Immunoreactive Insulin Secretion Research Articles

Insulin and C-Peptide Secretion in Non-Obese Patients with Polycystic Ovarian Disease

Plasma glucose, immunoreactive insulin (IRI) and C-peptide responses during an oral glucose tolerance test (oGTT) were assessed in 11 non-obese patients with polycystic ovarian disease (PCOD) and 11 reference subjects matched for age, height and weight. Also, 6 patients with PCOD and 6 normal women were subjected to intravenous glucose tolerance testing (ivGTT) On oGTT, all subjects exhibited normal glucose tolerance; however, PCOD patients had significantly higher mean plasma glucose levels at 30, 60, 90 and 120 min and higher mean incremental glucose areas. In addition the patients with polycystic ovaries showed higher mean basal IRI and C-peptide levels, higher mean glucose stimulated IRI and C-peptide levels and higher mean incremental IRI and C-peptide values. The molar ratios of C-peptide/IRI were significantly lower in the PCOD group at all time intervals after glucose stimulation when compared to the normal women. During ivGTT, there were significantly higher mean glucose levels at 5, 40, 50 and 60 min in the PCOD group when compared to the reference group. The IRI response to intravenous glucose in the PCOD women was similar to the reference group. The findings on oGTT suggest that non-obese patients with PCOD have increased pancreatic IRI secretion as well as impaired hepatic extraction of the hormone.

Islet secretion of immunoreactive thyrotropin-releasing hormone and the 'paracrine-like' effects of its exogenous administration.

In order to know more about the secretory pattern of islet TRH in response to glucose and its possible physiological relevance, the release of this hormone as well as that of insulin, glucagon, and somatostatin was radioimmunologically measured. Whereas the secretion of immunoreactive insulin and somatostatin by incubated rat islets is known to be dose-dependently stimulated by glucose, that of glucagon and TRH was inhibited by glucose. Similarly, palmitate dose-dependently inhibited islet glucagon and TRH release. Exogenous TRH exerted strong and dose-dependent effects on islet secretion of the other hormones at the same concentration range at which its hypophysiotropic effects are produced (10(-10) to 10(-8) mol/l). It inhibited the insulin response to glucose and blocked that of glucagon, whereas it enhanced glucose-induced stimulation of somatostatin. These results are suggestive of a possible paracrine inhibitory role of islet TRH, either directly exerted on the secretion of insulin and glucagon or partially mediated through the stimulation of somatostatin release.

Reversible impairment of glucose-induced insulin secretion in SHR/N-cp rats. Genetic model of type II diabetes.

The SHR/N-cp rat is a new genetically obese model for non-insulin-dependent diabetes mellitus. Expression of the diabetes is enhanced by a high-sucrose (54%) diet. After 4 wk on the diet, the cp/cp rats weigh significantly more than their +/? controls, have postprandial hyperglycemia (greater than 400 mg/dl), and are hyperinsulinemic, with immunoreactive insulin (IRI) levels 10- to 20-fold greater than controls. Total pancreatic IRI tends to be increased 1.6-fold in the cp/cp rats (although not significantly). There is no increase in pancreatic proinsulin content as a percent of total IRI. Studies of in vitro pancreatic function were carried out with the isolated nonrecirculating perfused pancreas method. The cp/cp rats (n = 10) showed impaired or absent IRI responses to 16.5 mM glucose, whereas +/? rats (n = 9) responded with classic biphasic curves. Comparison of insulin secreted in 20 min revealed a greater than 53% decrease in IRI secretion in cp/cp rats (P less than .05). A paradoxical hypersecretion of IRI at glucose concentrations of 0-2.7 mM was noted in cp/cp but not lean rats, i.e., 1.8 +/- 0.2 mU/min IRI in cp/cp rats vs. 0.04 +/- 0.007 mU/min in +/? rats. Perfusion of pancreases for 45 min with buffers containing no glucose resulted in restoration of a normal biphasic IRI response to 16.5 mM glucose in the cp/cp rats, whereas response in the lean rats was markedly reduced. Brisk IRI responses to 10 mM arginine in buffers with no glucose also occurred in cp/cp but not +/? rats. Glucagon secretion was relatively suppressed in the cp/cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Preventive action of phentolamine on adrenaline induced blood glucose elevation in humans.

A comparison of the action of adrenaline infusion and a combined adrenaline + alpha blocker (phentolamine, Regitine) infusion on blood glucose (BG), plasma immunoreactive insulin (IRI), BG/IRI ratio, C-peptide, and plasma cortisol levels was made in healthy young human subjects. The purpose of the experiment was to check, whether alpha block could abolish adrenaline-induced enhancement of blood glucose levels. The results show that during enhanced adrenaline levels, the use of regitine could indeed normalize blood glucose levels, not so much by increasing the IRI secretion, but by diminishing adrenaline-induced liver glycogenolysis via alpha receptors. This could be a model to prevent stress (adrenaline) induced metabolic deviations in diabetics, especially before and during predictable stress situations, e.g. examinations or surgery.

Insulinotropic effects of vanadate.

Vanadium compounds are known to affect multiple membrane and cytosolic phosphoenzymes from various tissues; the most characterized effect is the inhibition of Na+-K+-ATPase. Since we previously reported that immunoreactive insulin (IRI) secretagogues tend to inhibit rat islet cation-dependent ATPases, we examined the effects of sodium vanadate on rat IRI secretion from incubated and perifused rat islets. In the presence of 2.4 mM Ca2+, vanadate (10(-3) M) induced biphasic IRI secretion with a background glucose of 100 mg/dl. In the absence of extracellular Ca2+, IRI released from incubated islets by vanadate at 100 and 300 mg/dl glucose was doubled and tripled, respectively. Furthermore, this stimulatory effect was completely abolished by known inhibitors of IRI release such as somatostatin, epinephrine, and diphenylhydantoin. Although we found the expected dose-dependent inhibition by vanadate of islet membrane Na+-K+-ATPase activity, the mechanism of action of vanadate on IRI secretion remains unknown. Vanadate probably interacts in a complex fashion with different islet phosphoenzymes and may prove to be a useful probe to further unravel the mechanisms leading to insulin secretion.

Insulin secretion and glucose tolerance in patients with chronic bronchitis and bronchial asthma

Risk factors in the development of diabetes are various diseases of internal organs, especially those accompanied by inflammatory process.
 We investigated insulin secretion and glucose tolerance in patients with chronic bronchitis and bronchial asthma. There were 29 patients under observation: 21 patients were diagnosed with chronic bronchitis and 8 with bronchial asthma. Glucose tolerance was determined in all patients (50 g of glucose orally). Blood glucose content was determined by orthotoluidine method on an empty stomach, as well as 1 and 2 hours after glucose intake. At the same time, basal immunoreactive insulin secretion was studied.

Studies of midaglizole (DG-5128). A new type of oral hypoglycemic drug in healthy subjects.

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a novel alpha 2-adrenoceptor antagonist. Its effects on plasma glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) in healthy male volunteers were investigated. Volunteers received single oral administrations of midaglizole (150-500 mg), multiple increasing oral administration on 3 separate days (150-300 mg 3 times daily), or successive daily oral administration for 1 wk (200 mg 3 times daily). The hypoglycemic action of midaglizole was observed within 0.5-1.0 h after its administration and thereafter for 5 h. The maximum hypoglycemic effect was found 1.0-1.5 h after administration. Midaglizole decreased postprandial hyperglycemia in a dose-dependent manner. In the fasting state, midaglizole significantly increased IRI secretion and suppressed IRG secretion. Midaglizole inhibited epinephrine-induced platelet aggregation after successive administration for 1 wk (200 mg 3 times daily). The plasma half-life of midaglizole was only 3 h, and the drug was rapidly excreted into the urine and feces, with greater than 80% in its unchanged form, within 24 h. Midaglizole did not affect the results of any clinical or laboratory tests performed. Our data indicate that midaglizole is a possible hypoglycemic agent. Further clinical investigations are required to confirm its effects on diabetes mellitus.

Induction of insulin release in fibroblasts transfected with genomic rat islet DNA

L cells (tk −) were cotransfected with total genomic rat islet DNA and a plasmid containing thymidine kinase gene (ptk). Transfectants were tested for their ability to release insulin into the medium. At least 10% of the colonies contained immunoreactive insulin (IRI) during the initial two weeks. The insulin secreted competed linearly with rat insulin in RIA, the majority of the insulin antigenicity comigrating with rat insulin on G-50 Sephadex chromatography. With continuing propagation the IRI activity diminished; however 3 selected cultures demonstrated increased secretion of IRI following stimulation with glucose. These findings indicate that glucose-induced insulin secretion can be obtained in non-beta cells; however the frequency of success was below one stable transfection for every 5×10 8 Ltk − cells exposed to the transfection procedure.

Effect of epinephrine and norepinephrine on immuno-reactive insulin secretion from isolated islets of langerhans

Earlier studies have demonstrated the inhibitory nature of epinephrine and norepinephrine on pancreatic insulin release. The present study reports their effect on beta-cell IRI release in an isolated islet system. Results show that epinephrine and norepinephrine inhibit islet-IRI release at the 100-10 μM level. The alpha adrenergic blocker phentolamine (100 μM) but not the beta adrenergic blocker propranolol (100 μM) can reverse this catecholamine induced inhibition of islet-IRI release. This clearly suggests that epinephrine and norepinephrine inhibit insulin release via alpha-adrenergic pathway.

Influence of Ingested Load on Postprandial Insulin Secretion. Rôle of Gastric Inhibitory Polypeptide (GIP)

Two standard mixed meals including the same ingredients, and with different caloric values were ingested by 10 normal subjects. The plasma gastric inhibitory polypeptide (GIP) and immunoreactive insulin (IRI) as well as blood glucose (BG) were assayed during these meals at 0 (beginning of the meal) and after 30, 60, 120 and 180 min. BG was not significantly different between the two meals. At 30 min, the GIP peak was significantly higher in the case of the meal with the highest caloric (HC) value (499.5 +/- 112.0 vs. 273.4 +/- 57.5 pg/ml). Insulin was higher as well, although not in a significant way. At 120 min, the IRI was significantly higher (63.0 +/- 9.8 vs. 34.4 +/- 6.2 microU/ml) in the case of the HC meal. The HC meal induced a significantly higher insulinogenic index (0.29 +/- 0.05 vs. 0.14 +/- 0.07 mU litre g-1 ml-1). Integrated IRI and GIP responses of the HC meal were significantly higher than those of the meal with the lowest caloric value (IRI : 7.9 +/- 1.1 vs. 4.9 +/- 0.6 mU ml-1 180 min-1; GIP : 53.3 +/- 20.5 vs. 28.2 +/- 9.9 ng ml-1 180 min-1). The early (30 min) augmentation of IRI secretion after the ingestion of a larger meal is related to the insulinotropic action of the enhanced GIP secretion. The reasons for the late IRI increase are not obvious from this experiment. They might be of neural, nutrient, and/or intestinal origin.

Insulin suppressive effects of aminotetralin analogs and of dopamine

The study concerned the effects of 2-amino-6,7-(OH) 2-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN), dipropyl-A-6,7-DTN and dopamine on plasma levels of immunoreactive insulin (IRI) in cattle. During infusions of A-6,7-DTN, dipropyl-A-6,7-DTN and dopamine, the circulating levels of IRI decreased. In response to A-6,7-DTN, the levels of glucose increased whereas non-esterified fatty acids did not change. The decrease of IRI during additional infusions of A-6,7-DTN was not modified by prolonged administration of A-6,7-DTN. During infusions of A-6,7-DTN there was no increase in response to the administration of glucose and tolbutamide. However, if the β-adrenergic agonist isoproterenol was infused, IRI increased in the presence of A-6,7-DTN. During, infusions of the α-adrenergic blocking agent, phentolamine, levels of IRI increased within minutes while glucose did not change. Concomitant infusions of A-6,7-DTN and phentolamine caused IRI to decrease and the rise in glucose levels seen in the absence of phentolamine was inhibited. In conclusion, enhanced dopaminergic activity inhibited IRI secretion. The suppressive effects of A-6,7-DTN were due primarily to its dopaminergic properties, but A-6,7-DTN also possessed some characteristics of an α-adrenergic agonist. β-Adrenergic stimulation reversed the suppressive effects of A-6,7-DTN on IRI secretion.

Diabetogenic effect of pentamidine: In vitro and in vivo studies in a patient with malignant insulinoma

Pentamidine can cause hypoglycemia followed by hyperglycemia. The mechanism of this biphasic response is not known but has been reported to be similar to that of streptozotocin and N-3-pyridyl-N-p-nitrourea (Vacor). Pentamidine (4 mg/kg per day for 12 days) was used in a patient with malignant insulinoma after several unsuccessful debulking procedures and chlorozotocin therapy. Mean glucose and immunoreactive insulin levels (± SEM) before and after therapy were 80 ± 40 mg/dl versus 70 ± 50 mg/dl and 216 ± 12 μU/ml versus 198 ± 22 μU/ml, respectively. These were not significantly different. The patient's five-month-old malignant insulinoma monolayer cell culture was incubated with pentamidine (60 μg/ml) in the presence or absence of supplemented stimulatory medium consisting of glucose (300 mg/dl) and theophylline (20 μg/ml). Chloroquine (60 μg/ml) was added to inhibit lysosomal degradation of immunoreactive insulin. Aliquots of media for immunoreactive insulin determination were obtained at 30 minutes, 20 hours, 72 hours, and three weeks. The cells were examined by high-power light microscopy at each time interval. At 30 minutes, pentamidine alone caused passive release of immunoreactive insulin, 23 percent higher than control (p < 0.01). Stimulatory medium increased immunoreactive insulin 45 percent greater than control (p < 0.01). Pentamidine plus stimulatory medium had no additive effect on immunoreactive insulin released within 30 minutes. At the end of 20 hours, immunoreactive insulin was no different with pentamidine and/or stimulatory medium. However, the addition of chloroquine increased immunoreactive insulin by 35 percent above the medium with pentamidine and stimulatory medium (p < 0.01). At 72 hours, pentamidine suppressed immunoreactive insulin by 100 percent in all the media, irrespective of the presence or absence of stimulatory medium and/or chloroquine. At the end of three weeks, there was 50 percent suppression of immunoreactive insulin in the control medium, but pentamidine again completely suppressed immunoreactive insulin. High-power microscopy demonstrated intact cells in the control medium, whereas no cell structure could be detected in the media containing pentamidine at three weeks. In summary, pentamidine had no acute in vivo effect in a patient with malignant insulinoma. However, when used in an in vitro monolayer system, pentamidine caused (1) acute immunoreactive insulin release followed by inhibition of immunoreactive insulin secretion and (2) cytolysis of human malignant insulinoma cells in vitro.

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.

Effects of porcine secretin on exocrine and endocrine function in the isolated perfused rat pancreas.

The effects of both synthetic and pure natural porcine secretin on immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) release and on pancreatic exocrine secretion were studied in the isolated perfused rat pancreas. Synthetic porcine secretin stimulated a significant increase in pancreatic juice flow and amylase output at concentrations as low as 0.01 and 0.1 ng/ml, respectively. The maximal peak rate of both juice flow and amylase output was observed at 1 microgram/ml synthetic secretin. Synthetic secretin at concentrations up to 2 micrograms/ml and pure natural porcine secretin at a concentration of 1 clinical unit/ml had no effect on IRI secretion regardless of the glucose concentration (50, 100, or 150 mg/100 ml) in the perfusate. Both types of secretin, however, elicited a concentration-dependent increase in IRG secretion in the presence of 50 mg/100 ml glucose. The lowest synthetic secretin concentration causing a significant increase in IRG release was 0.1 ng/ml, and maximal stimulation was observed at 1 microgram/ml. These concentrations were similar to those eliciting minimal and maximal amylase release. Thus, synthetic and pure natural porcine secretin have been shown to not only stimulate pancreatic juice flow and amylase secretion but also to elicit IRG release from the isolated perfused rat pancreas.

Effect of Islet-Activating Protein (IAP), Purified from the Culture Medium of Bordetella pertussis, on the Secretion of Immunoreactive Insulin and Glucagon in Normal, Alloxan-Treated, and Depancreatized Dogs

Islet-activating protein (IAP) is a new active substance purified from the culture medium of Bordetella pertussis. This active protein possesses a molecular weight of 77,000 and an isoelectric point of pH 7.8. The nature of IAP action is characterized by the enhancement of insulin secretory response to glucose and other stimuli. In this experiment, the effect of IAP on the secretion of immunoreactive insulin (IRI) and glucagon (IRG) was investigated in conscious normal, alloxan-treated, and depancreatized dogs. On the 8th day after IAP injection, in normal and alloxan-treated dogs during the infusion of arginine or glucose, the plasma glucose level was lower and the IRI level was significantly higher compared with the saline controls. The IRG level showed no significant difference between IAP and saline control groups of normal dogs, but in alloxan-treated dogs the IRG level was significantly lower when compared with the saline control. This effect of IAP disappeared on the 30th day after injection in normal and alloxan-treated dogs. However, in depancreatized dogs, there was no effect on plasma glucose and gastrointestinal IRG levels. Anti-IAP antibody was not detected by PHA before or after IAP injection in any dogs, although a marked increase of heart rate was observed. These findings suggest that (1) IAP had an insulinotropic effect in dogs, (2) insulin deficiency induced by alloxan was partially overcome by IAP, (3) the effect of IAP on glucagon secretion might be secondarily related to the enhancement of insulin secretion, although a direct glucagon-lowering effect in alloxan-treated dogs could not be excluded, (4) a single administration of IAP did not produce anti-IAP antibody, and (5) an increase of heart rate was observed after IAP injection.

Adrenergic modulation of glucagon and insulin secretion in obese and lean humans.

The adrenergic modulation of immunoreactive insulin (IRI) and glucagon (IRG) secretion was studied in 5 massively obese subjects hospitalized ion a metabolic ward. Epinephrine was infused alone or in combination with propranolol, a beta adrenergic blocking drug, or with phentolamine, an alpha adrenergic blocking drug. Epinephrine infusion produced a significant (p less than .02) rise in IRG levels which was blocked by addition of either phentolamine or propranolol. Pure alpha adrenergic stimulation with propranolol-epinephrine infusion inhibited IRG secretion (p less than .02). IRI levels decreased with propranolol-epinephrine infusion (p less than .02), increased with phentolamine-epinephrine infusion, and were not affected by infusion of epinephrine alone. Glucose concentrations rose with all 3 infusions but were less with phentolamine-epinephrine. A control group of 4 lean outpatients on a ad lib diet demonstrated a similar pattern but the changes of IRG secretion were smaller than in the obese subjects and were not statistically significant. We conclude that in obese humans IRI secretion is increased by beta adrenergic stimulation, is decreased by alpha adrenergic stimulation, and is unaffected by combined alpha and beta adrenergic stimulation. In contrast, IRG secretion is stimulated by combined alpha and beta adrenergic stimulation, is inhibited by pure alpha adrenergic stimulation, and is unaffected by pure beta adrenergic stimulation.

The effect of sulpiride on the endocrine pancreas (author's transl)

In order to clarify the possible participation of dopaminergic control on the endocrine pancreas, a dopaminergic antagonist, sulpiride, was given intravenously to 12 normal subjects and 26 diabetics. After the intravenous administration of sulpiride with or without arginine HCl, blood samples were withdrawn at 0, 15, 30, 45, 60, 90 and 120 min and were stored at -20°C until the measurements of blood glucose, serum immunoreactive insulin (IRI) and plasma immunoreactive glucagon (IRG) were taken.In the first experiment, 100mg of sulpiride was administered solely to 5 normal subjects and 7 diabetics. Though blood glucose levels were not significantly changed, plasma IRG levels were significantly lower at 45 min after the injection in normal subjects and at each 30, 60 min in diabetics. From the results of the first experiment, sulpiride was thought to be able to suppress plasma IRG levels; then the second experiment was performed.In the second experiment, 7 normal subjects and 19 diabetics were employed. Both arginine HCl infusion and arginine HCl with 100mg sulpiride infusion were performed in order to compare the difference between IRI and IRG responses to the two provocations. In comparison with the arginine HCl infusion, IRI secretion seemed to be enhanced and IRG secretion seemed to be diminished in the simultaneous administration of arginine HCl and sulpiride. This was more obvious in comparing a glucagon or insulin area which was calculated by the integration of the curves circumscribed by a plasma IRG or serum IRI for the periods of 0-120 min. The glucagon area was significantly (p <0.05 in normal subjects; p <0.01 in diabetics) smaller in arginine HCl and sulpiride infusion than in arginine HCl alone. The insulin area seemed to be greater with the simultaneous administration of arginine HCl and sulpiride than with arginine HCl alone, but this difference was not significant.It was found through the two experiments that the dopamine antagonist, sulpiride, suppressed the basal and arginine-induced IRG secretion. Therefore, the results of the present study might suggest the existence of a dopaminergic system in the endocrine pancreas.

Ineffectiveness of protamine zinc somatostatin as a long-acting inhibitor of insulin and growth hormone secretion.

The present studies examined the duration of inhibitory action of a preparation of cyclic somatostatin (SRIF) in suspension with protamine zinc (PZ) on (1) physiologic growth hormone (GH) and immunoreactive insulin (IRI) secretion during feeding in the rat and (2) plasma IRI levels in a 10-year-old boy with idiopathic hyperinsulinemic hypoglycemia. Chronically cannulated adult male rats were administered 250 microgram PZ-SRIF subcutaneously twice daily at 12-h intervals for 7 days. Control animals received the PZ vehicle on the same schedule. On the test day, blood samples were obtained every 15 min for periods of 6 h following a single PZ-SRIF injection 1.5 h prior to sampling. Prominent GH secretory bursts were still evident in all PZ-SRIF-treated rats and these pulses occurred at the predictable time in relation to the light-dark cycle. Plasma IRI levels were typically elevated in response to feeding and no significant differences were observed in the mean 6-h GH, IRI, and glucose levels of PZ-SRIF-treated rats when compared with PZ-treated controls. In the boy with idiopathic hyperinsulinemic hypoglycemia, subcutaneous injection of 200 microgram PZ-SRIF depressed plasma IRI levels for only 30 min. These results suggest that PZ is not the agent of choice for significant prolongation of the inhibitory action of SRIF on IRI and GH secretion.

Role of the autonomic nervous system in the mediation of LHA electrical stimulation-induced effects on insulinemia and glycemia

The short-term effects of bilateral electrical stimulation of the lateral component of the lateral hypothalamic/medial forebrain bundle area (LHA) on peripheral plasma levels of glucose (G), immunoreactive insulin (IRI) and glucagon (IRG) were measured in food-deprived, anesthetized rats in the presence of continous low i.v. glucose infusion. In normal rats LHA stimulation induced a rapid but moderate rise in IRI in the presence of a simultaneous rapid rise in G. At the end of the 5 min stimulation period the glucose-induced IRI response was clearly attenuated. In rats receiving a continous phentolamine (i.v.) infusion, the rapid IRI response was much larger in spite of only marginal rises of G. These findings suggest that electrical LHA stimulation activates two opposing mechanisms on IRI secretion, an excitatory component which is masked in the normal animal by a sympathetic α-adrenergic inhibitory component. In an attempt to define the mediating pathway of this LHA stimulation-induced IRI excitatory component, both the parasympathetic and sympathetic divisions of the autonomic nervous system were pharmacologically and surgically manipulated, all in the presence of phentolamine infusion. Neither bilateral subdiaphragmatic vagotomy, atropine, propranolol infusion, nor spinal cord transection at T1 were able to block the IRI response. These findings are consistent with a humoral mediation of this IRI stimulatory response and support the existence of a lateral hypothalamic or hypophyseal factor which is released by LHA stimulation. The implications and physiological role of the LHA in the neural control of insulin secretion and ingestive behavior are discussed.

Adrenergic Modulation of Pancreatic Hormone Secretion in Utero: Studies in Fetal Sheep

To assess the functional maturity of adrenergic modulation of plasma concentration of glucose, as well as immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) secretion in utero, adrenergic agonists with or without beta (propranolol) or alpha (phentolamine) antagonists were infused to the chronically catheterized sheep fetus (n = 35) late in the third trimester. Mean +/- S.E. days at study was 129.5 +/- 1.5; term is 150 days. In 9 separate studies at gestational age 129 +/- 1 days, the infusion of saline for 3 hr was not associated with significant changes in the basal levels of glucose, IRG, or IRI. With epinephrine, 6 microgram/min (n = 6) glucose rose from 16.7 +/- 3.6 to 41.9 +/- 9.7 mg/dl, IRG rose from 75 +/- 8 to 219 +/- 45 pg/ml, and IRI fell from 22.6 +/- 1.7 to 12.7 +/- 3.5 microunits/ml (P less than 0.05 for each). Propranolol alone (n = 4) did not alter basal glucose or IRG but significantly suppressed IRI. Propranolol did, however, markedly attentuate the rise in glucose and IRG while exaggerating the fall in IRI during epinephrine infusion. Qualitatively similar but smaller responses were obtained with epinephrine, 0.4 microgram/min (n = 10). Similarly, elevation of glucose and suppression of IRI was obtained with norepinephrine, 2 microgram/min (n = 5), but IRG levels did not rise significantly. Alpha-Adrenergic blockade alone augmented IRI from 18 +/- 3 to 38 +/- 5 microunits/ml without affecting glucose or IRG concentrations; during alpha blockade, norepinephrine infusion failed to induce the rise in glucose, IRG remained unchanged, and IRI remained elevated (n = 5). 2-Deoxy-D-glucose, 200 mg IV over 30 min, did not affect glucose, IRG, or IRI (n = 5). Thus, appropriate adrenergic modulation of plasma concentrations of glucose, and of IRG and IRI secretion is established in the third trimester.