Effect of glucagon on plasma alanine and glutamine metabolism and hepatic gluconeogenesis in sheep.

Net hepatic uptakes of plasma alanine (Ala), glutamate (Glu), and glutamine (Gln) were measured before and during intraportal glucagon infusions in five normaland four insulin-and alloxan-treated (ITA), conscious, fed sheep. Since hyperinsulinemia is associated with glucagon administration, ITA sheep were used so that constant plasma insulin levels could be maintained. Glucose turnover was determined by a vena caval infusion of glucose-6-'3H. In addition, in ITA sheep, Ala-'14C wasinfused for measurement of plasma Ala turnover, its unidirectional organ metabolism, and contribution to glucose synthesis. During infusion of glucagon, the net hepatic uptake of Ala increased significantly (P is less than 0.01) from control values of 3.8 plus or minus 0.5 and 2.7 plus or minus 0.6 mmol/h to 5.9 plus or minus 1.0 and 5.5 plus or minus 0.8 mmol/h in normal and ITA sheep, respectively. Similarly, Gin uptake increased from 4.3 plus or minus 1.4 and 1.6 plus or minus 0.5 to 5.5 plus or minus1.6 and 3.7 plus or minus 1.0 mmol/h, respectively. The conversion of Ala to glucose increased from control values of 1.7 plus or minus 0.5 to 3.0 plus or minus 0.5 mmol/h.Arterial plasma Ala and Gin concentrations decreased about 25% during glucagon administration, presumably as a result of their increased hepatic uptakes. A decreasein utilization of plasma Ala, but no change in production was calculated for the nonhepatic tissues, indicating that glucagon increased gluconeogenesis from Ala at the expense of muscle protein synthesis. Glucagon thus has a direct effect on the liver butonly an indirect effect on other tissues.     

Quantitative aspects of insulin secretion and its hepatic and renal removal in sheep.

The secretion of insulin into the portal blood and its removal by the liver and kidneys in conscious fed sheep were determined by simultaneously measuring venoarterial plasma concentration differences and portal, hepatic, and renal plasma flows. The basal secretory rate of insulin was 0.43 +/- 0.03 U/h or 7.8 mU/kg-h. The secretory rate of insulin and the amount of insulin presented to the liver also were altered by 2-h intraportal infusions of glucagon (150 mug/h), insulin (1.17 U/h), and insulin (1.17 U/h) lus glucose (2.2 g/h). Hepatic removal under all conditions was about 50% of the insulin secretory rate, although the extraction ratio was only 0.08. Renal removal was 35% of the insulin secretory rate. The renal extraction ratio was 0.35. During insulin-induced hypoglycemia and also during starvation, the hepatic extraction ratio of insulin increased significantly, but the removal as a percentage of insulin secretion did not change. It appears that in sheep on a maintenance diet the basal secretory rate of insulin is less than that of nonruminant species and that, within physiological limits, the liver disposes of about one-half and the kidney about one-third of the insulin. Other tissues, presumably, remove the remaining 10--20%.     

Interorgan metabolism of amino acids in streptozotocin-diabetic ketoacidotic rat

Amino acid concentrations in whole blood, liver, kidney, skeletal muscle, and brain were measured and arteriovenous differences calculated for head, hindlimb, kidney, gut, and liver in control and streptozotocin-diabetic rats. In the control rats, glutamine was released by muscle and utilized by intestine, intestine released citrulline and alanine, liver removed alanine, and the kidneys removed glycine and produced serine. In diabetic rats, the major changes from the pattern of fluxes seen in the normal rat were the release of many amino acids from muscle, with glutamine and alanine predominating, and the uptake of these amino acids by the liver. Glutamine removal by the intestine was suppressed in diabetes, but a large renal uptake of glutamine was evident. Branched-chain amino acids were removed by the diabetic brain, and consequently, brain levels of a number of large neutral amino acids were decreased in diabetes.     

Effect of glucocorticoids on renal net glucose release in vivo in normal and diabetic rats

The effect of glucocorticoids on renal net glucose release in vivo in normal and diabetic rats was studied by the isotope-dilution method. Administration of hydrocortisone to normal fed rats increased renal net glucose release from 0.93 +/- 0.25 to 2.27 +/- 0.21 mg . dl-1 . min-1 and increased its contribution to blood glucose from 27.0 +/- 4.5 to 46.6 +/- 4.0%. The renal net glucose release and its contribution to blood glucose in adrenalectomized rats were 0.40 +/- 0.06 mg . dl-1 . min-1 and 16.3 +/- 1.4%, respectively, significantly less than those of normal control rats, and these parameters were raised to the levels of normal control rats by the administration of hydrocortisone. In rats with streptozotocin-induced diabetes, the renal net glucose release and its contribution to blood glucose were significantly increased to 2.22 +/- 0.51 mg . dl-1 . min-1 and 46.7 +/- 4.9%, respectively, and these parameters were normalized by adrenalectomy. These data indicate that glucocorticoids play an important role in regulation of renal net glucose release and its contribution to blood glucose in both normal and diabetic rats.     

Effects of glucagon and insulin on net hepatic metabolism of glucose precursors in sheep.

The net hepatic metabolism of amino glycerol, lactate, and pyruvate was determined in conscious fed sheep by multiplying the venoarterial concentration differences by the hepatic blood or plasma flow. In each experiment several sets of control blood samples were taken; glucagon or insulin then was infused intraportally for 2 h during which additional samples were taken. Four types of experiments were performed: 1) glucagon infusion (150 mug/h) into normal sheep, 2) glucagon infusion (100 mug/h) into insulin-treated alloxanized sheep, 3) insulin infusion (1.17 U/h) into normal sheep, and 4) insulin plus glucose infusion (12.3 mmol/h) into normal sheep. The second group of experiments was performed to prevent reflex hyperinsulinemia, and the fourth was performed to prevent reflex hyperglucagonemia. Glucagon directly stimulated the net hepatic uptake of alanine, glycine, glutamine, arginine, asparagine, threonine, serine, and lactate. Glucagon also stimulated lipolysis in adipose tissue. Insulin, on the other hand, appeared to have a lipogenic effect on adipose tissue and to stimulate directly the uptake of valine, isoleucine, leucine, tyrosine, lysine, and alanine only at extrahepatic sites. The study showed that, in sheep, the effects of glucagon primarily are on liver, and insulin's effects primarily are on skeletal muscle and adipose tissue where it promotes protein and lipid synthesis.     

Ammonia metabolism during exercise in man

Physical exercise is accompanied by increased plasma levels of ammonia but it is not known whether this rise primarily reflects accelerated formation in muscle or decreased removal by the liver. Consequently, leg and splanchnic exchange of ammonia was examined, using the catheter technique, in 11 healthy subjects at rest, during three consecutive 15 min periods of bicycle exercise at gradually increasing work loads (35%, 55% and 80% of maximum oxygen uptake) and for 60 min during post-exercise recovery. The basal arterial ammonia level was 22 +/- 2 mumol/l, the concentration rose curvilinearly in response to increasing work loads (peak value 84 +/- 12 mumol/l), and fell rapidly after exercise, reaching basal levels after 30-60 min. A linear regression was found for ammonia levels in relation to lactate concentrations at rest and during exercise (r = 0.85, P less than 0.001). A significant relationship was also observed between arterial ammonia and alanine levels (r = 0.75, P less than 0.001). Leg tissues showed a net uptake of ammonia in the basal state (2.4 +/- 0.5 mumol/min). During exercise this changed to a net production, which increased curvilinearly with rising work intensity (peak value 46 +/- 15 mumol/min) but reverted to a net ammonia uptake at 30-60 min after exercise. Splanchnic ammonia uptake (basal 12 +/- 2 mumol/min) did not change in response to exercise but increased transiently during the early post-exercise period. From the above observations we conclude that the hyperammonaemia of exercise comes primarily from muscle release, while the splanchnic removal of ammonia is essentially unaltered. Part of the ammonia formed in contracting muscle is most likely used in the synthesis of amino acids, mainly glutamine and probably alanine.     

Amino acid degradation and effect of leucine on pyruvate oxidation in rat atrial muscle

Both left and right atria from fasted rats produced significant amounts of 14CO2 during incubation with U-14C-labeled leucine, isoleucine, valine, alanine, glutamate, glutamine, aspartate, asparagine, proline, threonine, or lysine. This pattern of amino acid metabolism resembles that of skeletal muscle. Production of 14CO2 from [1-14C]leucine was 2.5-fold greater in atria from fasted than from fed rats and was due to greater alpha-ketoisocaproic dehydrogenase activity in the tissue from fasted animals. At normal plasma concentrations, leucine reduced the oxidation of glucose and lactate in atria from fasted but not from fed rats by inhibiting pyruvate oxidation and without altering the rate of glycolysis. Leucine also reduced glucose oxidation when added in the presence of ketone bodies or other amino acids and stimulated the release of lactate into the medium. Although the leucine skeleton can be completely oxidized to CO2 and thus can serve as an alternative fuel in fasting in place of glucose, oxidation of leucine (like glucose or lactate oxidation) accounts only for a very small fraction of the total oxygen consumption of the resting atria.     

Effects of methionine sulphoximine treatment on renal amino acid and ammonia metabolism in rats

Renal glutamine metabolism in relation to ammoniagenesis has been extensively studied during chronic metabolic acidosis, when arterial glutamine levels are reduced. However, little is known about the effects of reduced glutamine delivery on renal glutamine and ammonia metabolism at physiological systemic pH values. Therefore, a model of decreased arterial glutamine concentrations at normal pH values was developed using methionine sulphoximine (MSO). Renal glutamine and ammonia metabolism was measured by determining fluxes and intracellular concentrations after an overnight fast in ether anaesthetized normal rats, MSO-treated rats and their pair-fed controls. Moreover, fluxes and intracellular concentrations of several other amino acids were determined concomitantly. After 2 and 4 days of MSO treatment, arterial glutamine concentrations were reduced to 55%, while arterial ammonia concentrations increased by 70%. Kidney glutamine uptake reduced, but systemic pH was unchanged. Fractional extraction of glutamine remained unchanged, suggesting that also in vivo net uptake of glutamine by the kidney at subnormal levels is related to arterial glutamine concentrations. As a result, at day 2 but not at day 4, the kidney reduced the net release of ammonia into the renal vein and thus reduced net renal ammonia addition to body ammonia pools. Therefore at day 2, the kidney seems to play an important role in adaptation to both hyperammonaemia and hypoglutaminaemia.     

Glutamine transport by mitochondria isolated from normal and acidotic rats.

The transport of L-glutamine by isolated rat renal mitochondria was studied by means of a rapid-filtration (Millipore Filter Corp.) technique. The movement of glutamine from the incubation medium into the inner mitochondrial compartment (matrix) was inhibited by structural analogues (6-diazo-5-oxo-L-norleucine and glutamic acid), sulghydryl-binding agents (p-chloromercuri-benzoate and mersalyl), and inhibitors of mitochondrial oxidative metabolism (azide, antimycin A, and uncouplers of oxidative phosphorylation). These results suggest that glutamine is transported across the inner membrane of renal mitochondria by a carrier-mediated system that is linked to the processes of oxidative metabolism. The transport of glutamine by isolated renal mitochondria was increased two- to threefold by chronic (5-7 days) metabolic acidosis. However, short-term metabolic acidosis did not increase the glutamine transport capacity of isolated mitochondria. A hypothesis is presented for the regulation of mitochondrial glutamine transport, in vivo, during short-term and chronic acidosis.     

The oxidation of glucose, ketone bodies and acetate by the brain of normal and ketonaemic sheep.

1. The utilization and oxidation of glucose, acetate and ketone bodies by the brain of sheep has been determined from measurements of arteriovenous (A-V) differences and cerebral blood flow, as well as by infusing 14C-labelled metabolites. 2. The A-V difference for glucose was generally more than one sixth, on a molar basis, that of oxygen. 3. The mean rate of glucose utilization by the brain of conscious sheep (0-508 +/- 0-063 mumole/g per minute) was maintained even when the capillary glucose concentration was below 1-4 mM. 4. The amount of 14CO2 produced from [U-14C]glucose by the brain was consistent with glucose being the only energy source for the brain, even during hypoglycaemia and hyperketonaemia. 5. There was no appreciable production of lactate or pyruvate by the brain. 6. There was no significant A-V difference for acetate across the brain in normal or undernourished pregnant sheep. The small A-V differences that were measured show that less than 5% of the CO2 produced could be derived from acetate, a conclusion that is supported by experiments using [U-14C]acetate. 7. No significant A-V difference was detectable across the brain for 3-hydroxybutyrate or acetoacetate in normal fed, pregnant ketonaemic or even anaesthetized sheep infused with acetoacetate. Experiments in which [U-14C]-D(-)-3-hydroxybutyrate was infused also showed that less than 5% of CO2 was derived from ketone bodies. 8. In anaesthetized sheep infused with acetoacetate, measurements were made simultaneously across brain, heart and skeletal muscle. In contrast to the non-significant uptake of ketone bodies by the brain, uptake by heart and skeletal muscle was sufficient to account for nearly 60% of their oxygen consumption. 9. Experiments using [14C]hydroxybutyrate confirmed that during infusion of acetoacetate most of the CO2 produced by the heart, but not by the brain, was derived from ketone bodies. 10. In anaesthetized sheep ketone bodies penetrate only slowly into cerebrospinal fluid. 11. It is proposed that mechanisms for the utilization of ketones by the sheep brain have not evolved because glucose utilization by the brain is a smaller fraction of whole body glucose utilization than in man and rats.     

Influence of food deprivation and adrenal steroids on DNA synthesis in various mammalian tissues.

The DNA content of skeletal muscle increases as young rats grow. Food deprivation prevented this increase: total DNA remained constant, while muscle weight and RNA decreased. Diaphragms isolated from fasted rats incorporated [3H]thymidine into DNA far more slowly than tissues from fed rats. Incorporation returned to control levels on refeeding. Fasting for 24 or 48 h also markedly reduced [3H]thymidine incorporation by slices of liver, kidney, and brain. The factors responsible for this inhibition of DNA synthesis were investigated. Amino acids, insulin, or serum from fed or fasted rats failed to alter thymidine incorporation by muscle. Injection of hydrocortisone into normal rats reduced incorporation into kidneys, liver, and muscle within 4h. Incubation of hemidiaphragms with hydrocortisone suppressed [3H]thymidine incorporation within 2-3h. Adrenalectomy enhanced incorporation into DNA by diaphragm, liver, kidney, and brain. When fasted, adrenalectomized rats showed little or no suppression of [3H]thymidine incorporation and lost less weight than fasted controls. These data suggest that adrenal steroids are important in inhibiting DNA synthesis during normal growth and during fasting.     

Pyruvate carboxylase deficiency--insights from liver transplantation

Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.     

L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy

Hepatic encephalopathy (HE) is a common neuropsychiatric complication of liver disease affecting about 20-30% patients with cirrhosis. HE may only affect quality of life (e.g. impairments in attention; coordination; driving ability), but in some patients this progresses to coma and death; defining mortality in those with acute liver failure. HE is thought to occur through accumulation of ammonia as a by-product of protein metabolism. In liver failure ammonia accumulates to toxic levels, resulting in ammonia-associated brain swelling. Presently, there is no proven therapy for HE though recent studies suggest that during liver failure, ammonia removal by skeletal muscle (by conversion to glutamine) can be manipulated; also that ammonia and amino acid metabolism should be viewed in terms of their interorgan relationship. This led us to develop a novel concept for ammonia removal. Preliminary studies provide the proof of concept that the combination of L-ornithine (amino acid) with phenylactetate, as L-ornithine phenylacetate (OP), reduces toxic levels of ammonia by (1) L-ornithine acting as a substrate for glutamine synthesis from ammonia in skeletal muscle and (2) phenylacetate excreting the ornithine-related glutamine as phenylacetylglutamine in the kidneys. As both L-ornithine and phenylacetate are already available for human use, data showing its usefulness in ammonia lowering could translate quickly into providing the much needed therapy for HE patients.     

Glycogen depletion and resynthesis in the rat after downhill running

Summary to study the effect of downhill running on glycogen metabolism, 94 rats were exercised by running for 3 h on the level or down an 18° incline. Muscle and liver glycogen concentrations were measured before exercise and 0, 48 and 52 h postexercise. Rats were not fed during the first 48 h of recovery but ingested a glucose solution 48 h postexercise. Downhill running depleted glycogen in the soleus muscle and liver significantly more than level running (P<0.01). The amount of glycogen resynthesized in the soleus muscle and liver in fasting or nonfasting rats was not altered significantly by downhill running (P>0.05). On every day of recovery the rats were injected with dexamethasone, which induced similar increases in glycogen concentration in the soleus muscle and liver after the 52nd h of the postexercise period in the case of downhill and level running. The glycogen depletion and repletion results indicated that, under our experimental conditions, downhill running in the rat, a known model of eccentric exercise, affected muscle glycogen metabolism differently from eccentric cycling in humans.     

大鼠胰岛素瘤实验模型的建立及其应用

目的 通过移植大鼠胰岛素瘤INS-1细胞至糖尿病小鼠肾包膜下使之形成胰岛素瘤,并诱导其发生凋亡,建立可用于研究胰岛β细胞凋亡机制的动物模型.方法 将5×106 INS-1细胞接种于链脲霉素(STZ)造模的糖尿病小鼠左肾包膜下,监测动物空腹血糖和血清胰岛素水平的变化,当血糖趋近正常后摘取动物左侧肾脏并检测其血糖和血清胰岛素水平的变化;固定包埋摘取的肾脏,进行HE染色以及胰岛素的免疫组化染色,确定胰岛素瘤模型的建立.在胰岛素瘤动物模型中,腹腔给予毒胡萝卜素(TG)或软脂酸钠(PA),监测给药后动物空腹血糖的变化,当血糖浓度出现逆转时,摘取动物左侧肾脏,通过TUNEL原位染色法检测移植瘤细胞的凋亡.结果 将INS-1细胞移植到糖尿病小鼠肾包膜下后,从第9天开始,动物空腹血糖进行性降低,血清胰岛素水平逐渐升高,当动物血糖接近至正常时,摘取动物左肾导致动物血糖显著升高,在摘取的左肾可见明显的移植瘤,免疫组织化学染色显示移植瘤细胞为胰岛素阳性.在胰岛素瘤动物模型给予TG或PA刺激后,动物空腹血糖出现逆转,显著升高,血清中胰岛素含量明显降低,摘取动物左侧肾脏后,TUNEL原位染色发现移植瘤内有明显的细胞凋亡.结论 大鼠胰岛素瘤INS-1细胞肾包膜下移植可以建立胰岛素瘤动物模型,应用此动物模型可以在体内研究胰岛β细胞凋亡的机制.     

Food deprivation suppresses stress-induced rise in catabolic hormones with a concomitant tendency to potentiate the increment of blood glucose

The organism of a food-deprived animal is directed toward minimizing energy expenditure and plasma levels of catabolic hormones and glucose are also reduced. Stress, on the other hand, is associated with enhancement of metabolic processes, elevated plasma catabolic hormones, and higher glucose levels. The question arises as to whether food deprivation may be able to attenuate the rise of plasma catabolic hormones seen in stress. For this purpose the variations in triiodothyronine (T3), thyroxine (T4), cortisol and glucose in blood plasma of sheep were monitored during 101 hr of food deprivation and 5 hr of stress. Stress was evoked by isolation of individual sheep from the flock. Blood was sampled by venipuncture once a day during 4 days preceding the isolation stress. On the day of isolation, blood was taken 4 times at 1.5- to 2-hr intervals. Food deprivation lowered the T3, T4 and glucose levels to 45.0, 59.5 and 78.0 percent of the basal level, respectively. Plasma cortisol level did not change over the fasting period in sheep not having visual contact with fed animals. Maintaining such a contact elevated cortisol level maximally by 139 percent over basal level. This indicates that the involvement of an emotional factor seems to be necessary for manifestation of stress. Isolation stress acting on fed and fasting sheep increased all measured hormones and glucose levels. However, in fed sheep, the maximal levels of T3, T4 and cortisol were 72.5, 48.4 and 50.0 percent higher than in corresponding isolated and food-deprived animals. Inversely, the maximal concentration of plasma glucose was about 16.6 percent higher in food-deprived than in fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lactate metabolism in the isolated perfused rat kidney: relations to renal function and gluconeogenesis.

In the intact dog, decreases in both glomerular filtration rate and net renal Na+ reabsorption due to raised ureteral pressure were not associated with a decrease in renal lactate oxidation rate, although total renal CO2 production decreased in proportion to the changes in net renal reabsorption of Na+ and glomerular filtration rate. 2. In order to determine whether, in the absence of other added substrates, the metabolism of lactate supports only the 'basal' renal metabolism or can enhance renal function as well, the rate of lactate utilization and decarboxylation by the isolated perfused rat kidney have been quantified in relation to renal function and one measure of renal basal metabolism, glucose production. 3. The perfusate was Krebs-Ringer bicarbonate (pH 7-35-7-48) with Fraction V bovine serum albumin, 6g/100 ml. L-(+)-lactate was added to raise the lactate concentration from endogenous levels to 2-5, 5-0 or 10 mM. 4. We determined: net lactate utilization rate, lactate decarboxylation rate (14CO2 produced from L-(+)-[U-14C]lactate), net glucose production rate, and net re-absorptive rate of Na+. 5. The apparent Km and Vmax for lactate oxidation were 2-1 mM and 1-29 mumole.g-1.min-1 respectively. There was no apparent maximum for total lactate utilization rate due to continuing increases in glucose production rate as lactate concentration was raised. At ca. 10 mM lactate, glucose production accounted for about half of the total lactate utilized. Therefore the basal energy requirements of the kidney need not be constant since glucose production increases as lactate concentration is raised. 6. Both lactate oxidation rate and lactate utilization rate were significantly correlated with the net reabsorption of Na+ by the renal tubules, with the percentage of filtered Na+ reabsorbed and with the glomerular filtration rate. The major fraction of the net renal reabsorption of Na+ was probably supported by the metabolism of substrates either bound to albumin or derived from renal tissue since the percentage of filtered Na+ reabsorbed increased from ca. 78%, when no lactate was added, to 97% when initial lactate concentration was 10 mM. Therefore, addition of lactate increased both the basal mebabolism and tubular function. However, these observations do not permit us to conclude whether it was the presence of lactate, or its utilization by oxidative or by other pathways which enhanced net renal reabsorption of Na+ and the glomerular filtration rate.     

Effects of glucose and glutamine on the intensity of NAD precursor utilization in rats with transplanted tumors

The rate of nicotinamide utilization for the biosynthesis of NAD both in the liver and kidneys and in tumor tissue of rats with Walker's carcinosarcoma and Pliss' lymphosarcoma is shown to be limited by glucose. Glucose and glutamine increase the utilization of nicotinic acid in the liver and kidneys of rats with Walker's carcinosarcoma, in the kidneys of rats with Pliss' lymphosarcoma, and to a lesser extent, in Pliss' lymphosarcoma tumor tissue, but do not affect the utilization of nicotinic acid in Walker's carcinosarcoma. It is concluded that certain stages of the NAD biosynthesis pathway are impaired. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 9, pp. 282–285, September, 1995 Presented by L. A. Tiunov, Member of the Russian Academy of Medical Sciences)     

Effects of V.M.H. lesions on plasma insulin in the goose

The effects of bilateral electrolytic lesions of the ventromedial hypothalamus (V.M.H.) were examined in male geese. In addition to the known effects (hyperphagia, obesity and liver steatosis), V.M.H. lesions slightly increased plasma insulin level in the fasting and the fed state and largely enhanced insulin levels observed during an oral glucose and amino acid load. Therefore, V.M.H. lesions potentiate insulin release which may in turn participate in the development of hyperphagia and fattening in the goose as in mammals.     

Effects of maleate on carbohydrate metabolism in rats.

Intraperitoneal administration of maleate produced an increase in blood alpha-ketoacid, acetoacetate, and free fatty acids. The effect of this treatment on blood glucose levels depended on whether the rats were fed or fasted. In fed rats it was accompanied by slight, transient hyperglycemia connected with depletion of liver glycogen stores. In fasted animals moderate hypoglycemia was observed. The in vivo conversion of various precursors into blood glucose was not inhibited, suggesting that maleate does not affect hepatic gluconeogenesis. Neither was a direct effect on liver glycogenolysis observed. On the other hand, maleate inhibited renal gluconeogenesis from various substrates and stimulated anerobic glycolysis in kidney cortical alices. The data are interpreted in terms of increased utilization and decreased production of glucose by the kidney followed by secondary changes in liver carbohydrate metabolism.