Doses Of Glucagon Research Articles

Glucagon increases medullary interstitial electrolyte concentration in rat kidney.

In anesthetized rats, tissue electrical admittance of the inner medulla (a measure of total ion concentration in the interstitium), medullary blood flow (laser Doppler technique), and renal clearances were measured simultaneously before and during i.v. infusion of glucagon at 110 and 330 ng.min-1.kg-1 body weight. Admittance increased modestly, 5.4% after a large glucagon dose (p < 0.01), whereas medullary blood flow was stable. Glomerular filtration rate increased transiently and then fell during high-dose glucagon infusion. The increase in tissue electrolyte (mostly NaCl) concentration in the medulla observed with stable medullary blood flow and decreasing glomerular filtration rate indicates that stimulation of NaCl reabsorption in the medullary ascending limb of Henle's loop by glucagon was the mechanism underlying augmentation of medullary ionic hypertonicity. This suggests that glucagon can contribute to the urine concentration process.

Ethanol-induced free radical injury to the hepatocyte glucagon receptor

Plasma membrane receptors are essential in cellular homeostasis. Free radical generation and catalytic iron have been implicated in alcohol-induced liver injury; damage to plasma membrane receptors may be one important mechanisms of injury. The effect of ethanol-induced free radicals on hepatocyte receptor dysfunction was investigated in rodent models of free radical injury due to chronic alcohol administration. Receptors for glucagon and their postreceptor signal transduction pathway (cyclic AMP production [cAMP]) were investigated as sites of free radical injury in isolated perfused livers. Glucagon-stimulated cAMP decreased (15%–80%) over a range of physiological (submaximal) doses of glucagon after 6 weeks of ethanol feeding, while free radical generation (alkane evolution) increased greater than three to fourfold over baseline (ethane; 2.04 ± 0.36 vs. 0.58 ± 0.08 pmole/10 6 cell/hr, p < 0.01; pentane 3.15 ± 0.30 vs. 0.91 ± 0.16, p < 0.01). Iron loading (125 mg/kg IP) potentiated this inhibition of cAMP production (40%–95%) and further increased alkane production twofold (ethane 4.29 ± 0.78, pentane 5.76 ± 0.71). Scatchard analysis revealed decreased numbers of glucagon receptors paralleling cAMP responses. Free radical damage to hepatocyte cell membrane receptors may be an important mechanism of alcohol-induced liver injury.

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.

Effects of Glucagon Infusion, Alone or in Combination with Somatostatin, on Plasma Growth Hormone and Metabolite Levels in Young Female Turkeys Under Different Feeding Regimens

The lipolytic effect of glucagon alone or in combination with somatostatin-14 (SRIF-14) was studied in 9- to 11-wk-old female turkeys that either consumed feed ad libitum or were deprived of feed (FD) for 20 h. During the infusion of various doses of glucagon (.005 to 1.5 μg glucagon/min), blood samples were serially collected every 10 min for determination of plasma concentrations of growth hormone (GH) and energy-related metabolites [nonesterified fatty acids (NEFA), glucose, and triacylglycerol (TG)]. Glucagon infusion resulted in decreases (P < .05) in plasma GH in both groups of turkeys. During glucagon infusion, dose-dependent increases in both glucose and NEFA occurred, with greater relative increases in the ad libitum turkeys. In contrast, plasma TG was decreased by glucagon infusion in the ad libitum turkeys but unchanged in the FD turkeys. The effect of simultaneous infusion of SRIF-14 and glucagon on GH and NEFA concentrations varied depending on the previous hormonal treatment. Plasma glucose was not affected by SRIF-14 in either group of turkeys. The present studies show that: 1) glucagon is an important agent for directing carbohydrate and lipid metabolism in growing female turkeys; 2) SRIF-14 has little effect on carbohydrate metabolism, but does affect lipolysis in a complex manner with glucagon; and 3) in vivo, glucagon depresses plasma GH.

Acute growth hormone effects on amino acid and lipid metabolism.

The anabolic actions of GH are well known, although specific tissue responses and the mechanism of nitrogen conservation are less well understood. This study was designed to examine the acute metabolic effects of GH on whole body and regional protein metabolism, using an experimental protocol which controlled for confounding perturbations in other hormones by a simultaneous infusion of somatostatin. Control subjects received replacement doses of insulin, glucagon, and GH for the entire 7-h study period, whereas GH subjects received an identical protocol, except for an increased dose of GH sufficient to increase serum concentrations into the high-physiological range (12-20 ng/mL) for the final 3.5 h of the study (P < 0.001). Thirteen young, healthy male subjects were studied in the postabsorptive period; five served as control subjects and eight as treatment (GH) subjects. Each received continuous iv infusions of somatostatin, L-[13-C]leucine, and L-[2H5]phenylalanine throughout the study. Femoral arterial and venous sampling allowed for simultaneous measurements across the leg and in the whole body. C-Peptide levels were suppressed throughout the infusion; insulin, glucagon, insulin-like growth factor I, cortisol, epinephrine, norepinephrine, and glucose concentrations were not different between groups. Glycerol concentrations increased 3-fold in GH subjects during the final 3.5-h period (P = 0.04). Concentrations of several amino acids declined through the study, but no differences were observed between treatment groups. Leucine oxidation was reduced in GH compared to control subjects (P = 0.04). No changes in CO2 production or whole body leucine or phenylalanine flux were observed, whereas nonoxidative disposal of leucine was marginally higher in GH compared to control subjects (P = 0.07). By contrast, rates of appearance and disappearance of both leucine and phenylalanine across the leg all were relatively lower in GH compared to control subjects; leucine balance across the leg was reduced by GH (P = 0.03), whereas phenylalanine balance was not influenced by GH. Our data thus demonstrate an acute stimulatory effect of GH on lipolysis, a decrease in leucine oxidation, and no stimulation of muscle protein synthesis in spite of enhanced protein synthesis in nonmuscle tissue.

Triiodothyronine Attenuates Somatostatin Inhibition of Broiler Adipocyte Lipolysis

A study with broiler adipocytes in culture was undertaken to determine whether triiodothyronine (T3) potentiates lipolysis by increasing glucagon binding, by attenuating inhibition of lipolysis, or both. Fat cells isolated from abdominal fat were preincubated with T3 for .5 to 24 h before removal of T3 by washing and measurement of lipolysis. Preincubation of adipocytes with T3 enhanced (P < .05) basal as well as glucagon-stimulated lipolysis in a dose-response and time-dependent manner. Enhancement of lipolysis was maximal in the presence of 15 to 150 nM T3. Potentiation of lipolysis by 150 nM T3 was evident at 4 and 24 h but not at .5 h of pretreatment. Overall, T3 enhancement of lipolysis stimulated by submaximal doses of glucagon was similar in magnitude to enhancement of lipolysis stimulated by a maximal dose of glucagon but was greater (P < .05) than its enhancement of basal lipolysis. Pretreatment of adipocytes with T3 did not alter (P > .05) binding of 125 I-glucagon to cell-surface receptors. When fat cells were preincubated with 150 nM T3 for 24 h, the ability of somatostatin to inhibit basal and glucagon-stimulated lipolysis was reduced (P < .05). Thus, prolonged exposure of adipocytes to T3 did not increase lipolytic sensitivity to glucagon or binding of glucagon to cell-surface receptors. However, T3-treated adipocytes exhibited enhanced basal lipolysis, enhanced lipolytic responsiveness to glucagon, and attenuated inhibition of lipolysis by somatostatin.

Glucagon and the paraventricular hypothalamus: modulation of energy balance

The effects of glucagon injections (25, 100 and 200 ng) into the paraventricular nucleus of the hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. High doses of glucagon (100 and 200 ng) produced small and short-lasting increases in energy expenditure. The independence of these changes from changes in locomotor activity suggests that the thermogenesis represents a primary modulation and is not secondary to increased locomotion. All three doses of glucagon produced long-lasting and dose-related increases in respiratory quotient which were unrelated to any changes in locomotor activity. As with the changes in energy expenditure, this dissociation indicates that the effects are not secondary to changes in locomotor activity. These data constitute the first evidence that glucagon in the PVN modulates the metabolic parameters central to energy balance. In separate experiments, the three doses of glucagon increased blood glucose concentration over a one hour period, but they did not affect food and water intake and body weight over 24 h. These findings suggest that glucagon normally acts on the PVN in conditions of increased body fat to initiate autonomic mechanisms which increase glycemic levels, thermogenesis and carbohydrate utilization. These data constitute the first direct evidence for the involvement of the PVN in the regulation of energy balance by glucagon. The main effect of glucagon in the PVN is anabolic in that it increases dependence on carbohydrates as an energy substrate which results in a sparing of fat reserves.

Thyroid Hormone and Growth Hormone Regulation of Broiler Adipocyte Lipolysis

Broiler adipocytes in culture were utilized 1) to determine acute and chronic effects of triiodothyronine (T3) and growth hormone (GH) on lipolysis; and 2) to determine whether T3 and GH act synergistically to increase lipolysis. Short-term effects of T3 and GH on lipolysis were determined by measuring glycerol release from adipocytes incubated for 1 h with T3 or GH and glucagon (GLU). To investigate long-term effects, adipocytes were cultured for 24 h with T3, GH, or a combination of T3 and GH before removal of hormones by washing and assessment of lipolysis.Basal and GLU-stimulated lipolysis were not altered by short-term (1 h) incubation of adipocytes with T3 or GH. Pretreatment of adipocytes with T3 for 24 h increased (P < .05) basal lipolysis and lipolysis in the presence of low (.3 to 1.5 ng/mL) doses of GLU. Preincubation of adipocytes with GH for 24 h decreased (P < .05) glycerol release in response to maximal stimulatory doses (3 to 10 ng/mL) of GLU and increased (P < .05) glycerol release in response to .3 ng GLU/mL. Long-term pretreatment of adipocytes with a combination of T3 and GH produced a similar increase in lipolysis with .3 ng GLU/mL as pretreatment with either T3 or GH alone. Thus, T3 and GH did not act synergistically to increase lipolysis from broiler adipocytes.

Evidence against a putative role for glucagon as a physiological splanchnic vasodilator in man

1. Previous studies have suggested that glucagon in supraphysiological doses may mediate postprandial and hypoglycaemia-induced splanchnic vasodilatation in man and experimental animals. There are no reported studies investigating the role of glucagon in doses producing circulating concentrations within the physiological range. 2. Two separate studies were performed. In study 1, superior mesenteric artery blood flow was measured by Doppler ultrasound in six normal subjects during either saline or glucagon infusion at 1, 3 and 6 ng min-1kg-1, which resulted in circulating glucagon levels within the physiological range. Mean superior mesenteric artery blood flow fell during the 3 and 6 ng min-1kg-1 glucagon infusions (3 ng min-1kg-1: -31.8%, range -20 to -56% of baseline; 6 ng min-1kg-1: -20.7%, range -8 to -53% of baseline; P < 0.05). 3. In study 2, superior mesenteric artery blood flow was measured during hypoglycaemia induced by an insulin infusion in 12 normal subjects. In six of these subjects the effect of suppression of glucagon release during hypoglycaemia was assessed by pretreatment with the somatostatin analogue octreotide (0.8 microgram/kg subcutaneously) given 30 min before the insulin infusion. 4. The nadir in blood glucose concentration at the hypoglycaemic reaction was similar in both groups and glucose recovery was complete by 60 min after the hypoglycaemic reaction. Plasma catecholamine concentrations rose in both groups after the hypoglycaemic reaction. 5. Superior mesenteric artery blood flow rose at the hypoglycaemic reaction in both groups despite suppression of glucagon release with octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiology and management of self-poisoning with beta-blockers.

The prognosis of self-poisoning with beta-blockers is excellent, especially if medical management is started immediately but the wide variety of clinical symptoms and proposed treatments complicate the therapeutic strategy. Beta-blockers that are liposoluble or have marked anti-arrhythmic activity are more lethal (e.g. propranolol, sotalol). Similarly, pre-existing cardiac pathology or co-ingestion of psychotropic or cardioactive drugs increases mortality. The first-line symptomatic treatment is administration of atropine and volume-expanding fluids to treat bradycardia and hypotension, respectively. However atropine is often unsuccessful in reversing beta-blocker-induced bradycardia and repeated doses can provoke atropine poisoning. If symptomatic treatment fails, then antidotes should be administered in a precise order: first, high doses of glucagon, followed by isoproterenol, epinephrine, and the new inhibitors of phosphodiesterases. Mechanical ventilation should be started at the same time as pharmacological treatment in cases of severe collapse or prolonged QRS.

Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients

The aim of this study was to compare the effect of nasally administered glucagon in doses of 1 (A) and 2 mg (B), with 1 mg glucagon administered intramuscularly (C) in 12 C-peptide-negative IDDM patients. Spontaneous recovery (D) from insulin-induced hypoglycaemia in the same patients was used as reference. The mean age was 31.1 (21–48) years, diabetes duration 10.8 (2.7–31) years and HbA 1c 7.7 (6.5–9.8)%. Hypoglycaemia was induced by i.v. insulin infusion. When blood glucose (BG) reached about 2 mmol/l either glucagon was administered or the patients recovered spontaneously. BG nadir was 1.6 (1.1–2.3) mmol/l. BG increments during the first 15 min after glucagon administration were: (A) 1.9 ± 0.7 (0.4-3.0); (B) 2.5 ± 0.7 (1.5–3.5); (C) 2.5 ± 1.0 (1.2–4.7); and (D) 0.3 ± 0.4 (0–1.0) mmol/l, respectively. All treatments were more effective, measured as increments in BG, than spontaneous recovery, P<0.00001. There was no difference between nasal treatment with 2 mg (B) and i.m. treatment (C), both being more effective than 1 mg (A) nasal treatment, P<0.1. BG continued to increase up to 10 mmol/l 90 min after i.m. glucagon administration, whereas it stabilized at a level of 4.5–6 mmol/l, 30–45 min after nasal administration. Eighty percent of the patients had side-effects to nasal administration — local irritation, rhinitis or sneezing. Half of the patients sneezed, without correlation with the delivered dose of glucagon. None of the patients had side-effects which would preclude further treatment. In conclusion, nasal glucagon administration of 2 mg is as effective as 1 mg given intramuscularly in the treatment of insulin-induced hypoglycaemia.

The optimal dose of glucagon: what is enough.

The optimal dose of glucagon: what is enough.

Restoration of stable metabolic conditions during islet suppression in dogs.

These studies were undertaken to examine the stability of metabolic conditions during islet suppression with fixed-rate insulin and glucagon replacement. Somatostatin was infused peripherally at 0.8 microgram.min-1.kg-1, insulin was infused intraportally at 200 microU.min-1.kg-1, and glucagon was infused intraportally at 0, 0.6, 1, 2, 5, or 20 ng.min-1.kg-1 in conscious overnight-fasted dogs. [3-3H]glucose was infused for measurement of glucose kinetics. During infusion, plasma insulin was 7.2 +/- 0.4 microU/ml. Plasma glucagon rose linearly with glucagon dose, achieving basal levels at 2 ng.min-1.kg-1 infusion (164 +/- 18 vs. basal = 182 +/- 57 pg/ml). Plasma glucose and hepatic glucose output (HGO) decreased from basal at doses 0, 0.6, and 1 ng.min-1.kg-1, increased from basal at doses 5 and 20 ng.min-1.kg-1, and remained close to basal at dose 2 ng.min-1.kg-1 (92 +/- 20 vs. basal = 99 +/- 3 mg/dl and 2.4 +/- 0.2 vs. basal = 2.7 +/- 0.2 mg.min-1.kg-1 for glucose and HGO, respectively; P greater than 0.47). Glucose clearance and blood lactate were also closely matched to basal at dose 2 ng.min-1.kg-1. Coefficients of variation during 2 ng.min-1.kg-1 glucagon infusion (last hour) were 3.4, 4.6, 4.9, and 4.7% for glucose, HGO, clearance, and lactate, respectively. These findings indicate that fasting metabolic conditions, as inferred from blood glucose, lactate, insulin, and glucagon levels, and the rates of glucose production and uptake can be recreated in toto during fixed-rate islet hormone replacement.

Hepatic glucagon sensitivity and fasting glucose concentration in normal dogs.

We assessed hepatic glucagon sensitivity in overnight-fasted, conscious dogs. Six pancreatic replacement protocols were performed in each of five animals. Somatostatin was infused to inhibit endogenous insulin and glucagon, insulin was replaced intraportally at 200 microU.min-1.kg-1, and glucagon was infused intraportally at 0, 0.6, 1, 2, 5, or 20 ng.min-1.kg-1. One intravenous glucose tolerance test was also performed in each animal for measurement of insulin sensitivity (SI). During hormone replacement at a given glucagon dose, plasma glucose differed substantially among animals (P = 0.003). Therefore the dose required for restoration of euglycemia ("glucagon requirement") varied nearly sevenfold among animals, suggesting appreciable differences in glucagon sensitivity (GS). The latter was quantitated in individual animals as the initial slope of integrated glucose output vs. glucagon concentration. GS varied from 0.22 to 3.9 mg.kg-1.pg-1.ml among various animals and was inversely and significantly related to glucagon requirement. SI varied less (approximately 4-fold) and was not associated with glucagon requirement. These observations suggested that interanimal differences in glucose during hormone replacement were the result of substantial differences in GS. In addition, we found the GS of a given animal to be highly associated (P = 0.01) with its fasting glucose level. We conclude that GS varies substantially, and as such may be an important determinant of the fasting glucose level in normal animals.

Metabolic actions of glucagon and dexamethasone in liver of the ureogenic teleost Opsanus beta

Injection with pharmacological doses of dexamethasone (5 mg/kg) and/or bovine glucagon (1 mg/kg) exerts pronounced effects on toadfish liver compared with vehicle-treated control fish. Affected parameters include hepatic levels of glycogen and the activities of glutamate dehydrogenase, aspartate aminotransferase, malate dehydrogenase, and enzymes involved in NADPH generation as well as the kinetics of pyruvate kinase. Activities of tyrosine aminotransferase, however, a prime target for hormonal induction in mammals, remain unchanged in Opsanus. In subsequently isolated toadfish hepatocytes, metabolite concentrations and flux through gluconeogenesis are altered as are in vitro responses to epinephrine and catfish glucagon in previously injected fish. Contrary to existing mammalian models, short-term regulation of urea cycle activity can be ruled out for toadfish, since hormone treatments fail to influence the activity of two ornithine-urea cycle enzymes or the rate of hepatocyte-urea synthesis. Treatment-dependent increases in hepatic glutamine synthetase, the unique feeder enzyme for ammonia “nitrogen” in fish urea cycle, indicate a potentially pivotal role for this enzyme in longer-term regulation of ureogenesis.

Adenylate cyclase activity in crude liver membranes during chemical hepatocarcinogenesis in portacaval shunted rats

Hepatocarcinogenesis was initiated in rats with diethylnitrosamine (DEN) followed by a selection with 2-acetylamino-fluorene (2-AAF). Portacaval shunt was then performed in order to promote tumor development. Control rats were not submitted to the initiation--selection protocol and were sham-operated. In control rats, adenylate cyclase activity from crude liver membranes was stimulated 7- to 8-fold by maximal doses of glucagon (10(-6) M) or guanyl-5'-yl-imidophosphate [Gpp(NH)p] (10(-3) M), and 17-fold by a maximal (10(-5) M) dose of forskolin. Guanosine-5'-O-(2-thiodiphosphate) inhibited the response to forskolin (-38%) and to low doses of glucagon (-50%). The initiation--selection protocol increased the activity in basal conditions and in response to various stimuli. The portacaval shunt did not modify the activity of the enzyme with respect to basal activity or the response to glucagon. It significantly decreased the response to Gpp(NH)p (-45%) and to forskolin (-27%). The initiation--selection protocol increased the basal activity of the enzyme (+150%) and its response to Gpp(NH)p (+300%). When tumors developed, the activity of the cyclase further increased (+200%) and an inhibitory effect of GTP on the hormone-stimulated enzyme appeared (-40%). From these results, it is concluded that the promotion of hepatocarcinogenesis by portacaval shunt is coupled with modifications in the activity of adenylate cyclase in response to glucagon and guanylnucleotides.

Nickel-induced hyperglycaemia: the role of insulin and glucagon

Glucagon and insulin changes were measured in acute nickel-treated rats. Also, several parameters related to glucose homeostasis were evaluated. Nickel treatment caused an important and transitory rise in plasma glucose levels. These changes occurred simultaneously to hyperglucagonemia and hypoinsulinemia, leading to a drastic drop in the insulin/glucagon plasma ratio. In such a catabolic situation, hepatic and muscular glycogen levels remained almost unaltered. Hepatic fructose-2,6-bisphosphate (an indicator of gluconeogenic/glycolytic state) was drastically reduced a short time after nickel injection. Such events suggested that it was mainly gluconeogenesis and not glycogenolysis, which contributes to enhanced plasma glucose. Animals treated with large doses of glucagon did not mimic the hyperglycaemic responses induced by nickel, due to counteracting effects of insulin on plasma glucose. When diabetic rats were treated with nickel, the hyperglucagonemic response still remained, but plasma glucose levels did not increase at the same extent as when nickel was applied to control animals. Overall results suggest that both, glucagon and insulin changes are essential in the development of nickel-induced hyperglycaemia. Also, the lack of glycogenolytic response insinuates a direct or indirect inhibition of this process mediated by nickel and will need further investigation.

Insulin releasing action of N-terminal peptides of glucagon in dogs.

The relationship between the molecular structure and insulin releasing action of glucagon remains unknown. In order to investigate the direct action of N-terminal peptides of glucagon, glucagon (1-14), and glucagon (1-21) were studied using an in situ local circulation of the canine pancreas. These glucagon fragments as well as glucagon (1-29) were infused into the superior pancreaticoduodenal artery in a dose of 400 pmol for 10 min during the glucose or arginine infusion, and plasma insulin and glucagon in the superior pancreaticoduodenal vein were determined by radioimmunoassay. During the glucose infusion, glucagon (1-14) elicited a slight increase in plasma insulin, whereas glucagon (1-21) and (1-29) revealed significant changes in plasma insulin. In these experiments plasma glucagon did not change significantly following the administration of glucagon (1-14) or (1-21). During the arginine infusion all of the glucagon fragments studied enhanced insulin secretion markedly, whereas glucagon secretion was not affected. Furthermore, graded doses of glucagon (1-14) (50, 150, and 400 pmol) elicited an increase in plasma insulin in a dose-related manner. It is concluded from the present study that the N-terminal peptides of glucagon stimulate insulin release especially during the arginine infusion.

Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo

Our aims were to further characterize the stimulatory effect of glucagon on brown fat and to test the hypothesis that physiological levels of hyperglucagonemia would stimulate brown fat thermogenesis. In the first set of experiments, glucagon (1 mg/kg sc twice daily) or vehicle control was administered three times in 26 h. This large dose of glucagon produced increases in GDP binding to brown fat mitochondria. In addition, Scatchard analysis indicated a glucagon-induced increase in number of GDP binding sites without evidence for alteration in binding site affinity. No consistent increase in brown fat mitochondrial GDP binding was produced 2 h after a single injection of glucagon (1 mg/kg). In the second set of experiments, glucagon was administered intraperitoneally by constant osmotic minipump infusion. Glucagon in a dose of 150 micrograms.kg-1.day-1 for 5 days produced significant increases in GDP binding to brown fat mitochondria, whereas glucagon serum levels were increased but stayed within the usual physiological range. A larger dose of glucagon administered by constant infusion virtually eliminated body weight gain over 7 days while significantly increasing nucleotide binding (GDP) to brown fat mitochondria. An important role for glucagon in thermogenic regulation is suggested.

Ornithine Decarboxylase Induction in Partially Hepatectomized Rat Liver and Modes of Its Stimulation by Glucagon and Insulin

Hepatic ornithine decarboxylase (ODC) activity increases after partial hepatectomy and this activity is further stimulated by pharmacologic doses of glucagon and insulin. We now present data suggesting that glucagon and insulin stimulate ODC activity by distinct mechanisms. ODC activity increased progressively after partial hepatectomy and reached an initial peak at 4 h. Activity decreased to 50% of its peak value at 6 and 8 h and then rose progressively to a maximum at 12 h. Enzymatic activity was well correlated with the amount of hepatic immunoreactive ODC protein, thus suggesting that increased enzyme activity was due to increased amount of enzyme protein. Hepatic ODC mRNA increased gradually and continuously, reaching the maximal value by 12 h. In rats receiving glucagon after partial hepatectomy, ODC mRNA increased significantly by 2 h and enzyme immunoreactive protein and activity by 2 to 4 h as compared to controls. In contrast, insulin administration only induced a significant increase in enzyme immunoreactive protein and activity 10 to 12 h after partial hepatectomy. No significant changes in ODC mRNA level were observed. Our data suggest that the regulation mechanism of ODC induction following partial hepatectomy differs depending on the time after operation. Our data also suggest that while glucagon appears to regulate ODC activity by a transcriptional mechanism, insulin appears to operate at a post-transcriptional level.