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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiologic significance of glucocorticoids and insulin in the regulation of hepatic gluconeogenesis was investigated during a 48-hr starvation period by studying the factors presumed to control the rate of glucose synthesis in the final gluconeogenetic pathway. Rats were used, in which glucorticoids were removed by adrenalectomy before starvation, and in which serum insulin was kept constant before and after food withdrawal by pre-feeding with a proteinfree diet. It was found that adrenalectomized rats at constantly low serum insulin levels responded to starvation as rapidly, and to the same degree, as intact control subjects (1) by a significant increase in plasma glucagon and, consequently, in hepatic cAMP concentration; (2) by a coordinate elevation of the activities of hepatic pyruvate carboxylase, P-enolpyruvate carboxykinase, and fructose-1,6-diphosphatase; (3) by systematic alterations in the concentration of effectors of gluconeogenetic key enzymes; (4) by a shifting of the cytoplasmic NAD system towards the reduced state; (5) by a decrease in the intrahepatic concentration of glycogenic precursor substrates. These results suggest that the hepatic gluconeogenic response to starvation with respect to the regulatory factors 1-5 occurs independently from changes in the concentration of plasma glucocorticoids and insulin. The crossing over of the gluconeogenetic intermediates between pyruvate and P-enolpyruvate (PEP), which was observed in intact but not in adrenalectomized rats, supports the assumption that during starvation, glucocorticoids enhance the rate of glucose production by the liver predominantly by permitting hepatic cAMP to stimulate the yet undefined mechanism, which has been demonstrated in the isolated perfused rat liver to control the substrate flow between pyruvate and PEP.
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PMID:Physiologic significance of glucocorticoids and insulin in the regulation of hepatic gluconeogenesis during starvation in rats. 18 90

1. Measurements of pyruvate carboxylase, mitochondrial phosphoenolpyruvate carboxykinase (GTP), hexose bisphosphatase and glucose 6-phosphatase in developing sheep liver showed substantial activities of all enzymes in the foetus, especially towards the end of gestation. Cytosol phosphoenolpyruvate carboxykinase (GTP) in livers of mid-term foetuses was only 10% of the activity at birth. 2. All enzymes except pyruvate carboxylase showed 1.5-2-fold increases after birth. 3. Gluconeogenesis form [14C]actate could not be detected in chronically cannulated sheep foetuses at any developmental stage and was not initiated by the infusion of adrenaline or glucagon. 4. An active pathway of gluconeogenesis was evident in vivo within 2 min after natural birth or within 4 min after Caesarian delivery of term lambs, and was delayed in prematurely delivered lambs until breathing was established and the blood fully oxygenated. 5. It is proposed that oxygen availability initiates gluconeogenesis in the newborn lamb.
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PMID:The appearance of gluconeogenesis at birth in sheep. Activation of the pathway associated with blood oxygenation. 19 81

The insulin and glucose responses to glucagon infusions (27 microgram/hr) were determined in sheep before and after parenteral lead treatment (6 mg/kg intravenously). Glucose production was measured by primed continuous infusion of [6-3H]glucose. Glucagon and insulin concentrations before and during glucagon infusions were not significantly different between lead treatment and control experiments. Lead administration did not affect the concentration or production of glucose in the preinfusion period. However, depressed hyperglycemia during glucagon infusion in lead treated experiments tended to be associated with decreased glucose production. The reduced glucogenic response to glucagon may be the result of reduced function of pyruvate carboxylase, a key hepatic gluconeogenic enzyme in sheep, from lead induced impairment of mitochondrial function.
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PMID:Depression of hyperglycemic response to glucagon by parenteral lead administration in sheep. 64 58

Gluconeogenesis was studied in 3 cases of persistent neonatal hypoglycaemia. In 2 of the cases the labelling of blood glucose after i.v. injection of 1415C-alanine was reduced. In these 2 patients only 1.3-5% of the injected radioactivity was recovered in blood glucose, compared with 10% in normoglycaemic patients. The labelling of glucose from 14C-glycerol, as studied in one case, was not reduced. In this patient the labelling of blood glucose from C-alanine was improved after subtotal resection of the pancreas, and with increasing age. By the time of the isotope studies the plasma insulin was normal in all patients, and no deficiency of glucagon secretion could be detected after stimulation with an alanine load. A quantitative amino acid analysis of plasma revealed a moderate increase of some of the glucogenic amino acids. The results were interpreted as a deficiency of gluconeogenesis, probably at the phosphoenolpyruvate carboxykinase or pyruvate carboxylase step.
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PMID:Gluconeogenesis in infancy and childhood. II. Studies on the glucose production from alanine in three cases of persistent neonatal hypoglycaemia. 127 63

The effect of Ca2+ on the rate of pyruvate carboxylation was studied in liver mitochondria from control and glucagon-treated rats, prepared under conditions that maintain low Ca2+ levels (1-3 nmol/mg of protein). When the matrix-free [Ca2+] was low (less than 100 nM), the rate of pyruvate carboxylation was not significantly different in mitochondria from control and glucagon-treated rats. Accumulation of 5-8 nmol of Ca2+/mg, which increased the matrix [Ca2+] to 2-5 microM in both preparations, significantly enhanced pyruvate carboxylase flux by 20-30% in the mitochondria from glucagon-treated rats, but had little effect in control preparations. Higher levels of Ca2+ (up to 75 nmol/mg) inhibited pyruvate carboxylation in both preparations, but the difference between the mitochondria from control and glucagon-treated animals was maintained. The enhancement of pyruvate dehydrogenase flux by mitochondrial Ca2+ uptake was also significantly greater in mitochondria from glucagon-treated rats. These differential effects of Ca2+ uptake on enzyme fluxes did not correlate with changes in the mitochondrial ATP/ADP ratio, the pyrophosphate level, or the matrix volume. Arsenite completely prevented 14CO2 incorporation when pyruvate was the only substrate, but caused only partial inhibition when succinate and acetyl carnitine were present as alternative sources of energy and acetyl-CoA. Under these conditions, mitochondria from glucagon-treated rats were less sensitive to arsenite than the control preparations, even at low Ca2+ levels. We conclude that the Ca(2+)-dependent enhancement of pyruvate carboxylation in mitochondria from glucagon-treated rats is a secondary consequence of pyruvate dehydrogenase activation; glucagon treatment is suggested to affect the conditions in the mitochondria that change the sensitivity of the pyruvate dehydrogenase complex to dephosphorylation by the Ca(2+)-sensitive pyruvate dehydrogenase phosphatase.
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PMID:The role of the matrix calcium level in the enhancement of mitochondrial pyruvate carboxylation by glucagon pretreatment. 137 Apr 47

Effects of a 3-d mesenteric vein n-butyrate infusion (25 mmol/h) on net metabolism of nutrients by portal-drained viscera (PDV) and liver were measured in six Hereford x Angus steers. Steers were fed a pelleted 75% concentrate: 25% alfalfa diet at 135 kcal of ME/kg BW.75. Six measurements of blood flow and net metabolism of nutrients were obtained at hourly intervals immediately before beginning and ending n-butyrate infusion. Measurements were obtained during two trials, with three steers (457 kg BW, 28 mo of age in Trial 1; 478 kg BW, 19 mo of age in Trial 2) in each trial. The infusion of n-butyrate increased (P less than .01) net PDV release of n-butyrate. Infusion increased net liver removal of n-butyrate (P less than .01) and L-lactate (P less than .02) and release of beta-hydroxybutyrate (BOHB; P less than .02) and increased (P less than .03) liver extraction ratio for alanine. Net total splanchnic (PDV plus liver) release of n-butyrate (P less than .03) and BOHB (P less than .01) were increased, and net total splanchnic release of L-lactate (P less than .05) and propionate (P less than .07) were decreased by n-butyrate infusion. The infusion of n-butyrate decreased (P less than .01) net PDV release and liver removal of propionate in five of six steers. Infusion had no effect (P greater than .10) on insulin and glucagon concentration or net flux. In a companion in vitro study, L-lactate metabolism to glucose and CO2 by calf hepatocytes was decreased (P less than .08) by n-butyrate addition (2.5 mM). Effects of n-butyrate on liver L-lactate and alanine metabolism suggest that pyruvate carboxylase activity was increased, but our study failed to show a consistent effect of n-butyrate infusion on liver glucose production.
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PMID:Effects of mesenteric vein n-butyrate infusion on liver metabolism by beef steers. 164 99

A kinetic expression for rat-liver mitochondrial aspartate formation in situ was developed in order to determine whether hormonally induced decreases in 2-oxoglutarate levels can regulate hepatic gluconeogenesis from lactate via control of aspartate formation. Previous studies from this laboratory showed that 2-oxoglutarate can inhibit aspartate production by isolated mitochondria. These present studies were designed to probe the physiological significance of the decrease in 2-oxoglutarate levels observed when Ca2(+)-mobilizing gluconeogenic hormones are administered to isolate perfused rat livers. First, estimates were made of the kinetic constants which determine the rate of aspartate formation in isolated mitochondria. The concentrations of the substrates and products of this process were then measured in perfused livers. From these values, it was possible to estimate aspartate efflux from mitochondria in situ. The calculated rates of aspartate production were increased by decreases in 2-oxoglutarate levels which occurred when glucagon or phenylephrine was added to the perfused livers. Glucagon also effected an inhibition of pyruvate kinase, evidenced by the fact that the calculated rate of aspartate efflux equalled the rate of gluconeogenesis (the difference between the two is equivalent to the pyruvate-kinase flux). By contrast, in control livers and with phenylephrine stimulation, aspartate formation was higher than gluconeogenesis suggesting significant pyruvate-kinase flux in this condition. The calculations also show a correlating increase in flux through pyruvate carboxylase (30% with phenylephrine, 15% with glucagon, compared with approximately 50% increases in gluconeogenic flux). The mechanism of this increase is discussed.
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PMID:The mechanism of Ca2(+)-related control of gluconeogenesis in perfused liver. 167 8

1. The regulation of renal gluconeogenesis was studied in rats made septic by a caecal ligation and puncture technique. 2. Blood glucose concentrations were not markedly different in septic rats, but lactate, pyruvate and alanine concentrations were markedly increased, compared with sham-operated rats. Conversely, blood ketone body concentrations were significantly decreased in septic rats. Both plasma insulin and glucagon concentrations were markedly elevated in response to sepsis. 3. The maximal activities of glucose-6-phosphatase (EC 3.1.3.9), fructose-1,6-bisphosphatase (EC 3.1.3.11), pyruvate carboxylase (EC 6.4.1.1) and phosphoenolpyruvate carboxykinase (EC 4.1.1.49) were markedly decreased in kidneys obtained from septic rats, suggesting diminished renal gluconeogenesis. 4. Renal concentrations of lactate, pyruvate and other gluconeogenetic intermediates were markedly elevated in septic rats, whereas those of acetyl-CoA and fructose 2,6-bisphosphate were decreased and unchanged, respectively. 5. The rate of gluconeogenesis from added lactate, pyruvate and glycerol was decreased in isolated incubated renal tubules from septic rats. 6. Sepsis decreased the arteriovenous concentration difference for glucose, lactate, and alanine. Septic rats showed decreased net rates of glucose production and net rates of removal of lactate and alanine as compared with sham-operated controls. 7. It is concluded that the diminished capacity for renal gluconeogenesis in septic rats could be the result of changes in the maximal activities or regulation of key non-equilibrium gluconeogenic enzymes or both, but the effect of other factors (e.g. toxins) has not been excluded.
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PMID:Metabolic regulation of renal gluconeogenesis in response to sepsis in the rat. 217 16

The regulation of hepatic gluconeogenesis was studied in rats made septic by cecal-ligation and puncture technique. Blood glucose was not significantly different in septic rats, but lactate, pyruvate, and alanine were markedly increased. Conversely, blood ketone body concentrations were markedly decreased in septic rats. Both plasma insulin and glucagon were markedly elevated in septic rats. The maximal activities of glucose 6-phosphatase, fructose 1,6-biphosphatase, pyruvate carboxylase, and phosphenolpyruvate carboxykinase were decreased in livers obtained from septic rats suggesting a diminished hepatic gluconeogenesis. Hepatic concentrations of lactate, pyruvate, and other gluconeogenic intermediates were markedly increased in septic rats, whereas those of fructose 2,6-bisphosphate and acetyl-CoA were decreased. The rate of gluconeogenesis from added lactate, pyruvate, alanine, and glutamine was decreased in isolated incubated hepatocytes from septic rats. It is concluded that the diminished capacity of hepatic gluconeogenesis of septic rats could be the result of changes in the maximal activities or regulation of key nonequilibrium gluconeogenic enzymes or both but do not exclude other factors (e.g., toxins).
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PMID:Metabolic control of hepatic gluconeogenesis in response to sepsis. 268 81

The capacity for gluconeogenesis in the isolated amphibian retina was found to be approx. 70-fold greater with lactate than with glutamate as the gluconeogenic precursor, 1426 versus 21 pmol of glucose incorporated into glycogen/h per mg of protein. It was also found that 11-15% of the glucosyl units in glycogen are derived from C3 metabolites of the glycolytic pathway, suggesting that lactate is recycled within the retina. In concert with these metabolic observations, a full complement of the gluconeogenic enzymes was detected in retinal homogenates. These included: glucose-6-phosphatase, fructose-1,6-bisphosphatase, acetyl-CoA-dependent pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Agents that regulate the rate of gluconeogenesis in hepatic tissue were tested on the retina. At concentrations of glutamate and lactate that are presumed to be relevant physiologically, it was found that vasoactive intestinal peptide, ionophore A23187 and elevated [K+] each enhanced the rate of gluconeogenesis in Ringer containing 50 microM-glutamate, whereas in Ringer containing 8.5 mM-lactate these agents inhibited the rate of gluconeogenesis. Further, it was found that the classic gluconeogenic hormone glucagon inhibited gluconeogenesis in both glutamate- and lactate-containing Ringer. Retinal energy metabolism was found to be altered in lactate-containing Ringer, in that lactate production was suppressed completely. In addition, glycogen metabolism appeared to be dependent on increased cytosolic Ca2+ and was insensitive to increased retinal cyclic AMP.
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PMID:Gluconeogenesis in the amphibian retina. Lactate is preferred to glutamate as the gluconeogenic precursor. 290 49


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