Dynamics Of Insulin Secretion Research Articles

Effect of 2-bromostearate on glucose-phosphorylating activities and the dynamics of insulin secretion in islets of Langerhans during fasting.

Glucose-phosphorylating activity and insulin secretion were measured in homogenates of isolated rat islets and of perfused rat pancreas, respectively. Fasting for 96 h produced a significant decrease of both low-and high-Km glucose-phosphorylating activities and blocked the insulin secretory response to glucose. In the presence of glucose, 0.25 mM 2-bromostearate, a known inhibitor of fatty acid oxidation, partially restored the insulin response to glucose that was lost during fasting. This effect paralleled the restoration of glucose-phosphorylation activities (primarily the high-Km component) seen when islets isolated from 96-h-fasted rats were preincubated with 0.25 mM 2-bromostearate. It is concluded that fasting-induced adaptations of glucose-phosphorylating enzymes could account, at least in part, for the reduced insulin secretory response to glucose. 2-Bromostearate, an inhibitor of fatty acid oxidation, is able to restore both insulin secretory response and glucose-phosphorylating activities, suggesting possible interrelations among the correlated impairment in insulin secretion, islet glucose-phosphorylating activity, islet glucose metabolism, and the oxidation of fatty acids in the B-cell during fasting.

A theoretical model for insulin secretory dynamics in a hybrid artificial pancreas.

A theoretical model for insulin secretory dynamics in a hybrid artificial pancreas.

Mathematical modelling of stimulus-secretion coupling in the pancreatic B-cell. I. Dynamics of insulin release.

A mathematical model for cyclic AMP-Ca2+ interactions in pancreatic islets, defined in a previous study, was modified to include two new features. First, the cytosol and vacuolar Ca2+ pools were stratified in a cortical layer (representing 1 to 20% of the total cellular pool) and central core. Second, the changes in Ca2+ inflow and Ca2+ fractional outflow rate evoked by a rise in glucose concentration were discontinued during the 3rd and 4th min of stimulation. In this onion leaf sheet model, the biphasic pattern of glucose-induced insulin release could be simulated. This new model emphasizes the significance of both cytosol heterogeneity and signal discontinuity in the dynamics of insulin secretion.

Stimulation of insulin and glucagon secretion in organ culture of chick endocrine pancreas during embryonic life and after hatching

The effect of glucose, theophylline, and somatostatin on the hormonal secretion of cultured chick pancreatic splenic lobes isolated during embryonic life (15 and 18 days) and of glucose after hatching (2 and 9 days) was investigated. Splenic lobes were cultured in a medium composed of 90% CMRL-1066 and 10% heat-inactivated fetal calf serum during 1 to 5 days. The secretory profiles of insulin and glucagon, investigated as a function of age, showed that there was an increase in the secretory capacities of the organs between 15 days of incubation and 9 days after hatching. The study of the dynamics of insulin secretion as a function of glucose concentration showed that 30 m M was the most effective, and that after hatching the responsiveness of the tissue was lower than during embryonic life. At this glucose concentration an unexpected stimulation of glucagon secretion was observed at 15 days of incubation, and at 9 days after hatching. The effect of theophylline and somatostatin was studied in embryonic 18-day-old splenic lobes. Theophylline (10 m M) stimulated both insulin and glucagon secretion at low and high glucose concentrations, the effect on glucagon secretion being the most pronounced. Somatostatin (1 μg/ml) partially inhibited the 30 m M glucose-induced insulin output but had no effect either on the theophylline-induced insulin secretion or on the secretion of glucagon.

Dynamics of insulin and glucagon secretion by the isolated perfused cat pancreas

1. 1. The dynamics of insulin and glucagon secretion by the isolated perfused cat pancreas was studied in response to glucose and amino acid stimuli. 2. 2. Insulin secretion is biphasic in response to either glucose or amino acid stimuli. 3. 3. Glucose caused a much more pronounced first phase release than did a complete amino acid mixture; whereas glucose and the amino acid mixture stimulated late second phase insulin secretion equipotently. 4. 4. The same amino acid mixture produced a biphasic secretion of glucagon characterized by a rapid and transient spike-release which was followed by a substantial, relatively steady-state, second secretory phase. 5. 5. Various combinations of glucose and amino acids resulted in insulin secretion which suggests a simple additive stimuli phenomenon; whereas no such additive effect was observed with respect to amino acid stimulation of glucagon secretion. 6. 6. Instead, various of the amino acids appear to stimulate maximal glucagon secretion independently. 7. 7. Glucose failed to cause a suppression of amino acid induced glucagon release. 8. 8. The quantitative aspects of this study suggest that the cat pancreas is very responsive to amino acid modulation of hormone release, a fact which may well reflect the high amino acid content of the cat's diet.

Impaired insulin secretion in the spontaneous diabetes rats.

Dynamics of insulin and glucagon secretion were investigated by using a new model of spontaneous diabetes rats produced by the repetition of selective breeding in our laboratories. The perfusion experiments of the pancreas showed that the early phase of insulin secretion to continuous stimulation with glucose was specifically impaired, although the response of the early phase to arginine was preserved. The glucose-induced insulin secretion in the nineth generation (F8) which had a more remarkably impaired glucose tolerance was more reduced than in the sixth generation (F5). No significant difference of glucagon secretion in response to arginine or norepinephrine was noted between the diabetes rats and control ones. The present data indicate that the defective insulin secretion is a primary derangement in a diabetic state of the spontaneous diabetes rat. This defect in the early phase of glucose-induced insulin secretion suggests the specific impairment of the recognition of glucose by the pancreatic beta-cells. The spontaneous diabetes rats are very useful as a model of disease for investigating pathophysiology of non-insulin dependent diabetes mellitus.

Preservation of glucose tolerance and insulin secretory response to repeated glucose loads by the feeding of minimal glucose during prolonged fasting

The facilitation of glucose disposal (Staub-Traugott effect) and potentiation of serum insulin (IRI) concentration normally occurring after closely spaced intravenous glucose loads, are known to disappear after prolonged starvation. To study the effects of minimal amounts of glucose during fasting upon the insulin response and disposal of repeated intravenous glucose tolerance tests, obese volunteers were fasted for a mean of 25 ± 2 days, while receiving either 8 or 16 gm of oral glucose every 6 hr, and compared to totally fasted subjects without glucose supplementation. Weight loss rate and the fall in basal IRI and glucose levels were similar to those of totally fasted subjects. However, the Staub-Traugott effect and insulin secretory dynamics after stimulation by repetitive intravenous glucose loading were preserved by this glucose modified fast, while baseline serum glucagon levels (IRG) were significantly lower, and the basal IRI/IRG ratios were thus unchanged from the fed state. IRG and free fatty acid suppression were similar in the fed and glucose modified fasted states. Lactic acid levels increased as expected after the repeated glucose injections in the fed state, but failed to do so after the prolonged modified fast until the second and third repetitive glucose loads, in which a significant rise coincided with accelerated glucose disposal. It is suggested that minimal amounts of carbohydrate during fasting preserve the insulin potentiating action of glucose, preferentially sparing a delayed releasable pool of insulin, while protecting the glucose utilization mechanisms, including increased glycolysis, responsible for the Staub-Traugott effect.

Growth hormone secretory dynamics in streptozotocin diabetes: evidence of a role for endogenous circulating somatostatin.

The present studies examined the effects of streptozotocin-induced diabetes on the dynamics of GH, insulin (IRI), and glucose secretion in 68 chronically cannulated male rats. Animals were rendered diabetic by a single iv injection of streptozotocin (65 mg/kg) and sampled every 15 min for periods of 6h both before and at various times after treatment. The typical ultradian rhythm of GH secretion was evident in normal rats, with most peak GH values greater than 500 ng/ml (mean 6-h GH level, 125.3 ± 17.2 ng/ml). After streptozotocin administration, a significant depression in the amplitude of GH pulses was observed as early as 18 h post treatment (mean 6-h GH level, 54.4 ± 9.4 ng/ml; P < 0.01) concomitant with a marked elevation in plasma glucose levels and severe depression of plasma IRI levels. The amplitude and duration of the GH secretory episodes continued to decline over a 4-week period in the presence of persisting hyperglycemia and mostly undetectable plasma IRI levels. The pituitary GH concentratio...

Insulin secretory dynamics during development of rat pancreas.

The dynamics of insulin secretion during development of the fetal rat pancreas were investigated. The time of onset of glucose-induced insulin secretion was of special interest. Pancreases from 15- to 22-day-old fetal rats were perifused in vitro with low (0.5 or 0.9 mg/ml) or high (5 mg/ml) concentrations of glucose in the presence or absence of arginine and leucine. Levels of insulin in the perifusate were determined by radioimmunoassay. At day 17, a significant increase in perfusate insulin level was observed in response to arginine and leucine (each at 5 mM), This response was independent of a high concentration of glucose. In addition, perifusate insulin levels were augmented when the concentration of amino acids were kept constant and the glucose concentration was changed from a high level to a low level. On day 20, a monophasic, rapid-onset short-duration rise in insulin release with a high glucose concentration was observed. This response was enhanced by acetylcholine (2.7 x 10(-9) M). At days 21 and 22, insulin levels rose rapidly in the presence of high glucose and remained elevated. The results show that there is considerable precision in the timing of the onset and maturation of the glucose-induced insulin secretory response prenatally and reaffirm that insulin secretion by the fetal beta-cell varies with the stimulus applied.

Different dynamics of insulin secretion in the perfused pancreas of mouse and rat

The dynamics of insulin release were studied in the perfused pancreas of rats and mice. Perfusion of the rat pancreas with 20 mM D-glucose resulted in the classical biphasic release of insulin with a rising second phase. However, in normal C57BL/KsJ-mice and non-inbred mice, whether fed or starved, the second phase was nearly constant. The secretory dynamics of KsJ-mice were essentially the same, whether the glucose concentration was 30 or 20 mM, whether the medium contained 2.56 or mM Ca2+, and whether or not the medium was supplemented with 5 mM pyruvate, 5 mM glutamate, and 5 mM fumarate. Insulin secretion in these mice was almost totally inhibited by omission of Ca2+, and was markedly enhanced by 3-isobutyl-1-methylxanthine. Insulin release during the constant phase was reversed by lowering the glucose concentration. A second rise of glucose from 3 to 20 mM produced a secretory pattern very similar to the first response. These studies indicate that the dynamics of insulin secretion are somewhat different in rats and mice. Since similar results were obtained with C57BL/KsJ-mice and non-inbred mice, the liability of KsJ-mice to develop beta-cell failure when stressed by the mutated db gene is not related to the constancy of the second insulin secretory phase.

Insulin secretory dynamics after two consecutive intravenous stimulations with glucose and/or tolbutamide

Intravenous glucose and/or tolbutamide administered in two consecutive pulses 30 and 60 min apart to the same subjects using identical doses showed that insulin secretory response was altered during a subsequent stimulation and that this was modulated by the time factor. Insulin response was more sustained after the second glucose pulses and the insulin peak response was delayed and diminished if the second glucose dose was given 30 min after the first, but not if given 60 min later. It is suggested that the beta-cell membrane might remain partially depolarized above a certain glucose level or that a postulated signal relay mechanism might become saturated. Response to two tolbutamide pulses did not show these characteristics; however, the second insulin response was smaller than the first. When the first pulse was glucose and the second tolbutamide, or vice versa, the second responses were altogether different from those elicited by the double doses of either tolbutamide or glucose. To explain these characteristic patterns of insulin secretory dynamics, the existence of occult glucose receptors on the beta-cell that are opened up by tolbutamide was postulated. These studies do not support the two-pool theory, or at least restrict it to glucose-stimulated insulin response. The positive correlations between the first and the second insulin responses in all tests argue strongly against the existence of an insulin feedback mechanism in man.

184 INSULIN DEGRADATION WITHIN THE FETO-PLACENTAL UNIT

The concentration of insulin in fetal plasma is a resultant of factors stimulating insulin secretion and/or metabolic disposition. As part of investigations of the dynamics of fetal insulin secretion, aspects of insulin disposition in placenta and fetus were studied. Inactivation of insulin could occur by cleavage of disulfide bonds with glutathione-insulin trans-hydrogenase (GIT), and/or by proteolysis with specific or non-specific peptidases. Activity of GIT is negligible in fetal liver until day 18 of gestation, when the specific activity is 21 units/mg. protein, as compared to 127 units/mg. protein at term. Activity of GIT in fetal kidney and lung, during late gestation, is comparable to adult values. Non-GIT activity was excluded by incubation with N-ethyl maleimide. Placental GIT activity was constant throughout gestation. Identification of GIT as initial step in degradation of insulin by placental homogenates, microsomes and membrane preparations was established by Sephadex chromatography following sequential incubations with 125I-insulin. Intracellular distribution of GIT differs between placenta and liver, with much less activity in placental microsomes. These studies indicate that fetal liver cannot degrade insulin until late in pregnancy. It is probable that the placenta plays a significant role in disposition of insulin and, thus, in regulation of the plasma concentration of insulin in the rat fetus.

Dynamics of insulin secretion in dogs with alloxan diabetes

It was shown that hypoinsulinemia in the superior pancratico-duodenal vein and inhibition of the first phase of insulin secretion by the pancreas characteristic of alloxan diabetes of different severity was absent in the femoral vein. The data obtained in the insulin and glucose concentration study in the superior pancreatico-duodenal vein stressed the leading role of the pancreatic factor in the pathogenesis of alloxan diabetes in dogs. Analysis of these parameters in the peripheral femoral vein failed to reflect this statement adequately.

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose.

Nine offspring of two diabetic parents and 18 normals were studied with two intravenous glucose loads (o.5 gm./kg. body weight), 60 minutes apart. By thus stressing the beta cell, subtle defects could be identified in the prediabetics: (1) An inverse relationship between insulin peak response and insulin concentration 60 minutes postglucose was seen, a phenomenon exactly the opposite to that seen in normals. (2) Insulin peak response was delayed slightly after the first pulse and significantly after the second. (3) A less effective handling of the glucose load when compared with normals was brought out by the second stimulation. (4) There was a significant reduction in the insulin response per unit change in glucose after the first glucose pulse that was accentuated after the second pulse. This double-stimulation technique amplifies previously detected slight but significant defects in insulin secretion that might help to identify a diabetes-prone population.

The Effects of Long-term Therapy with Oral Hypoglycemic Agents on the Oral Glucose Tolerance Test Dynamics in Male Chemical Diabetics

The effect of fixed doses of oral hypoglycemic agents and placebo (diet alone) on the blood glucose, serum insulin, triglyceride, and cholesterol responses during oral glucose tolerance tests done annually for up to four years' follow-up was studied, in a double-blind manner, in five groups of mild male chemical diabetics. The drugs used were chlorpropamide (100 mg. O.D.), tolbutamide (500 mg. b.i.d.), phenformin (50 mg. O.D.), acetohexamide (250 mg. O.D.), and placebo. Each subject was given an individualized diet aimed at attaining and maintaining ideal weight. Comparison by chi-square analysis between the placebo group and each of the drug groups showed (a) no significant differences with regard to the number of subjects with normal glucose tolerance in each of the tests and (b) no change in the insulin secretion dynamics. Comparison between the initial test and each of the subsequent tests within each group showed (a) a greater number of subjects with normal glucose tolerance in the first follow-up test in the chlorpropamide group only, (b) no change in the insulin secretion dynamics except in the chlorpropamide group, where there was an increased insulin/glucose ratio in the first follow-up test, and (c) no change in the fasting serum triglyceride and cholesterol levels.

Serum insulin response to slow-rise glucose infusion in "genetic prediabetics" (offspring of two diabetic parents).

The insulin response to a programed slow-rise glucose infusion designed to mimic the postprandial rise in glucose was studied in five offspring of two diabetic parents (ODP) and seven normal subjects. The ODP had higher mean blood glucose levels towards the end of the infusion and during the postinfusion period. The rates of glucose disappearance calculate during the postinfusion period were comparable in the two groups. Despite the apparent similarity of serum insulin levels of ODP and normal subjects, the amount of insulin secreted per unit of glycemic stimulus was lower in the ODP group. When the glucose infusion test was preceded by an acute load of glucose, similar findings in the insulin secretory dynamics were found in the ODP group. These data suggest that an impairment in insulin secretion exists in ODP when they are challenged by the slow rise of blood glucose achieved by this type of an intravenous glucose infusion.

Studies on the dynamics and mechanism of glibenclamide-induced insulin secretion.

Sustained, 60-minute perfusion of glibenclamide (0.5, 1.5 and 10 mug/ml) elicits a one-phase insulin release profile, formed by a rapid secretion peak followed by a second peak with lower insulin levels than the former. Basal insulin secretion values are observed during the period comprised between 13 and 60 minutes of perfusion. Concurrent stimulation with glucose (100, 150, 200 and 300 mg%) plus glibenclamide (1 mug/ml) causes a marked rise in both phases of insulin secretion. The addition of glibenclamide does not modify the biphasic secretion pattern caused by maximal glucose concentration (400 mg%). The maximal values of both phases of secretion in the dose-response curve elicited by different glucose concentrations shift to the left when glibenclamide is added to the perfusate. The increase in insulin secretion caused by glibenclamide is not inhibited by puromycin. Both theophylline and phentolamine modify and increase the glibenclamide-induced insulin release pattern. Propranolol and imidazole inhibit glibenclamide-induced insulin release. Our results suggest that: 1. Glibenclamide increases beta cell sensitivity to glucose stimulation. 2. Glibenclamide and glucose induce secretion of insulin originating in the same compartment. 3. Modification of alpha and beta adrenergic receptors may modify glibodulate the beta cell response to glibenclamide.

Dynamics of insulin release and microtubular-microfilamentous system. VII. Do microfilaments provide the motive force for the translocation and extrusion of beta granules?

The active role played by beta-cell microfilamentous structures in the dynamics of insulin secretion was investigated by examining the influence of cytochalasin B upon various parameters of hormonal release by the isolated perfused rat pancreas. The view that the cytochalasin-induced changes in insulin release are due to a primary biophysical effect on microfilaments, rather than to an unrelated biochemical alteration of the beta-cell glucose-sensor device, was strengthened by the following observations: (1) the onset and disappearance of the cytochalasin B-induced facilitating action upon insulin release followed a time-course parallel to that characterizing the ultrastructural changes provoked by the drug in the distribution of beta-cell microfilamentous material; and (2) cytochalasin B facilitated leucine-induced insulin release in the presence of a very low glucose concentration. The mold metabolite was also found to transform transient secretory responses into biphasic ones and to prevent the reduction that normally affects the early response to insulinotropic agents when the pancreas is stimulated a few minutes after a prior and short exposure to glucose. The release of insulin evoked by either glucose or gliclazide was abolished in the absence of extracellular calcium, whether in the presence or absence of cytochalasin B. Theophylline and cytochalasin B exerted a synergistic effect upon glucose-induced insulin release. These data support the concept that calcium-dependent contractile events involving cytochalasin B-sensitive microfilamentous structures provide the motive force for both the intracellular translocation and exocytotic release of beta granules.

Cationic Environment and Dynamics of Insulin Secretion

Cationic Environment and Dynamics of Insulin Secretion