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Biomedical subjects

E Cerasi

Publications and source records attributed to E Cerasi.

At least 109 records · Page 6Linked to original sources
PubMed1982

Binding, internalization, and degradation of insulin in vascular endothelial cells.

The interaction of insulin with the vascular endothelium was studied using bovine aortic endothelial cells in monolayer cultures. Confluent cell cultures exhibited specific binding of 125I-insulin to high- and low-affinity cell surface receptor sites. Binding was reversible, saturable, and accompanied by internalization and degradation of the bound hormone in a temperature- and time-dependent manner. Pre-exposure of the cultures to insulin resulted in a time-dependent reduction in the availability of cell surface receptors (downregulation). It is concluded that the occurrence of reversible insulin binding and of insulin degradation in endothelial cells supports the concept that the vascular endothelium compartment may regulate the level of insulin in the circulation.

Animals↗
PubMed1982

Granule fusion and fission (discharge) are biochemically dissociable events of exocytotic hormone release.

Granule fusion and the subsequent fission leading to hormone discharge are distinct and separable events in exocytosis. As an index of fusion, we followed the recruitment of granule-bound somatostatin receptors to the islet surface, an event which accompanies secretion vesicle migration and insulin secretion. Granule fission was monitored by measuring insulin release. Substitution of the impermeant salt sodium isethionate for NaCl led to a 90% decrease in glucose-stimulated insulin release with no inhibition of somatostatin receptor recruitment. The phenothiazine drugs, trifluoperazine and promethazine, believed to inhibit calcium-sensitive proteins involved with stimulus-secretion coupling blocked insulin release and somatostatin receptor recruitment in parallel. This suggests that these agents suppress intracellular events promoting fusion of the secretion granule with the plasma membrane. IBMX appears to stimulate specifically granule fission since IBMX-induced insulin release occurs acutely without an increase in somatostatin receptor recruitment. Sodium isethionate, which inhibits granule lysis, blocked IBMX-stimulated insulin release.

1-Methyl-3-isobutylxanthine↗
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↗
PubMed1980

Insulin release, insulin sensitivity, and glucose intolerance.

Groups of subjects with different degrees of glucose intolerance were examined in order to determine, first, the capacity of the beta cells to release insulin upon glucose stimulation and, second, sensitivity to insulin. The groups were selected on the basis of fasting blood glucose value and tolerances to oral and intravenous glucose administration. The body weights, ages, and sexes of the subjects were well matched with those of control subjects with normal tolerances to oral and intravenous glucose administration. Computer analysis of the glucose and insulin curves during a standardized glucose infusion test made possible the measurement of the initiatory (parameters KI and IP) and potentiatory (parameter KP) effects of glucose on insulin release and of the sensitivity to endogenous insulin (parameter KG). In subjects with impaired oral but normal intravenous glucose tolerance tests, KG was decreased, KP was increased, and KI and IP were normal. However, in these subjects, KI and IP were considerably lower than in a matched group of control subjects with the same decrease in KG but with normal oral and intravenous glucose tolerance tets. In subjects in which both oral and intravenous glucose tolerance tests were impaired and in subjects with mild manifest diabetes, KI, IP, and KG were decreased whereas KP was normal. These data suggest that all stages of glucose intolerance are accompanied by a decreased ability of glucose to initiate insulin release and by decreased sensitivity to insulin. These derangements seem to be partially compensated for by enhancement of the capacity of glucose to potentiate insulin release in subjects with decreased oral but normal intravenous glucose tolerance tests.

Administration, Oral↗
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↗
PubMed1979

Effect of two sulphonylureas on the dose kinetics of glucose-induced insulin release in normal and diabetic subjects.

The effect of two second generation sulphonylureas, gliquidone and glibenclamide, on insulin secretion has been studied in the basal state and in combination with glucose infusions in normal controls, patients with mild maturity-onset diabetes, and subjects with normal glucose tolerance but low insulin response. When injected intravenously, gliquidone caused rapid elevation of plasma insulin, peaking at 5 min in all groups, while glibenclamide induced a slow rise in insulin. Insulin response was somewhat smaller than normal in diabetics and low insulin responders. In all groups, 25 micrograms/kg glibenclamide and 200 micrograms/kg gliquidone were equipotent in generating an insulin response at the basal state. Equipotent amounts of sulphonylureas were combined with glucose in fusions at three different dose levels. The glucose-insulin dose relationships, established by giving glucose alone, demonstrated curves that were flatter, and shifted to the right of the control in diabetics and low insulin responders, the changes being more marked in the former group. Addition of sulphonylurea induced a left shift in the dose-response relationships in controls and low insulin responders; under these conditions the effect of glibenclamide was more pronounced than that of gliquidone. The dose-response relation for glucose-induced insulin release was completely normalized in low responders when sulphonylureas were added. In the group of mild diabetics, insulin response to glucose was enhanced by sulphonylureas only to a modest extent, the dose-response curves remaining grossly abnormal.

Adult↗
PubMed1979

Glucose production by the perfused liver of the spiny mouse (Acomys cahirinus): sensitivity to glucagon and insulin.

Hepatic glucose production and its responses to glucagon and insulin were studied in perfused livers obtained from spiny mice (Acomys cahirinus)--rodents characterized by normoglycemia, decreased glucose tolerance and decreased insulin secretion--and from Swiss albino mice. The dose-response characteristics of glucagon-induced hepatic glucose output were similar in spiny and albino mice. However, maximally stimulated glucose production were significantly lower in the spiny mouse. Furthermore, the liver of the spiny mouse was more sensitive to the action of insulin: 0.5 X 10(-6) M insulin significantly inhibited the action of glucagon in spiny mice but not in albino mice. It is proposed that the increased sensitivity of the hepatic glucose output to insulin and the decreased maximal stimulation by glucagon may be factors that limit the negative effects of the impaired insulin secretion in spiny mice, thereby reducing the severity of the glucose intolerance. Analogous mechanisms may be present in the early stages of the diabetic syndrome in man.

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↗