IRI) And Glucagon Research Articles

A Comparison between Insulin and Glucagon Release from Orthotopically-Placed Islets of Langerhans and after Their Transplantation into the Liver of Diabetic Rats

The ability of islets of Langerhans to release insulin (IRI) and glucagon (IRG) after stimulation with glucose and arginine was analyzed by using isolated perfused pancreas of Lewis-rats and by using perfused liver three months after syngenic portal islet transplantation. Transplanted islets preserve their functional integrity so that the shape and magnitude of IRI and IRG release, respectively, can be compared with normal islet reactivity. They are able to release insulin after stimulation with 16 mM glucose having a typical biphasic secretion profile. The islet and B-cell volume, as well as the insulin and glucagon content of the recipient pancreas, are decreased significantly three months after islet transplantation when compared with healthy controls.

Effects of alcohol consumption and accompanying diet on metabolic response to arginine in chronic alcoholics.

To evaluate, in chronic alcoholics, the effects of accompanying diet on the release of insulin (IRI) and glucagon (IRG) and on the hepatic glucose production. We evaluated variations of the response to the infusion of arginine into 16 male and 8 female chronic alcoholics divided into three groups of eight subjects each before and after three weeks of treatment with: (1) an isocaloric diet plus 200 g/day of ethanol; (2) an hypocaloric diet without alcohol (17.5 kcal/kg/day); and (3) an isocaloric diet (35 kcal/kg/day). Statistical evaluation was done by Kruskall-Wallis ANOVA and by Wilcoxon matched-pairs signed rank test. After isocaloric diet plus ethanol both IRI/IRG ratios and plasma glucose during arginine testing remained unmodified; after the hypocaloric diet IRI/IRG remained unmodified and the arginine-induced plasma glucose rise was slightly but significantly reduced; after the isocaloric diet there was a strong decrease of the arginine-induced plasma glucose rise because of a significant increase in the insulin/glucagon ratio. In chronic alcoholics the replacement of the usual hypocaloric diet with an isocaloric one while maintaining alcohol consumption does not modify the metabolic response to arginine administration; the hypocaloric diet without alcohol increases insulin and glucagon release and slightly decreases liver glycogenolysis; the replacement of the usual hypocaloric diet with an isocaloric one together with alcohol withdrawal stimulates insulin, inhibits glucagon release and lowers glycogenolysis much more than observed with hypocaloric diet alone.

Effect of C-terminal fragments of glucagon on insulin secretion in dogs

Although the insulinotropic action of glucagon is well known, which parts of the glucagon molecule play an importent role in its action remain to be elucidated. To investigate the direct effect of the C-terminal peptides of glucagon on the endocrine function of the pancreas, glucagon(17–29), (21–29), (23–29), and (25–29) were studied using an in situ local circulation system of the canine pancreas. These glucagon fragments, as well as glucagon(1–29), were infused into the superior pancreaticoduodenal artery (PA) in a dosage of 400 pmol for 10 minutes during 0.5% glucose or 0.5% arginine infusion, and plasma insulin (IRI) and glucagon (IRG) levels in the superior pancreaticoduodenal vein (PV) were determined. During the glucose infusion, plasma IRI increased significantly following the administration of glucagon(23–29), (21–29), (17–29), or (1–29), but not glucagon(25–29). In these experiments, plasma IRG increased significantly following infusion of glucagon(21–29), (17–29), or (1–29). During the arginine infusion, all of the glucagon fragments studied enhanced insulin secretion, whereas plasma IRG was increased following the administration of glucagon(21–29), (17–29), or (1–29). In these experiments with glucose or arginine infusion, blood glucose in the femoral artery (FA) did not change significantly except for glucagon(1–29), which increased the blood glucose level. In addition, the administration of graded doses of glucagon(21–29) [50, 150, and 400 pmol] during the glucose infusion elicited an increase in plasma IRI in a dose-related manner. From the present study, it is concluded that the C-terminal peptides of glucagon enhanced insulin release, and that glucagon(21–29) is the minimum structure among the C-terminal glucagon fragments to stimulate insulin secretion.

Pancreatic glucagon secretion during a short period of hemorrhage in anesthetized dogs

Glucagon has been implicated in the hormonal metabolic response to hemorrhage. However, evidence for this has been obtained largely from observations of circulating plasma glucagon concentration. A clear increase in the pancreatic glucagon secretion remains to be demonstrated. Plasma concentrations of pancreatic immunoreactive glucagon (IRG) and insulin (IRI) were determined in portal venous and aortic blood, and plasma glucose in aortic blood. Dogs were bled (approximately 15 mL/kg) until aortic systolic blood pressure dropped to approximately 50% (70.5 +/- 8.1 mmHg, n = 7) (1 mmHg = 133.32 Pa) of its control value (135 +/- 7.1 mmHg, n = 7), and the hemorrhagic hypotension was maintained for 10 min. The net portal venous IRG delivery rate rose significantly and continued to increase during the hemorrhagic hypotension despite a significant fall in the portal venous blood flow. Aortic IRG increased significantly along with the increase in portal venous IRG delivery rate (r = 0.838, n = 42, p less than 0.01). The portal venous delivery rate of IRI decreased significantly in response to hemorrhage. The aortic IRG/IRI concentration ratio increased significantly during the hemorrhage-induced hypotension. Aortic glucose concentration increased significantly 5 min after hemorrhage and continued to rise until the end of the hemorrhagic hypotension. The present study demonstrates that the secretion of pancreatic glucagon actually increases during the early phase of hemorrhage. The results also indicate that the increase in aortic IRG during the hemorrhagic hypotension is due to the increased pancreatic glucagon secretion. It is suggested that the pancreatic glucagon may be involved in the early hyperglycemic response to hemorrhage.

Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas

To investigate the effects of stimulant interactions on α- and β-cell secretions, the differential effects of gastric inhibitory polypeptide (GIP) and cholinergic stimulation (CS) on insulin (IRI) and glucagon (IRG) release were examined during euglycemic, single-pass perfusion in the isolated human pancreas. Pancreata obtained from 12 cadaver organ donors were perfused for 15-min test periods with (a) 1 n M GIP (b) intrinsic CS via bipolar electrical stimulation (10 V, 5 msec, 10 Hz) of the splanchnic neural fibers during simultaneous perfusion with 4 μ M phentolamine and 6 μ M propranolol, or (c) GIP and CS. The integrated response of IRI and IRG demonstrated that IRI release was stimulated 308 ± 52 μU/g-min by GIP, 366 ± 73 μU/g-min by CS, and 560 ± 50 μU/g-min by GIP and CS ( P < 0.05). IRG release was stimulated 111 ± 33 pg/g-min by GIP, 34 ± 12 pg/g-min by CS, and 90 ± 36 pg/g-min by GIP and CS. Combined hormonal and cholinergic stimulation was additive for IRI release, but not for IRG release. We conclude that the interaction of neural and hormonal islet cell stimuli is cell-type specific. This may result in selective impairment of hormone release after pancreatic denervation.

Increased β-Cell Secretory Responsiveness to Ceruletide and TPA in Streptozocin-Induced Mildly Diabetic Rats

We examined the effects of various stimuli on immunoreactive insulin (IRI) and glucagon (IRG) release from perfused pancreases isolated from control and streptozocin-induced diabetic (STZ-D) rats. Diabetes was induced by injecting 30 mg/kg STZ into rats fasted for 16-18 h 12-17 days before our experiments. Glucose (11.1 mM) caused a distinct biphasic pattern of IRI release from the control pancreas, whereas the first phase was marginal and the second phase was absent in the diabetic pancreas. Arginine (20 mM)-induced IRI release was similar in both groups, whereas IRG release was greater in the control rats than in the diabetic rats. Thus, this model of STZ-D simulates a certain class of non-insulin-dependent diabetes mellitus (NIDDM). In these diabetic animals, the cholecystokinin (CCK) analogue ceruletide (620 pM) caused a significantly greater increase in IRI release in the presence of 5.6 mM glucose than in the control rats, but ceruletide caused a similar IRG release in both groups. Because CCK and ceruletide stimulate phosphoinositide turnover in pancreatic islets, we examined the effects of carbachol and phorbol ester TPA on IRI release in the presence of 5.6 mM glucose. Carbachol (10 microM), which is thought to generate similar second messengers as ceruletide, induced greater IRI release in diabetic than in control rats. TPA (100 nM) caused a significantly greater increase in IRI release from the diabetic than the control pancreas. Our results demonstrate that the insulin-releasing mechanism involved in protein kinase C activation is enhanced in this model of NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Disopyramide induces insulin secretion and plasma glucose diminution: Studies using the in situ canine pancreas

The mechanism of disopyramide-induced hypoglycemia, a life-threatening complication in the antiarrhythmic drug treatment, is still controversial. To elucidate this, we have evaluated plasma insulin (IRI) and glucagon (IRG) responses in the pancreatic vein (PV) of the in situ pancreas as well as responses of plasma IRI, IRG, and glucose in the femoral artery (FA) to disopyramide phosphate administration in anesthetized dogs. First, infusion of disopyramide at a dose of 50 mg for ten minutes directly into the pancreatic artery, but not the vehicle, increased significantly plasma IRI concentration in the PV ( P < .05 or less), where the IRI response started within three minutes and reached a peak of 2.8-fold preinfusion value at 30 minutes after starting the infusion (n = 7). Plasma IRI concentration in the FA also increased slightly but significantly ( P < .05). Plasma IRG concentration in the PV initially decreased significantly ( P < .05 or less) and in the FA at one point ( P < .05) during the infusion, and then increased significantly after cessation of the infusion, showing a peak of 1.9-fold preinfusion value at 60 minutes in the PV and the FA ( P < .05). Plasma glucose concentration in the FA decreased slowly and significantly after the infusion ( P < .05 or less) and fell by 16% of the baseline value at 60 minutes ( P < .05). Second, infusion of disopyramide at a dose of 7 mg/kg body weight (BW) for ten minutes into the femoral vein induced a peak of serum disopyramide concentration of 13.7 ± 2.8 μg/mL at ten minutes, which corresponds to a twofold to threefold concentration of the human therapeutic level (n = 4). The disopyramide infusion, but not vehicle, induced a significant increment of plasma IRI concentration in the PV at ten minutes ( P < .05), accompanying a very slight IRI rise in the FA. Plasma IRG concentration in the PV again increased after the cessation of the infusion ( P < .05). Arterial plasma glucose level decreased significantly by 14% at 60 minutes ( P < .01). The present results indicate that disopyramide provokes a prompt and significant insulin secretion, and also induces a concomitant fall of plasma glucose level in face of an ongoing IRG secretion. The results thus suggest that the disopyramide-induced glucose fall is caused by decreased hepatic glucose output due to the hepatic action of insulin released by the drug rather than by increased peripheral glucose uptake due to the peripheral action of insulin. It may be an additional explanation for the glucose fall that disopyramide blunts the hepatic glucose output, which should be stimulated by the augmented glucagon secretion. Thus, if combination of the present glucose-lowering factors occurs in the elderly and malnourished patients with the impaired hepatic and renal function, who especially have poor hepatic glycogen storage and gluconeogenic activity, the disopyramide-induced hypoglycemia may easily develop.

Plasma glucagon response to intravenous alanine in obese and non-obese subjects.

To investigate glucagon (IRG) and insulin (IRI) responses to alanine infusion in obesity and to assess the effect of body weight reduction with respect to hormonal balance, we compared six obese subjects with nine normal weight controls. None of the subjects were diabetic by OGTT criteria. Plasma IRI and IRG were measured following IV alanine at a rate of 0.1 g/kg over a period of 2 min. Our obese subjects had an increase in IRG response to alanine, which was due to decreased suppression of alpha-cell function due to insulin resistance. Weight reduction via calorie restriction reduced insulin demand, resulting in reduced plasma IRI by restoring beta-cell function, and the IRG response was paradoxically decreased as compared with that before weight loss. It is conceivable that improvements in insulin sensitivity after body weight reduction may re-establish the normalization of pancreatic beta-cell function and the insulin-induced inhibition of IRG secretion. Our obese subjects were characterized by decreased IRG secretion which was reflected in a change in body weight reduction.

Protein-energy malnutrition in pregnant rats improves the adaptation of the endocrine pancreas in malnourished offspring and induces insulin resistance after rehabilitation.

1. In developing countries, malnutrition begins during pregnancy and lactation. Glucose intolerance is a problem of importance during protein-energy malnutrition (PEM). We therefore studied glucose homeostasis in rats weaned from undernourished mothers. 2. On weaning, 156 male Wistar rats, born from deprived mothers (75 g casein/kg diet), were fed ad lib on either a balanced diet (180 g casein/kg; group DR), or a protein-deficient diet (50 g casein/kg; group DD). At seven time intervals (weeks 0, 1, 3, 5, 8, 16 and 23) twelve rats were weighed, fasted overnight and then decapitated. Blood glucose, plasma insulin (IRI) and glucagon (IRG) levels and pancreatic insulin and glucagon contents were determined. 3. In DR and DD rats blood glucose, which was normal at weaning, dropped in the 1st week and then increased slowly. DR rats were hyperglycaemic from week 16. IRI continually increased during the experiment from near-normal values to hyperinsulinic levels in DR rats; in group DD, it remained stable until week 8 before increasing. IRG, which was very low at weaning, increased to normal levels in the 1st week in group DR; in group DD, it fell slightly during the study. Pancreatic hormone contents were much higher than after normal pregnancy and lactation. 4. We compared these results with those of a previous study with rats born from normal mothers: at weaning in the second experiment the rats were already well adapted to malnutrition. The plasma ratio IRI:IRG in DD rats showed two phases of adaptation: weeks 0-5 when glucose homeostasis did not change and weeks 5-23 when it became increasingly normal. At the end of the experiment DR rats still had a lower body-weight than normal rats but were insulin-resistant.

Effects of beta non-selective and beta 1 selective adrenergic blocking agents on glucagon secretion from isolated perfused rat pancreas.

To characterize beta-receptors which affect pancreatic A-cell activity, the effects of propranolol (beta non-selective blockade) and metoprolol (beta 1 selective blockade) were evaluated on epinephrine modulated insulin (IRI) and glucagon (IRG) release both in basal state and during metabolic stimulus (arginine 20 mM). The isolated perfused rat pancreas model with the exclusion of stomach and duodenum was used. Epinephrine infusion (at 10(-7) M) caused a prompt and sustained increase in basal IRG secretion and significantly potentiated glucagon release in response to metabolic stimulus. Insulin secretion was markedly suppressed by epinephrine both in basal conditions and during metabolic stimulus. Propranolol (at 10(-7) M) and metoprolol (at 10(-7) M) infusion clearly and similarly counteracted epinephrine stimulatory effects on IRG secretion but failed to elicit any significant effect on the epinephrine inhibited IRI release either in basal state or during the metabolic stimulus. These results suggest that, at least in the rat, the adrenergic stimulation of IRG release is mediated through a beta 1 receptor.

The mechanism of vagal nerve stimulation of glucagon and insulin secretion in the dog.

The mechanism of vagal nerve stimulation of glucagon (IRG) and insulin (IRI) secretion was investigated in halothane-anesthetized dogs. Both ventral and dorsal branches of the thoracic vagi were stimulated electrically (10 Hz, 5 msec, 13.5 mA, 10 min) below the heart. Arterial and superior pancreaticoduodenal venous plasma were sampled, superior pancreaticoduodenal venous plasma flow was measured, and net pancreatic output of IRG and IRI were calculated. During vagal nerve stimulation (n = 15) net pancreatic output of IRG doubled (delta = +0.83 +/- 0.28 ng/min, P less than 0.01; baseline = 0.81 +/- 0.15 ng/ min) and IRI quadrupled (delta = +3.5 +/- 1.5 mU/min, P less than 0.025; baseline = 1.1 +/- 0.3 mU/min). Arterial glucose levels increased by 7 +/- 2 mg/dl from 108 +/- 3 mg/dl (P less than 0.005). After atropine pretreatment (n = 7), the pancreatic IRI response to vagal nerve stimulation was +0.71 +/- 0.28 mU/min (P less than 0.025), a reduction of 80%. In contrast, atropine pretreatment changed neither the IRG response (delta = +0.87 +/- 0.36 ng/min; P less than 0.05) nor the arterial glucose response (delta = +9 +/- 3 mg/dl; P less than 0.025) to vagal nerve stimulation. Hexamethonium pretreatment (n = 9) abolished the pancreatic IRG response (delta = +0.13 +/- 0.11 ng/min; NS), the arterial glucose response (delta = +0.5 +/- 1.9 mg/dl; NS) and the pancreatic IRI response (delta = +0.16 +/- 0.31 mU/min; NS) to vagal nerve stimulation. It is concluded that vagal nerve stimulation in the dog produces a moderate increase of IRG secretion, mediated by a nonmuscarinic (peptidergic?) mechanism, and a marked increase of IRI secretion, mediated by a muscarinic mechanism. Both responses are dependent on nicotinic transmission.

Lack of effect of thyrotropin-releasing hormone (TRH) on the peripheral plasma levels of pancreatic glucagon in man.

Based on the fact that human pancreas has thyrotropin-releasing hormone (TRH) immunoreactivity and bioactivity, we studied the effect of TRH on peripheral plasma levels of pancreatic glucagon (IRG) and insulin (IRI) in healthy subjects. During the infusion of 400 micrograms TRH for 120 min basal plasma IRI and IRG levels did not change significantly. In addition, intravenous infusion of 400 micrograms TRH did not affect the increments in the plasma IRG levels and the decrements in the blood glucose during insulin hypoglycemia.

Glucoregulation in alloxan-diabetic dogs

In order to establish whether a prolonged subnormal secretion of insulin may affect glucoregulation against hypoglycemic stimuli, the level of plasma glucose was decreased in alloxan-diabetic dogs by the infusion of either 50 μg/kg · min phlorizin (PHL), ie, reducing the concentration of plasma glucose without hyperinsulinemia; or with 7 mU/kg · min insulin (combined hyperinsulinemia and hypoglycemia). The concentration of glucose, immunoreactive glucagon (IRG), and insulin (IRI) and catecholamines were followed in the plasma. Hepatic glucose production (Ra) and the overall rate of glucose removal from the circulation were calculated by a tracer method. During a 200-minute infusion of PHL plasma glucose fell from 328 ± 29 to 114 ± 16 mg/dL, while IRG rose from a mean of 470 ± 123 to 623 ± 200 pg/mL, however this increase was significant only in 3 out of 6 dogs. There was no change in the plasma level of epinephrine. Plasma IRI decreased significantly, the IRI IRG ratio remained low, and Ra did not increase. When the animals were treated with insulin for one week, plasma glucose was restored to normal, while plasma IRI and the IRI IRG ratio were raised above the normal level. Under these circumstances the infusion of PHL increased plasma IRG significantly from 59 ± 5 to 110 ± 32 pg/mL, decreased IRI slightly, and increased Ra by an average of 50 ± 16%. No measurable change in plasma glucose was observed indicating the restoration of nonhypoglycemic glucoregulation. In diabetic dogs during a 95-minute infusion of insulin, plasma glucose dropped from a mean of 338 ± 5 to 74 ± 24 mg/dL. Plasma IRG fell from 379 ± 151 to 151 ± 33 pg/mL, and there was a small increase in plasma epinephrine. Ra was decreased significantly from 5.1 ± 0.4 to 4.1 ± 0.7 mg/kg · min. Conclusions: ( A) In alloxan-diabetic dogs the absence of a regulatory increase in hepatic glucose production in response to a decrease of plasma glucose (as distinct from hyperinsulinemia) is due to the absence of, or only marginal increase in glucagon secretion and/or a reduced sensitivity of the liver to a decrease in the ambient concentration of glucose. ( B) The regulatory response is restored by a one-week long treatment with insulin. ( C) During simultaneous hyperinsulinemia and hypoglycemia the plasma concentration of glucagon decreases together with the rate of hepatic glucose production. ( D) Insulin deprivation for a few days significantly interferes with the regulatory response to a decreasing concentration of plasma glucose both in the presence or absence of simultaneous hyperinsulinemia.

Alpha-adrenergic system in the modulation of pancreatic A and B cell function in normal rats

The role of the alpha-adrenergic system in the control of pancreatic A and B cell function was investigated in an isolated perfused rat pancreas model. Two experimental procedures were performed. In the first one we evaluated the effects of two distinct concentrations (10(-8) M and 10(-7) M) of five adrenergic substances, with varying degrees of potency on the alpha-adrenergic presynaptic receptor, on insulin (IRI) and glucagon (IRG) release induced by arginine (20 mM) plus glucose (6.6 mM). In the second procedure we studied the effects of the two alpha-blocking agents yohimbine (alpha 2-blocker) and prazosin (alpha 1-blocker) at 10(-7) M on epinephrine-modulated IRI and IRG response to the same combined metabolic stimulus. The inhibitory activity on basal and metabolically induced IRI secretion of the agonists was superimposable on their potency on the presynaptic alpha 2-adrenergic receptors. Similarly, the alpha 1-blocking agent prazosin was less effective than the alpha 2-blocker yohimbine in counteracting the inhibitory effects of epinephrine on basal and arginine plus glucose-induced insulin release. The alpha-cell activity was clearly stimulated by epinephrine, whereas selective alpha-adrenergic drugs showed no significant action on IRG secretion. Both alpha-blockers were ineffective on basal IRG release, while they had some potentiating effect on the epinephrine-induced glucagon release in basal state and during the metabolic stimulus, without a significant difference between the two drugs. We conclude that, at least in the isolated perfused rat pancreas, alpha 2-adrenergic receptors are involved in the inhibition of IRI release induced by catecholamines. On the contrary, the alpha-adrenergic system does not seem to play an essential role in the regulation of IRG secretion; the potentiation of the epinephrine-induced stimulation of A cell function by the alpha-adrenergic blockade could be accounted for by a greater availability of the catecholamine at the beta-receptor binding sites.

Effects of cysteamine and antibody to somatostatin on islet cell function in vitro. Evidence that intracellular somatostatin deficiency augments insulin and glucagon secretion.

In this study we have characterized the effects of cysteamine (CHS) on the cellular content and release of immunoreactive somatostatin (S-14 LI), insulin (IRI), and glucagon (IRG) from monolayer cultures of neonatal rat islets. Incubation of cultures with 0.1-10 mM CHS for 1 h led to an apparent, dose-dependent reduction of cellular S-14 LI that was 50% of control at 0.3 mM, 87% at 1 mM, and 95% at 10 mM. IRI content was unaffected by CHS up to 1 mM, but at 10 mM 90% loss of IRI occurred. All concentrations were without effect on IRG content. The loss of S-14 LI and IRI was completely reversible with time, but with different recovery rates for the two hormones (48 h for S-14 LI, and 72 h for IRI). Released S-14 LI rose progressively with increasing doses of CHS from 21 +/- 2.5 pg/ml per hour to 41 +/- 1.4 pg/ml per hour at CHS concentrations of 5 mM and 10 mM. IRI and IRG secretion were both also significantly enhanced (by 55% and 88%, respectively), despite the elevated medium S-14 LI. Since CHS reduced cellular S-14 LI but augmented medium S-14 LI, the relative effects of CHS (1 mM) and immunoneutralization with antibody to S-14 LI on IRI and IRG secretion were tested. Anti S-14 LI alone stimulated basal IRG (67%) but not IRI. Cultures rendered S-14 LI deficient with both CHS and anti-S-14 LI exhibited threefold and 2.3-fold potentiation of IRG and IRI secretions, respectively, greater than that expected from the separate effects of the two agents. Increasing medium glucose from 2.8 mM to 16.7 mM stimulated IRI release by 86% and suppressed IRG by 53%. CHS (1 mM) and anti-S-14 LI further augmented stimulated IRI release, by 30%; although 16.7 mM glucose suppression of IRG was still maintained under these conditions, the quantitative IRG response was significantly greater. These results suggest that CHS induces an apparent loss of islet S-14 LI, and at high doses, of IRI as well, but has no effect on A cells. Complete islet S-14 LI deficiency augments IRI and IRG secretion over a wide range of glucose concentrations, suggesting a physiological role of D cells on B cell and A cell regulation. D cell modulation of B cells requires cellular but not extracellular S-14 LI, being mediated probably though direct intracellular communication, whereas the A cells seem to be regulated by both direct contact as well as through locally secreted S-14 LI.

Effects of (−)-(R)-1-( p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat

Effects of the new cardiotonic and selective β 1-adrenergic agonist TA-064, (−)-(R)-1-( p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on circulating concnetrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg ( ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective β-adrenergic antagonist) and practolol (a selective β 1-adrenergic antagonist). The non-selective β-adrenergic agonist isoproterenol and the selective β 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective β 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the β-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.

Islet-activating protein (IAP)-induced adrenergic modulation of pancreatic A and B cell in dogs.

Islet-activating protein (IAP) is a substance purified from the culture medium of Bordetella pertussis, and its main action is characterized by the enhancement of secretory response to glucose and other stimuli in pancreatic islet. In this experiment, the effect of IAP on epinephrine-induced secretion of immunoreactive insulin (IRI) and glucagon (IRG) was investigated in normal dogs. Epinephrine suppressed IRI secretion and it had a little increment to IRG secretion in control group, while IRI and IRG secretions were significantly increased by epinephrine in IAP pretreated group. Using beta-blocker (Propranolol) with epinephrine, these increments of IRI and IRG secretions in IAP pretreated group were abolished. However, using alpha-blocker (Phentolamine) with epinephrine, these secretions of IRI and IRG in IAP pretreated group were much more increased than epinephrine alone induced secretions. Blood glucose levels were lower in IAP pretreated group than in control group throughout the loading tests in all of the experiments. These findings suggest that (1) IAP decreases blood glucose level and (2) IAP enhances epinephrine-induced secretion of insulin and glucagon by acceleration of beta-adrenergic effect and by reduction of alpha-adrenergic suppression in dogs.

Plasma responses of pancreatic polypeptide, glucagon and insulin in normal and alloxan diabetic dogs, and their regional levels in the pancreas

The plasma responses of pancreatic polypeptide (PP), glucagon (IRG) and insulin (IRI) after administration of beef soup were studied in normal and alloxan diabetic dogs kept in a poor metabolic state for 4 weeks, and their regional levels in the pancreas were determined and compared at the uncinate process, head, body and tail. The plasma PP levels of the diabetic dogs were significantly higher than those of the normal dogs and they increased after beef soup administration in both groups. The plasma IRG levels did not change significantly after beef soup administration in either group, but significantly high levels were found in the diabetic dogs. The IRI content in the normal dog pancreas was highest at the tail, followed in order by the body, head and uncinate process, and was decreased to about one-tenth to one-fortieth in the alloxan diabetic dogs. On the other hand, the amounts of PP in the pancreas of both normal and diabetic dogs were greatest at the uncinate process, followed in order by the head, body and tail. In an inverse relationship with the PP findings, the IRG content in the pancreas was highest at the tail and lowest at the uncinate process in both kinds of dogs. The differences in both PP and IRG between diabetic and normal dogs were generally not significant. These results show that irrespective of the high plasma levels of PP and IRG in the diabetic dogs, their levels in the pancreas did not change significantly.

Plasma responses and pancreatic content of pancreatic polypeptide, glucagon and insulin in alloxan diabetic and normal dogs and their immunohistological studies.

Responses of plasma pancreatic polypeptide (PP), glucagon (IRG) and insulin (IRI) after administration of beef soup were studied in normal and alloxan diabetic dogs and their regional content in the pancreas was determined in normal and four or twelve weeks alloxan diabetic dogs. Plasma PP levels of the diabetic dogs were significantly higher than those of the normal dogs and they increased after beef soup administration in both groups. Higher levels of IRG were also found in the diabetic dogs, although IRG increased significantly after beef soup ingestion only in normal dogs. The amounts of PP in the pancreas of normal and diabetic dogs were greatest at the uncinate process, followed in order by the head, body and tail. The IRG content in the pancreas was highest at the tail and lowest at the uncinate process in both dogs. The differences in both PP and IRG in pancreas between normal and diabetic dogs kept in a poor metabolic state for one or three months were not significant in any region of the pancreas. Immunocytochemical studies also suggested these findings. These results show that, irrespective of high plasma levels of PP and IRG in the diabetic dogs, their levels in the pancreas did not change significantly as also indicated by histological studies.

アルギニンおよびデキサメサゾン負荷後のケトーシス牛の血漿脂質と関連ホルモンの変動

Arginine treatment was performed on four cows with ketosis and two healthy cows. Other cows were treated with dexamethazone. Each cow received 320g of arginine or 20mg of dexamethazone into the jugular vein. After infusion, blood samples were collected 9-13 times from this vein to determine pancreatic insulin (IRI) and glucagon (IRG), and blood glucose and lipid components.Low responses of IRG and IRI were observed on two of the four cows affected with ketosis. They were also observed in the healthy cows and the other two affected cows after having recovered from ketosis. One of the affected cows showed extremely high levels of IRG and IRI after arginine treatment. Response of IRI was later than a rise in glucose in the affected cows treated with dexa-methazone, as compared with the healthy ones.From the results mentioned above it seemed that ketosis might be related to hormonal disturbance in glucose metabolism.