Effect of hormones on hepatocyte gluconeogenesis in different models of acute uraemia

Hepatocytes isolated from the livers of starved, sham-operated, bilaterally nephrectomised and ureter-ligated rats as well as rats with ischaemic acute renal failure were used for a comparative study of the effects of different hormones on gluconeogenesis. In all tested groups dibutyryl-3':5'-adenosine monophosphate inhibits glucose synthesis from pyruvate whereas this process is not affected by glucagon and only slightly activated by adrenalin. In contrast, gluconeogenesis from dihydroxyacetone was stimulated by all three hormones at the expense of the conversion of dihydroxyacetone to lactate. In the presence of l-serine adrenalin, glucagon and dibutyryl cAMP also stimulate glucose synthesis, which is more marked in bilaterally nephrectomised and ureter-ligated animals. In half of the experiments with bilaterally nephrectomised rats (group BN 2), lack of sensitivity of hepatocytes to all tested hormones on gluconeogenesis from serine or dihydroxyacetone was observed. The beta-adrenergic antagonist propranolol reduced the stimulatory effect of adrenalin on glucose synthesis from serine and abolished the influence of catecholamines in the presence of dihydroxyacetone and pyruvate. This suggests that both alpha- and beta-receptors are involved in the activation of hepatic gluconeogenesis. Insulin and parathyroid hormone did not change the rate of glucose synthesis in any of the experimental groups.     

Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.     

大鼠胆源性脓毒症时的肝脏糖异生功能及相关激素环境的改变

急性胆源性肝损害所致多系统器官功能不全的机理尚不完全清楚。作者采用肝脏原位灌注法测定了大鼠急性胆道感染（AOC）所致脓毒症时肝脏糖异生功能的改变，并对AOC后机体重要理糖激素环境的变化及其对精异生功能的影响进行了探讨。结果表明：AOC后24小时大鼠肝脏糖异生功能明显降低，血乳酸和促糖激素水平明显升高，胰岛素显著降低，血糖约维持在正常水平的2．5倍。AOC48小时，大鼠肝脏糖异生功能进一步降低，血乳酸浓度继续增加，但促糖激素无继续升高或明显下降，胰岛素显著上升，血糖水平较AOC24小时明显下降。提示AOC早期大鼠肝脏糖异生功能即有明显降低，此时机体可通过增加糖异生基质和改变理糖激素环境维持应激所需要的高血糖水平；后期肝脏糖异生功能进一步受损，机体代偿功能明显紊乱，血糖浓度明显降低，这可能是胆源性多系统辞官功能不全发生发展的病理生理机理之一。     

The gluconeogenetic ability of hepatocytes in various types of acute uraemia

Liver cells were prepared from untreated controls, rats with various models of acute uraemia (uranyl nitrate-treated, bilaterally nephrectomised and ureter-ligated rats, rats with acute ischaemic renal failure) and sham-operated animals. Hepatocyte glucose output, pyruvate utilisation and lactate production were determined in the presence of Krebs-Ringer bicarbonate buffer with different pH values (7.1, 7.4, 7.6) using pyruvate, dihydroxyacetone, serine and fructose as substrates. In the presence of pyruvate and dihydroxyacetone a significant increase of glucose production in hepatocytes from bilaterally nephrectomised and ureter-ligated rats was observed. However, pyruvate-generated glucose production in the hepatocytes of uranyl nitrate-treated animals was unchanged, while a diminished glucose output was seen in the presence of dihydroxyacetone. A marked increase in glucose and lactate production in the presence of serine was observed in the hepatocytes of uranyl nitrate-treated, ureter-ligated and binephrectomised rats. However, lactate production from dihydroxyacetone in the liver cells of uranyl nitrate-treated animals was inhibited. In contrast to other types of uraemia, in acute ischaemic renal failure there is significantly lower hepatocyte glucose production using pyruvate as a substrate, but unchanged glucose generation from dihydroxyacetone or serine.     

Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats

Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.     

Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin.

To better define the modifications of liver gluconeogenesis and citric acid cycle, or Krebs' cycle, activity induced by insulin deficiency and the effects of metformin on these abnormalities, we infused livers isolated from postabsorptive or starved normal and streptozotocin-induced diabetic rats with pyruvate and lactate (labeled with [3-13C]lactate) with or without the simultaneous infusion of metformin. Lactate and pyruvate uptake and glucose production were calculated. The 13C-labeling pattern of liver glutamate was used to calculate, according to Magnusson's model, the relative fluxes through Krebs' cycle and gluconeogenesis. These relative fluxes were converted into absolute values using substrate balances. In normal rats, starvation increased gluconeogenesis, the flux through pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PC-PEPCK), and the ratio of PC to pyruvate dehydrogenase (PDH) flux (P < 0.05); metformin induced only a moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes resembled those of starved control livers, with increased gluconeogenesis and flux through PC-PEPCK. Starvation induced no further modifications in the diabetic group. Metformin decreased glucose output from the liver of starved diabetic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were decreased (P < 0.05) by metformin in both groups of diabetic rats. In conclusion, insulin deficiency increased in this model of diabetes gluconeogenesis through enhanced uptake of substrate and increased flux through PC-PEPCK; metformin decreased glucose production by reducing the flux through PC-PEPCK.     

The effect of hemorrhagic stress on liver gluconeogenesis. An isolated rat liver perfusion study with three-carbon units as substrates

This effect of hypovolemic stress on hepatic gluconeogenesis has been studied using isolated perfused organs obtained from starved rats subjected to 60 min hemorrhagic hypotension at 70 mmHg. Four different substrates were used: lactate, pyruvate, glycerol and alanine. The substrates were added without any stress endocrine stimulation in the perfusate. Using a recirculating system and supraoptimal substrate availability, a significant higher rate of gluconeogenesis was confirmed for the stressed donor livers: glycerol (+100%), alanine (+97%), lactate (+64%) and pyruvate (+62%). Glucose accumulation was linear for all control and experimental groups. In the absence of added stress hormones, known to stimulate gluconeogenesis, the findings are concordant with an in vivo hormone activation of key enzymes in the gluconeogenic pathway, persisting for the 60 min duration of the in vitro perfusion.     

Role of energy charge and redox state for hepatocyte gluconeogenesis of acutely uremic rats

Hepatocytes were isolated from rats following bilateral nephrectomy, ureter ligation or sham operation under sodium pentobarbital (Nembutal) anesthesia to investigate the potential role of energy charge and redox state for the gluconeogenetic ability of liver cells. Ketogenesis from l-serine, sodium pyruvate or dihydroxyacetone was significantly higher in hepatocytes of acutely uremic rats indicating higher concentration of reducing equivalents in the mitochondria. During incubation, the mitochondrial redox state characterized by beta-hydroxybutyrate/acetoacetate ratio moved into direction of reduction in all experimental groups, whereas cytosolic redox state characterized by lactate/pyruvate ratio shifted to the oxidative state indicating lack of cytosolic reducing equivalents. Hepatocyte ATP and oxoglutarate production of ureter-ligated rats were significantly higher compared with binephrectomized or sham-operated animals independent of the substrates used. Simultaneously, energy charge showed values higher than 0.85 only in hepatocytes of ureter-ligated animals indicating high energy supply for energy requiring processes. We conclude that hepatic gluconeogenesis and ketogenesis of acutely uremic rats are limited by a lack of cytosolic reducing equivalents independent of cell energy supply.     

Activation by vanadate of glycolysis in hepatocytes from diabetic rats

In hepatocytes from starved streptozocin-induced diabetic rats, vanadate increases the glycolytic flux because it raises the levels of fructose-2,6-bisphosphate (Fru-2,6-P2), the main regulatory metabolite of this pathway. This effect of vanadate on Fru-2,6-P2 levels is time and dose dependent, and it remains in cells incubated in a calcium-depleted medium. Vanadate is also able to counteract the decrease on Fru-2,6-P2 levels produced by glucagon, colforsin, or exogenous cAMP. However, vanadate does not modify 6-phosphofructo-2-kinase and pyruvate kinase activities, but it does counteract the inactivation of these enzymes induced by glucagon. Likewise, Fru-2,6-P2ase activity is also not affected by vanadate. In addition, vanadate is able to increase the production of both lactate and CO2 in hepatocytes from streptozocin-induced diabetic rats incubated in the presence of glucose in the medium. Vanadate behaves as a glycolytic effector in these cells, and this effect may be related to its ability to normalize blood glucose levels in diabetic animals.     

Hepatic effects of chlorpropamide: inhibition of glucagon-stimulated gluconeogenesis in perfused livers of fasted rats.

In perfused livers of rats fasted for 24 h, glucagon (5 x 10(-10) M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 x 10(-3) M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle. In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.     

Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation

Liver-specific PEPCK knockout mice, which are viable despite markedly abnormal lipid metabolism, exhibit mild hyperglycemia in response to fasting. We used isotopic tracer methods, biochemical measurements, and nuclear magnetic resonance spectroscopy to show that in mice lacking hepatic PEPCK, 1) whole-body glucose turnover is only slightly decreased; 2) whole-body gluconeogenesis from phosphoenolpyruvate, but not from glycerol, is moderately decreased; 3) tricarboxylic acid cycle activity is globally increased, even though pyruvate cycling and anaplerosis are decreased; 4) the liver is unable to synthesize glucose from lactate/pyruvate and produces only a minimal amount of glucose; and 5) glycogen synthesis in both the liver and muscle is impaired. Thus, although mice without hepatic PEPCK have markedly impaired hepatic gluconeogenesis, they are able to maintain a near-normal blood glucose concentration while fasting by increasing extrahepatic gluconeogenesis coupled with diminishing whole-body glucose utilization.     

Gluconeogenesis in tumor-influenced hepatocytes

The growth of a tumor leads to alterations in host carbohydrate metabolism. In this study we examined gluconeogenic capacity and amino acid transport in tumor-influenced and control rat hepatocytes. Serum glucose level decreased with increasing tumor burden and a significant correlation (r = -0.80) was observed. Hepatic glycogen content was similar in both groups after an overnight fast. Endogenous glucose production was 27% higher in tumor-influenced hepatocytes. The presence of 10mM of alanine led to 72% stimulation of gluconeogenesis in tumor-influenced hepatocytes as compared to 48% stimulation in control hepatocytes. The same trends were present when lactate was used as a substrate. Alanine transport into the cells was increased in tumor-influenced hepatocytes by 55% +/- 5% at a physiologic level of substrate. In conclusion, gluconeogenesis from alanine and lactate is significantly increased in tumor-influenced hepatocytes despite decreased serum glucose levels. This is associated with increased gluconeogenic capacity and accelerated alanine transport.     

Isoflurane partially preserves energy balance in isolated hepatocytes during in vitro anoxia

We investigated whether a volatile anesthetic (1.5% isoflurane or 1.0% halothane) or an added anaerobic energy source (10 mM glucose or fructose) could act directly on liver cells to protect energy status during 20-30 min of anoxia. We used hepatocytes freshly isolated from fed rats or rats that had fasted, suspended them in Krebs' buffer, and incubated them in sealed flasks under O2/CO2 or N2/CO2 (95%:5%). The adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio (ATP/ADP) measured cellular energy balance--the balance between overall ATP supply and demand. Lactate levels measured the extent to which ATP was supplied by the nonmitochondrial pathway, (anaerobic) glycolysis. Maximum values of energy balance were seen in cells from fed rats incubated in the presence of glucose and O2. When glucose was replaced by fructose, ATP/ADP decreased and lactate increased. During anoxia (O2 replaced by N2), increases in lactate were also seen with glucose; and ATP/ADP decreased to similarly low values with both substrates. In cells from fasted rats, ATP/ADP decreased significantly below the value for cells from fed rats only in the presence of glucose and O2. Compared with cells from fed rats, cells from fasted rats showed decreased lactate in the face of decreased ATP/ADP, suggesting that glycolysis was impaired. Isoflurane partially prevented anoxia-induced decreases in ATP/ADP. This protective effect on energy balance occurred equally with glucose and fructose, but was not seen in cells from fasted rats or with halothane. Thus, 1 MAC isoflurane and some factor(s) related to the fed state combined to protect partially the energy balance in anoxic liver cells through action(s) at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of gestational hyperglycemia on glucose metabolism and its hormonal control in the fasted, newborn rat during the early postnatal period

To evaluate the effects of gestational hyperglycemia on glucose metabolism and its regulation in the fasted rat during the early postnatal period, unrestrained rats were continuously infused with glucose during the last week of pregnancy. Control rats were infused with distilled water. Newborns were studied during the first six postnatal hours. At birth, newborns from glucose-infused rats, compared with controls, showed higher plasma glucose levels, increased plasma insulin, and lower plasma glucagon and catecholamine concentrations. Between birth and 2 h postpartum, newborn rats from both groups exhibited a marked hypoglycemia, which was, however, more severe in newborns from glucose-infused rats (15 mg/dl) than in controls (26 mg/dl). During the first four postnatal hours, plasma insulin concentration remained higher, while plasma glucagon and catecholamine concentrations remained lower in newborns from hyperglycemic rats. At 6 h, the glycemia reached normal values and the concentrations of the different hormones were similar in controls and newborns from glucose-infused mothers. Concurrently, in the newborns from glucose-infused rats, hepatic glucose production was altered, as they were unable to mobilize liver glycogen stores during the six postnatal hours. Despite slightly delayed phosphoenolpyruvate carboxykinase induction, the rate of gluconeogenesis from 10 mmol/L lactate estimated on isolated hepatocytes was higher in newborns from hyperglycemic mothers than in controls. These results show that gestational hyperglycemia compromises the metabolic and hormonal adaptation of the newborn rat to early extrauterine life; the striking feature of these neonates is the absence of mobilization of liver glycogen stores, which can probably be explained by fetal and neonatal hyperinsulinism associated with the defect of counterregulatory hormones.     

Morphologic and functional changes in sympathetic nerve relationships with pancreatic alpha-cells after destruction of beta-cells in rats

Insulin-dependent diabetes mellitus (IDDM) in humans is accompanied by an attenuation of the response of glucagon to hypoglycemia. To identify an animal model of IDDM with alpha-cell unresponsiveness to glucopenia in which to pursue morphologic and in vitro functional investigation of the lesion, pancreases isolated from rats with IDDM induced by streptozocin (STZ) or occurring spontaneously in BB/W rats were perfused with buffer containing 150, 25, and 150 mg/dl of glucose. In both forms of IDDM the normal glucagon rise during glucopenia was markedly impaired, suggesting an abnormality comparable to that of human IDDM. Studies of the insular sympathetic apparatus were conducted in these rat models. Electron-microscopic examination of peri-insular nerve endings disclosed no discernible abnormality in either form of rat IDDM. However, morphometric analysis of contacts between [3H]norepinephrine-labeled sympathetic nerve terminals and alpha-cells in pancreases from STZ-induced diabetic (STZ-D) rats revealed a 65-70% reduction in direct contacts. An 80% reduction in the number of nerve endings (not labeled) in direct contact with alpha-cells was also noted in the BB/W diabetic rats. Norepinephrine reuptake, studied only in the STZ-D group, was not impaired. The availability of local endogenous norepinephrine to alpha-cells and their sensitivity to exogenous norepinephrine was determined by perfusing 2, 5, or 10 micrograms/ml of tyramine, a releaser of endogenous norepinephrine, and norepinephrine at a concentration that in pancreases from nondiabetic rats gave a quantitatively similar glucagon response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic studies in subjects following thermal injury, Intermediary metabolites, hormones and tissue oxygenation

Hormone-metabolite interrelationships were investigated in 21 burned subjects. Patients showed raised blood concentrations of glucose, the gluconeogenic substrates, lactate, pyruvate, alanine and glycerol, and hypertriglyceridaemia. Plasma cortisol levels were raised especially in the early stage. Plasma glucagon levels were high with peak values 3–4 days after the initial injury, while insulin levels were inappropriately low. The extent of these metabolic changes correlated with the extent of injury. Plasma cortisol showed strong correlations over the first 5 days with blood alanine, lactate, total gluconeogenic substrates, plasma NEFA (non-esterified fatty acids) and blood total ketone bodies, whereas the correlations for glucagon, if present, were much weaker. Conversely there were strong negative correlations between insulin and plasma NEFA, blood glycerol and total ketone bodies; similar correlations were noted for the [insulin]: [glucagon] molar ratio.

The data suggest the important roles of elevated cortisol levels and insulin insufficiency in the metabolic response to burn injury.     

Metabolism of forearm tissues in man. Studies with glucagon.

The role of glucagon in regulating peripheral tissue metabolism in man was assessed in the present studies. To do this, glucagon was infused for two hours into the brachial artery to produce a high but physiologic increment in the glucagon content of arterial blood supplying ipsilateral tissues. Metabolic effects on muscle and on subcutaneous adipose tissue plus skin were sought in seven overnight-fasting subjects and seven subjects starved briefly (60 hours). In the overnight-fasted group the infusion increased bassl glucagon concentration by 1,216 pg./ml. but was without effect on forearm tissue metabolism of glucose, lactate,glycerol, or amino acids. Starvation significantly reduced basal insulin (11.0 to 7.4 muU./ml.) and increased endogenous glucagon (116 to 134 pg./ml.). Basally, there was substantial ketone utilization and a decrease in glucose consumption by both muscle and subcutaneous adipose tissue plus skin. The glucagon infusion increased basal glucagon by 784 pg./ml. Muscle balances of glucose, lactate, acetoacetate, amino acids, and glycerol were unaffected. The metabolism of glucose, lactate, acetoacetate, glycerol, and free fatty acids by subcutaneous adipose tissue plus skin was also unchanged. It is concluded that physiologic increments of glucagon lasting two hours are without effect on forearm tissues in overnight-fasted and briefly starved man.     

Metabolic changes in the liver graft monitored continuously with microdialysis during liver transplantation in a pig model

Microdialysis provides the opportunity to continuously monitor metabolic changes in tissue. The aim of the study is to monitor metabolic changes in the liver graft over time during transplantation in a pig model. Fourteen littermate female pigs with a body weight of 30 to 34 kg were used for seven orthotopic liver transplantations. Intrahepatic implantation of a microdialysis catheter into the liver graft was performed in the donor. Microdialysis samples were collected at 20-minute intervals during the donor operation, cold preservation, and for 7 hours after reperfusion in the recipient. Glucose, lactate, pyruvate, and glycerol concentrations were measured. After cold perfusion, glucose, lactate, and glycerol levels increased, whereas pyruvate levels decreased rapidly. During cold storage, glucose and glycerol levels increased, whereas lactate levels remained stable and pyruvate levels were undetectable. During implantation of the liver graft, glucose, lactate, and glycerol levels showed an accelerated increase. After portal reperfusion, glucose, lactate, and glycerol levels continued to increase for another 40 to 60 minutes, after which they decreased and finally settled at normal levels. At this time, pyruvate levels increased, with a peak within 2 hours after reperfusion, and then decreased to normal levels. Calculated lactate-pyruvate ratio increased after cold perfusion and remained stable during cold storage. During rewarming, it showed an accelerated increase, but after reperfusion, it decreased rapidly. Rewarming and reperfusion are most harmful to the liver, reflected by an accelerated increase in glucose and glycerol levels and lactate-pyruvate ratio. High intrahepatic glucose levels during ischemia appear to be a liver-specific event, which may represent glycogen degradation in injured hepatocytes. (Liver Transpl 2002;8:424-432.)     

Control of glycogen synthase and phosphorylase in hepatocytes from diabetic rats. Effects of glucagon, vasopressin, and vanadate

Although glycogen synthase is present in a highly inactivated state in hepatocytes from streptozocin-induced diabetic rats, glucagon, vasopressin, and vanadate are still able to further decrease the basal activity of the enzyme. This inactivation was observed with the low-to-high glucose 6-phosphate activity ratio assay. The inactivation of glycogen synthase occurred concomitantly with the activation of glycogen phosphorylase. When hepatocytes from diabetic rats were incubated with [32P]phosphate and then with the agents and when the 32P-labeled glycogen synthase was immunoprecipitated, we observed that the 32P bound to the 88,000-Mr subunit increased in all cases. All the [32P]phosphate was located in two cyanogen bromide fragments of the enzyme, indicating that the enzyme was phosphorylated at multiple sites. The fragments were precisely those phosphorylated by glycogenolytic hormones in hepatocytes from normal rats. These results demonstrated that hepatic glycogen synthase, although highly inactive, is under potential hormonal control in diabetes and that the enzyme has not reached its maximal level of phosphorylation. Furthermore, they indicated that vanadate behaves as a glycogenolytic agent regarding its effects on glycogen-metabolizing enzymes in hepatocytes from diabetic rats.     

Characterization of stages in development of obesity-diabetes syndrome in sand rat (Psammomys obesus)

Sand rats (Psammomys obesus) maintained on a diet providing a free choice between laboratory chow and salt bush (Atriplex halimus) were classified into four groups differing in extent of the diabetic syndrome: A, normoglycemic-normoinsulinemic; B, normoglycemic-hyperinsulinemic; C, hyperglycemic-hyperinsulinemic; or D, hyperglycemic with reduced insulin levels. The metabolic pattern of these groups was characterized by measuring the uptake of fatty acid-labeled, very-low-density lipoprotein-borne triglycerides (VLDL-TG) and [3H]-2-deoxyglucose (2-DOG) into muscle and adipose tissues; incorporation of [14C]alanine into glycogen in vivo; gluconeogenesis from lactate, pyruvate, and alanine in hepatocytes; the effect of insulin on glycogen synthesis from glucose; the oxidation of albumin-bound [1-14C]palmitate and [14C]glucose in strips of soleus muscle; activities of muscle and adipose tissue lipoprotein lipase; and activities of rate-limiting enzymes of glycolysis, gluconeogenesis, and fatty acid synthesis in liver. In group A, uptake of VLDL-TG and activity of lipoprotein lipase were higher in adipose tissue and lower in muscle than in albino rats. In the liver, gluconeogenesis and the activity of phosphoenolpyruvate carboxykinase, as well as lipid synthesis and the activity of NADP-malate dehydrogenase, were higher than in albino rats, whereas activity of pyruvate kinase was lower. In group B, uptake of VLDL-TG by adipose tissue and muscle and lipoprotein lipase activity were similar or higher than in group A. Uptake of 2-DOG by muscle and adipose tissue and activity of liver phosphoenolpyruvate carboxykinase were lower than in group A. In groups C and D, uptake of VLDL-TG and lipoprotein lipase activity in muscle were further increased.(ABSTRACT TRUNCATED AT 250 WORDS)