Splanchnic Uptake Research Articles

Splanchnic uptake and release of energy substrates in the fasting baboon infant.

Estimates of splanchnic energy substrate exchange in the primate infant have been obtained using a baboon model. The splanchnic bed of the fasting baboon newborn released glucose at an estimated rate of 14.5 +/- 5.0 mumol/min X kg body weight. Splanchnic glucose release in the fasting 5-7 wk old baboon infant proceeded similarly at an estimated rate of 15.5 +/- 4.5 mumol/min X kg body weight. The principal precursors taken up by the splanchnic bed were lactate, glycerol, and alanine. Uptake of alanine correlated in a linear fashion with glucose release. Lactate was the most important precursor in both age groups. Glucose recycling through lactate is an active mechanism in the primate fetus as well as in the young of other species.

Altered immunologic function and nitrogen metabolism associated with depression of plasma growth hormone.

The specific role of endogenous growth hormone in regulating nitrogen metabolism during surgical stress and infection remains unclear. We have studied splanchnic amino acid uptake and plasma concentrations in patient groups exhibiting growth hormone hypersecretion or relative growth hormone depression in response to stress. Splanchnic amino acid uptake was similar in both groups although plasma levels were significantly higher in the presence of depressed growth hormone production suggesting increased net peripheral proteolysis. In association with this latter observation. T lymphocyte subset analysis revealed a greater incidence of depressed helper to suppressor cell ratios in the presence of depressed growth hormone suggesting a greater impairment of cellular immunity.

Direct assessment of splanchnic uptake and metabolic effects of human and porcine insulin.

The hepatic vein catheterization technique was used to quantitate the splanchnic uptake and the metabolic effects of biosynthetic human insulin (BHI) and porcine insulin (PI) in normal man. BHI and PI were infused into a peripheral vein (0.9-1.3 mU kg-1 min-1) for 60 min together with SRIH (0.6 mg/h) to inhibit endogenous insulin secretion and glucose to induce moderate hyperglycemia (9-10 mmol/liter). During the infusion period, arterial-hepatic venous difference of plasma C-peptide as well as splanchnic C-peptide output fell by more than 98% indicating virtually complete cessation of endogenous insulin release. Under these conditions, the arterial-hepatic venous differences in plasma insulin concentrations represent a valid and direct measurement of splanchnic insulin uptake. During BHI infusion, arterial insulin levels rose to 82 +/- 11 (SE) microU/ml (range: 33-105 microU/ml). Splanchnic insulin uptake paralleled the rise of arterial insulin, reaching 430 +/- 72 microU kg-1 min-1 at 60 min. No appreciable difference between BHI and PI was demonstrable. A highly significant correlation between arterial insulin concentrations and splanchnic insulin uptake was found (r = 0.816; P less than 0.001). Accordingly, both fractional splanchnic insulin extraction and splanchnic insulin clearance remained unchanged throughout insulin infusion and averaged 70 +/- 4% and 5.3 +/- 2 ml kg-1 min-1, respectively. With BHI infusion, splanchnic glucose balance (-8.5 +/- 0.9 mumol kg-1 min-1, basal) became positive (7.3 +/- 1 mumol kg-1 min-1). In contrast, basal splanchnic lactate uptake was inhibited by BHI and there was lactate production (from 3.4 +/- 0.9 to -1.7 +/- 1.4 mumol kg-1 min-1). Similar changes in splanchnic glucose and lactate metabolism occurred during PI infusion. These studies indicate that: 1) A considerable amount of insulin (70 +/- 4%) is extracted by the splanchnic bed on a single passage, after exogenous administration of either human insulin or PI; 2) over a physiological range of insulin concentrations (33-105 microU/ml) a linear relationship exists between arterial insulin concentrations and splanchnic insulin removal; and 3) BHI and PI do not differ appreciably with respect to their uptake and metabolic effects at the splanchnic level.

Carbohydrate and lipid metabolism in cirrhosis. Evidence that hepatic uptake of gluconeogenic precursors and of free fatty acids depends on effective hepatic flow.

Splanchnic arteriovenous differences for several intermediary metabolites of carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in seven normal subjects, eight patients with cirrhosis, and six patients with cirrhosis after surgical portosystemic shunt ( SPSS ) after an overnight fast. Arteriovenous differences in the legs were also determined together with flux measurement. The individual turnover rates of acetoacetate (AcAc) and 3 hydroxybutyrate (beta OHB) were also determined by means of isotopic techniques. Splanchnic gluconeogenic precursors and FFA uptakes were lower in cirrhotic patients with SPSS than in normal subjects (P less than 0.05 and P less than 0.01, respectively). Splanchnic triglyceride output was also lower in cirrhotic patients with SPSS than in normal subjects (P less than 0.01), whereas no significant differences were found for AcAc, beta OHB, and glucose release. In the group of cirrhotic patients without SPSS , those patients with negligible signs of portal systemic shunt and normal splanchnic blood flow had uptake of gluconeogenic precursors and of FFA normal or higher than that of normal subjects, whereas those patients with signs of spontaneous portal systemic shunt behaved like cirrhotic patients with SPSS . Alanine release from the leg was lower in both cirrhotic patient groups. Tracer determined hepatic output of AcAc and beta OHB was higher in cirrhotic patients with SPSS (P less than 0.05). Plasma clearance rates of AcAc and beta OHB were significantly elevated in both cirrhotic patient groups. Close agreement was found between tracer and catheterization techniques in the evaluation of ketone body production in cirrhotic patients with SPSS , whereas in cirrhotic patients without SPSS tracer determined hepatic output was slightly lower, possibly because of extrahepatic splanchnic tissue ketone body uptake. In conclusion, our data in patients with cirrhosis indicate that: 1) splanchnic uptake of gluconeogenic precursors and of FFA was related to the degree of portal systemic shunt, e.g. to the degree of effective hepatic blood flow; 2) liver triglyceride but not ketone body output was decreased by the impaired FFA (and glycerol) liver uptake; 3) the higher circulating levels of gluconeogenic precursors (except alanine) and of FFA appeared at least partially due to lower hepatic removal of these metabolites; and 4) peripheral use of ketone bodies was increased and alanine release from the leg reduced in patients with cirrhosis.

Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise.

Nine insulin-dependent diabetics and six healthy controls were studied at rest, during, and after 60 min of bicycle exercise at a work load corresponding to 45% of their maximal oxygen intake. The catheter technique was employed to determine splanchnic and leg exchange of metabolites. FFA turnover and regional exchange was evaluated using [14C]oleate infusion. Basal glucose (13.8 +/- 1.1 mmol/l), ketone body (1.12 +/- 0.12 mmol/l), and FFA (967 +/- 110 mumol/l) concentrations were elevated in the diabetics in comparison with controls. In the resting state, splanchnic ketone acid production in the diabetics was 6-10-fold greater than in controls. Uptake of oleic acid by the splanchnic bed was increased 2-3-fold, and the proportion of splanchnic FFA uptake converted to ketones (61%) was threefold greater than in controls. In contrast, splanchnic fractional extraction of oleic acid was identical in diabetics and controls. A direct relationship was observed between splanchnic uptake and splanchnic inflow (plasma concentration X hepatic plasma flow) of oleic acid that could be described by the same regression line in the diabetic and control groups. During exercise, splanchnic ketone production rose in both groups. In the control group the increase in ketogenesis was associated with a rise in splanchnic inflow and in uptake of oleic acid, a rise in splanchnic fractional extraction of oleate, and an increase in the proportion of splanchnic FFA uptake converted to ketone acids from 20-40%. In the diabetic group, the increase in ketogenesis occurred in the absence of a rise in splanchnic inflow or uptake of oleic acid, but was associated with an increase in splanchnic fractional extraction of oleic acid and a marked increase in hepatic conversion of FFA to ketones, so that the entire uptake of FFA was accountable as ketone acid output. Splanchnic uptake of oleic acid correlated directly with splanchnic oleic acid inflow in both groups, but the slope of the regression line was steeper than in the resting state. Plasma glucagon levels were higher in the diabetic group at rest and during exercise, while plasma norepinephrine showed a twofold greater increment in response to exercise in the diabetic group (to 1,400-1,500 pg/ml). A net uptake of ketone acids by the leg was observed during exercise but could account for less than 5% of leg oxidative metabolism in the diabetics and less than 1% in controls. Despite the increase in ketogenesis during exercise, a rise in arterial ketone acid levels was not observed in the diabetics until postexercise recovery, during which sustained increments to values of 1.8-1.9 mmol/l and sustained increases in splanchnic ketone production were observed at 30-60 min. The largest increment in blood ketone acids and in splanchnic ketone production above values observed in controls thus occurred in the diabetics after 60 min of recovery from exercise. We concluded that: (a) In the resting state, increased ketogenesis in the diabetic is a consequence of augmented splanchnic inflow of FFA and increased intrahepatic conversion of FFA to ketones, but does not depend on augmented fractional extraction of circulating FFA by the splanchnic bed. (b) Exercise-induced increases in ketogenesis in normal subjects are due to augmented splanchnic inflow and fractional extraction of FFA as well as increased intrahepatic conversion of FFA to ketones. (c) When exercise and diabetes are combined, ketogenesis increases further despite the absence of a rise in splanchnic inflow of FFA. An increase in splanchnic fractional extraction of FFA and a marked increase intrahepatic conversion of FFA to ketones accounts for the exaggerated ketogenic response to exercise in the diabetic. (d) Elevated levels of plasma glucagon and/or norepinephrine may account for the increased hepatic ketogenic response to exercise in the diabetic. (e) Ketone utilization by muscle increases during exercise but constitutes a quantitatively minor oxidative fuel for muscle even in the diabetic. (f) The accelerated ketogenesis during exercise in the diabetic continues unabated during the recovery period, resulting in an exaggerated postexercise ketosis.

Splanchnic galactose uptake in patients with cirrhosis following single injection

The galactose elimination capacity is used as a quantitative liver function test and is supposed to express the functioning liver cell mass. Clinical observations indicate, however, that the galactose elimination capacity overestimates functioning liver cell mass, and we therefore compare hepatic (splanchnic) and extrahepatic, extrarenal galactose elimination after a single injection of galactose in 23 patients with reduced liver function. The galactose elimination capacity was consistently greater than the hepatic (splanchnic) galactose elimination rate, estimated during liver vein catheterization. The difference was on the average 0.68 mmol min-1 (SD +/- 0.19, P less than 0.001) or about 40% of the galactose elimination capacity. If this difference, partly or fully, is due to extrahepatic extrarenal elimination, the clinical test for galactose elimination needs a correction (of the order of magnitude of 0.7 mmol min-1) to serve as an absolute measure of the hepatic functional capacity, but since the hepatic uptake rate may be underestimated following a single injection, the correction may be smaller.

Splanchnic exchange of glucose, amino acids and free fatty acids in patients with chronic inflammatory bowel disease.

In order to study arterial concentrations and splanchnic exchange of substrates and hormones in patients with chronic inflammatory bowel disease three patients with Crohn's disease and four with ulcerative colitis were studied using the hepatic venous catheter technique. Systemic turnover and regional exchange of free fatty acid were evaluated using intravenous infusion of 14C-labelled oleic acid. All measurements were made in the postabsorptive, overnight fasted state. Arterial glucose concentrations were 10% lower in the patients but net splanchnic glucose output was similar in patients and controls. Glucose precursor uptake (lactate, pyruvate, and glycerol), however, was increased two to five fold in the patients. Arterial amino acid concentrations were generally reduced but net splanchnic amino acid uptake was the same in patients and controls. Arterial concentrations of free fatty acid and oleic acid as well as systemic and fractional turnover were similar in patients and controls. The patients' splanchnic uptake of oleic acid was increased more than three fold in comparison with controls. Splanchnic release of oleic acid was also augmented in the patients. Both arterial concentrations and splanchnic production of ketone bodies were raised in the patients. The proportion of splanchnic free fatty acid uptake which could be accounted for by ketone body production was significantly greater in the patients (37 +/- 4%) than the controls (20 +/- 5%, p less than 0.025). Estimated hepatic blood flow was 55% greater (p less than 0.01) in the patients as compared with the controls (1930 +/- 150 vs 1240 +/- 70 ml/min), while splanchnic oxygen uptake was similar in the two groups. From these findings it is concluded that patients with chronic inflammatory bowel disease show (1) markedly increased hepatic blood flow, reflecting an inflammatory hyperaemia in the splanchnic region, (2) a normal net splanchnic glucose output, (3) accelerated hepatic gluconeogenesis as well as ketogenesis, probably as a consequence of the altered hormonal milieau, and (4) low concentrations of most amino acids possibly because of protein malabsorption. These findings underscore the importance of adequate protein and carbohydrate administration to this patient group.

The 75-g oral glucose tolerance test: effect on splanchnic metabolism of substrates and pancreatic hormone release in healthy man.

To determine the effect of the 75 g oral glucose tolerance test on carbohydrate and lipid metabolism, the splanchnic exchange of glucose, lactate, pyruvate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate as well as the release of insulin, C-peptide, glucagon and pancreatic polypeptide were evaluated in eight healthy male volunteers in the basal state and for 150 min following glucose ingestion. Oral glucose loading was followed by a rapid rise in splanchnic output of glucose (mean +/- SEM; 154 +/- 12 mmol/150 min), pyruvate (1.2 +/- 1.2 mmol/150 min) and lactate (8.6 +/- 2.0 mmol/150 min), whereas there were reductions in the splanchnic uptake of non-esterified fatty acids (-10.7 +/- 4.4 mmol/150 min) and the splanchnic output of beta-hydroxybutyrate (-4.8 +/- 3.3 mmol/150 min) and acetoacetate (-3.0 +/- 1.2 mmol/150 min). In parallel, splanchnic output of insulin (12.3 +/- 2.7 nmol/150 min), C-peptide (36.1 +/- 5.0 nmol/150 min) and transiently of pancreatic polypeptide rose, whereas that of glucagon fell (-0.58 +/- 0.21 nmol/150 min). Even at 150 min after glucose ingestion, splanchnic output and arterial concentrations of glucose, lactate, insulin and C-peptide were still above their respective basal values while those of non-esterified fatty acids and glucagon were reduced. Taking into account the partial suppression of endogenous glucose production by ingested glucose it is concluded that, in normal postabsortive man, only 49-63% of a 75 g oral glucose load is retained by the splanchnic bed during the first 150 min, the rest being available for non-hepatic tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Splanchnic glucose metabolism during leg exercise in 60-hour-fasted human subjects.

An increased mobilization of the hepatic glycogen is necessary for the maintenance of glucose homeostasis during exercise. To examine the effect of exercise on glucose metabolism when the hepatic glycogen stores are depleted, five prolonged-fasted (60-h, PF) subjects were investigated. Arterial concentrations and splanchnic exchange of glucose and gluconeogenic precursors were studied at rest and during exercise (40 min, 60% of VO2max) using the hepatic venous catheter technique. Five overnight-fasted subjects (OF) served as controls. In the resting state, arterial glucose concentration (3.0 +/- 0.2 mmol/liter) and splanchnic glucose output (SGO) (0.3 +/- 0.1 mmol/min) were 30 and 55% lower, respectively, in the PF than in the OF subjects. During exercise SGO rose in both groups, but the increase was smaller in the PF subjects so that at the end of work SGO (0.9 +/- 0.2 mmol/min) was only one-third of that in the OF group (2.5 +/- 0.4 mmol/min). During exercise in the PF state the arterial lactate concentration (5.0 +/- 1.1 mol/liter) and the splanchnic lactate uptake (1.1 +/- 0.3 mmol/min) were threefold and twofold higher, respectively, than in the OF state. In the PF state, the splanchnic uptake of gluconeogenic precursors could account for more than 80% of the splanchnic glucose production both at rest and during exercise. Despite the lower SGO in the PF state, blood glucose concentrations rose during exercise, indicating a diminished peripheral glucose uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans.

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production.

Splanchnic and renal metabolism of insulin in human subjects: a dose-response study.

Kinetic analyses of insulin metabolism were performed in 32 healthy subjects with hepatic-venous or renal-venous catheters, in whom steady-state conditions of hyperinsulinemia or hyperglycemia were achieved with the use of the glucose-insulin clamp technique. In the basal state, the splanchnic bed removed 42 +/- 2% of the insulin influx. After graded insulin infusions with maintenance of euglycemia, stable arterial insulin levels of 35-1,430 microU/ml were attained. Splanchnic insulin extraction was constant (approximately 60%) at physiological insulin levels but fell (to 29 +/- 1%, P less than 0.02) at supraphysiological (greater than 500 microU/ml) concentrations. The metabolic clearance rate of infused insulin was essentially constant within the physiological concentration range. Hyperglycemia (+125 mg/100 ml) did not alter splanchnic insulin extraction. Basally, the kidneys extracted 0.04 +/- 0.01 mU X min-1 X kg-1 or 25 +/- 5% of arterial insulin. Renal insulin clearance (3.9 +/- 0.4 ml X min-1 X kg-1) represented over 80% of the extrasplanchnic insulin clearance. Hyperglycemia (+125 mg/100 ml) had no effect on renal insulin extraction. In conclusion, a) both splanchnic and renal insulin removal are independent of glycemia and increase in proportion to plasma insulin concentration within the physiological range; b) splanchnic uptake is the dominant mechanism of removal of insulin from the circulation whether the route of delivery is portal or peripheral; and c) the kidneys account for the greater part of extrasplanchnic insulin metabolism.

Effects of dietary substitution of mixed amino acids for glucose on the splanchnic metabolism of plasma triglycerides, cholesterol, carbohydrates, and amino acids in conscious fed baboons

Splanchnic metabolism was studied in the fed state during prolonged constant intravenous administration of tracer amounts of [9,10]- 3H palmitic acid and the calculated isocaloric intraduodenal administration (13 mg/min · kg body wt 0.75) of either (1) glucose, (2) 15% mixed amino acids and 85% glucose or (3) 45% mixed amino acids and 55% glucose to conscious, restrained female baboons that had been maintained on a similar diet (supplemented in essential nutrients) for the previous 9 days. Secretion of plasma triglycerides from the splanchnic region was quantified from splanchnic flow and radiochemical measurements of transsplanchnic gradients of 3H-labeled free fatty acids and triglycerides. Mean splanchnic secretion of plasma triglycerides increased significantly as the proportion of dietary calories derived from amino acids was varied from 0 to 15 to 45% (mean values 1.1 ± 0.1, 2.6 ± 0.2 and 4.2 ± 0.3 μmol/min kg body wt 0.75, respectively, p < 0.05). Increased triglyceride secretion was attributable to both significantly higher rates of esterification of free fatty acids taken up in the splanchnic region to triglycerides released into hepatic venous blood plasma (mean values 10 ± 1, 16 ± 2 and 34 ± 5%, respectively) and to significantly higher rates of secretion of triglycerides derived from precursors other than free fatty acids. Higher intake of amino acids was also associated with both higher plasma concentrations of cholesterol and higher values for hepatic oxidation of cholesterol to bile acids. Arterial blood concentrations and splanchnic uptake of glycerol rose with decreasing glucose (increasing mixed amino acid) administration, whereas plasma concentrations and splanchnic retention of amino acids generally increased.

Role of the kidney in the metabolism of fructose in 60-hour fasted humans.

Arterial (A) and renal venous (RV) concentrations and net splanchnic exchange of glucose, fructose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during a 135-min intravenous infusion of fructose at 2 mmol/min in healthy subjects after a 60-h fast. After 45 min of the fructose infusion, somatostatin (9 microgram/min) was infused for 60 min to induce hypoglucagonemia. Fructose infusion resulted in a net uptake of this hexose by the kidney as well as the splanchnic bed. Estimated renal uptake of fructose could account for the disposal of 20% of the administered fructose load while splanchnic uptake accounted for 38%. The fructose infusion resulted in a rise in blood glucose of 0.9 mmol/L, a 35% increase in net glucose output from the splanchnic bed, and a consistent net output of glucose from the kidney (A-RV = -0.17 +/- 0.05 mmol/L as compared with 0 +/- 0.03 in the basal state, P less than 0.02). Net glucose release from the kidney could account for 55% of the net renal uptake of fructose. The fructose infusion also resulted in a marked change in renal lactate balance from a net uptake in the basal state (A - RV = 0.05 +/- 0.01 mmol/L) to a net output during fructose administration (A - RV = -0.10 +/- 0.04). Administration of somatostatin resulted in a fall in arterial glucagon levels and a 35% decrease in splanchnic glucose output but failed to alter the arterial-renal venous difference for glucose observed during the fructose infusion. We conclude that in 60-h fasted man: (a) intravenous infusion of fructose results in a net uptake of this hexose by the kidney as well as the liver, (b) this uptake is accompanied by stimulation of renal as well as hepatic glucose production and renal production of lactate, and (c) hypoglucagonemia inhibits splanchnic but not renal glucose output during fructose infusion. These data indicate that the kidney is an important site of fructose disposal and that glucose and lactate are end products of renal fructose metabolism.

Evidence for an augmented glucagon dependence of hepatic glucose production in cirrhosis of the liver.

The role of endogenous glucagon in maintaining hepatic glucose production after an overnight fast in patients with cirrhosis of the liver was studied with arterial-hepatic-venous catheterization and using somatostatin to suppress glucagon secretion. Arterial glucagon levels were elevated in eight cirrhotics to 290 +/- 90 pg/ml (SEM) compared to 100 +/- 10 pg/ml (P less than 0.02) in five normal controls, and they were lowered during administration of somatostatin (SRIF; 250 microgram/h) by a mean of 154 pg/ml and 39 pg/ml in cirrhotics and controls, respectively. Basal net splanchnic glucose production (NSGP) was similar in patients with and without cirrhosis (approximately 100 mg/min) but declined more markedly during 30 min of SRIF in cirrhotics to a net splanchnic uptake of glucose of 30 +/- 20 ml/min, as opposed to a fall of NSGP by 44 +/- 2 mg/min in controls (P less than 0.01). To assure that NSGP declined during SRIF infusion due to the fall of glucagon levels, SRIF was combined with a glucagon infusion at 150 ng/m2 . min in four cirrhotics and in five control subjects. Arterial glucagon levels were elevated to a mean of 650 pg/ml and 559 pg/ml in cirrhotics and controls, respectively. NSGP increased after 40 min of SRIF and glucagon replacement to 179 +/- 33 mg/min in cirrhotics and significantly more, to 412 +/- 68 mg/min, in controls (P less than 0.01). Thus, hepatic glucose production during basal and elevated glucagon levels suggested hepatic resistance to glucagon in cirrhosis. Nevertheless, endogenous glucagon played an augmented stimulatory role in maintaining glucose production in the normal range since there was an exaggerated fall of hepatic glucose output during glucagon suppression.

Quantitative aspects of L(+)-lactate metabolism in human beings.

The production rate of endogenous L(+)-lactate in the resting human being can be calculated from results of experiments during which isotopic or unlabelled lactate is infused. The merits of the different experimental techniques are discussed, although all published methods have given similar results, namely a resting production rate of about 1.3 mol . (70 kg body wt)-1 . 24 h-1. This result is similar to that found in sheep, but lower than that in dogs and rats. L(+)-lactate production in human subjects is unchanged after fasting for 36-168 h, a finding which contrasts with some animal experiments. It is not known whether this represents a true species difference or a difference in diet. Net splanchnic uptake of L(+)-lactate in the resting human being is about 0.4 mol 24 h-1 although the normal liver has the capacity to metabolize more than this. The kidney is an important site of L(+)-lactate utilization in rats, but there is no information about its role in normal human beings. There are conflicting reports concerning the uptake of L(+)-lactate by resting skeletal muscle, but there is no evidence that resting muscle can metabolize lactate.

Influence of hyperthyroidism on splanchnic exchange of glucose and gluconeogenic precursors.

Arterial concentrations and splanchnic exchange of glucose, amino acids, lactate, pyruvate, and glycerol were determined in 14 hyperthyroid patients and 12 healthy controls. Seven of the patients were restudied after 5-12 mo of medical management at which time there was chemical and clinical evidence of a euthyroid state. The arterial level of glucose was slightly higher (+10%) in the patient group and the glycerol concentration was three times greater among the patients. The plasma levels of the glycogenic amino acids, alanine, glycine, and serine were decreased by 20-30%, while the concentrations of leucine, isoleucine, and tyrosine were increased by 20-80%. The levels of lactate and pyruvate were similar in patients and controls as were insulin and glucagon concentrations. Splanchnic glucose output in the patient group was 35% lower than in controls. However, total splanchnic uptake of glucogenic precursors was 100% higher than in controls and showed a direct linear correlation with serum triiodothyronine. Total precursor uptake could account for 75% of splanchnic glucose output in the patients, compared to 26% in controls. The increase in uptake of lactate, alanine, and other amino acids was due to a 35-80% rise in splanchnic fractional extraction plus a 20% rise in estimated hepatic blood flow. When the patients were restudied after medical treatment splanchnic exchange of glucose and glucose precursors had reverted to normal values. The present findings demonstrate that in hyperthyroidism (a) total splanchnic glucose output is reduced in relation to controls, (b) splanchnic uptake of gluconeogenic precursors is accelerated, largely due to a rise in fractional extraction of precursor substrates and to a smaller extent, as a result of an increase in hepatic blood flow, and (c) these changes revert to normal when a euthyroid state has been achieved.

Interrelationship between splanchnic and leg exchange of glucose and other blood‐borne energy metabolites during abdominal surgical trauma

Summary. In eight patients undergoing cholecystectomy, measurements of leg blood flow, splanchnic blood flow and arterio‐venous differences in oxygen, glucose, lactate, pyruvate, glycerol, 3‐hydroxybutyrate and alanine were made. Splanchnic glucose release averaged 1 1 mmol/min. The uptake of glucose into leg tissue was low. The rise in arterial glucose concentration was about I mmol/h during surgery. At the end of surgery splanchnic oxygen uptake was increased by 70% and the alanine uptake into the same region was comparable to that described in patients with septic complications of surgery. The plasma insulin concentration was low compared with the arterial glucose level.The data suggest that during abdominal surgery (a) increase in arterial glucose concentration can be fully accounted for by slightly increased splanchnic glucose release and a low peripheral utilization; (b) release of gluconeogenic substrates from peripheral tissues is balanced by splanchnic uptake; (c) disturbed relation between glucose and insulin, enhanced gluconeogenesis, increased splanchnic oxygen uptake and fat‐mobilizing lipolysis are in accordance with a raised sympatho‐adrenergic activity.

Influence of leucine on arterial concentrations and regional exchange of amino acids in healthy subjects.

1. L-Leucine was given to healthy, post-absorptive subjects as a continuous intravenous infusion (300 mumol/min) during 2 1/2 h. Arterial blood concentrations and regional exchange amino acids were measured across the splanchnic region, the brain and a leg, by the catheter technique. Renal clearance of amino acids was also determined. 2. During the infusion of leucine its concentration rose four- to six-folds, while the concentrations of several other amino acids declined continually, the effect being most pronounced for isoleucine (-55% of initial value), methionine (-55%), valine (-40%), tyrosine (-35%) and phenylalanine (-35%). 3. The infused leucine was taken up by muscle tissue (55%), by the splanchnic region (25%) and by the brain (10%). Neither leg-muscle release nor splanchnic uptake of aromatic amino acids was affected. Renal clearance and tubular reabsorption of amino acids were uninfluenced by leucine infusion. The uptake of isoleucine and methionine by the brain, seen in the basal state, was inhibited during leucine infusion. 4. The marked reduction in the concentrations of the aromatic amino acids, the uptake of leucine by the brain and the inhibition of brain methionine uptake, which accompany leucine infusion in healthy subjects, may be of relevance for the treatment of patients with portal-systemic encephalopathy.

The contrasting responses of splanchnic and renal glucose output to gluconeogenic substrates and to hypoglucagonemia in 60-h-fasted humans.

SUMMARY Arterial concentrations and splanchnic as well as renal exchange of glucose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during intravenous infusion of alanine or glycerol in healthy subjects who had fasted for 60 h. After 45 min of infusion of alanine or glycerol, somatostatin administration (SRIF, 9 μg/min) was added to induce hypoglucagonemia. Alanine infusion, at a rate of 1 mmol/min, was accompanied by an 80% rise in splanchnic glucose output (SGO) and a small (16%) rise in arterial glucose. Splanchnic alanine uptake, which rose fivefold to sixfold above basal, could account for the entire rise in SGO. Intravenous administration of glycerol (1 mmol/min) resulted in an elevation of blood glucose (+ 9%) but no significant change in SGO, even though glycerol uptake by the splanchnic tissues rose eightfold above basal levels. Measurements of renal exchange of glucose indicated a small but statistically significant release of glucose from the kidney (0.04 ± 0.01 mmol/min) in the basal state, which accounted for 10% of total (renal plus splanchnic) glucose production. Administration of glycerol at a rate of 2 mmol/min resulted in a rise in renal glucose output to 0.16 ± 0.03 mmol/min, which could be accounted for in its entirety by renal glycerol uptake. In contrast, infusion of alanine (2 mmol/min), did not alter the renal glucose exchange. Infusion of SRIF was accompanied by a significant fall in the arterial glucagon level in all studies. Concomitante, large decreases in arterial glucose and SGO were observed during both alanine and glycerol administration. However, splanchnic uptake of gluconeogenic precursors was not influenced by SRIF administration. The elevated renal glucose output seen during glycerol administration was not altered by SRIF infusion. It is concluded that, in 60-h-fasted man, (a) renal glucose output contributes significantly to total glucose production, (b) administration of glycerol stimulates renal glucose production, (c) alanine infusion increases splanchnic but may not affect renal glucose output, and (d) hypoglucagonemia inhibits splanchnic but not renal glucose output. These data indicate that hepatic and renal gluconeogeneses respond differently with respect to stimulation by specific substrates and to their dependence on basal glucagon levels.

Amino acid metabolism and the liver in renal failure

The study of amino acid metabolism across the splanchnic organs can be useful for investigating derangements in nitrogen metabolism in chronic renal insufficiency. For this purpose, arterial-hepatic venous differences for 19 free amino acids, ammonia and urea, determined in whole blood, were measured in six patients with chronic renal insufficiency and in six subjects with normal renal function. In normal conditions, the hepatosplanchnic bed significantly extracts glutamine, alanine, glycine, serine, threonine, lysine, arginine, phenylalanine, valine, tyrosine, histidine, leucine, and ammonia, and releases glutamate, citrulline, and urea. In chronic renal insufficiency, glutamine uptake decreases, serine, valine and ammonia uptake disappears, proline extraction becomes present, citrulline output is no longer detectable and glutamate release falls slightly. Furthermore, the splanchnic uptake of ammonia and the output of urea into the hepatic veins are markedly reduced. Since glutamine and ammonia are major substrates for urea synthesis, their lower uptakes, as observed in renal insufficiency, may be consistent with the reduced urea output. The changes in splanchnic metabolism observed in chronic renal insufficiency have a minor effect on the abnormalities in circulating amino acids. Finally, the splanchnic metabolism shows an important role in the homeostasis of circulating tyrosine and proline.