The Effect of Acute Uraemia on Gluconeogenesis in Isolated Perfused Rat Livers

Abstract. The effect of acute uraemia on glucose and urea formation by isolated perfused livers of fasting rats was investigated.
The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the poorly metabolizable amino acids valine, leucine, and iso-leucine. In the presence of a mixture of amino acid3 (serine, threonine, lysine, glutamic acid, ornithine, and citrulline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by at least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.     

Possible sites of interaction of acute renal failure with amino acid utilization for gluconeogenesis in isolated perfused rat liver

Experiments were performed to elucidate the mechanisms involved in the enhanced conversion of amino acids to glucose in acute uraemic rats. Increased gluconeogenesis from a mixture of serine, threonine, lysine, glutamate, ornithine and citrulline was confirmed using a non-recirculating perfusion system. Stimulation was concentration dependent, being most pronounced at physiological amino acid concentrations. Stimulation of glucose and urea formation could be mimicked by using serine alone whereas with lactate and pyruvate inhibition of gluconeogenesis was observed. Serine dehydratase activity was significantly elevated following nephrectomy. Further, the uptake of the non-metabolize amino acid alpha-aminoisobutyrate was considerably increased. It is concluded that serine may play a special role as substrate for the additional glucose formation in acute uraemic rats, probably mediated by an activation of serine dehydratase. Acceleration of amino acid transport seems to represent an additional component of stimulation of amino acid utilization in acute uraemia.     

The effect of acute uraemia on gluconeogenesis in isolated perfused rat livers

Abstract. The effect of acute uraemia on glucose and urea formation by isolated perfused livers of fasting rats was investigated. The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the poorly metabolizable amino acids valine, leucine, and isoleucine. In the presence of a mixture of amino acids (serine, threonine, lysine, glutamic acid, ornithine, and citrulline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by at least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.     

Renal and intestinal calcium-binding proteins in normal and uraemic rats

The effect of chronic uraemia on the concentrations of the 28 kDa renal and 9 kDa intestinal calcium-binding proteins (calbindin-D28K and calbindin-D9K) was investigated in rats. Calbindin-D9K was measured by a competitive enzyme-linked immunoadsorbent assay and calbindin-D28K by rocket immunoelectrophoresis. Chronic uraemia was induced by 5/6 nephrectomy and the results were compared to sham-operated animals. Rats were fed on a diet containing 0.9% calcium and 1.2% phosphorous. Plasma creatinine and plasma urea were elevated in the nephrectomized rats (p less than 0.001), while plasma-1,25-dihydroxycalciferol vitamin D and fractional calcium absorption were unchanged. Plasma parathyroid hormone was significantly elevated in the uraemic rats. The concentration of calbindin-D28K in renal tissue was increased (p less than 0.001) in rats with chronic uraemia and a direct correlation was found between renal calbindin-D28K and plasma urea (p less than 0.05). Intestinal calbindin-D9K correlated inversely with plasma creatinine (p less than 0.05), but the mean level of calbindin-D9K was unchanged in this model of moderate chronic uraemia. Thus, different regulatory mechanisms control levels of calbindin-D9K and calbindin-D28K.     

Metabolic control of hepatic gluconeogenesis in response to sepsis

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).     

罗痛定对脑缺血/再灌注损伤大鼠器官组织一氧化氮合酶的影响

目的观察大鼠脑缺血/再灌注（I/R）损伤不同阶段肺、肝、肾组织一氧化氮合酶（NOS）的活性变化,探讨罗痛定的作用机制。方法选择76只SD大鼠,按改良的四血管阻塞法建立脑I/R损伤模型。随机分为假手术组、I/R损伤组和罗痛定治疗组,后两组分别于再灌注2、6、12、24和48h处死大鼠,测定肺、肝、肾组织不同类型NOS活性。结果I/R损伤组总NOS（tNOS）活性于再灌注2、12和24h均较假手术组显著升高（P〈0.05或P〈0.01）,尤以12h时上升最显著（P均〈0.01）;2h时以结构型NOS（cNOS）活性上升为主（P均〈0.05）;12h时以诱生型NOS（iNOS）活性上升为主（P均〈0.01）,至24h仍较高（P均〈0.05）,48h时基本接近假手术组水平。与I/R损伤组比较,罗痛定治疗组各组织cNOS活性在2h时上升更显著（P均〈0.05）,iNOS在12h以后明显下降（P〈0.05或P〈0.01）。结论在脑I/R损伤不同阶段肺、肝、肾组织中不同类型NOS活性不同,发挥作用不同;罗痛定可以通过调节不同类型NOS活性减轻组织损伤。     

依达拉奉对脓毒血症大鼠血及肝SOD、CAT、自由基的影响

目的观察依达拉奉(ED)对脓毒血症大鼠血及肝超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和自由基的影响。方法SD大鼠30只分为假手术组、手术对照组、ED治疗组(下称治疗组),手术对照组和治疗组均予盲肠结扎穿刺法制作大鼠脓毒血症模型,术前15 min及术后3 h各皮下注射乳酸左氧氟沙星20 mg/kg,治疗组于术前15 min及术后3 h各皮下注射ED 5 mg/kg,三组术后18 h采血和取肝组织测SOD、CAT、羟自由基(OH),并对肝组织进行显微镜、电镜检查。结果手术对照组大鼠肝组织显微镜下可见肝细胞浊肿,水样变,电镜下可见肝细胞核轻度固缩,内质网扩张,治疗组大鼠肝组织病理改变不明显。手术对照组血及肝组织OH活力与假手术组比较明显升高,差异有统计学意义,手术对照组血及肝组织SOD、CAT活力与假手术组比较明显降低,差异有统计学意义;治疗组血及肝组织OH活力与手术对照组比较明显降低,差异有统计学意义,治疗组血SOD、CAT活力与手术对照组比较明显升高,差异有统计学意义。结论ED能降低脓毒血症大鼠血和肝组织OH活力,升高血和肝组织SOD、CAT活力,提高清除自由基和抗氧化能力,具有保护肝功能作用,值得临床推鉴使用。     

Studies on Urea Cycle Enzymes in Rat Liver during Acute Uraemia

Abstract. Activities of urea cycle enzymes were measured in the liver of starved rats 12 and 48 h after bilateral nephrectomy. Control experiments (sham-operated, starved rats) revealed that the activities of only two enzymes of the cycle are altered in the uraemic state: argininosuccinic acid synthetase (EC 6. 3. 4. 5.), which is considered to be rate limiting for urea production and carbamyl phosphate synthetase (EC 2. 7. 2. 5.). Alterations in ornithine concentration of the liver, a possible cause of an increased urea production rate, could not be detected previously (21). Our present results do not support the concept that a decrease of the activity of ornithine-6-amino transferase (EC 2. 6. 1. 13), leading to an increase in the ornithine content of the liver is responsible for the accelerated urea production rate in the liver of acute uraemic rats.     

Metabolic regulation of renal gluconeogenesis in response to sepsis in the rat

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.     

L-谷氨酰胺与肝脏大部分切除后的再生

背景：L-谷氨酰胺作为DNA和谷胱甘肽等合成的氮前体,在肝组织再生,肝细胞增殖的过程中扮演着极其重要的角色。目的：观察经饮食由来补充L-谷氨酰胺对大鼠肝脏大部切除后肝再生能力的影响。方法：Wistar大鼠随机分组3组,L-谷氨酰胺组和L-丙氨酸组大鼠肝切除前分别灌服10%L-谷氨酰胺或10%L-丙氨酸,肝切除后继续加入饮用水中饮用,对照组肝切除前后均使用饮用水。结果与结论：大鼠肝切除后72hL-谷氨酰胺组肝再生率明显高于对照组及L-丙氨酸组（P〈0.05）。肝切除后24h和72hL-谷氨酰胺组肝细胞增殖均明显高于对照组和L-丙氨酸组（P〈0.01;P〈0.05）。肝切除后24h和72h总RNA水平在两种氨基酸与对照组之间差异无显著性意义。肝切除后72h基因组DNA的含量L-谷氨酰胺组显著高于对照组和L-丙氨酸组（P〈0.05）。提示肝损伤围手术期投用高浓度L-谷氨酰胺对大鼠肝再生有促进作用,而投用L-丙氨酸则没有此作用。     

Concentrations ofd-lactate and its related metabolic intermediates in liver,blood, and muscle of diabetic and starved rats

This is a report investigating the methylglyoxal (MG) bypass in animals, by whichd-lactate is produced from triosephosphate via MG. Rats were made diabetic using streptozotocin or starved for 72 h.d-Lactate and various metabolites related to it, such asl-lactate, pyruvate, methylglyoxal, glucose, and inorganic phosphate, were measured in the blood plasma, liver, and skeletal muscle of the rats. Diabetic and starved rats had significantly higher levels ofd-lactate in plasma, liver, and skeletal muscle compared with the control group. In contrast, pyruvate levels in plasma, liver, and skeletal muscle was markedly lower than normal in diabetic and starved rats.l-Lactate level lowered markedly in plasma, liver, and skeletal muscle of starved rats and elevated in liver of diabetic rats. Differences between plasmal-lactate level for diabetes and control were not significant. MG level was significantly elevated in plasma and depressed in livers and muscles of starved rats as well as livers of diabetic rats. Hepatic glycerol content was markedly increased in those states. Enzyme activities related tod- andl-lactate, such as pyruvate kinase, phosphofructokinase, aldolase, and glyoxalase I, were measured in the livers of these rats. Pyruvate kinase activity decreased in these states, but other enzyme activities showed no significant changes.d-Lactate was much more excreted thanl-lactate in the urine of diabetic and fasted rats compared with normal rats.     

BIOCHEMICAL STUDIES ON SHOCK : I. THE METABOLISM OF AMINO ACIDS AND CARBOHYDRATE DURING HEMORRHAGIC SHOCK IN THE RAT

During and following the production of shock by hemorrhage in the normal, suprareno-demedullated, and suprarenalectomized rat, the following significant changes in amino acid and carbohydrate metabolism have been observed. 1. In the intact, suprareno-demedullated, and suprarenalectomized rat there is a progressive rise in the whole blood and plasma amino acid nitrogen levels during and after a fatal, shock-inducing hemorrhage. The rate of rise varies inversely with the survival time. In animals surviving the hemorrhage there is little or no elevation in whole blood amino acid levels during the 8 hours following hemorrhage, and a decrease in 24 hours due to hemodilution. The plasma amino acids, however, rise slightly. 2. The blood amino acid nitrogen elevation occurs only after the blood pressure has fallen to between 85 and 90 mm. of Hg. 3. The blood keto acids, as pyruvate, and the blood lactate become elevated during shock in the normal, suprareno-demedullated and suprarenalectomized rat. 4. In the normal fasted rat with low liver glycogen stores the blood sugar may rise moderately or may not rise at all during hemorrhagic shock. In animals with high liver glycogen levels (fed rats or fasted rats previously fed high protein diets) shock generally induces a marked hyperglycemia. In both groups hypoglycemia may occur terminally. 5. In the suprareno-demedullated and suprarenalectomized rats shock is always accompanied by a fall in the blood sugar. 6. There is no significant difference between the liver glycogen levels of suprareno-demedullated rats fasted 48 hours and those similarly fasted but surviving 24 hours after a hemorrhage. The blood chemical changes have been interpreted as due to a decrease in hepatic function resulting from early anoxia of the liver and to the later effects of anoxia on the peripheral tissues causing an increased rate of protein breakdown and of glucose utilization and an accumulation of lactate and pyruvate in the blood and tissues.     

Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity

As in women receiving oestrogens the administration of 17beta-oestradiol to ovariectomized female rats caused a rise in fasting plasma triglycerides and a fall in plasma glucose. Progesterone, on the other hand, had no significant effects. In the oestradiol treated rats, the portal vein basal insulin levels were slightly reduced. Oestradiol, however, had a marked suppressive effect on the alpha cells of the pancreas resulting in a greater reduction in basal glucagon and impaired glucagon response to alanine infusions. The relative insulin to glucagon (I/G) molar concentration ratio in portal vein blood was increased. Oestradiol also produced a dose dependent increase in the activity of the liver lipogenic enzymes, acetyl CoA carboxylase and fatty acid synthetase. On the other hand, the activity of the gluconeogenic rate limiting enzyme phosphoenol-pyruvate carboxykinase (PEPCK) was inhibited. The cross-over pattern of gluconeogenic intermediates confirmed inhibition of gluconeogenesis at this step, an effect which is similar to that induced by relative insulin 'excess'. Progesterone produced an increase in the portal vein insulin concentrations. Both the basal and the alanine-stimulated glucagon levels were also increased. The I/G molar ratio in portal vein blood of progesterone treated rats remained unaltered and the hepatic lipogenic and gluconeogenic enzyme activities were similar to control animals. These data suggest that insulin activity is increased relative to glucagon in the liver of oestradiol-treated rats due to the rise in portal vein I/G ratio. The changes in liver lipogenic and gluconeogenic enzymes and the alterations in fasting plasma triglycerides and glucose in response to oestrogens could be secondary to this effect.     

Different cation transport inhibitor in malignant renal hypertension and in uraemia

1. We investigated whether the previously reported circulating frusemide-like factor in rats with malignant renal hypertension was specific to this syndrome, or was also present in rats with chronic uraemia. 86Rb uptake (K+ transport) of monolayers of vascular smooth muscle cells was measured in the plasma of rats with malignant one-kidney, one-clip hypertension and of uraemic rats (60-70% nephrectomy). 2. Compared with control plasma, ouabain-insensitive 86Rb uptake of cells was reduced and ouabain-sensitive 86Rb uptake was unchanged in the plasma of rats with malignant hypertension. The reverse was found in the plasma of uraemic rats. 3. Inhibition of ouabain-sensitive 86Rb uptake of cells occurred in the plasma of rats with malignant hypertension when an angiotensin II antagonist was added to the reaction mixture. 4. The findings confirm the presence of a frusemide-like plasma factor in malignant hypertension and a ouabain-like plasma factor in uraemic. The presence of a ouabain-like plasma factor in malignant hypertension is camouflaged by an elevated circulating angiotensin II level, which stimulates K+ transport.     

丙酮酸乙酯对脓毒症大鼠肠黏膜屏障功能保护作用的研究

目的 观察丙酮酸乙酯(ethyl pyruvate ,EP)干预治疗对脓毒症大鼠生存率和肠黏膜屏障的影响.方法 ①EP对脓毒症大鼠生存率的影响:无特定病原雄性SD大鼠100只随机分为假手术组(A组)、脓毒症组(B组)、EP早期治疗组(C组)及EP延迟治疗组(D组),每组25只,利用盲肠结扎穿孔法(cecal ligation and puncture,CLP)制作大鼠脓毒症模型,各组均于术后6、12、18、24、36、48、60、72 h腹腔内注射给药3 mL,C、D组分别于术后6、12 h开始予EP(40 mg/kg),A、B两组同法予等量林格乳酸钠溶液(ringer lactate solution ,RLS),每隔12 h记录死亡情况,分析比较5 d生存率;②EP对脓毒症大鼠肠黏膜屏障的影响:80只无特定病原雄性SD大鼠随机分为四组,每组20只,分组及给药方法与方法一相同,术后24、48 h各处死10只.测定各时间点血浆D-乳酸、DAO的变化,同时用透射电镜观察术后48 h肠黏膜上皮细胞超微结构的变化.采用Kaplan- Meier生存分析法进行生存分析,多组均数间比较采用单因素方差分析的方法, 多组均数间两两比较采用SNK-q检验,P＜0.05为差异有统计学意义.结果 A、B、C、D四组大鼠5 d生存率分别为100%、24%、68%、56%,与B组相比,C、D组大鼠5 d生存率明显提高(P<0.05),C、D组间差异无统计学意义(P＞0.05);与B组相比,C、D组术后24 h和48 h血浆D-乳酸含量明显下降(P<0.01);与B组相比,C组、D术后24 h和48 h血浆DAO活性明显下降(P<0.01),C、D组术后24、48 h血浆D-乳酸含量、DAO活性差异无统计学意义(P＞0.05);电镜下C、D组肠黏膜上皮细胞损伤较B组明显减轻,细胞间紧密连接较清楚.结论 脓毒症时肠黏膜损伤严重,EP早期与延迟干预治疗能有效保护肠黏膜屏障,提高5 d生存率,具有抗脓毒症作用 .     

Time course of changes in hepatic metabolism in response to sepsis in the rat: impairment of gluconeogenesis and ketogenesis in vitro

The time course (12, 24 and 48 h) of changes in blood metabolites, and in gluconeogenesis and ketogenesis, in isolated hepatocytes from rats made septic by caecal ligation and puncture was measured. Blood glucose was not significantly different in septic rats, but lactate was increased at 12, 24 and 48 h; pyruvate and alanine were increased at 48 h. The blood ketone body concentrations were decreased at all times studied after induction of sepsis. These changes were accompanied by increased plasma insulin in the septic rats. The rate of hepatic lipogenesis in vivo was increased at 24 and 48 h. There were appreciable increases in the hepatic concentrations of alanine (200%), lactate (200%) and pyruvate (100%) as well as other intermediates in the gluconeogenic pathway. The hepatic concentrations of acetyl-CoA and ketone bodies were decreased. The rate of gluconeogenesis from added lactate, pyruvate, alanine and glutamine was depressed in isolated hepatocytes from septic rats at 24 and 48 h. The basal rate of ketogenesis or the rate from butyrate in isolated hepatocytes was not significantly altered by sepsis, whereas the rate from oleate was decreased at all time points. It is concluded that there is an impairment of the capacity for gluconeogenesis and ketogenesis in livers of septic rats. The latter may be due to decreased entry of long-chain acyl-CoA into the mitochondria for oxidation. The possibility that these changes are in part brought about by the hyperinsulinaemia associated with the sepsis is discussed.     

Maximal activity of phosphate-dependent glutaminase and glutamine metabolism in septic rats

The activity of phosphate-dependent glutaminase and glutamine metabolism by tissues known markedly to utilize or synthesize glutamine (or both) were studied in rats made septic by cecal ligation and puncture technique and compared with the same measures in rats that underwent sham operation (laparotomy). Blood glucose level was not markedly different in septic rats, but lactate, pyruvate, alanine, and glutamine levels were markedly increased. Conversely, blood ketone body concentrations were significantly decreased in septic rats. Both plasma insulin and glucagon levels were markedly elevated in response to sepsis. The maximal activity of phosphate-dependent glutaminase was decreased in the small intestine, increased in the kidney and mesenteric lymph nodes, and unchanged in the liver of septic rats. Arteriovenous concentration difference measurements across the gut showed a decrease in the net glutamine removed from the circulation in septic rats. Arteriovenous concentration difference measurements for glutamine showed that both renal uptake and skeletal muscle release of the amino acid were increased in response to sepsis, whereas measurements across the hepatic bed showed a net uptake of glutamine in septic rats. Enterocytes isolated from septic rats exhibited a decreased rate of utilization of glutamine and production of glutamate, alanine, and ammonia, whereas lymphocytes isolated from septic rats showed an enhanced rate of utilization of glutamine and production of glutamate, aspartate, and ammonia. It is concluded that, during sepsis, glutamine uptake and metabolism are enhanced in renal and lymphoid tissue but decreased in that of the small intestine, with increased rates of release by skeletal muscle; however, the liver appears to utilize glutamine in septic rats.     

Isozymes of Aspartate Aminotransferase in Rat Liver during Acute Uraemia

Abstract. Total activity of aspartate-aminotransferase (GOT; EC 2.6.1.1) and activities of the cytoplasmic (c-GOT) and mitochondrial (m-GOT) isozymes were measured in rat liver 24 and 48 h after bilateral nephrectomy.
24 h after nephrectomy no significant differences in enzyme activities could be detected between uraemic animals and sham-operated controls. However 48 h after nephthrectomy the total activity of GOT increased significantly. Fractional tissue extraction revealed an elevation of only the cytoplasmic isozyme (c-GOT), due to a selective increase of this enzyme fraction. No significant change could be noticed of the mitochondrial isozyme (m-GOT). These results are discussed with regard to an increased gluconeogenesis in rat liver 48 h after bilateral nephrectomy.     

Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.

The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.     

Effects of chronic uraemia on the formation of glucose and urea plus ammonia from L-alanine, L-glutamine and L-serine in isolated rat hepatocytes

The effects of chronic uraemia on glucose production and nitrogen release (urea plus ammonia formation) from alanine, glutamine or serine in isolated rat hepatocytes were studied. Uraemia increased the rate of formation of urea plus ammonia from all three amino acids by 38-93% when they were present at a final concentration of 10 mmol/l. At lower concentrations (2 mmol/l) the rate of nitrogen release was not significantly increased. Hepatocytes from normal rats whose food intake had been restricted to the level of that of uraemic rats did not show the increased rates of nitrogen release. The increased rates of nitrogen release with hepatocytes from uraemic rats were not accompanied by increased rates of glucose synthesis. Instead, accumulation of metabolic intermediates occurred: lactate and pyruvate (alanine or serine as substrates) and glutamate (glutamine as substrate). Livers of uraemic rats had increased activities of glutaminase (30%) and serine dehydratase (100%). Hepatocytes from normal rats treated with phlorhizin to increase the plasma glucagon/insulin ratio behaved in a similar manner to hepatocytes from uraemic rats. They had increased serine dehydratase activity, and increased rates of utilization of serine or glutamine. The possible implications of these findings for human uraemia are discussed.