Plasma Immunoreactive Insulin Levels Research Articles

Effect of secretin on plasma insulin and glucagon in man.

To investigate the effect of physiological doses of secretin on pancreatic A and B cell functions, secretin was infused at a rate of 0.5, 1.0 and 2.0 clinical unit per kg body weight per hr into eight normal men for 30 min or 60 min after an over-night fast, and changes in plasma immunoreactive insulin (IRI) and glucagon immunoreactivity (GI) were measured while monitoring circulating secretin levels by a radioimmunoassay. During the infusion of secretin, the plasma immunoreactive secretin (IRS) levels rose to 140-390 pg/ml which was within a range of the physiological fluctuation in plasma secretin levels reported hitherto. No significant alteration of plasma IRI and GI levels could be demonstrated during these simulated physiologic infusions of secretin. These data suggest that, in humans, the physiological dose of secretin does not influence insulin and glucagon secretion from the pancreas in the basal state.

Effect of maternal glucose infusions on fatty acid transport across the placenta in rabbits.

Glucose infusions given intravenously to 28-day-pregnant rabbits increased maternal and fetal plasma immunoreactive insulin levels and decreased maternal concentrations of circulating free fatty acid (FFA). Fetal plasma FFA were only slightly depressed and umbilical venous-arterial concentration differences were unchanged both for total FFA and for individual fatty acids in the FFA fraction. The mean umbilical venous concentration was twice that of maternal levels in the infused group, but about the same concentration in untreated rabbits. It is concluded that the infused glucose, or the high insulin levels provoked by it, or both, caused an increased flow of FFA to the fetus, probably from sources other than the maternal plasma FFA.

Effect of changes in plasma levels of free fatty acids on plasma glucagon, insulin, and growth hormone in man

A regulatory role of acute changes in plasma concentration of free fatty acids on glucagon secretion has been suggested. We have studied the effect of such changes on plasma levels of glucagon, insulin, and growth hormone in man. Basal plasma levels of immunoreactive glucagon (IRG) were only slightly raised in 11 healthy subjects when the mean concentration of free fatty acids (FFA) was depressed to levels as low as 0.315 ± 0.043 (SEM) m M by infusion of nicotinic acid. Basal levels were increased modestly when the mean FFA level was elevated to 3.027 ± 0.184 m M by infusion of a triglyceride emulsion (Intralipid) with heparin. The plasma IRG response to intravenous arginine was unaffected by high or low levels of plasma FFA. These findings contrasted with the effects upon plasma levels of immunoreactive insulin (IRI) and growth hormone (IGH). During elevation of FFA levels, the mean basal level of plasma IRI increased by 100%, and the IRI response to arginine increased by 50%. Concomitantly, basal IGH levels and the plasma IGH response to arginine were suppressed markedly by elevation of FFA levels. The results of these studies do not offer support for a significant role of variation in plasma level of FFA as a regulator of acute changes in plasma IRG in man. An influence of changing levels of FFA on insulin secretion was found, and an effect on levels of growth hormone was confirmed.

Effect of caloric restriction on basal insulin levels and the in vivo lipogenesis and glycogen synthesis from glucose in the Koletsky obese rat

Fasting plasma immunoreactive insulin levels increased with age in hyperinsulinemic Koletsky obese rats, being almost four times as high as in lean siblings at 3 mo (40 ± 5 μU/ml) and rising steadily to 82 ± 4 μU/ml at 6 mo (about seven times higher than lean siblings). Restricting the food intake of the obese rats markedly reduced but did not normalize the hyperinsulinemia, which in these rats was accompanied by normal plasma glucose concentrations. The incorporation in vivo of D-U- 14C-glucose into tissue lipids and glycogen was measured 1 hr after the intravenous injection of 1 g glucose (containing 100 μCi D-U- 14C-glucose) per kg body weight in obese rats eating ad libitum, obese rats after 3 mo on a restricted food intake, and lean siblings. All tissues (heart, diaphragm, skeletal muscle, and adipose tissues and liver) of obese rats exhibited a significantly greater lipogenesis from glucose than those of lean siblings. Dietary restriction of the obese rats reduced the 14C incorporation into lipid to levels not significantly different from lean controls in all tissues except skeletal muscle and liver, where, although greatly reduced, lipogenesis was still significantly higher than in lean rats. Glycogen synthesis tended to be greater in all tissues of obese rats than in lean animals. Dietary restriction of obese rats did not greatly affect glycogen synthesis.

Effect of vagotomy on hyperinsulinemia in obese rats with hypothalamic lesions.

With the purpose of investigating the pathogenesis of obesity and hyperinsulinemia in rats with hypothalamic lesions (HTL), HTL were made in vagotomized rats, and the development of obesity was serially followed up to 15 weeks as well as the changes of plasma triglyceride and immunoreactive insulin (IRI) levels. Even in vagotomized rats, obesity developed after HTL and plasma triglyceride and IRI levels increased significantly. However, obesity was slightly less in grade and occurred later as compared with sham-vagotomy-HTL rats. Plasma IRI levels in vagotomized rats significantly correlated with the body weight, Lee's index, the weight of adipose tissue and plasma triglyceride level. Similar results were also obtained in rats with HTL which were pair-fed following vagotomy. These results suggest that the hyperinsulinemia in obese rats with HTL may be involved not only by hypersecretion of insulin mediated by hypothalamo-vagal nerve system but also by some insulin-antagonistic factors such as increases of adipose tissues and plasma lipids.

Catecholamine-induced changes in plasma glucose and insulin levels in the unanesthetized rabbit.

Isoproterenol (ISO) produced dose-related increases in plasma immuno-reactive insulin (IRI) levels in unanesthetized rabbits, whereas epinephrine produced no significant changes. Dose rats of ISO or glucose that produced similar peak increases in glucose levels also produced similar increases in plasma IRI, but the responses to ISO occurred later and were of longer duration than the responses to glucose. Propranolol blocked the increase in plasma IRI produced by ISO, but the ISO-induced rise in plasma glucose was antagonized imcompletely. These data provide supporting evidence for the suggestion that the hyperglycemic activity of ISO in vivo is limited by concurrent ISO-induced changes in peripheral IRI levels.

Ultradian growth hormone rhythm in the rat: effects of feeding, hyperglycemia, and insulin-induced hypoglycemia.

Temporal patterns of plasma GH, immunoreactive insulin (IRI), and glucose were defined by obtaining serial blood samples from freely-moving male rats bearing chronic intracardiac venous cannulae. Blood was withdrawn every 15 min for periods of 6 h. Plasma GH and IRI were determined by radioimmunoassay. The typical ultradian rhythm of GH secretion was evident in each undisturbed animal (peaks greater than 200 ng/ml; troughs less than 1 ng/ml; mean period: 3.40 +/-0.08 h). Basal plasma IRI and glucose levels fluctuated minimally. There was no significant correlation between plasma GH and IRI, GH and glucose, or IRI and glucose levels in unfed rats. The rhythmic GH secretory patterns of feeding animals (mean period: 3.12 +/-0.16 h; peaks greater than 200 ng/ml; troughs less than 1 ng/ml) were similar to those of non-feeding animals (mean period: 3.34 +/-0.15 h; peaks greater than 200 ng/ml; troughs less than 1 ng/ml) despite large fluctuations in plasma IRI levels and a wide variation in the number and size of the meals taken. No consistent relation was observed between the ingestion of meals and the bursts of GH secretion. The mean period of the GH rhythm was not significantly altered by hyperglycemia (mean period; 3.25 +/- 0.08 h), although the amplitude of the pulses of half of the hyperglycemic rats was markedly depressed. Insulin-induced hypoglycemia caused a significant depression in the amplitude of the GH pulses; however, the pattern of this response was not consistent. Despite wide variability in the GH response, the magnitude and time course of recovery of the plasma glucose levels was similar in all animals. These results suggest that GH secretion in the rat is regulated primarily by an endogenous ultradian rhythm which is not dependent on changes in plasma glucose or IRI levels, and continues to function independently of feeding behavior. It is unlikely that GH is an important physiologic regulator of glucose homeostasis in this species.

Hyperinsulinism in the dog due to pancreatic islet‐cell tumour: a report on three cases

ABSTRACTHypoglycaemia due to hyperinsulinism caused by an islet‐cell tumour, in three male Boxer dogs aged 9, 81/2 and 81/2 years respectively, is described.The clinical signs, the laboratory findings and the histological picture of the tumour of the pancreas which led to the diagnosis are discussed. The plasma immunoreactive insulin level (IRI), after 24‐hours fasting, or after stimulation by glucose, was elevated in only one case, but the ‘amended insulin‐glucose ratio’ was clearly increased in the other two cases, compared with normal dogs.

Changes in Adenylate Energy Charge of the Liver After an Oral Glucose Load

Changes in the adenine nucleotide metabolism after an oral glucose load were studied in the liver of normal and alloxan-diabetic rats. Changes in the energy charge were positively correlated with those in the blood glucose and plasma immunoreactive insulin levels. One hour after an oral glucose load when the plasma immunoreactive insulin levels increased maximally, the energy charge increased maximally from 0.846 to 0.867 (P less than 0.001). The increase in the energy charge was accompanied by a concomitant decrease in the ADP levels (P less than 0.05). The respiratory control ration, state 3 respiration per unit of cytochrome a (+a3), and DNP-induced ATPase activity per unit of cytochrome a (+a3) increased significantly. The adenylate kinase and pyruvate kinase activities in the liver remained unchanged. On the other hand, the energy charge in the liver of alloxan-diabetic rats did not increase significantly after an oral glucose load. It was suggested that an increase in the energy charge of the liver is attributable to the more rapid flux of intermediary metabolism in the enhanced ADP-phosphorylating reactions by mitochondria, owing to an elevated level of insulin available to the hepatic cells.

Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs.

The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin's effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.

Inhibitory effect of somatostatin on dibutyryl cyclic AMP-induced insulin and growth hormone release in human subjects

The effect of somatostatin on the responses of blood glucose, plasma immunoreactive insulin (IRI), growth hormone (GH), and free fatty acids (FFA) to the injection of dibutyryl cyclic AMP (DBC) was studied in six normal volunteers. DBC, when injected alone, induced a rapid increase in blood glucose and plasma IRI levels, while GH concentrations showed a less marked and more delayed increase and plasma FFA showed a clear downtrend. Somatostatin infusion suppressed the GH and IRI release induced by DBC, potentiated its hyperglycemic effect and changed the pattern of FFA. These results suggest that somatostatin inhibits hormone secretion distal to the generation of cyclic AMP.

Pancreatectomy in the chicken: Does an extra-pancreatic source of insulin exist?

The possibility of an extrapancreatic source of insulin in aves was studied in adult Single Comb White Leghorn chickens. The effect of partial pancreatectomy (99%) on plasma glucose and immunoreactive insulin (IRI) levels, as well as the tolerance of these depancreatized birds to a glucose load was estimated. Evaluation also was made of the action of tolbutamide in partially depancreatized, totally depancreatized, and sham-operated chickens. Results obtained indicate that partial pancreatectomy (99%) has only transient effects (several days) on plasma glucose and IRI levels. Also, surgical extirpation of the pancreas does not prevent tolbutamide-induced hypoglycemia secondary to insulin release, although such surgery does impair glucose tolerance concomitant with a diminished release of assayable IRI in response to an injected glucose load. Although remnant (1%) pancreatic tissue (splenic lobe) was observed to increase (up to 550%) in size 16 days after partial pancreatectomy, removal of this remnant in a second operation neither abolished circulating IRI 20 hr later nor did it prevent the characteristic hypoglycemic response to injected tolbutamide. The data presented herein suggest the existence of accessory β-islet tissue, yet to be located/described or, alternatively, the presence of a nonpancreatic source of insulin in the chicken.

CARBOHYDRATE METABOLISM IN PRE‐ECLAMPSIA

Intravenous glucose tolerance tests were performed on 30 primigravidae with pre-eclampsia and 15 normal primigravidae in late pregnancy. The groups were matched for age, height and weight and had no stigmata of potential diabetes. Plasma glucose, plasma immunoreactive insulin and plasma placental lactogen (HPL) levels were measured before (fasting) and at timed intervals after the glucose challenge; the glucose response was expressed as the increment index. The patients with severe pre-eclampsia had significantly lower fasting plasma glucose levels than those with mild pre-eclampsia and normal pregnancies. The mean increment index in both the severe and mild pre-eclamptic groups was significantly lower than that of the normal pregnant group. Fasting HPL levels were significantly lower in patients with severe pre-eclampsia than in those who had mild pre-eclampsia or a normal pregnancy. Both the fasting plasma insulin and insulin response following glucose injection were lower in patients with severe pre-eclampsia than in those with mild pre-eclampsia or a normal pregnancy. The differences however were not statistically significant. The results of this study suggest that carbohydrate metabolism in severe pre-eclampsia is altered to an extent similar to that in patients with chemical gestational diabetes, and this alteration may be due to maternal beta-cell anoxia caused by the vascular changes in pre-eclampsia.

Effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell following sulphonylurea and isopropyl-noradrenaline.

The effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell was studied in mice. Treatment with vinblastine (1.1 mumole/mouse) resulted in a 75% decrease of the amount of normal microtubules and the appearance of characteristic paracrystals. Basal plasma immunoreactive insulin levels were depressed to about 60% of the control level. The dose-response pattern for insulin release (first phase) following two chemically unrelated insulin secretagogues, the potent sulphonyl-urea derivative, glibenclamide, and the beta-adrenegic agonist L-isopropylnoradrenaline, (L-IPNA), was tested with and without vinblastine pretreatment. The dose-response curves for L-IPNA-induced insulin release in vinblastine-treated and control animals did not deviate significantly from each other, whereas insulin release following glibenclamide was almost totally suppressed by vinblastine except at the lowest dose level. Injection of maximal doses of glibenclamide or L-IPNA did not alter the ultrastructural changes induced by vinblastine in the B-cells. It is suggested that the microtubular system of the B-cell might play a minor role for certain insulin-releasing processes and/or that vinblastine might have other important effects on the insulin secretory machinery.

Gastric Operations and Glucose Homeostasis: II. Glucagon and secretin

Alimentary hyperglycemia in patients who have undergone gastric operations may be due, in part, to altered intestinal signals for glucose disposition. We measured glucose, immunoreactive insulin (IRI) pancreatic glucagon (IRG), and glucagon-like immunoreactivity (GLI) after oral glucose in patients with prior antrectomy or vagotomy and pyloroplasty and in normal individuals. All subjects had normal assimilation coefficients for intravenous glucose, which suggests that the responsiveness of the pancreatic beta-cells had not been altered by the surgical procedures. The early hyperglycemic response to oral glucose and the associated elevation of plasma GLI were much greater and the IRI levels slightly higher in both experimental groups in comparison to normal subjects. A decrease in the level of IRG, albeit not statistically significant, was noted in all groups after the ingestion of glucose. In gastrectomy patients, secretin infusion during repeated oral glucose tolerance tests partially corrected the hyperglycemia and lowered plasma GLI and IRI levels. The responses of the vagotomy and pyloroplasty patients and of the normal subjects were not altered by secretin infusion. We conclude that the intolerance or oral glucose after gastric surgery may be related to elevated GLI levels, and that the beneficial effect of secretin may be due to its ability to decrease these levels.

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.

Comparative insulinogenic effects of glucose, arginine and glucagon in patients with diabetes mellitus, endocrine disorders and liver disease.

In order to compare the insulinogenic effects of glucose, arginine and glucagon, plasma immunoreactive insulin levels following oral glucose loading (50 g), intravenous arginine infusion (30 g for 45 min) and intravenous glucagon injection (1 mg) were determined in patients with diabetes mellitus, various endocrine diseases and chronic hepatitis. In patients with Cushing’s syndrome, plasma insulin responses to all three stimuli were exaggerated, whereas they were low in patients with pheochromocytoma. In other diseases, certain disparities were observed in plasma insulin responses. In patients with mild diabetes mellitus, insulin secretion elicited by glucose seems to be selectively impaired, because arginine and glucagon caused a rise in plasma insulin not significantly different from that in normal subjects. In patients with hyperthyroidism, plasma insulin responses to arginine and glucagon were either absent or limited, although rather a exaggerated response was noted following oral glucose loading. On the contrary, exaggerated responses to arginine and glucagon, and limited response to glucose were observed in hypothyroidism. In patients with chronic hepatitis, the responses of plasma insulin to glucose and arginine were both exaggerated, whereas the response to glucagon was comparable to that in normal subjects. These disparate responses suggest that glucose, arginine and glucagon act on the B-cell via different mechanisms.

Glucose, insulin, pancreatic glucagon and glucagon-like immunoreactive materials in the plasma of normal and diabetic children. Effect of the initial insulin treatment.

Pancreatic glucagon (PG) and other glucagon-like immunoreactive materials (GLI) were measured in the plasma of normal and of newly diagnosed untreated diabetic children, using an antiglucagon serum (AGS) highly specific for pancreatic glucagon (AGS 18) and an AGS which crossreacts with extracts of intestinal mucosa (AGS 10). Gut GLI was considered to be the difference between "total" GLI (AGS 10) and PG (AGS 18). Glucose and immunoreactive insulin (IRI) were also measured. PG, total GLI and gut GLI were significantly elevated in children with severe insulin insufficiency and were reduced to normal by insulin treatment, even though a significant fasting hyperglycemia was still present. In three diabetic children who had high initial plasma IRI levels the three glucagon fractions were normal. We conclude that insulin insufficiency is characterized not only by high plasma levels of PG as previously reported, but also of gut GLI. These abnormalities can be corrected by the administration of insulin.

Studies of immunoreactive insulin secretion in NZO mice in vivo.

Studies of immunoreactive insulin (IRI) secretion have been performedin vivo in NZO mice. After an overnight fast, plasma IRI levels were 2–5 times higher in NZO than in control white mice. The IRI response to arginine, 10 mg/kg IV or isoprenaline, 10 Μ/kg IV, was similar in time in the two mice, but IRI increments were greater in the NZO animals. With glucagon 1 Μg/kg IV or aminophylline 25 mg/kg IV the initial secretory response was delayed compared to control mice. Glucose 1.0 g/kg IV elicited a markedly attenuated initial response in NZO mice. When IRI responses were related to basal IRI levels, NZO mice showed smaller initial responses (1–5 min) to all agents tested. Later responses were comparable in the two groups when compared in this way. Diphenylhydantoin, 40 mg/kg administered intraperitoneally 30 min before glucose, 1.0 g/kg IV did not affect glucose-induced insulin secretion in control animals, but abolished it in the NZO mice. These observations suggest the existence of a defect in the IRI release mechanism of the NZOΒ cell situated at a point in the stimulus secretion coupling mechanism common to all the agents examined.

Short-term effects of oestradiol benzoate in normal, hypophysectomized and alloxan-diabetic male rats.

SUMMARY Studies were undertaken to determine the effects and possible mode of action of 17β-oestradiol benzoate (OEB) in alloxan-diabetic male rats. Adlibitum or pair-fed normal, diabetic, and hypophysectomized rats received daily subcutaneous injections of 10 μg OEB for 10 days. In normal rats, OEB decreased plasma glucose, increased plasma immunoreactive insulin, growth hormone and corticosteroid levels, increased pancreatic β-cell granulation, and enhanced glucose stimulation of insulin release in vitro. In alloxan-diabetic rats, OEB treatment decreased urinary glucose excretion, increased plasma growth hormone and corticosteroid levels and slightly enlarged the pancreatic islets of Langerhans. In hypophysectomized rats, OEB decreased plasma glucose, increased plasma insulin levels, and slightly enlarged the pancreatic islets of Langerhans. These results suggest that OEB affects experimental diabetes by a direct action on the pancreas, promoting insulin formation, and possibly by an indirect action mediated through hypophysial secretions.