Immunoreactive Insulin Secretion Research Articles

Metabolic effects of glucose, mannose, galactose, and fructose in man.

The effects of various hexoses upon immunoreactive insulin (IRI) secretion, glucose disposal, and gastric inhibitory polypeptide (GIP) release have been compared in 10 normal nonobese men. Rapid iv infusion (0.5 g/kg in 3 min) of D-mannose resulted in significant ITI release, the peak levels approaching those after D-glucose infusion. D-Galactose, however, was ineffective. The 60-min urine excretions of mannose, galactose, and glucose were 35 +/- 7%, 16 +/- 4%, and 5.5 +/- 0.7% (mean +/- SEM) of the administered dose, respectively. All subjects also received 50 g oral glucose, mannose, galactose, and fructose on different days, each followed by an iv glucose infusion 30 min later. The ingestion of glucose or galactose resulted in a similar increment of GIP (P less than 0.01), followed by a similar increment in the IRI response to iv glucose. Furthermore, the glucose disposal rate increased 2.5-fold compared to that after iv glucose alone (P less than 0.001). However, oral msnnose or oral fructose caused no significant GIP release, yet the IRI response to a subsequent iv glucose load was moderately augmented after oral mannose or oral fructose when compared to iv glucose alone. In addition, there was a similar enhancement of glucose disposal of the iv glucose load after both oral mannose and oral fructose (P less than 0.01). From these studies we conclude that 1) galactose does not elicit IRI secretion per se, yet, like glucose, potentiates GIP and IRI secretion; 2) mannose, despite weak transport across gut or kidney, evokes significant betacytotropic effects; and 3) mannose- and fructose-induced enhancement of glucose disposal might be mediated by a factor(s) other than GIP.

Altered regulation of insulin secretion in isolated islets of different sizes in aging rats

Glucose-stimulated secretion of immunoreactive insulin (IRI) was examined in perifused pancreatic islets of Langerhans of different sizes isolated from fed and fasted, Sprague-Dawley rats aged 2- to 24-months. Small and large islets show distinctly different biphasic secretory responses which are modified during starvation or aging. The rate of IRI secretion is several fold greater in large than in small islets, irrespective of donor age or nutritional status. Starvation severely reduces the rate of IRI secretion, essentially abolishing the stimulatory effect of glucose in small islets from fasted, old rats. Aging inhibits IRI secretion, but to a far greater degree in small than in large islets. The increased number of large islets in the pancreas of aging rats may represent a physiological compensatory response to the diminished functional capability of small islets with respect to glucose-stimulated secretion of IRI.

Carbohydrate Metabolism in Women Receiving d-Norgestrel for Postcoital Contraception(+)

39 women (19-40 years old) were studied to assess any influence of d-norgestrel on blood glucose metabolism (BG) immunoreactive insulin (IRI) and nonesterfied fatty acids (NEFA) when administered postcoitally for contraception. 11 with IUDs inserted were controls; and 28 received d-norgestrel (400 mcg) after each sexual intercourse. These were further divided into duration-of-treatment groups. Responses to the parameters were subtle. An increase in fasting IRI and IRI response to glucose load a decrease in fasting BG and no changes in NEFA or K-glucose values were observed. Positive correlations between IRI peaks and the number of pills ingested during the last menstrual cycle suggested a dose-related effect. 400 mcg of d-norgestrel given postcoitally slightly influenced carbohydrate metabolism. Decreased insulin sensitivity by peripheral tissues probably led to augmented IRI secretion to maintain glucose utilization at a normal rate.

Impairment of glucose-induced insulin secretion and glucose tolerance during colchicine treatment.

The effect of acute and chronic colchicine treatment on glucose-induced immunoreactive insulin secretion and glucose tolerance was examined in fasting, unanesthetized, and unrestrained rats with indwelling jugular vein and aortic catheters. In the first study, intravenous glucose tolerance tests were performed by rapidly administering a glucose pulse (150 mg. intravenously) one hour after acute treatment with colchicine (0.5 mg. per kilogram of body weight, intravenously) or vehicle (control). Acute colchicine treatment caused significant suppression of glucose-induced insulin secretion and also markedly impaired glucose disappearance rates. In the second study, chronic colchicine treatment (in the lower dose of 0.2 mg. per kilogram of body weight, intraperitoneally, daily for 10 days) caused significant suppression of biphasic insulin secretion in response to a primed-constant glucose infusion (150 mg. of glucose pulse followed by 6 mg. per minute constant glucose infusion for 60 minutes) as compared with control rats (vehicle injection, intraperitoneally, daily for 10 days). Due to this marked decrease in biphasic insulin secretion, serum glucose concentrations were significantly higher between 10 and 45 minutes in the colchicine-treated rats than in the control rats. Therefore, acute and chronic colchicine treatment causes marked inhibition of glucose-induced insulin secretion and impairment of glucose tolerance in the intact rat. These observations suggest there is a need to evaluate carbohydrate metabolism in patients receiving colchicine treatment.

Epinephrine enhancement of potassium-stimulated immunoreactive insulin secretion. Role of beta-adrenergic receptors

Epinephrine enhancement of potassium-stimulated immunoreactive insulin secretion. Role of beta-adrenergic receptors

Epinephrine Enhancement of Potassium-stimulated Immunoreactive Insulin Secretion Role of Beta-adrenergic Receptors

Although epinephrine stimulates insulin release by activation of beta-adrenergic receptors, its dominant effect (mediated by stimulation of alpha-adrenergic receptors) is an inhibition of insulin secretion that is powerful enough to suppress the secretory activity of insulin's most potent stimulants. The insulin-secretory response to potassium chloride (KCl) infusion, however, is not suppressed; in fact, in ureter-ligated dogs simultaneously infused with 360 microgram. epinephrine per hour and 2 mEq. KCl per kilogram per hour, insulin release is actually increased about threefold (over controls). Propranolol blockade of beta-adrenergic receptors essentially abolishes the insulin response to KCl infusion, with and without epinephrine. It is unlikely that KCl, like epinephrine, provokes insulin release by direct stimulation of the beta-adrenergic receptors of the beta cells of the pancreatic islets. However, potassium in some way enhances the beta adrenergic (secretory) activity of epinephrine and blunts its usually dominant alpha-adrenergic (inhibitory) effect.

Direct neural inhibition of insulin secretion in response to systemic hypoglycemia.

The innervated pancreas of an anesthetized small "pancreas" dog was cross-perfused with blood from a large "support" dog in order to separate neural from blood-borne influences on the immunoreactive insulin secretion rate (ISR). The arterial plasma reducing sugar (sugar) concentration could be varied independently in the pancreas dog systemic circulation and in its pancreas. After tying of the hepatic arteries and portal vein in the pancreas dog, its systemic arterial plasma sugar concentration was allowed to fall in 10 experiments. This was prevented in five control experiments by intravenous glucose infusion (7 mg/kg-min). In all experiments, pancreatic arterial plasma sugar concentration was sustained, and at 40 min it was elevated 50 mg/100 ml by glucose infusion into the pancreatic blood supply. Bilateral splanchnic nerve section at 120 min caused an increase of the ISR in all experiments, but a greater rise occurred from the pancreases of the 10 dogs allowed to become hypoglycemic (P less than .02). In two further experiments, the splanchnic nerves were not cut, and no rise in ISR occurred. In conclusion, systemic hypoglycemia can inhibit insulin secretion by means of the splanchnic nerves.

Plasma immunoreactive insulin and somatotropin in delirium tremens and alcoholic hallucinosis.

The glucose tolerance curve in alcoholics in delirium tremens was similar to that seen in hepatogenic diabetes. The secretion of immunoreactive insulin and somatotropin after glucose was similar in patients with delirium tremens and alcoholic hallucinosis.

Dose-response study of the inhibiting effect of somatostatin on growth hormone and insulin secretion in normal subjects and acromegalic patients

A dose-response study of the effect of somatostatin on plasma growth hormone (GH) and immunoreactive insulin (IRI) levels was performed in normal subjects and acromegalic patients. In normal subjects 150 μg of somatostatin completely suppressed GH and IRI responses to arginine, while with 75 and 37.5 μg only a partial suppression was usually observed. Basal levels of plasma IRI were significantly lowered within 15 min from the start of somatostatin injection at each of the three dose levels. In three acromegalics the doses of 150 and 75 μg of somatostatin were effective in lowering both GH and IRI levels; the dose of 37.5 μg was still effective in lowering plasma IRI levels, while GH levels were not significantly modified. A dose of somatostatin inhibiting GH secretion without affecting insulin secretion has not been found either in acromegalics and in normals. It was concluded that the effects of somatostatin on GH and IRI secretion cannot be easily dissociated.

Neural inhibition of insulin secretion from the isolated canine pancreas.

By using an isolated in situ, cross-perfused pancreas preparation, direct neural effects on the immunoreactive insulin secretion rate (ISR) were separated from blood-borne influences. Blood from a large, anesthetized "support" dog was perfused through the pancreas of a small, anesthetized "pancreas" dog. Both splanchnic nerves of the pancreas dog were cut above the diaphragm and stimulated simultaneously (10 Hz, 0.1-ms pulses, 5-15 mA) for three 10-min periods, twice before and once during a pancreatic arterial phentolamine infusion (10 or 20 mug/min). Splanchnic nerve section caused a transient increase whereas stimulation caused a decrease in ISR. Phentolamine infusion blocked this decrease. In control experiments, an epinephrine infusion (25 or 50 mug/kg per min) was made into the systemic circulation of the pancreas dog instead of the first and second neural stimulations. No decrease in ISR occurred. Later neural stimulation (in the absence of phentolamine) was accompanied by a decrease in the ISR in three of four dogs. the ISR can be inhibited by direct neural imput to the pancreas, and this inhibition is mediated by alpha-adrenergic receptors.

Dynamics of tolbutamide, glucose, and insulin interrelationships following varying doses of intravenous tolbutamide in normal subjects.

Four healthy adult subjects received intravenous tolbutamide (TOL) at six different doses (twenty-four tests): 0.0625 gm., 0.125 gm., 0.25 gm., 0.5 gm., 1.0 gm. and 1.5 gm. Blood glucose (BG), serum immunoreacctive insulin (IRI) and serum TOL levels were determined before and for 180 minutes after TOL. There was a highly significant correlation of the dose of TOL with the peak IRI (p less than .01), zero to ten minute IRI area (p less than .001), and zero to sixty minute IRI area (p less than .001) and with the decline in BG expressed as zero to sixty minute BG area (p less than .001). Similar significant correlations were observed between levels of TOL and both IRI and BG. At each dose level the IRI response correlated significantly with the BG fall. An additional eighteen subjects received the 1.0 gm. dose. In these, serum TOL levels did not correlate with either BG or IRI. These subjects also received intravenous glucose (0.5 gm. per kilogram body weight). BG levels did not correlate with IRI. However, there were striking correlations between TOL and glucose-stimulated peak IRI (p less than .001), zero to ten minute IRI area (p less than .05). The mean (plus or minus SEM) space of distribution for glucose (G.S.) and tolbutamide (TLS.) was found to be 13.45 plus or minus 0.71 and 6.34 plus or minus 0.31 L., respectively. There was a significant dose-response relationship exists between TOL and IRI. TOL- and glucose-induced IRI secretion dynamics suggest strong similarities between mechanisms of rapid IRI release and/or size of available IRI storage pools.

Enzyme‐Induced Modifications of Beta Cell Function

Abstract. The effects upon immunoreactive insulin (IRI) release of beta cell membrane modifications induced by pronase, a mixture of proteolytic enzymes extracted from Streptomyces griseus, have been studied in isolated islets of Langerhans. Pretreatment of the islets for 90 min with 4 μg/ml pronase did not modify their IRI content; it slightly increased the basal rate of IRI release and potentiated the secretory response to glucose, leucine and tolbutamide during incubation. In perifused islets, the rapid phase of IRI secretion in response to glucose was more markedly enhanced than the late phase. After preincubation with 4 μg/ml pronase, glucose‐induced IRI release was reversible and abolished in the absence of calcium. Pretreatment for 90 min with 500 μg/ml pronase decreased IRI content of the islets by approximately 25% and provoked a pronounced but transient rise of basal IRI release. This was considered to be a leakage of IRI from damaged beta cells since it persisted in a medium deprived of calcium. The rapid secretory phase in response to glucose was preserved in perifused islets whereas the late phase was markedly reduced. The secretory responses to leucine and tolbutamide were almost completely obliterated. When pretreatment with pronase was carried out in a calcium‐depleted medium, basal IRI release from islets preincubated with 500 μg/ml pronase was only slightly increased whereas IRI secretion induced by glucose was inhibited by 40 and 65%, respectively in islets pretreated with 4 and 500 μg/ml pronase. These results indicate that pronase‐induced modifications of the beta cell membrane influence IRI secretion in a way which depends on the concentration of the enzyme and the presence of extracellular calcium. They are considered to support the hypothesis that membrane systems are involved in IRI releasing mechanisms.

Cationic environment and dynamics of insulin secretion. II. Effect of a high concentration of potassium.

The effects of 24 mM K+ upon the dynamics of immunoreactive insulin (IRI) release were studied in perifused rat islets in the absence of glucose and in its presence at concentrations of 50 and 300 mg. per 100 ml. Raising external K+ to 24 mM in the absence or in the presence of glucose (50 mg. per 100 ml.) was rapidly followed by a transient discharge of IRI. This rapid secretory phase was markedly inhibited in a medium containing 1 mM Na+ and was totally obliterated in a Ca2+-free medium. The early IRI response to a simultaneous increase of glucose to 300 mg. per 100 ml. and of K+ to 24 mM was enhanced while the late response was not significantly modified. In contrast, the same rise in glucose concentration after a twenty-five minute perifusion in a medium containing 24 mM K+ provoked markedly diminished early and late phases of IRI release. Under both experimental conditions, the effect of glucose was almost completely abolished in a medium containing 1 mM Na+. The stimulant action of glucose was not restored when K+ concentration was lowered from 24 to 6 mM at the time of glucose increase, but was normal if this diminution of K+ occurred ten minutes earlier. It is hypothesized that modifications in IRI secretion rate induced by 24 mM K+ result from changes in membrane permeability for Ca2+.

Effects of hypoglycemic sulfonamides on glucagon and insulin secretion in ducks and dogs.

Infusions of tolbutamide (1 mg./kg. min.), glibenclamide (2.5 μg./kg. min.), or glymidine Na (1 mg./kg. min.) in ducks produced a prompt fall in plasma immunoreactive glucagon (IRG), a prompt rise in plasma immunoreactive insulin (IRI) and a subsequent fall in plasma glucose. In dogs, the infusions of these three sulfonamide drugs also caused a rise in IRI and subsequent hypoglycemia, but no specific changes in IRG level in the pancreatic vein and the femoral artery. The infusion of glibenclamide (0.013 μg./kg. min.) into the pancreatic artery of a dog increased IRI secretion and produced a fall in plasma glucose but did not affect IRG level in the pancreatic vein. Carboxytolbutamide, which lacks hypoglycemic activity, failed to influence IRG and IRI in ducks. The results suggest that the hypoglycemic effect of sulfonamide drugs is mediated by insulin release and, in ducks but not in dogs, by suppression of glucagon secretion. The cause of this species difference is unknown, but the present results and additional data suggest that ducks may be much more dependent than dogs on glucagon for carbohydrate metabolism.

Impairment of growth hormone and insulin secretion in hyperthyroidism.

Abstract. The pattern of growth hormone (GH) and im‐munoreactive insulin (IRI) secretion in response to insulin hypoglycaemia, arginine infusion and oral glucose load has been investigated in a group of hyperthyroid subjects. In twenty patients, compared with twenty normal controls, GH secretion was significantly reduced in response to both insulin hypoglycaemia and arginine infusion. Arginine‐induced IRI secretion was also clearly decreased. In ten patients who had undergone a 100 g oral glucose load, hyperglycaemia failed to suppress GH levels, which increased paradoxically. Slightly impoverished IRI secretion and impaired glucose tolerance were observed in these subjects. In five patients, re‐examined soon after restoration of euthyroidiszn, no significant changes in glucose tolerance and IRI secretion were noted; instead, a slightly improved GH response to the provocative stimuli and the restoration of a normal GH suppression by glucose were observed. – The possibility is emphasized that in hyperthyroidism an enhancement of the catecholamine effect induced by thyroid hormones is involved in the diminished GH and IRI secretion.

Effect of intrapancreatic injection of potassium and calcium on insulin and glucagon secretion in dogs.

Acute changes in plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) levels in the pancreatic vein of dogs were studied following rapid pulse injections of CaCl2, KCl and glucose into the pancreatic artery. Blood from the pancreatic vein was taken continuously by changing the collection tubes every five seconds. IRI secretion was stimulated by all three agents within thirty seconds, while IRG secretion was stimulated by the injection of KCl but not by CaCl2 or glucose. Detailed comparisons of IRI responses revealed that IRI release occurred most rapidly after the injection of KCl and most slowly after the injection of glucose. Stimulation of IRI and IRG release occurred simultaneously after KCl injection. The data suggest that potassium stimulates α and β cells directly, without increasing calcium influx. The slower insulin-releasing effect of glucose, as compared with the cations, supports the theory that glucose acts by increasing calcium uptake.

Monolayer cultures derived from neonatal hamster pancreas: stimulation of immunoreactive insulin secretion and biosynthesis.

SummaryMonolayer cultures derived by enzymatic dispersion of neonatal hamster pancreas consist predominantly of AF+-granulated epithelioid cells, release newly synthesized immunoreactive insulin, and respond to the insulinotropic action of glucose and tolbutamide. These findings provide evidence that endocrinologically competent beta cells are present in these pancreatic monolayer cultures.

Defective immunoreative insulin secretion in the Acomys cahirinus.

In vivo studies of immunoreactive insulin (IRI) secretion and electron microscopic studies of pancreatic morphology have been performed in the spiny mouse, acomys cahirinus. A defective IRI release was demonstrated in response to glucose 1.0 gm./kg., arginine 200 mg./kg., glucagon 1 mg./kg., isoprenaline 20 μg./kg., aminophylline 240 mg./kg. and dibutyryl cyclic AMP 60 mg./kg., administered intraperitoneally when compared to normal Swiss white mice. The defect appeared to involve both phases of IRI release. Electron microscopic evidence supported the concept of defective IRI release in this species. Of particular interest was the frequent occurrence in B cells of autophagic vacuoles comparable to those described for other cells undergoing secretory arrest. It is suggested that the defect of IRI release involves some basic mechanism concerned with the transport of insulin out of the B cell.

Studies of insulin and growth hormone secretion in a subject with hepatoma and gypoglycemia.

SUMMARY Studies of immunoreactive insulin (IRI) and human growth hormone (HGH) secretion were undertaken in a subject with chronic hypoglycemia associated with hepatoma. Fasting IRI concentrations were below 3 μU./ml. at glucose concentrations of 30 mg./100 ml. IRI secretion was not stimulated by acutely administered glucose, tolbutamide, glucagon or arginine. IRI concentrations rose after tolbutamide when plasma glucose was raised to 100 mg./100 ml. by sustained glucose infusion. Fasting ILA (muscle, adipose) levels were not elevated. Fasting HGH concentrations were below 5 mμg./ml.; secretion was stimulated by arginine despite hypoglycemia. During glucose administration, HGH concentrations rose to 45 mμg./ml. as FFA levels fell from 2,250 to 233 μEq./L. Estimated total glucose utilization rate was high (7.5 mg./kg./hr. at a plasma glucose concentration of 100 mg./100 ml.). Conclusions (1) Glucose, or some metabolic product is required for human insulin secretion; (2) HGH secretion after arginine is not inhibited at low glucose concentrations; (3) FFA may exert an inhibitory role in HGH regulation; (4) Hypoglycemia in our subject with hepatoma was associated with increased glucose utilization, not with hyper-insulinism.

Effect of hypothermia on the secretion of immunoreactive insulin in response to glucose.

Insulin levels in the serum of peripheral venous blood samples from normothermic (37 °C) and hypothermic (24.5 ± 0.5 °C) dogs were estimated by immunoassay before and after the intravenous injection of glucose. In contrast to the rapid rise and fall of glucose levels and insulin levels in normothermic dogs following glucose injection, in most of the hypothermic dogs blood sugar levels rose and were sustained above normal levels throughout the test. These changes were accompanied by elevations in blood insulin levels which were sustained or progressively increased. Several hypothermic animals showed a reduced insulin response despite similar changes in blood glucose.