Animals↗