Evaluation of hepatic and whole body glycogen metabolism in humans during repeated administrations of small loads of 13C glucose

BACKGROUND: Postprandial suppression of endogenous glucose production and regulation of glucose homeostasis involve alterations of whole body and hepatic glycogenolysis and glycogen breakdown. These parameters can be estimated by the simultaneous measurement of net total and exogenous, (13)C-labeled, glucose oxidation. METHODS: Eight subjects were studied on 3 occasions, while receiving oral loads of 60 mg, 120 or 180 mg (13)C glucose/kg every hour for 4 consecutive hours. Net glucose oxidation was calculated from indirect calorimetry, and exogenous glucose oxidation from (13)CO(2) production. These parameters were evaluated during the hour following the fourth glucose load. Whole body endogenous glycogen breakdown was calculated as (net glucose oxidation) - (exogenous glucose oxidation). Total glycogen synthesis was calculated as (glucose load) - (exogenous glucose oxidation). Whole body glucose turnover was measured with 6.6 (2)H(2) glucose. The systemic appearance of oral, (13)C labeled glucose was monitored, and the suppression of endogenous glucose production was calculated. RESULTS: Plasma glucose tracers had reached near steady state during the hour following the fourth glucose load. Glucose ingestion dose-dependently suppressed endogenous glycogen breakdown and stimulated total glycogen synthesis. Endogenous glycogen breakdown was completely inhibited with 180 mg oral glucose/kg. Endogenous glucose production was suppressed in a dose-dependent way, but remained positive with all 3 doses. The first pass splanchnic glucose uptake averaged 25-35%. CONCLUSION: Repeated administration of small doses of (13)C labeled glucose allow to reach near steady state conditions after four hours, and to non-invasively evaluate whole body glycogen turnover and hepatic glucose metabolism.     

Hepatic glucose metabolism in humans--its role in health and disease

The liver is mainly responsible for maintaining normal concentrations of blood glucose by its ability to store glucose as glycogen and to produce glucose from glycogen breakdown or gluconeogenic precursors. During the last decade, new techniques have made it possible to gain further insight into the turnover of hepatic glucose and glycogen in humans. Hepatic glycogen varies from approximately 200 to approximately 450 mM between overnight fasted and postprandial conditions. Patients with type-1 diabetes (T1DM), type 2 diabetes (T2DM) or partial agenesis of the pancreas exhibit increased endogenous glucose production and synthesize only 25-45% of hepatic glycogen compared with non-diabetic humans. This defect can be partly restored in T1DM by combined long- and short-term optimized treatment with insulin. In T2DM, increased gluconeogenesis was identified as the main cause of elevated glucose production and fasting hyperglycaemia. These patients also exhibit augmented intracellular lipid accumulation which could hint at a link between deranged glucose and lipid metabolism in insulin-resistant states.     

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

Summary The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (1.5mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-³H-glucose turnover were 20–25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41±4 vs 8±6 mol·min^–1·kg^–1. p < 0.001) but did not further decrease 3-³H-glucose turnover. Elevated nonesterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability. Increased glycogen synthesis, however, compensates for decreased glycolytic flux so that glucose turnover is not decreased. When liver glycogen stores are high, an acute increase in non-esterified fatty acid availability impairs suppression of hepatic glucose output. A chronic increase in non-esteriefid fatty acid availability may lead to insulin resistance by increasing glycogen stores.     

Labeled CO(2) production and oxidative vs nonoxidative disposal of labeled carbohydrate administered at rest

Carbon isotopes (*C) have been extensively used in man to describe oxidative vs nonoxidative disposal of an exogenous load of labeled carbohydrate (*C-CHO) at rest in various experimental situations. It is hypothesized that V*CO(2) reflects *C-CHO oxidation. However, when glycogen is synthesized through the indirect pathway (which is responsible for approximately 50% of glycogen storage), *C could be lost, diluted, and exchanged in the pyruvate-lactate pool, in the pool of tricarboxylic acid cycle intermediates, as well as at the entrance of the tricarboxylic acid cycle, and along the pathway of gluconeogenesis. This could result in a lower *C/C in the glycogen stored than in the CHO administered, in an increased production of *CO(2), and, respectively, in an overestimation and an underestimation of the oxidative and nonoxidative disposal of the CHO load. Results from the present experiment offer a support to this hypothesis. Over a 10-hour period after ingestion of a (13)C-pasta meal (313+/-10 g dry mass or 258+/-8 g of glucose) in 12 healthy subjects (6 men and 6 women), exogenous CHO oxidation computed from V(13)CO(2) (recovery factor, 0.54) significantly exceeded total CHO oxidation computed by indirect respiratory calorimetry corrected for urea excretion: 154.2+/-2.6 vs 133.5+/-3.2 g. In an additional study conducted in rats, (13)C/(12)C in glycogen stores was significantly approximately 50% lower than in the (13)C-CHO ingested, over a wide range of enrichment. These results suggest that because of dilution, loss, and exchange of *C in the indirect pathway of glycogen synthesis, the oxidative vs nonoxidative disposal of exogenous *C-CHO cannot be accurately tracked from V*CO(2).     

The effect of enteric galactose on neonatal canine carbohydrate metabolism

Newborn pups were assigned to a fasting group or to a group receiving intravenous glucose alimentation. Glucose turnover was determined during steady state equilibration of simultaneously infused [6-³H] glucose. Thereafter, pups from each group received 0.625 g/Kg of either oral [U-¹⁴C] galactose or [U-¹⁴C] glucose. In fasted or intravenously alimented pups enteric glucose resulted in a rapid and sustained elevation of blood glucose concentrations. Systemic appearance of carbon-14 label from enteric glucose increased rapidly as did the enrichment of blood [¹⁴C] glucose specific activity. In those pups given enteric galactose, blood glucose values were equivalent to that in the glucose fed groups, however carbon-14 appearing in blood glucose and blood glucose specific activity were significantly lower. The peak values for the rates of appearance and disappearance of systemic glucose were significantly lower in pups fed galactose than among pups fed glucose. Glucose clearance was also significantly lower in these pups despite equivalent plasma insulin responses. Among fasting pups hepatic glycogen content was significantly higher in those given either oral glucose or galactose when compared to a completely starved control group. In contrast, among alimented pups galactose administration significantly enhanced hepatic glycogen content compared to those fed glucose. Similarly, enteric substrate label incorporation into hepatic glycogen was enhanced in both groups given oral labeled galactose. In addition, hepatic glycogen synthase (glucose-6-phosphate independent) activity was increased only among alimented pups fed galactose when compared to completely fasted pups. In conclusion these data suggest that following gastrointestinal galactose administration, hepatic carbohydrate uptake is augmented while glycogen synthesis may be enhanced. Augmented glycogen synthesis following galactose administration may reflect alterations in hepatic glycogen synthase activity or enhanced hepatic carbohydrate uptake.     

Pathways of hepatic glycogen formation in humans following ingestion of a glucose load in the fed state

The relative contributions of the direct and the indirect pathways to hepatic glycogen formation following a glucose load given to humans four hours after a substantial breakfast have been examined. Glucose loads labeled with [6-(14)C]glucose were given to six healthy volunteers along with diflunisal (1 g) or acetaminophen (1.5 g), drugs excreted in urine as glucuronides. Distribution of 14C in the glucose unit of the glucuronide was taken as a measure of the extent to which glucose was deposited directly in liver glycogen (ie, glucose----glucose-6-phosphate----glycogen) rather than indirectly (ie, glucose----C3-compound----glucose-6-phosphate----glycogen). The maximum contribution to glycogen formation by the direct pathway was estimated to be 77% +/- 4%, which is somewhat higher than previous estimates in humans fasted overnight (65% +/- 1%, P less than 0.05). Thus, the indirect pathway of liver glycogen formation following a glucose load is operative in both the overnight fasted and the fed state, although its contribution may be somewhat less in the fed state.     

Assessment of postprandial hepatic glycogen synthesis from uridine diphosphoglucose kinetics in obese and lean non-diabetic subjects

BACKGROUND: Obese patients are frequently characterized by insulin resistance and decreased insulin-mediated glycogen synthesis in skeletal muscle. Whether they also have impaired postprandial hepatic glycogen synthesis remains unknown. AIM: To determine whether postprandial hepatic glycogen synthesis is decreased in obese patients compared to lean subjects. METHODS: Lean and obese subjects with impaired glucose tolerance were studied over 4h after ingestion of a glucose load. Hepatic uridine diphosphoglucose kinetics were assessed using 13C-galactose infusion, with monitoring of urinary acetaminophen-glucuronide isotopic enrichment to estimate hepatic glycogen kinetics. RESULTS: Estimated net hepatic glycogen synthesis amounted to 18.6 and 22.6% of the ingested load in lean and obese subjects, respectively. CONCLUSION: Postprandial hepatic glycogen metabolism is not impaired in non-diabetic obese subjects.     

Effect of a 3-day fast on glucose storage and oxidation in obese hyperinsulinemic diabetics

Glucose disposal was measured for a 3-hr period after a 100-g oral glucose load by means of a new adaptation of continuous indirect calorimetry in 6 obese hyperinsulinemic diabetics and 5 nonobese normal subjects who served as the control. While total glucose oxidized during the 3-hr test was not significantly lower in the obese diabetic group (31 ± 3 g) than in the control group (37 ± 3 g), a marked impairment of net glucose storage was observed in the former group (26 ± 7 g) in comparison to the control group (64 ± 3 g; p < 0.001). This marked decrease in net glucose storage suggests that a limited capacity for glucose storage might play a major role in glucose intolerance in these cases of obese hyperinsulinemic diabetes. In the obese diabetic group, after a 3-day fast supplemented with protein, the plasma glucose values dropped significantly both in the fasting state and in response to the glucose load. This was accompanied by a marked improvement of glucose storage (52 ± 9 versus 26 ± 7 g before the fast; p < 0.001), a decrease in glucose urinary loss (5 ± 1 g versus 14 ± 4 g prior to fast), but a marked impairment in glucose oxidation (13 ± 1 g versus 31 ± 3 g before fast; p < 0.001). In the control group, a moderate impairment of glucose tolerance was observed, probably related to the important decrease in glucose oxidation (12 ± 3 g versus 37 ± 3 g prior to fast), in spite of the increase in glucose storage (82 ± 4 g versus 64 ± 3 g prior to fast). These observations suggest that glucose intolerance observed in obese hyperinsulinemic diabetics in the postabsorptive state might result at least in part from deficiency in net glucose storage capacity. The marked lowering of the plasma glucose tolerance curve in the same subjects after a 3-day period of fast is probably a consequence of the overall effect of a decrease in the glucose pool and an increase in net glucose storage in spite of a decrease in glucose oxidation and in urinary glucose loss. It does not exclude, however, other factors, such as changes in tissue insulin sensitivity.     

Glycogen synthesis versus lipogenesis after a 500 gram carbohydrate meal in man

The respiratory exchange and urinary nitrogen excretion of 6 healthy male subjects (age 21 +/- 1 yr; body weight 70 +/- 2 kg; means +/- SD) were followed for 10 hr after ingestion of a large amount of carbohydrates (CHO) in the form of bread, jam, and fruit juice, equivalent to 479 g of starch. Peak values for blood glucose (6.6 +/- 0.6 mM; mean +/- SEM) and plasma insulin (139 +/- 26 microU/ml) were reached after 90 min at which time the nonprotein respiratory quotient (NP-RQ) had risen to 0.97. During the next 8 hr glucose levels remained near 5.5 mM while insulin declined gradually to 22 +/- 7 microU/ml. The average NP-RQ remained in the range of 0.91 to 0.98, though individual values exceeding 1.0 for very short periods were observed. The increase in energy expenditure above basal rates corresponded to a specific dynamic action (SDA) of 5.9 +/- 0.6%. Assuming the CHO load to be completely absorbed after 5 hr, and allowing for glucose oxidation calculated from the gas exchange data, the glycogen content of the subject's body tissue had then increased by 408 +/- 19 g. During the 10 hr after the meal, 133 g CHO, 17 g fat and 29 g protein were oxidized, providing respectively 66%, 19% and 15% of caloric expenditure, and leaving a gain in glycogen stores estimated at 346 +/- 12 g. The data imply that: (1) The capacity for glycogen storage in man in larger than generally believed, and (2) Fat synthesis from CHO will not exceed fat oxidation after one high-carbohydrate meal, even if it is uncommonly large. When a single high-carbohydrate meal is consumed, dietary CHO merely has the effect of reducing the rate of fat oxidation. These findings challenge the common perception that conversion of CHO to fat is an important pathway for the retention of dietary energy and for the accumulation of body fat.     

The onset of liver glycogen synthesis in fasted-refed lean and genetically obese (fa/fa) rats

Summary Lean and genetically obese (fa/fa) rats were fed ad libitum, or fasted for 17 h and then meal-fed for varying time intervals. During refeeding, glucose-6-phosphatase activity of lean rats declined to the low value that was present in livers of fasted obese rats and which remained unchanged in the obese group during the meal. Refeeding also resulted in increases in hepatic concentrations of glucose-6-phosphate and fractose-6-phosphate, fructose 1,6-bisphosphate, fractose-2,6-bisphosphate, -glycerophosphate, pyruvate and lactate in lean and obese rats, absolute values being higher in the fasted obese than in the fasted lean group. Obese animals had higher postprandial portal blood insulin, glucose and lactate concentrations than lean animals. In spite of this, the rate of hepatic glycogen deposition was the same in both groups and was accompanied by similar glycogen synthase a levels. Following refeeding, phosphorylase was transiently inactivated in livers of lean but not of obese animals, while glycogen synthase was inactivated in both groups. The data suggest that (1) in lean animals refeeding was associated with a stimulation of liver glycolysis, presumably by insulin; (2) in fasted obese rats hepatic glycolysis was already in a stimulated state and was only slightly enhanced further after the meal, in keeping with their unaltered hyperinsulinaemia; (3) there was an increased turnover of liver glycogen or a resistance to insulin stimulation of glycogen synthesis in fa/fa rats during refeeding.     

Assessment of the postprandial pattern of glucose metabolism in nondiabetic subjects and patients with non-insulin-dependent diabetes mellitus using a simultaneous infusion of [2(3)H] and [3(3)H] glucose

Glucose turnover determined with tritiated isotopes of glucose is subject to potential error due to glucose/glucose-6-phosphate cycling and/or cycling through glycogen. To determine the extent to which these processes alter the apparent pattern of postprandial glucose metabolism, we measured glucose turnover simultaneously with [2(3)H] glucose (an isotope that minimally cycles through glycogen but is extensively detritiated during glucose/glucose-6-phosphate cycling) and [3(3)H] glucose (an isotope that is not detritiated during glucose/glucose-6-phosphate cycling but can cycle through glycogen). Glucose turnover was measured in patients with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic subjects both before and after ingestion of a carbohydrate meal isotopically with labeled [6(14)C] glucose. In the postabsorptive state hepatic glucose appearance was higher (P less than .05) when determined with [2(3)H] glucose than with [3(3)H] glucose in the diabetic patients, but not in the nondiabetic subjects. After glucose ingestion the integrated responses of glucose appearance, systemic entry of ingested glucose, and hepatic glucose release all were higher (P less than .05) when determined with [2(3)H] glucose compared to [3(3)H] glucose in both the diabetic and nondiabetic subjects. However, the absolute difference between glucose turnover measured with [2(3)H] and [3(3)H] glucose were similar in the diabetic and nondiabetic subjects. Both isotopes provided a similar assessment of postprandial carbohydrate metabolism, indicating that either isotope can be used with equal efficacy to compare postprandial carbohydrate metabolism in patients with NIDDM and nondiabetic subjects.     

The effects of cortisol treatment on carbohydrate and protein metabolism in Fundulus heteroclitus

In male Fundulus heteroclitus captured during the fall, 5 daily injections of cortisol (200 μg/fish or approximately 20 μg/g body wt) produced significant elevations in serum cortisol and hyperglycemia in both fed and fasted fish. Only fasted fish responded with an increase in liver glycogen. No consistent changes attributable to hormone injection occurred in serum protein, amino acid, liver protein, liver amino acids, or liver alanine aminotrasferase. A single cortisol injection (20 μg/g body wt) in fasted fish produced elevated blood glucose levels which persisted for 48 hr and followed serum cortisol changes closely. Again, no significant changes were seen in liver glycogen or in protein metabolism. We conclude that in F. heteroclitus, blood glucose is the major carbohydrate reservoir influenced by cortisol elevation. Protein catabolism appears not to be the source of the glucose elevation. Reduced peripheral glucose utilization and gluconeogenesis from lactate or glycerol are suggested as alternative sources.     

Mobilisation of enterocyte fat stores by oral glucose in humans

BACKGROUND AND AIMS: When a high fat oral load is followed several hours later by further ingestion of nutrients, there is an early postprandial peak in plasma triacylglycerol (TG). The aim of this study was to investigate the location and release of lipid from within the gastrointestinal tract. METHODS: Ten healthy patients undergoing oesopho-gastro-duodenoscopy (OGD) were recruited. At t=0, all patients consumed a 50 g fat emulsion and at t=5 hours they consumed either water or a 38 g glucose solution. OGD was performed at t=6 hours and jejunal biopsy samples were evaluated for fat storage. A subgroup of five subjects then underwent a parallel metabolic study in which postprandial lipid and hormone measurements were taken during an identical two meal protocol. RESULTS: Following oral fat at t=0, samples from patients that had subsequently ingested glucose exhibited significantly less staining for lipid within the mucosa and submucosa of the jejunum than was evident in patients that had consumed only water (p=0.028). There was also less lipid storage within the cytoplasm of enterocytes (p=0.005) following oral glucose. During the metabolic study, oral glucose consumed five hours after oral fat resulted in a postprandial peak in plasma TG, chylomicron-TG, and apolipoprotein B48 concentration compared with oral water. CONCLUSION: After a fat load, fat is retained within the jejunal tissue and released into plasma following glucose ingestion, resulting in a peak in chylomicron-TG which has been implicated in the pathogenesis of atherosclerosis.     

Altered mechanism of glucagon-mediated hepatic glycogenolysis during long-term starvation in the rat.

The effect of long-term starvation on glucagon-mediated hepatic glycogenolysis was investigated in the rat in vivo. Following glucagon (50 microgram/kg i.v.) fed rats showed rapid phosphorylase activation but no change in synthase-I activities. In contrast, rats fasted 72 hr (long-term fasting) showed rapid synthase inactivation but no significant phosphorylase activation. Rats fasted 24 hr (short-term fasting) demonstrated coordinated inactivation of synthase and activation of phosphorylase. Hepatic cyclic AMP responses were greater in fasted rats. Hepatic glycogen concentrations in rats fasted 72 hr were approximately 30% of fed levels. After glucagon, comparable decrements in hepatic glycogen and increments in plasma glucose concentrations were seen in fed and 72-hr groups. The diminished responsiveness of the hepatic phosphorylase system in rats fasted 72 hr was not attributable to altered cyclic AMP-dependent protein kinase or phosphorylase kinase activities. However, the diminished responsiveness could be ascribed to diminished total phosphorylase with nearly complete activation in the basal state. In fed and fasted rats, synthase decrements after glucagon correlated closely with basal levels of synthase-I. Thus, it is proposed that the enzymatic mechanism of glucagon-mediated hepatic glycogenolysis differs in fed and fasted rats. It is also proposed that partial hepatic glycogen reaccumulation during long-term fasting could be physiologically important for glucose homeostasis.     

Swim training increases glucose output from liver perfused in situ with glucagon in fed and fasted rats

The effect of endurance swim training (3 hours per day, 5 days/week, for 10 weeks) on hepatic glucose production (HGP) in liver perfused in situ for 60 minutes with glucagon and insulin was studied in Sprague-Dawley rats. The experiments were performed in fed rats and in rats fasted for 24 hours, but with lactate (8 mmol/L) added to the perfusion medium. Liver glycogen content was significantly lower in fasted than fed rats (fasted untrained and trained: 14 +/- 4 and 11 +/- 3 micromol glycosyl U/g of liver wet weight (WW); fed untrained and trained: 205 +/- 11 and 231 +/- 11 micromol glycosyl U/g of liver WW; not significantly different in trained and untrained rats). Glucagon increased HGP in the 4 experimental groups, but the increases were more rapid and pronounced in trained than in untrained rats in both fed and fasted states. HGP values (area under the curve [AUC] in micromol/g of liver WW) were significantly higher in trained fed (112.1 +/- 7.1 v 85.9 +/- 12.2 in untrained rats) than in trained fasted rats (50.8 +/- 4.4 v 34.7 +/- 3.6 in untrained rats). When compared with untrained rats, the total amount of glucose released by the liver in response to glucagon in trained rats was approximately 30% higher in the fed state and approximately 45% larger in the fasted state. These results indicate that endurance training increases the response of both glycogenolysis and gluconeogenesis to glucagon.     

Hepatic nonoxidative disposal of an oral glucose meal in patients with liver cirrhosis.

Seven patients with liver cirrhosis and five healthy subjects were studied over 4 hours after ingestion of a glucose meal to determine whether alterations of hepatic nonoxidative glucose disposal participate in the pathogenesis of impaired glucose tolerance. Hepatic uridyl-diphosphoglucose (UDPG) turnover was calculated from the isotopic enrichment of urinary acetaminophen glucuronide during continuous infusion of 13C-galactose and used as an index of hepatic glycogen synthesis. Patients with cirrhosis had postprandial hyperglycemia and decreased glucose clearance, but hepatic UDPG turnover was not altered (1.84 +/- 0.29 mg/kg fat-free mass min v 1.76 +/- 0.15 in controls, nonsignificant). It is concluded that hepatic postprandial glycogen synthesis is unaltered in patients with advanced cirrhosis, demonstrating important hepatic functional reserve.     

Time-courses of hepatocellular hyperpolarization and cyclic adenosine 3',5'-monophosphate accumulation after partial hepatectomy in the rat. Effects of fasting for 48 hours and intravenous injection of glucose

Hepatic cell membrane potentials, hepatic cyclic adenosine 3',5'-monophosphate concentrations, and blood glucose levels were measured in anesthetized rats before, and at various times after, partial hepatectomy. In fed rats, hyperpolarization became evident 1-3 h postoperatively, reached its first peak at 4 h, and was maintained for approximately 36 h. The early phase of hyperpolarization was preceded by depletion of glycogen from the liver remnant and occurred during a decline of blood glucose concentrations below the level in sham-operated rats. Preoperative exhaustion of glycogen stores by fasting for 48 h resulted in marked hyperpolarization within 15 min after partial hepatectomy. In fasted rats, an intravenous injection of glucose (10 mmol X kg-1) caused a delay in hyperpolarization when given 30 min before partial hepatectomy, or a transient normalization of the membrane potentials when given 30 min after partial hepatectomy. Liver tissue cyclic adenosine 3',5'-monophosphate concentrations in fed rats remained largely unchanged 2 h after partial hepatectomy but increased greatly at 4 h. On the other hand, in fasted rats a significant increase was seen within 30 min. Glucose administration to fasted rats depressed cyclic adenosine 3',5'-monophosphate concentrations in the liver remnant. The results suggest that intensified gluconeogenesis, partly mediated by cyclic adenosine 3',5'-monophosphate, could be the event underlying early hepatocellular hyperpolarization induced by partial hepatectomy.     

The role of the liver in metabolic homeostasis: Implications for inborn errors of metabolism

Summary The mechanisms by which the liver maintains a constant supply of oxidizable substrates, which provide energy to the body as a whole, are reviewed. During feeding, the liver builds up energy stores in the form of glycogen and triglyceride, the latter being exported to adipose tissue. During fasting, it releases glucose and ketone bodies. Glucose is formed by degradation of glycogen and by gluconeogenesis from gluconeogenic amino acids provided by muscle. Ketone bodies are produced from fatty acids, released by adipose tissue, and from ketogenic amino acids. The major signals which control the transition between the fed and the fasted state are glucose, insulin and glucagon. These influence directly or indirectly the enzymes which regulate liver carbohydrate and fatty acid metabolism and thereby orient metabolic fluxes towards either energy storage or substrate release. In the fed state, the liver utilizes the energy generated by glucose oxidation to synthesize triglycerides. In the fasted state it utilizes that produced by-oxidation of fatty acids to synthesize glucose. The mechanisms whereby a number of inborn errors of glycogen metabolism, of gluconeogenesis and of ketogenesis cause hypoglycaemia are also briefly overviewed.     

Lactic acidosis--emphasis on the carbon precursors and buffering of the acid load

We have compared the capacity of major organs to produce lactic acid from endogenous sources relative to their ability to buffer that proton load. We deduced that the ultimate source for the rapid production of a very large amount of lactic acid must be hepatic and/or muscle glycogen or exogenous glucose, because the quantity of endogenous glucose is quite small and the rate of net protein catabolism is too slow. Of the organs examined, only the liver of fed persons can produce sufficient lactic acid to markedly overwhelm its own buffer capacity plus that of the ECF and other tissues. Moreover, it is important to realize that a fasted (low hepatic glycogen) subject who lacks the stimulus for muscle glycogenolysis can only develop a modest degree of acute lactic acidosis owing to a limited precursor availability; under these circumstances, hypoglycemia and/or localized tissue necrosis could be the major threats to that patient. We present two examples with more chronic lactic acidosis without hypoxia emphasizing that tissue catabolism may be necessary to support high rates of lactic acid production, and we suggest that a high plasma lactate concentration need not be present to observe a large turnover of this metabolite.     

Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart

To assess the effects of fasting on recovery of function and exogenous glucose metabolism after 15 minutes of total ischemia, we perfused isolated working rat hearts from fed and fasted animals. Hearts were perfused in a recirculating system with bicarbonate buffer containing glucose (10 mM). Mechanical performance, release of marker proteins for ischemic membrane damage (lactate dehydrogenase, myoglobin, citrate synthase), and the concentrations of lactate and glucose in the perfusion medium were measured serially. Tissue metabolites were also measured. Fasting raised the myocardial glycogen content by 25%. Cardiac performance of perfused hearts from fed and fasted animals was the same during the preischemic and the post-ischemic period. The time of return of function to preischemic values was significantly less in hearts from fasted rats (2.3 versus 7.8 minutes, p less than 0.025). The release of cytosolic and mitochondrial marker proteins was significantly lower in hearts from fasted rats than in hearts from fed rats. Glucose metabolic rates during control and reperfusion were unchanged for hearts from fasted rats, but decreased for hearts from fed rats during reperfusion. The adenine nucleotide content at the end of ischemia was higher in hearts from fasted animals than in hearts from fed animals. We conclude that increasing glycogen levels prior to ischemia improves recovery of function, lessens membrane damage, and prevents loss of adenine nucleotides.