Glucagon Secretion In Rats Research Articles

Differential contribution of alpha and beta cell dysfunction to impaired fasting glucose and impaired glucose tolerance.

People with isolated impaired fasting glucose (IFG) have normal beta cell function. We hypothesised that an increased glucose threshold for beta cell secretion explains IFG. We used graded glucose infusion to examine the relationship of insulin secretion rate (ISR) and glucagon secretion rate (GSR) with rising glucose. We studied 39 non-diabetic individuals (53 ± 2 years, BMI 30 ± 1 kg/m2), categorised by fasting glucose and glucose tolerance status. After an overnight fast, a variable insulin infusion was used to maintain glucose at ~4.44 mmol/l (07:00 to 08:30 hours). At 09:00 hours, graded glucose infusion commenced at 1 mg kg-1 min-1 and doubled every 60 min until 13:00 hours. GSR and ISR were calculated by nonparametric deconvolution from concentrations of glucagon and C-peptide, respectively. The relationship of ISR with glucose was linear and the threshold for insulin secretion in isolated IFG did not differ from that in people with normal fasting glucose and normal glucose tolerance. GSR exhibited a single-exponential relationship with glucose that could be characterised by G50, the change in glucose necessary to suppress GSR by 50%. G50 was increased in IFG compared with normal fasting glucose regardless of the presence of impaired or normal glucose tolerance. These data show that, in non-diabetic humans, alpha cell dysfunction contributes to the pathogenesis of IFG independently of defects in insulin secretion. We also describe a new index that quantifies the suppression of glucagon secretion by glucose.

1376-P: Comparison of a-Cell Response to Intravenous or Oral Glucose in Nondiabetic Humans

Type 2 Diabetes (T2DM) and prediabetes are characterized by β-cell and α-cell dysfunction which can occur independently. Defects in α-cell response to rising glucose can be evaluated with an oral or intravenous challenge: the former reflects normal physiology, the latter is unaffected by incretins or gut motility. We compared Glucagon Secretion Rate (GSR) in response to rising glucose during a Graded Glucose Infusion (GGI) and an Oral Glucose Tolerance Test (OGTT) . We studied 39 non-diabetic, weight-stable subjects (53 ± 2 yrs, 29 ± 1 Kg/M2) , with different fasting and glucose tolerance status. All subjects underwent a 75g OGTT and a GGI, with glucose infusion doubling every hour for 4 hours. GSR was calculated by deconvolution from plasma concentrations of glucagon on both study days (GSRGGI and GSROGTT) . The suppression of GSRGGI could be described with a single-exponential relationship between GSR and glucose concentrations. The slope of the log-transformed secretion line allows estimation of the change in glucose necessary to suppress GSR by 50% (G50) . This index of suppressibility is elevated in people with impaired fasting glucose compared to normal fasting glucose (2.7 ± 0.2 vs. 3.8 ± 0.4 mmol/L, p=0.01) . Intriguingly, GSROGTT, exhibited a delayed response to rising glucose (compared to GSRGGI) , during the early part of the OGTT. However, the relationship of GSROGTT to glucose did not differ from that of GSRGGI during the fasting state and at the time of peak postprandial suppression. This allowed the calculation of G50 during the OGTT, which was similar to that observed during the GGI (R2=0.66) and correlated with weight, age and fasting glucose (R2=0.49) . These data demonstrate the ability of a novel index (G50) , to reproducibly quantify α-cell suppression by oral or intravenous glucose in non-diabetic subjects. Future studies will be necessary to determine if this relationship also applies to T2DM and how gastrointestinal and other factors alter the rate of GSR suppression during an OGTT. Disclosure M.C.Laurenti: None. A.Manduca: None. C.Cobelli: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. Funding National Institutes of Health (DK078646, DK116231)

263-OR: Higher Glycemic Threshold for Glucagon Suppression in Impaired Fasting Glucose and Impaired Glucose Tolerance

Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. Graded Glucose Infusion (GGI) is a technique used to assess Insulin Secretion Rate (ISR) in response to rising glucose concentrations. We used GGI to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 32 nondiabetic, weight-stable individuals (54 ± 2 yrs, 29 ± 1 Kg/M2) categorized on the basis of fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/L (until 08:30) enabling the subsequent measurement of the glycemic threshold for ISR and GSR. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. β-cell responsivity (Φ) was estimated from the relationship of ISR to glucose. The glycemic threshold for glucagon suppression was higher in subjects with impaired fasting glucose (IFG) than normal fasting glucose (NFG), 10.9 ± 0.8 vs. 8.3 ± 0.5 mmol/L, p<0.01, IFG vs. NFG respectively. This was also the case in subjects with impaired glucose tolerance (IGT) compared to normal glucose tolerance (NGT), 10.3 ± 0.7 vs. 8.5 ± 0.7 mmol/L, p=0.05. Φ did not differ in subjects with IGT vs. NGT (p=0.33) or in subjects with IFG vs. NFG (p=0.48). The glycemic threshold for stimulation of ISR was higher in subjects with IFG than NFG, 5.7 +/- 0.3 vs. 5.0 +/- 0.1 mmol/L, p<0.01, IFG vs. NFG respectively, but no different in subjects with IGT vs. NGT, 5.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/L, p=0.06, IGT vs. NGT respectively. These data show that in nondiabetic humans, IFG but not IGT is associated with a higher glycemic threshold for insulin secretion, and both IFG and IGT are associated with a higher glycemic threshold for glucagon suppression. Disclosure J. D. Kohlenberg: None. M. C. Laurenti: None. A. M. Egan: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk. Funding Endocrine Fellows Foundation (DK078646DK116231)

Hypoglycemia attenuates acute amylin-induced reduction of food intake in male rats

The ability of amylin to inhibit gastric emptying and glucagon secretion in rats is reduced under hypoglycemic conditions. These effects are considered part of a fail-safe mechanism that prevents amylin from further decreasing nutrient supply when blood glucose levels are low. Because these actions and amylin-induced satiation are mediated by the area postrema (AP), it is plausible that these phenomena are based on the co-sensitivity of AP neurons to amylin and glucose. Using hyperinsulinemic glucose clamps in unrestrained and freely-feeding rats, we investigated whether amylin's ability to inhibit food intake is also reduced by hypoglycemia (HYPO). Following an 18 h fast, rats were infused with insulin and glucose for 45 min to clamp blood glucose at baseline levels (between 90 and 100 mg/dL). HYPO (approximately 55 mg/dL) was induced between 45 and 60 min and then maintained for the remainder of the clamp. Rats were injected with amylin (20 µg/kg) or saline and offered normal chow at 85 min. Food intake was measured at 30 and 60 min after amylin. Control hyperinsulinemic/euglycemic (EU) rats were maintained at approximately 150 mg/dL (which is a physiological periprandial glucose level) before and after amylin injection. Terminal experiments tested the effect of amylin to induce the phosphorylation of ERK, a marker of amylin action in the AP, in EU and HYPO conditions. Amylin significantly reduced 30- and 60-min food intake in EU rats, but the effect at 60-min was attenuated in HYPO rats. Interestingly, glucose infusion rate had to be dramatically reduced at meal onset in saline-treated, but not in amylin-treated, EU or HYPO rats; this suggests that meal-related glucose appearance in the blood was inhibited by amylin under both EU and HYPO. Finally, amylin induced a similar pERK response in the AP in EU and HYPO rats. We conclude that amylin's action to decrease eating is blunted in hypoglycemia, and this effect seems to be downstream from amylin-induced pERK in AP neurons. These data allow us to extend the idea of a hypoglycemic brake on amylin's actions to its food intake-reducing effect, but also demonstrate that amylin can buffer meal-induced glucose appearance at EU and HYPO levels.

Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes.

Glucagon is a metabolically important hormone, but many aspects of its physiology remain obscure, because glucagon secretion is difficult to measure in mice and rats due to methodological inadequacies. Here, we introduce and validate a low-volume, enzyme-linked immunosorbent glucagon assay according to current analytical guidelines, including tests of sensitivity, specificity, and accuracy, and compare it, using the Bland-Altman algorithm and size-exclusion chromatography, with three other widely cited assays. After demonstrating adequate performance of the assay, we measured glucagon secretion in response to intravenous glucose and arginine in anesthetized mice (isoflurane) and rats (Hypnorm/midazolam). Glucose caused a long-lasting suppression to very low values (1-2 pmol/l) within 2 min in both species. Arginine stimulated secretion 8- to 10-fold in both species, peaking at 1-2 min and returning to basal levels at 6 min (mice) and 12 min (rats). d-Mannitol (osmotic control) was without effect. Ketamine/xylazine anesthesia in mice strongly attenuated (P < 0.01) α-cell responses. Chromatography of pooled plasma samples confirmed the accuracy of the assay. In conclusion, dynamic analysis of glucagon secretion in rats and mice with the novel accurate sandwich enzyme-linked immunosorbent assay revealed extremely rapid and short-lived responses to arginine and rapid and profound suppression by glucose.

Can somatostatin antagonism prevent hypoglycaemia during exercise in type 1 diabetes?

The prevention and management of exercise-induced hypoglycaemia remains a challenge for patients with type 1 diabetes. Strategies involving changes to insulin dosing and/or carbohydrate consumption in anticipation of or during different types of exercise have proved to be helpful but not sufficient to fully prevent the hypoglycaemic risk. Meanwhile, the defect in glucagon secretion in response to hypoglycaemia in diabetes and the contributory role of somatostatin to this dysregulation constitute an important therapeutic target. In this issue of Diabetologia (DOI 10.1007/s00125-016-3953-0 ), Leclair et al show that selective somatostatin receptor 2 antagonists can enhance glucagon secretion in rats with streptozotocin-induced diabetes during exercise. The implications of their interesting findings are discussed, as well as limitations and potential for clinical applications, together with other glucagon-based options for tackling exercise-induced hypoglycaemia in diabetes.

Investigation of Transport Mechanisms and Regulation of Intracellular Zn2+ in Pancreatic α-Cells

During insulin secretion, pancreatic alpha-cells are exposed to Zn(2+) released from insulin-containing secretory granules. Although maintenance of Zn(2+) homeostasis is critical for cell survival and glucagon secretion, very little is known about Zn(2+)-transporting pathways and the regulation of Zn(2+) in alpha-cells. To examine the effect of Zn(2+) on glucagon secretion and possible mechanisms controlling the intracellular Zn(2+) level ([Zn(2+)](i)), we employed a glucagon-producing cell line (alpha-TC6) and mouse islets where non-beta-cells were identified using islets expressing green fluorescent protein exclusively in beta-cells. In this study, we first confirmed that Zn(2+) treatment resulted in the inhibition of glucagon secretion in alpha-TC6 cells and mouse islets in vitro. The inhibition of secretion was not likely via activation of K(ATP) channels by Zn(2+). We then determined that Zn(2+) was transported into alpha-cells and was able to accumulate under both low and high glucose conditions, as well as upon depolarization of cells with KCl. The nonselective Ca(2+) channel blocker Gd(3+) partially inhibited Zn(2+) influx in alpha-TC cells, whereas the L-type voltage-gated Ca(2+) channel inhibitor nitrendipine failed to block Zn(2+) accumulation. To investigate Zn(2+) transport further, we profiled alpha-cells for Zn(2+) transporter transcripts from the two families that work in opposite directions, SLC39 (ZIP, Zrt/Irt-like protein) and SLC30 (ZnT, Zn(2+) transporter). We observed that Zip1, Zip10, and Zip14 were the most abundantly expressed Zips and ZnT4, ZnT5, and ZnT8 the dominant ZnTs. Because the redox state of cells is also a major regulator of [Zn(2+)](i), we examined the effects of oxidizing agents on Zn(2+) mobilization within alpha-cells. 2,2'-Dithiodipyridine (-SH group oxidant), menadione (superoxide generator), and SIN-1 (3-morpholinosydnonimine) (peroxynitrite generator) all increased [Zn(2+)](i) in alpha-cells. Together these results demonstrate that Zn(2+) inhibits glucagon secretion, and it is transported into alpha-cells in part through Ca(2+) channels. Zn(2+) transporters and the redox state also modulate [Zn(2+)](i).

Protein tyrosine phosphatase 1B is located with glucagon vesicles, and its concentration is inversely correlated with the rate of glucagon secretion of INR1G9 cells.

High concentrations of protein tyrosine phosphatase (PTP) were found with secretory vesicles of glucagon-producing INR1G9 cells by electron microscopic immunocytochemistry, using a polyclonal antiserum specific for the PTP1B/T-cell (TC)PTP subfamily of PTP. Since TCPTP protein and mRNA were below the detection limit in the cells but significant amounts of PTP1B and mRNA were recognised by a specific monoclonal antibody and a mRNA probe we conclude, that the PTP associated with the vesicles is PTP1B. Only reverse transcriptase (RT)-PCR with primers specific for PTP1B yielded a product of the expected nucleotide sequence. Thus, we conclude that the PTP associated with the vesicles is PTP1B. The presence of vanadate for 48 h attenuated PTP1B expression and caused reduction of steady-state levels of the phosphatase. These conditions also led to a continuing increase in the steady-state rate of glucagon release by the cells. This rate and tyrosine phosphatase levels showed an inverse relationship, suggesting a suppressive role of PTP1B on the regulated secretion of glucagon by INR1G9 cells.

Defective Insulin and Glucagon Secretion in Isolated Perfused Pancreata of Diabetic WBN/Kob Rats

To elucidate the pathophysiology of diabetes mellitus in male WBN/Kob rats, we performed pancreatic perfusion experiments and histopathological studies. Intraperitoneal glucose tolerance tests showed a diabetic pattern in 12-month-old WBN/Kob rats. In perfused pancreata of WBN/Kob rats, both the first and the second phases of insulin secretion in response to a 16.7 mM glucose challenge were markedly reduced compared with those in age-matched Wistar rats (p < 0.01, respectively). Furthermore, the insulin secretion rate in response to glucopenia (1.4 mM) was significantly higher (p < 0.05) and the decrement in insulin secretion was significantly lower (p < 0.05) in WBN/Kob rats. The decrement in glucagon secretion with 16.7 mM glucose was significantly blunted (p < 0.001), and the glucagon secretion rate in response to glucopenia was also significantly lower in WBN/Kob rats than in controls (p < 0.01). Although insulin secretion in response to 10 mM arginine was also moderately reduced in WBN/Kob rats (p < 0.05), the glucagon secretion rates in response to 10 mM arginine were similar in the two groups. Histopathological examination revealed widespread disappearance of acinar cells and islets, inflammatory changes, and marked fibrosis in the pancreata of WBN/Kob rats. Immunohistochemical studies showed decreased numbers of B cells in the islets of WBN/Kob rats. These findings suggest that this WBN/Kob rat strain is a useful model for studying not only pathogenesis, but also pathophysiology, i.e., defective hormonal secretion, in some types of human diabetes mellitus.

Specific Inhibition of Rat Pancreatic Insulin or Glucagon Release by Receptor-Selective Somatostatin Analogs

A group of new peptide ligands displaying high selectivity for binding to somatostatin receptor subtypes 2, 3 or 5 have been used to characterize somatostatin receptor involvement in the inhibition of glucagon secretion in rats. It was found that NC-8-12 and DC-25-100, which have high affinity for SSTR2 and much less affinity for the type 5 receptor, were by far the most potent inhibitors of glucagon secretion with EC(50)s of 48 and 18 nmole, respectively, relative to somatostatin itself(EC50 131 nmole). These two analogs were actually much less potent than somatostatin in inhibiting glucose-stimulated insulin release. In contrast, DC-23-99 (a type 5 receptor selective analog), which was previously found to be a more potent inhibitor of insulin secretion than somatostatin, had considerably less potent (EC50 410 nmole) effects on glucagon release. The SSTR3-specific ligands, DC-25-12 and DC-25-20, were not effective at the doses tested. The differing spectra of activities of these analogs suggest that inhibition of insulin and glucagon secretion in rats is mediated by entirely different somatostatin receptor populations.

Effects of diazoxide on α- and β-cell function in isolated perfused rat pancreas

To elucidate the effects of diazoxide on insulin and glucagon secretion at normal, high and low glucose concentrations and 10 mmol/l arginine, we performed pancreatic perfusion experiments. The insulin secretion rate in response to 16.7 mmol/l glucose was dose-dependently suppressed by concomitant infusion of diazoxide (100 and 300 μmol/l). Both the first and second phases of glucose-stimulated insulin secretion were significantly reduced in the presence of diazoxide as compared with controls. Basal glucagon secretion rate at 5.6 mmol/l glucose was significantly reduced by the administration of both 100 and 300 μmol/l diazoxide. Furthermore, the glucagon secretion rate at a high glucose concentration (16.7 mmol/l) was significantly lower with 300 μmol/l diazoxide than in the control. The glucagon secretion rate with glucopenia (1.4 mmol/l) was also significantly lower with 100 and 300 μmol/l diazoxide than in the control. The insulin secretion rate in response to 10 mmol/l arginine was also dose-dependently suppressed by concomitant infusion of diazoxide. The glucagon secretion rate in response to 10 mmol/l arginine was, however, significantly higher with 100 μmol/l diazoxide while not being significantly different with 300 μmol/l diazoxide. These findings suggest that some mechanism(s) which can be inhibited by diazoxide is involved in glucagon, as well as insulin, secretion in isolated perfused rat pancreas.

Alpha 2-adrenergic modulation of pancreatic glucagon secretion in rats

The present study was designed to clarify the mechanism of adrenergic modulation of pancreatic glucagon secretion in rats under physiological conditions by 1) epinephrine infusion alone or together with adrenergic blockers and 2) administration of adrenergic agonists. Intravenous infusion of epinephrine alone (1 μg/kg/min, equal to 0.7 nmol/kg/min) caused a significant increase in glucagon secretion. Phentolamine (an alpha blocker) or yohimbine (an alpha 2 blocker) administration completely inhibited the increase of glucagon secretion caused by epinephrine infusion, but neither the administration of bunazosin (an alpha 1 blocker) nor beta blockers inhibited it. Infusion of clonidine (an alpha 2 agonist) caused significant increase of glucagon secretion even at a low dose of 0.5 nmol/kg/min, although infusion of neither an alpha 1 nor a beta 2 agonist caused it even at the high dose of 40.0 nmol/kg/min. It is concluded that the alpha 2 receptor mechanism plays the most important role in the adrenergic modulation of glucagon secretion in rats under physiological conditions.

Selective stimulation of glucagon secretion by β2‐adrenoceptors in isolated islets of Langerhans of the rat

1. In rat isolated islets of Langerhans the selective beta 2-adrenoceptor agonist, clenbuterol (1 to 20 microM), significantly increased the level of adenosine 3':5'-cyclic monophosphate (cyclic AMP) within 2 min of incubation. 2. The cyclic AMP response to clenbuterol was inhibited in the presence of the selective beta 2 adrenoceptor antagonist, ICI 118551 (0.1 or 10 microM) but remained unchanged when the beta 1-antagonist, atenolol (0.1 microM) was administered. 3. Despite causing an elevation in cyclic AMP, clenbuterol (up to 20 microM) failed to influence insulin secretion at any glucose concentration tested, even in the presence of a phosphodiesterase inhibitor. 4. By contrast, clenbuterol elicited a dose-dependent rise in the rate of glucagon secretion; the maximal agonist-induced increase in secretion was two fold, a response equivalent to that observed with 20 mM L-arginine. 5. ICI 118551 significantly inhibited the rise in glucagon secretion induced by clenbuterol (up to 20 microM). 6. The results indicate that the rat islet A cell population is equipped with functional beta 2-adrenoceptors which influence glucagon secretion via the second messenger cyclic AMP, but that the B cells are deficient in functional beta-receptors.

Insulin and glucagon secretion in rats: effects of calcitonin gene-related peptide

Immunoreactive calcitonin gene-related peptide (CGRP) has been shown to occur in intrapancreatic nerves and islet somatostatin cells in the rat. Therefore, we investigated the effects of CGRP on insulin and glucagon secretion in the rat. CGRP was infused i.v. at one of 3 dose levels (4.3, 17 or 68 pmol/min). Infusion of CGRP alone was found to elevate basal plasma levels of both insulin and glucagon. In contrast, CGRP impaired the plasma insulin responses to both glucose (7 mg/min; P < 0.001) and arginine (8.5 mg/min; P < 0.001), and inhibited the arginine-induced increase in plasma glucagon concentrations ( P < 0.001). Since CGRP and somatostatin are colocalized within the D-cells, we also infused CGRP and somatostatin together at equimolar dose levels (17 pmol/min), with glucose (7 mg/min). By that, the increase in plasma insulin concentrations decreased more rapidly than during infusion of either peptide alone. Since α 2-adrenoceptor activation is known to inhibit glucose-stimulated insulin secretion, we also infused CGRP together with the specific α 2-adrenoceptor antagonist yohimbine (37 nmol/min). In that way, the plasma insulin-lowering effect of CGRP was prevented. We have shown in the rat: (1) that CGRP stimulates basal insulin and glucagon secretion; (2) that CGRP inhibits stimulated insulin and glucagon secretion; (3) that CGRP and somatostatin more rapidly induce a potent inhibitory action on glucose-stimulated insulin secretion when given together; and (4) that the α 2-adrenoceptor antagonist, yohimbine, counteracts the inhibitory action of CGRP on glucose-stimulated insulin secretion. We suggest that CGRP is of importance for the regulation of insulin and glucagon secretion in the rat. The mechanisms behind the islet effects of CGRP can not be established by the present results, though they apparently require intact α 2-adrenoceptors.

The effect of mazindol on insulin and glucagon secretion in rats with ventromedial hypothalamic obesity

<b>The effect of mazindol on insulin and glucagon secretion in rats with ventromedial hypothalamic </b><b>obesity </b>

Epinephrine potentiates adenosine-stimulating effect on glucagon secretion.

The aim of the present work is to investigate a possible interaction on glucagon secretion between adenosine, a compound released by tissues in energy-deficient states, and epinephrine, the hormone of stress largely implicated in such conditions. The study was performed using the isolated perfused rat pancreas in presence of a physiological glucose concentration (5 mM). Epinephrine administered at a low concentration (0.01 microM) was ineffective on glucagon secretion, and adenosine at 1.65 microM was previously shown to be moderately stimulating. This nucleoside alone induced a transient increase of glucagon secretion rate that peaked at 300% of basal value at 2 min; in presence of epinephrine (ineffective per se) the rise induced by the nucleoside alone was doubled. This potentiating effect was not observed with the neurotransmitter norepinephrine at the dose tested. Propranolol (1 microM) did not alter the potentiating effect of epinephrine but this effect was completely suppressed by the alpha-blocker, phenoxybenzamine (6 microM). In conclusion epinephrine potentiates an adenosine-stimulating effect on glucagon secretion; this effect seems more specific for the adrenal medulla hormone epinephrine, since norepinephrine at the same dose is ineffective; it is mediated via alpha-adrenergic receptors. It is attractive to speculate that epinephrine and adenosine act in potentiating synergism on glucagon secretion; this might be of physiological importance during stressful energy-deficient situations.

Restoration of the A cell response to glucose in isolated rat islets of Langerhans

This study investigated the modulatory effects of forskolin, phorbol 12-myristate 13-acetate (PMA) and arginine on pancreatic glucagon secretion in response to changes in glucose concentrations. Glucose, on its own (0, 5, 9 and 18 mM), did not modify glucagon secretion from A cell-rich isolated rat islets of Langerhans. In the presence of 20 μM forskolin, glucagon release was stimulated dose-dependently on lowering the external glucose concentration to 0 mM. Sensitivity to glucose was achieved in the presence of either PMA or arginine; both agents also significantly enhanced glucagon release at all glucose concentrations tested. The responses of the B cells in these experiments were as expected from the available literature. These results indicate that (a) the endogenous rate of glucagon secretion in the isolated islet preparation was minimal and was insensitive to glucose, (b) sensitivity of the A cells to glucose could be restored by either arginine or agents which alter the concentration or activity of proposed cellular second messengers.

Hepatic glucagon clearance during insulin induced hypoglycemia.

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Maternal Zinc Deficiency of Food Restriction on Rat Fetal Pancreas. 2. Insulin and Glucagon

The influence of a maternal dietary deficiency of zinc, or food restriction on the content and in vitro secretion of pancreatic hormones was measured in rat fetuses on day 19 of gestation. Pregnant Sprague-Dawley rats were fed a zinc-deficient diet (0.4 ± 0.1 ppm zinc) ad libitum or a zinc-supplemented control diet (100 ppm zinc) either ad libitum or with restricted intake. The insulin content of the fetal pancreas was lower in fetuses from rats subjected to zinc deprivation or to food restriction than in controls. The lower insulin content of fetal pancreata from zinc-deficient rats was related to a lower than normal proportion of insulin-containing beta cells. The lower insulin content of fetal pancreata from rats subjected to food restriction was related to a less than normal amount of insulin per beta cell. Glucagon concentration in the fetal pancreas was lower than normal in response to zinc deficiency but not to food restriction. Fetal hormone release in vitro was also influenced by the maternal diet. The rate of insulin secretion in vitro was normal in fetuses from zinc-deficient rats, but was accelerated in those from females subjected to calorie restriction. The rate of glucagon secretion in vitro was lower than normal in the pancreata of zinc-deficient fetuses. We conclude that insulin and glucagon levels in the fetus were affected by maternal zinc deficiency and, to a lesser extent, by calorie restriction.zinc deficiency calorie restriction insulin glucagon pancreatic enzymes

Glucagon secretion in rats with islet cell tumors induced by streptozotocin.

Glucagon secretion in rats with islet cell tumors induced by streptozotocin.