Gluconeogenic Precursors Research Articles

In vivo amino acid metabolism of gut and liver during short and prolonged starvation.

During starvation, splanchnic organs are proportionally more affected by protein loss than other organs. Amino acid membrane transport is one of the regulating mechanisms of protein turnover, but until now in vivo data were lacking. To study in vivo phenylalanine and tyrosine membrane transport and protein turnover in splanchnic organs, a primed continuous infusion of L-[2,6-3H]phenylalanine was given to control rats (postabsorptive) and after short (40 h) and prolonged (112 h) starvation. Data were analyzed using a three-compartment model previously used in muscle membrane transport studies. Inward and outward amino acid plasma-tissue membrane transport rates in both the liver and gut were upregulated after prolonged starvation. Metabolic shunting of phenylalanine and tyrosine increased in the gut but decreased to zero in the liver after prolonged starvation. In conjunction with this, gut and liver protein turnover increased after prolonged starvation. In the liver the net uptake of gluconeogenic precursors also increased, indicative for increased gluconeogenesis. The observed changes in amino acid metabolism in both splanchnic organs after prolonged starvation may reflect an adaptation of the gut and liver to nutritional deprivation and could be of benefit during refeeding.

Effects of lactate on glucose metabolism in healthy subjects and in severely injured hyperglycemic patients

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.

In humans, endurance training markedly reduces the rate of hepatic glucose production during exercise. To determine whether this is due to a reduction in glycogenolysis, in gluconeogenesis, or in both processes, six men were studied at rest and during 2 h of cycle ergometer exercise at 60% pretraining peak O2 consumption (VO2peak), both before and after completion of a strenuous endurance training program (cycling at 75-100% VO2peak for 45-90 min/day, 6 days/wk for 12 wk). The overall rate of glucose appearance (Ra) was determined using a primed continuous infusion of [6,6-2H]glucose, whereas the rate of gluconeogenesis (Rgng) was estimated from the incorporation of 13C into glucose (via pyruvate carboxylase) from simultaneously infused [13C]bicarbonate. Training did not affect glucose kinetics at rest but reduced the average Ra during exercise by 42% [from 36.8 +/- 3.8 to 21.5 +/- 3.6 (SE) mumol.min-1.kg-1; P < 0.001]. This decrease appeared to be mostly due to a reduction in hepatic glycogenolysis. However, the estimated Rgng during exercise also decreased significantly (P < 0.001) with training, falling from 7.5 +/- 1.6 mumol.min-1.kg-1 (23 +/- 3% of total Ra) before training to 3.1 +/- 0.6 mumol.min-1.kg-1 (14 +/- 3% of total Ra) after training. These training-induced adaptations in hepatic glucose metabolism were associated with an attenuated hormonal response to exercise (i.e., higher insulin and lower glucagon, norepinephrine, and epinephrine concentrations) as well as a reduced availability of gluconeogenic precursors (i.e., lower lactate and glycerol concentrations). We conclude that endurance training reduces both hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.

Forearm muscle insulin resistance during hypoglycemia: role of adrenergic mechanisms and hypoglycemia per se.

The forearm perfusion technique was used 1) to quantify the muscle metabolism of glucose and gluconeogenic precursors in response to insulin-induced hypoglycemia and 2) to assess the role of catecholamines and glucose concentration, pe se. Insulin (0.5 mU.kg-1.min-1) was infused for 4 h in three groups of healthy volunteers. In group I (n = 6), blood glucose (BG) was maintained at its basal level (4.5 +/- 0.1 mmol/l). In group II (n = 7), BG was allowed to fall to approximately 3 mmol/l. Group III (n = 6) was similar to group II except that propranolol was infused also. In addition, at 240 min, hypoglycemia was locally corrected by intrabrachial glucose infusion while maintaining the systemic milieu unperturbed. In group I, forearm glucose uptake (FGU) increased from 4.7 +/- 1.3 to a mean value of 37.8 +/- 5.0 mumol.l-1.min-1, whereas in group II it remained unchanged (8.3 +/- 2.0 mumol.l-1.min-1). In group III, propranolol partially prevented the suppression of FGU that increased to 21.6 +/- 5.2 mumol.l-1.min-1 (P < 0.05 vs. group II). Local correction of hypoglycemia normalized the FGU response (36.5 +/- 8.0 mumol.l-1.min-1). Muscle release of lactate, but not of alanine, was slightly higher during hypoglycemia (P = not significant). Forearm blood flow remained unchanged in groups I and III, whereas it increased by approximately 40% in group II (P < 0.05). It is concluded that, during mild hypoglycemia 1) extreme insulin resistance develops in the skeletal muscle, mediated by beta-adrenergic stimulation and reduced glucose mass effect and 2) mobilization of gluconeogenic precursors is only weakly activated.

Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man.

To compare glutamine and alanine as gluconeogenic precursors, we simultaneously measured their systemic turnovers, clearances, and incorporation into plasma glucose, their skeletal muscle uptake and release, and the proportion of their appearance in plasma directly due to their release from protein in postabsorptive normal volunteers. We infused the volunteers with [U-14C] glutamine, [3-13C] alanine, [2H5] phenylalanine, and [6-3H] glucose to isotopic steady state and used the forearm balance technique. We found that glutamine appearance in plasma exceeded that of alanine (5.76 +/- 0.26 vs. 4.40 +/- 0.33 mumol.kg-1.min-1, P < 0.001), while alanine clearance exceeded glutamine clearance (14.7 +/- 1.3 vs. 9.3 +/- 0.8 ml.kg-1.min-1, P < 0.001). Glutamine appearance in plasma directly due to its release from protein was more than double that of alanine (2.45 +/- 0.25 vs. 1.16 +/- 0.12 mumol.kg-1.min-1, P < 0.001). Although overall carbon transfer to glucose from glutamine and alanine was comparable (3.53 +/- 0.24 vs 3.47 +/- 0.32 atoms.kg-1.min-1), nearly twice as much glucose carbon came from protein derived glutamine than alanine (1.48 +/- 0.15 vs 0.88 +/- 0.09 atoms.kg-1.min-1, P < 0.01). Finally, forearm muscle released more glutamine than alanine (0.88 +/- 0.05 vs 0.48 +/- 0.05 mumol.100 ml-1.min-1, P < 0.01). We conclude that in postabsorptive humans glutamine is quantitatively more important than alanine for transporting protein-derived carbon through plasma and adding these carbons to the glucose pool.

Effect of acute glucagon removal on metabolic response to infection in conscious dog.

This study examined the acute role of glucagon in sustaining the increased hepatic gluconeogenesis observed in the conscious infected dog. After a basal sampling period, arterial glucagon levels were selectively decreased for 180 min by a peripheral infusion of somatostatin and basal intraportal infusion of insulin (GGN deficient; n = 6). In a separate protocol (GGN replaced; n = 5) glucagon was also infused intraportally to maintain the glucagon level at that seen during sepsis. Tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism and gluconeogenesis. In the GGN-deficient group the arterial plasma glucagon level fell from 416 +/- 49 to 88 +/- 21 pg/ml, whereas in the GGN-replaced group it remained elevated throughout (321 +/- 48 to 248 +/- 22 pg/ml). When glucagon was reduced, endogenous glucose production decreased by 1.6 +/- 0.3 mg.kg-1.min-1, and an exogenous glucose infusion was required to maintain euglycemia. Glucose metabolism remained unaltered when glucagon was replaced. When glucagon was deleted, net hepatic gluconeogenic precursor uptake was not altered. In contrast, the efficiency of gluconeogenesis was decreased by 33% compared with the GGN-replaced group. Liver biopsies taken at the end of the experiment indicated that a diversion of gluconeogenic carbon to glycogen accounted for 50% of the fall in gluconeogenic efficiency. In summary, the basal hyperglucagonemia seen during an infection helps sustain glucose production both through its effects on hepatic glycogen metabolism and on gluconeogenic efficiency.

THE IMPACT OF INFECTION ON GLUCONEOGENESIS IN THE CONSCIOUS DOG

The effect of infection on gluconeogenesis was assessed in the chronically catheterized conscious dog. Dogs were studied 42 h after implantation of a sterile (n = 7) or an Escherichia coli containing (n = 7) fibrinogen clot into the peritoneum (54 h fasted). Infection increased arterial plasma glucagon and cortisol (4.2- and 2.1-fold, respectively), but it did not alter arterial plasma insulin, catecholamines, or glucose concentrations. Infection increased tracer ([3-3H]glucose) determined glucose production and utilization and net hepatic glucose output by 35%. Net hepatic alanine and lactate uptake were also increased by 34 and 54%, respectively, without an alteration in their net hepatic fractional extraction. The intrahepatic efficiency of conversion of [14C]alanine to [14C]glucose was not decreased in the septic dog (.77 +/- .08) vs. .95 +/- .10 in noninfected and infected, respectively). Intestinal glucose uptake and lactate release were increased approximately twofold. The increase in intestinal lactate release accounted for 35% of the increase in net hepatic lactate delivery seen in response to infection. In conclusion, a good model of hypermetabolic infection was developed in which the characteristic increases in hepatic glucose production and gluconeogenesis were observed in the fasted state. The increase in gluconeogenesis was due to an increase in hepatic gluconeogenic precursor uptake with no impairment in the net fractional hepatic extraction of gluconeogenic precursors or the efficiency of gluconeogenesis. In addition, the intestine is a significant contributor to the increase in gluconeogenic precursor supply seen in response to infection.

Gut-derived proteolysis during insulin-induced hypoglycemia: the pain that breaks down the gut.

The metabolic events associated with early response to injury have received little attention because of the confounding effects of the hemodynamic alterations that normally occur during this early phase. We have used a well established and reproducible model of insulin-induced hypoglycemia in the conscious dog to define the glucose and amino acid kinetic alterations as well as the hormonal and interorgan amino acid and gluconeogenic precursor flux characteristics of the "ebb" phase of postinjury metabolism. The results from our whole-body response have demonstrated on enhanced rate of whole body proteolysis and amino acid oxidation. The site of the majority of the proteolytic response has been demonstrated to be the extra-hepatic splanchnic tissues or gut. These findings have been supported by studies focusing on the specific organ changes, which have demonstrated alterations compatible with impaired proliferation at the level of the gut mucosa. Furthermore, the regulation of this gut-derived proteolysis has been demonstrated to be mediated by the glucopenia at the level of the central nervous system. The specific site of this response is still elusive; however, the mediators seem to involve not only the traditional hormonal and neurotransmitter pathways but also the release of endogenous opioids and opiates. Although a cause-effect relationship has not yet been demonstrated for the control of gut-derived proteolysis by opioids and opiates, we present evidence that leads us to hypothesize that relationship as a possible regulatory mechanism.

Metabolic Effects and Fate of Succinic Acid Methyl Esters in Rat Hepatocytes

The metabolic fate and metabolic effects of succinic acid methyl esters were examined in rat isolated hepatocytes. Both the monomethyl ester (SAM) and dimethyl ester (SAD) of succinic acid inhibited D-glucose metabolism. Such an inhibition affected, in order of increasing severity, the direct incorporation of D-glucose into glycogen and futile cycling between the hexose and its 6-phosphate ester, the phosphorylation of D-glucose, the generation of triose phosphates from the hexose, and the production of 14C-labeled lactate, pyruvate, and amino acids from D-[U- 14C]glucose and its oxidation. The dimethyl ester of [1,4- 14C]succinic acid ([1,4- 14C]SAD) or [2,3- 14C]succinic acid ([2,3- 14C]SAD) was efficiently converted to acidic metabolites. The oxidation of [1,4- 14C]SAD largely exceeded that of [2,3- 14C]SAD. Inversely the generation of newly formed radioactive D-glucose and glycogen appeared higher in cells exposed to [2,3- 14C]SAD, rather than [1,4- 14C]SAD. It is proposed that SAM and SAD are suitable nutrients both to cover the energy need of hepatocytes and to act as gluconeogenic precursors.

The effect of acute glucagon removal on the metabolic response to stress hormone infusion in the conscious dog

The effect of acute glucagon removal on glucose metabolism following long-term (70-hour) stress hormone infusion (day 3) was investigated in 20-hour-fasted conscious dogs. Stress hormone infusion increased arterial plasma glucagon, cortisol, epinephrine, and norepinephrine (∼ fivefold), as well as arterial plasma glucose (Δ82 ± 16 mg/dL) and insulin (Δ26 ± 5 μU/mL). After assessing basal glucose metabolism on day 3, the long-term glucagon infusion was discontinued (n = 6), and the remaining hormones were infused for an additional 180 minutes. Constant glycemia was maintained by an exogenous glucose infusion. In five dogs, the stress hormone infusion containing glucagon was continued for 180 minutes. Glucose production and gluconeogenesis were assessed using tracer and arteriovenous-difference techniques. Acute removal of glucagon decreased arterial plasma glucagon from 220 ± 24 to 32 ± 4 pg/mL and net hepatic glucose output (Δ1.6 ± 0.3 mg/kg/min). Net hepatic handling of lactate, alanine, and glycerol was not altered. The efficiency of gluconeogenesis, on the other hand, was decreased by 40%. Liver biopsies taken following discontinuation of glucagon indicated that both 3H- and 14C-glucose accumulated in glycogen. The calculated rate of plasma glucose and gluconeogenic precursor diversion to glycogen increased by fivefold and fourfold, respectively. The increased gluconeogenic precursor diversion to glycogen accounted for 58% of the decrease in the efficiency of gluconeogenesis. In conclusion, acute removal of glucagon during stress hormone infusion decreased net hepatic glycogenolysis in the face of prevailing hyperglycemia and hyperinsulinemia, while having minimal effects on the gluconeogenic process per se.

Lipolysis and gluconeogenesis from glycerol during weight reduction with very-low-calorie diets

The aim of this study was to determine if the rates of lipolysis and the conversion of glycerol into glucose are higher during weight reduction with a ketogenic than a nonketogenic very-low-calorie diet (VLCD). Sixteen obese women were randomly assigned to consume either a ketogenic or nonketogenic 615-kcal/d diet for 28 days while confined to a metabolic ward. Glycerol and glucose rates of appearance (R as) and the conversion of glycerol into glucose were measured before and after 14 and 28 days of treatment with a simultaneous, primed, constant infusion of U-[ 14C]-glycerol and 6-[ 3H]-glucose. Resting energy expenditure (REE) and rates of substrate oxidation were measured by indirect calorimetry. Data were analyzed by repeated-measures ANOVA. There were no diet or time effects on the plasma glycerol concentration or glycerol R a. There was a modest but significant time effect on the glucose R a and on the conversion of glycerol into glucose when expressed as a percentage of the glycerol or glucose R a. However, even after 28 days of treatment, the conversion of glycerol into glucose accounted for only 16% and 58% of glucose and glycerol R as, respectively. At day 28, plasma glucose and alanine concentrations were lower and the rate of protein oxidation was higher in the ketogenic than in the nonketogenic VLCD group. We conclude that in severe obesity, (1) the rates of lipolysis and gluconeogenesis from glycerol are not increased by altering the composition of the VLCD; (2) glycerol is a minor gluconeogenic precursor during weight reduction; and (3) nonketogenic VLCDs are more advantageous than ketogenic VLCDs in maintaining normal plasma glucose concentration and promoting protein sparing.

Impact of Metabolism by Extragastrointestinal Tissue on Secretory Rate of Milk Proteins

This paper reviews the current state of knowledge about the postabsorptive utilization of AA. Data on the duodenal entry of AA and the projected output of these same AA as milk protein demonstrate significant losses. Within the essential AA, these losses range from 70% for Thr to 40% for Met and Lys. For Val, almost half of the loss is due to its use for nonsecretory purposes by the mammary gland; values decrease to 0% for other AA. The liver is the other major organ, apart from the portal-drained viscera, that is responsible for significant AA disposal. Interactions of Met metabolism with other methyl sources and gluconeogenic precursors that can alter the Met requirement also are discussed. Data on the transhepatic and transsplanchnic AA balance in lactating cows, and the coordinated use of these balances with duodenal flow and mammary balance, are needed. Further research also is needed into the functionality of use of AA for purposes other than milk protein synthesis to determine whether excess catabolism of AA occurs; assuming it does, more efforts are needed to identify regulation of AA disposal in the crucial tissues.

The effect of the hepatic nerves on the disposition of a mixed meal by conscious dogs.

We examined the disposition of a mixed meal by nine conscious dogs fasted for 24 hours with surgical hepatic denervation. The results were compared with those from identical studies carried out previously in 13 hepatic-innervated dogs. Net gut release of glucose and gluconeogenic precursors (assessed with the arteriovenous difference technique), the resulting blood glucose and plasma insulin concentrations, and the hepatic glucose load were remarkably similar in the two groups. Net hepatic glucose uptake was 4.8 +/- 3.6 g in hepatic-denervated and 7.7 +/- 3.3 g in hepatic-innervated dogs. Cumulative net hepatic lactate release in hepatic-denervated dogs was 4.3 +/- 1.4 g of glucose equivalents, half the value for hepatic-innervated dogs. Net hepatic carbon intake was similar in the two groups. Hepatic lipogenesis, oxidation, and net glycogen synthesis were qualitatively similar between groups. In conclusion, the disposition of a mixed meal by hepatic-innervated and hepatic-denervated dogs was very similar. Subtle alterations in net hepatic balance of substrates (tendencies toward decreases in net hepatic glucose uptake and lactate release) made net carbon retention in denervated livers virtually identical with that in innervated livers. When other compensatory mechanisms are intact, hepatic denervation does not significantly alter hepatic disposition of a mixed meal.

Effect of beta-receptor blockade on splanchnic and muscle metabolism during prolonged exercise in men

The importance of beta-receptor stimulation for the metabolism and circulation in the liver and exercising muscle was studied in six men during 3 h of leg exercise at 50% of maximum oxygen uptake. At 160 min of exercise, 0.15 mg propranolol/kg body wt was given intravenously. The results were compared with a previously studied control group examined in the same way but without beta-receptor blockade. The data show that beta-blockade during prolonged leg exercise, compared with exercising controls, results in 1) reduced splanchnic and leg blood flows (P < 0.005-0.01); 2) higher epinephrine and norepinephrine levels (P < 0.001); 3) unchanged respiratory exchange values, indicating unchanged carbohydrate oxidation; 4) a less marked drop in leg glucose uptake, suggesting reduced muscle glycogenolysis; 5) a higher splanchnic glucose output (P < 0.05) but lower splanchnic uptakes of lactate and glycerol after propranolol (P < 0.025-0.01), i.e., diminished uptake of gluconeogenic precursors, indicating accelerated hepatic glycogenolysis; and 6) unchanged glycerol levels with a lower splanchnic glycerol uptake, indicating reduced lipolysis. The data imply that, despite lower glycogen stores during prolonged exercise, liver glycogenolysis, as opposed to exercising muscle glycogenolysis, may be accelerated during beta-receptor blockade.

Role of glucagon in the metabolic response to stress hormone infusion in the conscious dog.

The impact of the absence of an increase in glucagon on the metabolic response to stress hormone infusion was investigated. We studied 11 conscious dogs fasted for 20 h before (day 0) and after (day 3) a 70-h stress hormone infusion containing glucagon, cortisol, epinephrine, and norepinephrine that increased their respective levels approximately sixfold. Five additional dogs were studied on day 0 and were then infused with the same stress hormone infusion but without glucagon. Glucose production and gluconeogenesis were assessed using tracer and arteriovenous difference techniques. The absence of an increase in glucagon during stress hormone infusion attenuated the increase in arterial plasma glucose concentration (delta 81 +/- 16 vs. delta 28 +/- 6 mg/dl) but did not significantly alter the increase in the rate of glucose appearance (delta 1.7 +/- 0.3 vs. delta 1.1 +/- 0.4 mg.kg-1.min-1). However, it eliminated the increase in net hepatic glucose output (delta 0.7 +/- 0.3 vs. delta 0.0 +/- 0.4 mg.kg-1.min-1) primarily because of an increase in hepatic glucose uptake. In addition, the stress hormone-induced increase in net hepatic gluconeogenic precursor uptake (delta 0.7 +/- 0.3 vs. delta 0.2 +/- 0.1 mg of glucose.kg-1.min-1) and the efficiency of gluconeogenesis (delta 0.19 +/- 0.07 vs. delta 0.01 +/- 0.05) were attenuated. Glucagon thus plays a pivotal role in the metabolic response to stress hormone infusion by sustaining gluconeogenesis through a stimulatory effect on the hepatic gluconeogenic precursor uptake as well as on the efficiency of gluconeogenesis within the liver.

Absence of Glycogen Cycling in Cultured Rat Hepatocytes

Glycogen synthesis and degradation were studied in cultured rat hepatocytes prelabeled by incubation with [ 14C]glucose or [ 14C]galactose. During prelabeling about 75% of the accumulated glycogen was synthesized from glucose and about 25% from gluconeogenic precursors. Following the labeling period, glycogen synthesis and degradation were estimated at 5 and 12.5 mM glucose and varying concentrations of insulin and glucagon. At 12.5 mM glucose and 10 nM insulin the accumulation of glycogen was comparable to in vivo values, whereas the level of radioactivity in prelabeled glycogen remained constant. Further addition of 0.1 nM glucagon resulted in constant values of both content and radioactivity of glycogen. Increasing the concentration of glucagon to 10 nM resulted in a parallel decrease of content and radioactivity in glycogen. At 5 mM glucose, 10 nM insulin, and 0.1 nM glucagon both the content and the radioactivity of glycogen were constant, whereas addition of 10 nM glucagon resulted in a parallel decrease of content and radioactivity of glycogen, which was 64% higher than that observed with 12.5 mM glucose. In the absence of insulin, prostaglandin D 2 had effects similar to those of 10 nM glucagon, whereas no effects was observed in the presence of insulin. From these results and from calculated rates of glucose 6-phosphate formation, it is concluded that the rate of glycogen degradation is less than 10% of the rate of synthesis under conditions favoring glycogen accumulation. At conditions favoring glycogen degradation (10 nM insulin plus 10 nM glucagon or prostaglandin in the absence of insulin) no synthesis could be detected. Results from cells prelabeled with [ 14C]galactose suggested that glycogen degradation is not an absolutely ordered process, but that some random degradation takes place.

Augmented glucoregulatory hormone concentrations during exhausting exercise in mildly iron-deficient rats

We hypothesized that augmented responses of glucoregulatory hormones in iron deficiency would enhance liver and muscle glycogenolysis, leading to increased gluconeogenic precursor (lactate) supply and upregulation of hepatic gluconeogenesis. Female weanling rats were randomly placed on either a mildly iron-deficient (-Fe; 15 mg Fe/kg diet) or an iron-sufficient (+Fe; 50 mg Fe/kg diet) diet for 4 wk and studied at rest and during exhaustive treadmill running. Hemoglobin was 9.0 +/- 0.2 and 13.1 +/- 0.3 g/dl in -Fe and +Fe, respectively, after 3.5 wk of dietary iron deficiency. Arterial plasma epinephrine (Epi), norepinephrine (NE), adrenocorticotropic hormone (ACTH), corticosterone, insulin, and glucagon levels were similar at rest in both groups, as were liver, gastrocnemius, and superficial and deep vastus medialis glycogen levels. Liver and kidney phosphoenolpyruvate carboxykinase (PEPCK) activities were similar in both groups. Maximum O2 consumption was decreased (22%) in -Fe. Respiratory exchange ratio (CO2 production/O2 consumption) was unaffected at rest but increased at maximum O2 consumption in -Fe. Time to exhaustion during a standardized running test (13.4 m/min, 0% grade) was decreased 45% in -Fe (63 +/- 5 vs. 116 +/- 10 min). During exercise, euglycemia was maintained in both groups, but blood lactate was elevated in -Fe. The mean net glycogen utilization during exercise was increased in liver (43%), soleus (33%), and superficial vastus medialis (106%) and decreased in the gastrocnemius (36%) in -Fe. Liver and kidney PEPCK activities were increased similarly at exhaustion in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hepatic nerves on disposition of an intraduodenal glucose load.

We examined the disposition of a continuous 4-h intraduodenal glucose infusion (8 mg.kg-1 x min-1, labeled with [1-13C]glucose and [3-3H]glucose) in nine conscious hepatic-denervated dogs. Cumulative net hepatic uptakes (in grams of glucose equivalents) were 13.7 +/- 2.5 glucose, 3.1 +/- 0.6 gluconeogenic amino acids, and 0.8 +/- 0.1 glycerol. Net hepatic glycogen synthesis totalled 11.0 +/- 0.9 g, 55-62% via the direct pathway. All values were similar to those in hepatic-innervated dogs. Glycogen synthase activity and rate of glycogen synthesis were positively correlated (r2 = 0.913, P < 0.05). Variability in net hepatic glycogen synthesis and the mass of glycogen synthesized via the indirect pathway was reduced in hepatic-denervated dogs (P < 0.05). In conclusion, the glycemic response and rate of net glycogen synthesis during an intraduodenal glucose infusion was no different in hepatic-denervated and -innervated dogs. Net hepatic glucose uptake was sufficient to account for all net hepatic glycogen synthesis and lactate production, consistent with an intrahepatic source of gluconeogenic precursors for glycogen synthesis via the indirect pathway. Hepatic nerves appear responsible for much of the variability in net hepatic glycogen synthesis and in the mass of glycogen synthesized via the indirect pathway in normal dogs.

Dose‐response effects of lactate infusions on gluconeogenesis from lactate in normal man

Lactate is the predominant gluconeogenic precursor in man. To determine the dose-response relationships between plasma lactate concentration and rates of lactate incorporation in plasma glucose (lactate gluconeogenesis, LGN), we infused 17 normal volunteers with sodium lactate for 180 min at rates ranging from 6 to 40 mumol kg-1 min-1 and measured [U-14C]lactate incorporation into plasma glucose, as well as rates of lactate and glucose appearance in plasma. With the highest lactate infusions, plasma lactate increased up to 7 mM (compared to 1.1 +/- 0.13 mM during control sodium bicarbonate infusions, n = 10) and LGN averaged 4.73 +/- 0.23 mumol kg-1 min-1 (compared to 1.57 +/- 0.26 mumol kg-1 min-1 in bicarbonate control experiments, P < 0.001). The data relating plasma lactate concentration to LGN best fit a sigmoidal curve which plateaued at plasma lactate concentrations of approximately 6 mM and yielded an ED50 of 2.04 +/- 0.20 (SD) mM and a Vmax (6.25 +/- 1.2) (SD) (mumol kg-1 min-1). The sum of the basal rate of lactate appearance and the rate of lactate infusion was not significantly different from the overall rates of lactate appearance during the lactate infusions (35.8 +/- 2.2 vs. 34.8 +/- 2.9 mumol kg-1 min-1, P = 0.23). Thus, our results support the view that infusion of exogenous lactate does not suppress endogenous lactate appearance in plasma.

Impact of chronic stress hormone infusion on hepatic carbohydrate metabolism in the conscious dog

The effects of chronic administration of counterregulatory hormones on hepatic glycogenolysis and gluconeogenesis were investigated. We studied 14 20-h fasted conscious dogs prior to (day 0) and after a 70-h stress hormone (SHI, n = 7) or saline (n = 7) infusion (day 3). Glucose production and gluconeogenesis were assessed using tracer and arteriovenous difference techniques. SHI increased plasma glucagon, cortisol, epinephrine, and norepinephrine levels approximately fivefold. SHI increased the arterial plasma glucose and insulin concentrations (110 +/- 2 to 204 +/- 19 mg/dl and 13 +/- 2 to 36 +/- 3 microU/ml on day 3). Tracer-determined glucose appearance and net hepatic glucose output were increased 80 and 60%, respectively. Net hepatic lactate uptake and fractional extraction were increased by 11.2 +/- 3.8 and 0.51 +/- 0.18 mumol.kg-1 x min-1, respectively, as was net hepatic glycerol uptake (1.0 +/- 0.6 mumol.kg-1 x min-1). Net hepatic fractional alanine extraction was also increased by 0.37 +/- 0.03 mumol.kg-1 x min-1; however, net hepatic alanine uptake was not altered. The efficiency of alanine conversion to glucose almost doubled (0.33 +/- 0.05 to 0.59 +/- 0.09). Renal glucose production was also increased, accounting for 33% of the increase in glucose turnover. This increase was paralleled by an increase in renal gluconeogenic precursor uptake. In conclusion, SHI created marked hyperglycemia and hyperinsulinemia and elevated glucose production from both the liver and the kidney, with gluconeogenesis accounting for approximately 70% of the response.