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Biomedical subjects

V Grill

Publications and source records attributed to V Grill.

At least 199 records · Page 11Linked to original sources
PubMed1983

Modulation by IBMX, fasting and experimental diabetes of glibenclamide-induced islet hormone release from the perfused rat pancreas.

The impact of increased c-AMP levels, short-term fasting as well as experimental diabetes on glibenclamide-induced secretion of somatostatin, insulin and glucagon was studied in the isolated perfused rat pancreas. Dose-response curves revealed that 1 microgram/ml of glibenclamide (in the presence of 3.3 mmol/l of glucose) induced maximal stimulation of insulin and near maximal stimulation of somatostatin release, but did not significantly affect glucagon release. A combination of glibenclamide and the phosphodiesterase inhibitor IBMX synergistically and equally increased both B- and D-cell secretion. Fasting the rats for 24 h significantly suppressed the insulin and glucagon responses to glibenclamide while the concomitant somatostatin response was slightly enhanced. Rats injected with alloxan 3 days prior to perfusion were rendered either moderately diabetic or severely ill with ketoacidosis. Their insulin responses were poor or absent, respectively. In the moderately diabetic rats glibenclamide-induced somatostatin release was blunted while it was abolished in the ketotic rats. The results indicate that glibenclamide-induced B- and D-cell secretion are both modulated by c-AMP, that short-term fasting differentially affects B- and D-cell secretion and that D-cell secretion is inhibited in alloxan diabetes of short duration. It is concluded that the balance of effects by glibenclamide on hormones of the endocrine pancreas may depend on the nutritional and metabolic environment.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Difference in calcium dependency of insulin, glucagon and somatostatin secretion in response to glibenclamide in perfused rat pancreas.

The extracellular calcium requirements for insulin, glucagon and somatostatin release induced by 1 microgram/ml of glibenclamide have been compared in the perfused, isolated rat pancreas. In the absence of glucose, the drug evoked insulin release equally well at physiological (2.6 mmol/l) and low (0.25 mmol/l) levels of total calcium. In contrast, glibenclamide evoked somatostatin release at 2.6 but not at 0.25 mmol/l of calcium. At 2.6 mmol/l of calcium, glibenclamide evoked bimodal effects (stimulation followed by inhibition) on glucagon secretion. At 0.25 mmol/l of calcium, basal secretory rates of glucagon were elevated and a small stimulatory effect of glibenclamide was seen. Addition of 0.5 mmol/l of EGTA to media with low calcium concentrations uniformly abolished the A, B and D cell secretory responses to glibenclamide. The possible modulation of calcium dependency by a non-stimulatory concentration of glucose was tested by its addition at 3.3 mmol/l to the perfusion media. Glucose enhanced glibenclamide-induced insulin secretion, both at 0.25 and 2.6 mmol/l of calcium. However, at 0.25 mmol/l of calcium, the enhancing effect of glucose was more pronounced than at 2.6 mmol/l. At 2.6 mmol/l of calcium, glucose diminished the somatostatin and abolished the glucagon response to glibenclamide. At 0.25 mmol/l of calcium, glucose did not influence somatostatin release while the presence of the sugar diminished basal and glibenclamide-induced glucagon secretion. The present data confirm the requirement of extracellular calcium for A, B and D cell secretion, demonstrating different calcium dependencies for the cell types and indicate that this dependency can, in part, be modulated by glucose.

Animals↗
PubMed1982

Nutrient-induced priming of insulin and glucagon secretion. Effects of alpha-ketoisocaproic acid.

UNLABELLED: Previous exposure to glucose enhances the insulin and depresses the glucagon response to subsequent stimulation with different secretagogues. Induction of these priming effects of glucose requires the metabolism of the sugar. To investigate whether induction of the priming effect of glucose is coupled to glycolysis, other nutrients were tested for their ability to mimic the glucose effect. In isolated perfused rat pancreas prior exposure for 30 min to 10 mM D-glyceraldehyde or 10 mM alpha-ketoisocaproic acid (KIC) enhanced the insulin response to subsequent stimulation with 3-isobutyl-methylxanthine (P less than 0.01); 20 mM pyruvate, 10 mM octanate, 20 mM succinate, or 20 mM citrate were ineffective. The priming effect of KIC was also investigated in relation to subsequent stimulation with a second, identical pulse of KIC. Five millimolar KIC evoked a marked first phase insulin release, followed by a small and constant second phase insulin release. When KIC was reintroduced, the first phase was enhanced (by 100%), and the peak response appeared 1 min earlier; whereas second phase insulin release was unaffected. A priming effect of KIC on arginine-induced glucagon secretion was tested after perfusion for 20 min with 10 mM KIC before the introduction of 8 mM L-arginine. Previous exposure to KIC did not significantly inhibit glucagon secretion, whereas the concomitant insulin release was augmented. CONCLUSION: the ability of nutrient secretagogues to induce priming of insulin secretion does not depend on the glycolytic pathway but may correlate with the degree of oxidative metabolism of these substrates.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat.

The effects of gastric inhibitory polypeptide (GIP) on insulin secretion as well as on the intra-islet accumulation of [3H]cyclic AMP were investigated in isolated pancreatic islets of the rat. In the presence of 6.7 mmol/l of glucose, 3.0 and 30 nmol/l of GIP induced both insulin and [3H]cyclic AMP responses, while lower and higher concentrations of the peptide were ineffective. A coupling of the two parameters was also found with regard to interaction between glucose and GIP. Thus while 30 nmol/l of GIP was stimulatory together with 6.7, 16.7 or 33.3 mmol/l of glucose, the peptide stimulated neither insulin release, nor the accumulation of [3H]cyclic AMP in the presence of a low concentration of glucose (3.3 mmol/l). The concomittant release of insulin and somatostatin was studied in the perfused pancreas in order to assess a possible influence by somatostatin on the dose-response pattern for GIP-induced insulin release. In this preparation 1.0 to 10 nmol/l of GIP stimulated insulin and somatostatin secretion; however while these concentrations were equipotent on insulin release, 10 nmol/l of GIP stimulated somatostatin release more than 1 nmol/l, indicating differences in dose-response curves for the GIP-induced stimulation of the two hormones. It is concluded that 1) modulation of GIP-induced insulin release is coupled to changes in cyclc AMP response in the islet, 2) GIP-induced somatostatin secretion may influence the concomittant insulin response.

Animals↗
PubMed1982

The Staub-Traugott effect. Evidence for multifactorial regulation of a physiological function.

Previous exposure to large amounts of glucose facilitates the disposal of a subsequent load of the sugar (priming or Staub-Traugott effect). We have investigated whether, in man, the classical effect can also be induced by more physiological loads of glucose and whether a priming effect is accompanied by augmented insulin release. To facilitate interpretation of results, a second exposure to glucose was imposed at a time point following the first exposure when the subjects were again euglycaemic. Initial infusion of glucose significantly diminished the hyperglycaemia seen after the subsequent ingestion of 1.75 g/kg of glucose. The corresponding incremental insulin response was diminished while the integrated absolute levels of the hormone were unaffected by prior i.v. glucose. Initial ingestion of 0.5 g/kg of glucose slightly reduced the glycaemic but did not affect the insulin response to a second oral load. Initial ingestion of the same oral glucose load clearly facilitated the disposal of 12.5 g of glucose subsequently injected i.v. Again, this effect of priming with glucose was not accompanied by any priming effect on insulin levels. The lack of enhancement of peripherally measured insulin secretion seemed, if anything, to overestimate B-cell secretory rates since the ratio of insulin to C-peptide was increased (from 37 to 89) after priming with glucose, suggesting that the hepatic clearance of insulin was decreased during the second glucose challenge. It is concluded that (1) facilitation of glucose disposal by previous glucose administration can be induced by amounts of glucose equivalent to those associated with meal intake, (2) enhancement of insulin release is not an obligatory component of the facilitated glucose disposal, (3) decreased hepatic clearance of insulin may accompany the Staub-Traugott effect.

Adult↗
PubMed1981

Previous exposure to glucose enhances somatostatin secretion from the isolated perfused rat pancreas.

Previous exposure to glucose enhances insulin and depresses glucagon secretion by the pancreas. We have investigated whether secretion of somatostatin is also influenced by a glucose priming effect. In perfused rat pancreas from 36 h fasted rats a 5 min pulse of arginine (8 mmol/l) rapidly elicited a peak of somatostatin release. A similar somatostatin response was evoked by a second, identical, pulse of arginine after perfusion with "basal" glucose (3.9 mmol/l) for 45 min. On the other hand when 27.7 mmol/l D-glucose, was administered for 20 min between arginine pulses, there was significant stimulation of somatostatin secretion. When arginine was re-introduced 15 min after the cessation of the pulse of elevated glucose the magnitude of the arginine-induced peak (min 0-2 of stimulation) was increased from 16.2 +/- 4.1 to 33.1 +/- 4.7 pg/2 min, p less than 0.01, relative to the first stimulation with arginine. None of these effects of glucose could be reproduced by D-galactose. The somatostatin response to arginine was higher in pancreata from fed than from 36 h fasted animals as was also basal release (22.8 +/- 5.0 vs 9.0 +/- 2.0 pg/min). In the fed state the response to the second pulse of arginine was however reduced by 50% after perfusion with "basal" glucose. This decrease in responsiveness was counteracted by perfusion with 27.7 mmol/l glucose for 20 min between the arginine pulses. It is concluded that previous exposure to an elevated concentration of glucose enhanced D-cell responsiveness to arginine in the fasted as well as the fed state.

Animals↗
PubMed1981

Time and dose dependencies for priming effect of glucose on insulin secretion.

Short-term exposure to glucose increases insulin secretion during subsequent stimulation. This priming effect of glucose was further investigated in the perfused rat pancreas. A 5-min pulse of 27.7 mM glucose enhanced the response to a second pulse of the sugar after a 5- or 30-min period of 3.9 mM glucose. With a 10-min pulse of 27.7 mM glucose, the priming effect tended to persist also after a 60-min but not after a 90-min rest period. The priming effects of glucose were also evaluated from enhancement of stimulation 15 min later with 3-isobutyl-l-methylxanthine (IBMX). A 10-min pulse of 8.3 and 27.7, but not 5.6 mM glucose enhanced IBMX-induced insulin secretion. Cycloheximide did not abolish the priming effect of glucose on IBMX-induced insulin secretion. Conclusions are 1) priming is rapidly induced; 2) it persists longer than the time of induction; 3) threshold concentrations of glucose that induce priming are similar to those that initiate insulin secretions; and 4) mechanisms causing priming may not involve protein synthesis.

1-Methyl-3-isobutylxanthine↗
PubMed1980

Role of cyclic AMP in insulin release evoked by glucose and other secretagogues.

A close coupling in time-course and dose-dependency exists between cyclic AMP and insulin responses to glucose as tested in isolated islets of Langerhans from the rate and other species. Other secretagogues are also capable of inducing a cyclic AMP response. Under circumstances where the insulin response is reduced, secretion can, however, proceed without a measurable increase in cyclic AMP. "Classical" cyclic AMP-raising agents such as the methylxanthines are unable to induce substantial insulin release in the absence of glucose; however, short-term previous exposure to 27.7 mM glucose transforms 3-isobutyl-1-methylxanthine into a potent insulin-releasing agent. It is concluded that 1) all secretagogues share the stimulation of cyclic AMP as part of the insulinogenic signal; 2) a cyclic AMP response may be needed only for optimal secretory responsiveness of the B-cell; 3) whether a rise in cyclic AMP is solely sufficient to trigger insulin secretion depends on the extent to which a "memory" of exposure to glucose is present in the B-cell.

1-Methyl-3-isobutylxanthine↗
PubMed1979

The metabolism of cyclic AMP and glucose in isolated islets from Acomys cahirinus.

Glucose-induced cyclic (3H) AMP accumulation, insulin secretory responses and the metabolism of glucose were studied in pancreatic islets from Acomys cahirinus. 27.7 mmol/l of glucose stimulated neither islet cyclic (3H) AMP accumulation nor insulin release during the first 5 min of incubation. Stimulation by glucose of cyclic (3H) AMP was observed after 15 min of incubation and insulin release was markedly stimulated between 15 and 30 min. The utilization of glucose, measured as the production of (3H)2O from (5--3H) glucose was stimulated by glucose after 10 min and proceeded at an apparently linear rate during a 20 min incubation period. In incubations of 5 min, glibenclamide, glucagon or chloromercuribenzene-p-sulphonic acid failed to stimulate islet cyclic (3H) AMP accumulation. 3-isobutyl-l-methylxanthine in a concentration of 1.0 mmol/l was the only agent tested that elevated rapidly (1 min) islet cyclic (3H) AMP. None of the agents tested elicited an insulin secretory response in 5 min incubations. It is concluded that 1) no gross defect is apparent in the utilization of glucose by Acomys islets, 2) the secretory derangement of the Acomys is associated with a delayed cyclic AMP response to glucose, 3) however a decreased level of cyclic AMP cannot be the sole explanation for the delayed insulin secretion in the Acomys.

Animals↗
PubMed1979

Role of cyclic AMP in glucagon-induced stimulation of hepatic glucose output in man.

The interrelationship between glucagon action on splanchnic glucose output and cyclic AMP production was studied in healthy volunteers after hepatic venous catheterization. Glucagon was infused according to four different protocols to achieve arterial levels ranging from 300 to 9000 ng/l. Infusion of glucagon which resulted in arterial levels of the hormone of 4000-9000 ng/l was associated with a marked increase in net splanchnic cyclic AMP production and in the arterial levels of the cyclic nucleotide. The rise in cyclic AMP efflux from the splanchnic area was transient but an augmented splanchnic production was still evident after 30 min of glucagon infusion. Splanchnic glucose output rose 3-5 fold. Infusion of glucagon at lower rates, resulting in arterial levels of 300-900 ng/l, did not measureably stimulate the efflux of cyclic AMP from the splanchnic area. In spite of this, splanchnic glucose output rose 2-3 fold and the blood glucose level increased 20-50% during glucagon infusion at these lower rates. It is concluded that (1) factors other than cyclic AMP are rate limiting in the stimulation of hepatic glucose production, and (2) although cyclic AMP is an established 'second messenger' of glucagon action, other factors may also be of importance in mediating the physiological response of this hormone.

Adult↗
PubMed1979

Glucose memory of pancreatic B and A2 cells: evidence for common time-dependent actions of glucose on insulin and glucagon secretion in the perfused rat pancreas.

The influence of previous exposure to glucose on the subsequent B- and A(2)-cell secretory responses to arginine was investigated in the perfused pancreas of the rat. Arginine (8 mM) was administered in two brief (9 min) pulses separated by a period of 66 min. In pancreata from 18-h-fasted animals the two pulses of arginine elicited biphasic glucagon secretory responses, while stimulation of insulin release was barely detectable. When 27.7 mM glucose was administered for 30 min during the intervening period up to 20 min before the second pulse of arginine, the glucagon response to arginine was diminished by 55% while the insulin release was markedly increased in comparison with the first pulse. 8.3 mM glucose, when administered before the second pulse of arginine, exerted effects that were smaller but otherwise similar to those of 27.7 mM glucose.The inclusion of 3.9 mM glucose during the stimulation periods with arginine decreased the glucagon and greatly increased the insulin secretory response. Under these conditions, previous exposure to 27.7 mM glucose inhibited the glucagon and enhanced the insulin response to the second stimulatory pulse of arginine to the same relative degree as when arginine was administered alone. Diazoxide (2 mM), when administered together with 27.7 mM glucose, almost completely inhibited insulin release induced by the presence of glucose, yet did not influence the modulation exerted by glucose on the subsequent insulin and glucagon secretory response to arginine. Conversely, these effects of the glucose pulse could not be reproduced by 1 mug/ml of porcine insulin. Previous exposure to glyceraldehyde (10 mM) mimicked the glucose effects.Also, in pancreata from fed rats, previous exposure to 27.7 mM glucose markedly inhibited subsequent arginine-induced glucagon secretion while the concomittant insulin response was enhanced.IT IS CONCLUDED THAT: (a) both A(2)- and B-cell responsiveness is modulated by a previous exposure to glucose which produces opposite effects in the two cell types, (b) this action of glucose does not depend on its insulin-releasing capacity, and (c) instead, a "memory" of glucose is induced as a consequence of the metabolism of the sugar in the A(2) and B cells.

Animals↗
PubMed1978

Immediate and time-dependent effects of glucose on insulin release from rat pancreatic tissue. Evidence for different mechanisms of action.

Glucose-induced insulin secretion is enhanced by a preceeding glucose stimulus. The characteristics of this action of glucose were investigated in perfused pancreas and collagenase-isolated islets of Langerhans. A 20- to 30-min pulse of 27.7 mM glucose enhanced both the first and second phase of insulin release in response to a second glucose stimulus by 76-201%. This enhancement was apparent as an augmented maximal insulin release response to glucose. The effect of priming with glucose was seen irrespective of whether the pancreatic tissue was obtained from fed or fasted rats. Separating the two pulses of hexose by a 60-min time interval of exposure to 3.3 mM glucose did not abolish the potentiation of the second pulse. Omission of Ca(++) as well as the inclusion of somatostatin or mannoheptulose during the first pulse abolished insulin secretion during this time period; however, only the inclusion of mannoheptulose deleted the potentiation of the second pulse. d-Glyceraldehyde, but not pyruvate, d-galactose, or 3-isobutyl-1-methylxanthine, could substitute for glucose in inducing potentiation. In islets labeled with [2-(3)H]adenine, the [(3)H]cyclic AMP response to glucose was increased by 35% when measured after 1 min, but was increased only marginally after 2-10 min of stimulation with a second pulse of glucose. The production of (3)H(2)O from glucose was not affected by glucose priming. It is concluded that (a) the induction of the glucose-induced, time-dependent potentiation described here is dependent on glucose metabolism but not on stimulation of cyclic AMP, calcium fluxes, or insulin release per se; (b) the mechanisms that mediate the pancreatic "memory" for glucose are unknown but do not seem to involve to a major extent an increased activity of the adenylate cyclase-cyclic AMP system of the beta-cell; (c) the evidence presented supports the hypothesis of a dual role of glucose for insulin release.

Animals↗
PubMed1978

Interacting effects of sulfonylureas and glucose on cyclic AMP metabolism and insulin release in pancreatic islets of the rat.

The effects of tolbutamide and glibenclamide on the metabolism of cyclic AMP were investigated in pancreatic islets of the rat. Changes in cyclic AMP were assessed by measuring [(3)H]cyclic AMP after labeling of the islets with [2-(3)H]adenine. In the presence of a nonstimulatory concentration of glucose (3.3 mM), both sulfonylureas caused a rapid increase in islet [(3)H]cyclic AMP, which declined within 5 (tolbutamide) or 10 min (glibenclamide). In the absence of glucose, the glibenclamide effect was shortened, but the initial (1 min) response of [(3)H]-cyclic AMP was unaffected. Glucose could be substituted with d-glyceraldehyde but not pyruvate for prolongation of the glibenclamide response. The effect of glucose withdrawal on the glibenclamide response was reproduced by the addition of d-mannoheptulose to glucose containing media. The [(3)H]cyclic AMP response to glibenclamide was influenced by prior exposure of the islets to glucose, a 30-min preincubation with 27.7 mM glucose, enhancing the response to the sulfonylurea over a subsequent 5-min stimulation period. Sulfonylureas exerted their effects at low but not at high glucose concentrations, i.e., shifted the glucose dose-response curve to the left both for [(3)H]cyclic AMP accumulation and insulin release. On the other hand, increasing concentrations of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, progressively augmented the effects of the drugs. Omission of Ca(++) from the incubation media inhibited both the glucose and the sulfonylurea [(3)H]-cyclic AMP and insulin responses. Epinephrine (1 muM) partially inhibited the [(3)H]cyclic AMP response to both glucose and sulfonylurea, whereas insulin release was completely abolished. It is concluded that the sulfonylurea effects on islet cyclic AMP are intimately related to those of glucose. It is suggested that sulfonylureas exert a major part of their action by facilitating the effect of glucose on the beta-cell adenylate cyclase; the increased cyclic AMP level, in its turn, enhances the secretion rate of insulin.

Adenylyl Cyclases↗