Starvation in human pregnancy: hypoglycemia, hypoinsulinemia, and hyperketonemia.

In women fasted during the second trimester of pregnancy, concentrations of glucose and insulin in the plasma fell to a greater extent and ketone acid concentrations in the blood rose more rapidly than in nonpregnant controls. Nitrogen excretion in the urine, particularly ammonia, was increased in the pregnant group. Continuous glucose utilization by the conceptus may exaggerate and accelerate the metabolic consequences of starvation.

Obesity: evidence of decreased secretion of glucagon.

The increase in concentration of glucagon in plasma caused by infusion of alanine was reduced in obese subjects as compared to that in nonobese control subjects. This was true when the subjects were in the postabsorptive state as well as after an 84-hour fast, at which time the basal glucagon concentration had risen in the nonobese subjects, but remained unaltered in the obese group.

Alanine: key role in gluconeogenesis.

Of 20 amino acids measured, alanine is the principal amino acid released by forearm muscle of man, in accord with its being the principal amino acid extracted by liver for gluconeogenesis. This occurs in both the postabsorptive state and after 4 to 6 weeks of starvation, when total amino acid release is markedly diminished.

Glucagon binding and adenylate cyclase activity in liver membranes from untreated and insulin-treated diabetic rats.

To investigate the role of hepatic glucagon receptors in the hypersensitivity to glucagon observed in insulin-deprived diabetics, liver plasma membranes were prepared from control rats and from streptozotocin-induced diabetic rats some of whom were treated with high-dose and low-dose insulin. The untreated diabetic animals exhibited hyperglycemia, weight loss, hypoinsulinemia, and hyperglucagonemia. High-dose insulin treatment (2 U Protamine-zinc-insulin/100 g per day) resulted in normoglycemia, normal weight gain, mild hyperinsulinemia, and return of glucagon levels toward base line. The low-dose (1 U protamine-zinc-insulin/100 g per day) insulin-treated diabetic group demonstrated chemical changes intermediate between the untreated and the high-dose insulin-treated animals. In liver plasma membranes from the untreated diabetic rats, specific binding of (125)I-glucagon was increased by 95%. Analysis of binding data suggested that the changes in glucagon binding were a consequence of alterations in binding capacity rather than changes in binding affinity. Furthermore, in the untreated diabetic rats, both basal and glucagon (2 muM)-stimulated adenylate cyclase activity were twofold higher than in controls. In the high-dose insulin-treated diabetic rats, glucagon binding and basal and glucagon-stimulated adenylate cyclase activity were normalized to control values, whereas low-dose insulin treatment resulted in changes intermediate between control and untreated diabetic rats. In contrast to glucagon-stimulated adenylate cyclase activity, fluoride-stimulated adenylate cyclase activity was similar in all groups of rats. Liver plasma membranes from untreated and insulin-treated diabetic animals degraded (125)I-glucagon to the same extent as control rats. The specific binding of (125)I-insulin in the untreated diabetic animals was 40% higher than in control rats. In low-dose insulin-treated diabetic rats, insulin binding was not significantly different from that of control rats, whereas in the high-dose insulin-treated group in whom plasma insulin was 70% above control levels, insulin binding was 30% lower than in control rats. These findings suggest that alterations in glucagon receptors may contribute to the augmented glycemic and ketonemic response to glucagon observed in insulin-deprived diabetics.

Amino acid metabolism in exercising man.

Arterial concentration and net exchange across the leg and splanchnic bed of 19 amino acids were determined in healthy, postabsorptive subjects in the resting state and after 10 and 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Arterio-portal venous differences were measured in five subjects undergoing elective cholecystectomy. In the resting state significant net release from the leg was noted for 13 amino acids, and significant splanchnic uptake was observed for 10 amino acids. Peripheral release and splanchnic uptake of alanine exceeded that of all other amino acids, accounting for 35-40% of total net amino acid exchange. Alanine and other amino acids were released in small amounts (relative to net splanchnic uptake) by the extrahepatic splanchnic tissues drained by the portal vein. During exercise arterial ananine rose 20-25% with mild exertion and 60-96% at the heavier work loads. Both at rest and during exercise a direct correlation was observed between arterial alanine and arterial pyruvate levels. Net amino acid release across the exercising leg was consistently observed at all levels of work intensity only for alanine. Estimated leg alanine output increased above resting levels in proportion to the work load. Splanchnic alanine uptake during exercise exceeded that of all other amino acids and increased by 15-20% during mild and moderate exercise, primarily as a consequence of augmented fractional extraction of alanine. For all other amino acids, there was no change in arterial concentration during mild exercise. At heavier work loads, increases of 8-35% were noted for isoleucine, leucine, methionine, tyrosine, and phenylalanine, which were attributable to altered splanchnic exchange rather than augmented peripheral release. The data suggest that (a) synthesis of alanine in muscle, presumably by transamination of glucose-derived pyruvate, is increased in exercise probably as a consequence of increased availability of pyruvate and amino groups; (b) circulating alanine serves an important carrier function in the transport of amino groups from peripheral muscle to the liver, particularly during exercise; (c) a glucose-alanine cycle exists whereby alanine, synthesized in muscle, is taken up by the liver and its glucose-derived carbon skeleton is reconverted to glucose.

Influence of endogenous insulin secretion on splanchnic glucose and amino acid metabolism in man.

Splanchnic exchange of glucose, 20 individual amino acids, lactate, and pyruvate was studied in normal subjects in the postabsorptive state and after stimulation of endogenous insulin secretion by infusion of glucose at two dose levels. In the basal state, mean splanchnic glucose production was 3.4 mg/kg per min. A net uptake of lactate, pyruvate, and nine amino acids was observed, with alanine accounting for half of the total splanchnic-amino acid extraction. Infusion of glucose at 25 mg/kg per min for 20 min resulted in a fivefold increase in arterial insulin levels and in reversal of splanchnic glucose balance to a net uptake. Splanchnic uptake of alanine, glycine, phenylalanine, lactate, and pyruvate fell by 30-60% due to a reduction in fractional extraction of these substrates, inasmuch as their arterial concentrations did not decline.Administration of glucose at 2 mg/kg per min for 45 min resulted in a 19 mg/100 ml increase in arterial glucose concentration and a doubling of arterial insulin levels. Despite the small increment in insulin, hepatic glucose production fell by 85%. Splanchnic exchange of amino acids, lactate, and pyruvate was unaltered. Estimated total glucose utilization during the infusion was no greater than in the basal state, indicating lack of stimulation of peripheral glucose uptake. IT IS CONCLUDED THAT: (a) inhibition of hepatic glucose production associated with glucose infusion and large increments in insulin levels occurs in the absence of a decrease in the concentration of circulating gluconeogenic substrate, suggesting an hepatic rather than peripheral effect; (b) the liver is the primary target organ whereby glucose homeostasis is achieved with small increments in insulin; (c) the relatively greater sensitivity of the liver's response to insulin as compared with an effect of insulin on the peripheral tissues, may be a consequence of the higher levels of endogenous insulin in portal as compared with peripheral blood.

Lactate and glucose exchange across the forearm, legs, and splanchnic bed during and after prolonged leg exercise.

The net exchange of glucose and lactate across the leg and the splanchnic bed and the arterialdeep venous (A-DV) differences for these substrates in the forearm were determined in healthy subjects during 3-3.5 h of leg exercise (bicycle ergometer) at 58% maximum O(2) uptake and during a 40-min post-exercise recovery period. Leg glucose uptake rose 16-fold during exercise and throughout the exercise period exceeded splanchnic glucose output. The latter reached a peak increment (3.5 times basal) at 90 min and fell by 60% during the third hour. As a result, blood glucose declined 40%, reaching frank hypoglycemia (blood glucose, <45 mg/dl) in 50% of subjects at 3.5 h. Splanchnic lactate uptake rose progressively during exercise to values four times the basal rate at 3 h in association with a rise in arterial lactate to 1.5 mM. There was, however, no significant net output of lactate from the legs beyond 90 min of exercise. In contrast, the A-DV lactate difference in the forearm became progressively more negative throughout exercise, reaching values three times the basal level at 3.5 h. The rise in arterial lactate during exercise was proportional to the elevation in plasma epinephrine, which rose ninefold. During recovery, splanchnic lactate uptake rose further to values six times the basal rate, whereas lactate output by the legs was no greater than in the basal state. The A-DV lactate difference in the forearm became even more negative than during exercise, reaching values four times basal. During exercise as well as recovery, forearm uptake of blood glucose could account for no more than 25-67% of forearm lactate release. Leg glucose uptake during recovery was threefold to fivefold higher than in the basal state in the face of plasma insulin concentrations that were 60% below basal and in association with a respiratory exchange ratio of 0.7. We conclude that (a) during prolonged leg exercise at 58% maximum O(2) uptake an imbalance between splanchnic glucose production and leg glucose utilization results in a fall in blood glucose that may reach hypoglycemic levels in healthy subjects; (b) there is a marked increase in the uptake of lactate by the splanchnic bed that cannot be attributed to increased output of lactate from the exercising legs; (c) lactate is released by forearm muscle and, together with other relatively inactive muscle, may be an important source of the increased lactate turnover during and after prolonged leg exercise; (d) the increasingly negative A-DV lactate difference in the forearm cannot be accounted for by uptake of blood glucose, suggesting the breakdown of glycogen in forearm muscle during and after leg exercise; (e) increased glucose uptake by the legs in association with hypoinsulinemia during recovery suggests an increase in insulin sensitivity that permits glycogen repletion in previously exercising muscle in the absence of food ingestion; and (f) the evidence for increased lactate output in the forearm and augmented glucose uptake in the legs during recovery raises the possibility that after leg exercise glycogen stores are decreasing in muscle that was relatively inactive (e.g., that of the forearm) while increasing in the previously exercising leg muscles.

Glucagon and insulin binding to liver membranes in a partially nephrectomized uremic rat model.

To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15+/-1 mg/100 ml, creatinine 0.7+/-0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30+/-2 mg/100 ml, creatinine 2.2+/-0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46+/-3 mg/100 ml, creatinine 4.20+/-0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95+/-4 vs. 125+/-11 mg/100 ml), plasma insulin (28+/-9 vs. 52+/-11 muU/ml), and plasma glucagon (28+/-5 vs. 215+/-18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals. In liver plasma membranes from nephrectomized rats, specific binding of (125)I-glucagon was increased by 80-120%. Furthermore, glucagon (2 muM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of (125)I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded (125)I-glucagon and (125)I-insulin to the same extent as control rats. THESE RESULTS DEMONSTRATE THAT: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.

Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus.

The inter-organ flux of substrates after a protein-rich meal was studied in seven healthy subjects and in eight patients, with diabetes mellitus. Arterial concentrations as well as leg and splanchnic exchange of amino acids, carbohydrate substrates, free fatty acids (FFA), and ketone bodies were examined in the basal state and for 3 h after the ingestion of lean beef (3 g/kg body wt). Insulin was withheld for 24 h before the study in the diabetic patients. In the normal subjects, after protein ingestion, there was a large amino acid release from the splanchnic bed predominantly involving the branched chain amino acids. Valine, isoleucine, and leucine accounted together for more than half of total splanchnic amino acid output. Large increments were seen in the arterial concentrations of the branched chain amino acids (100-200%) and to a smaller extent for other amino acids. Leg exchange of most amino acids reverted from a basal net outut to a net uptake after protein feeding which was most marked for the branched chain amino acids. The latter accounted for more than half of total peripheral amino acid uptake...

Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise.

Splanchnic and peripheral exchange of glucose and gluconeogenic substrates was examined in 12 healthy subjects during 2 h of arm or leg exercise on a bicycle ergometer and during a 40-min postexercise recovery period. The work intensity corresponded to 30% of the maximal pulmonary oxygen uptake. The regional exchange of substrates was evaluated using catheter technique and indicator dilution methods for blood flow measurements. Our findings indicate that prolonged arm exercise as compared with exercise with the legs results in a greater increase in heart rate (25-40%) and a more marked reduction in splanchnic blood flow (10-30%) as well as higher arterial concentrations of lactate, free fatty acids, and catecholamines. The respiratory exchange ratio was consistently higher with arm exercise. In addition, arm exercise results in a greater fractional extraction and utilization of glucose by exercising muscle as well as a greater hepatic gluconeogenesis from lactate and glycerol. During recovery from prolonged arm exercise, leg muscle becomes an important site of lactate release to the splanchnic bed, despite a lack of net glucose uptake by the leg. Simultaneously, arm muscle shows an increase in glucose uptake in the absence of a net release of lactate. These coincident but discordant processes in the leg and arm during recovery suggest the occurrence of a redistribution of muscle glycogen from previously resting (leg) muscle to previously exercising (arm) muscle.

Influence of physiologic hyperglucagonemia on basal and insulin-inhibited splanchnic glucose output in normal man.

To evaluate the effects of physiologic hyperglucagonemia on splanchnic glucose output, glucagon was infused in a dose of 3 ng/kg per min to healthy subjects in the basal state and after splanchnic glucose output had been inhibited by an infusion of glucose (2 mg/kg per min). In the basal state, infusion of glucagon causing a 309 +/- 25 pg/ml rise in plasma concentration was accompanied by a rapid increase in splanchnic glucose output to values two to three times basal by 7-15 min. The rise in arterial blood glucose (0.5-1.5 mM) correlated directly with the increment in splanchnic glucose output. Despite continued glucagon infusion, and in the face of stable insulin levels, splanchnic glucose output declined after 22 min, returning to basal levels by 30-45 min. In the subjects initially receiving the glucose infusion, arterial insulin concentration rose by 5-12 muU/ml, while splanchnic glucose output fell by 85-100%. Infusion of glucagon causing an increment in plasma glucagon concentration of 272 +/- 30 pg/ml reversed the inhibition in splanchnic glucose production within 5 min. Splanchnic glucose output reached a peak increment 60% above basal levels at 10 min, and subsequently declined to levels 20-25% below basal at 30-45 min. These findings provide direct evidence that physiologic increments in plasma glucagon stimulate splanchnic glucose output in the basal state and reverse insulin-mediated inhibition of splanchnic glucose production in normal man. The transient nature of the stimulatory effect of glucagon on splanchnic glucose output suggests the rapid development of inhibition or reversal of glucagon action. This inhibition does not appear to depend on increased insulin secretio.

Splanchnic and leg exchange of glucose, amino acids, and free fatty acids during exercise in diabetes mellitus.

The influence of exercise on leg and splanchnic exchange of substrates was examined in eight insulin-dependent diabetics 24 h after withdrawal of insulin and in eight healthy controls studied at rest and after 40 min of bicycle ergometer exercise at 55-60% of maximal capacity. In four of the diabetic subjects, basal arterial ketone acid levels were 3-4 mmol/ liter (ketotic diabetics) and in the remainder, below 1 mmol/liter (nonketotic diabetics). ,ree fatty acid (FFA) turnover and regional exchange were evaluated with 14-C- labeled oleic acid. Leg uptake of blood glucose rose 13-18 fold during exercise in both the diabetics and controls and accounted for a similar proportion of the total oxygen uptake by leg muscles (25-28%) in the two groups. In contrast, leg uptake of FFA corresponded to 39% of leg oxygen consumption in the diabetic group but only 27% in controls. Systemic turnover of oleic acid was similar in the two groups. Splanchnic glucose output increased during exercise 3-4 fold above resting levels in both groups. In the diabetics, splanchnic uptake of lactate, pyruvate, glycerol, and glycogenic amino acids rose more than twofold above resting levels and was fourfold greater than in exercising controls. Total precursor uptake could account for 30% of the splanchnic glucose output in the diabetic group. In contrast, in the controls, total splanchnic uptake of glucose precursors was no greater during exercise than in the resting state and could account for no more than 11% of splanchnic glucose output. The augmented precursor uptake during exercise in the diabetics was a consequence of increased splanchnic fractional extraction as well as increased peripheral production of gluconeogenic substrates. The arterial glucagon concentration was unchanged by exercise in both groups, but was higher in the diabetics. In the diabetic subjects with ketosis in the resting state, exercise elicited a rise in arterial glucose and FFA, an augmented splanchnic uptake of FFA, and a 2-3 fold increase in splanchnic output of 3-hydroxybutyrate. Uptake of 3-hydroxybutyrate by the exercising leg rose more rapidly than splanchnic production, resulting in a fall in arterial levels of 3-hydroxybutyrate. It is concluded that (a) glucose uptake by exercising muscle in hyperglycemic diabetics is no different from that of controls; (b) splanchnic glucose output rises during exercise to a similar extent in diabetics and controls, while uptake of gluconeogenic substrates is markedly higher in diabetics and accounts for a greater proportion of total splanchnic glucose output; (c) exercise in diabetic patients with mild ketosis is associated with a rise in blood glucose and FFA levels as well as augmented splanchnic production and peripheral uptake of ketone bodies.

Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man.

Plasma concentrations of glucagon, insulin, glucose, and individual plasma amino acids were measured in normal nonobese and obese subjects before and after 3 days of dexamethasone treatment (2 mg/day) and in patients with Cushing's syndrome. The subjects were studied in the basal postabsorptive state and following the infusion of alanine (0.15 g/kg) or ingestion of a protein meal. In nonobese subjects dexamethasone treatment resulted in a 55% increment in basal glucagon levels and in a 60-100% increase in the maximal glucagon response to alanine infusion or protein ingestion. In obese subjects, basal glucagon rose by 110% following dexamethasone, while the response to alanine increased fourfold. In patients with Cushing's syndrome basal glucagon levels were 100% higher and the glucagon response to alanine infusion was 170% greater than in normal controls.Dexamethasone treatment in normal subjects resulted in a 40% rise in plasma alanine concentration which was directly proportional to the rise in basal glucagon. The remaining 14 amino acids were unchanged. In the patients with Cushing's syndrome alanine levels were 40% higher than in normal controls and were directly proportional to basal glucagon concentrations. No other plasma amino acids were significantly altered in the group with Cushing's syndrome. It is concluded that (a) glucocorticoids increase plasma glucagon concentration in the basal state and in response to protein ingestion or aminogenic stimulation; (b) this effect of glucocorticoids occurs in the face of obesity and persists in chronic hypercorticism; (c) hyperalaninemia is a characteristic of acute and chronic glucocorticoid excess, and may in turn contribute to steroid-induced hyperglucagonemia; and (d) increased alpha cell secretion may be a contributory factor in the gluconeogenic and diabetogenic effects of glucocorticoids.

Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans.

The effects of continuous infusions of insulin in physiologic doses on glucose kinetics and circulating counterregulatory hormones (epinephrine, norepinephrine, glucagon, cortisol, and growth hormone) were determined in normal subjects and diabetics. The normals received insulin at two dose levels (0.4 and 0.25 mU/kg per min) and the diabetics received the higher dose (0.4 mU/kg per min) only. In all three groups of studies, continuous infusion of insulin resulted in an initial decline in plasma glucose followed by stabilization after 60-180 min. In the normal subjects, with the higher insulin dose there was a fivefold rise in plasma insulin. Plasma glucose fell at a rate of 0.73+/-0.12 mg/min for 45 min and then stabilized at 55+/-3 mg/dl after 60 min. The initial decline in plasma glucose was a result of a rapid, 27% fall in glucose output and a 33% rise in glucose uptake. Subsequent stabilization was a result of a return of glucose output and uptake to basal levels. The rebound increment in glucose output was significant (P < 0.05) by 30 min after initiation of the insulin infusion and preceded, by 30-45 min, a significant rise in circulating counterregulatory hormones. With the lower insulin infusion dose, plasma insulin rose two- to threefold, plasma glucose initially fell at a rate of 0.37+/-0.04 mg/min for 75 min and stabilized at 67+/-3 mg/dl after 75 min. The changes in plasma glucose were entirely a result of a fall in glucose output and subsequent return to base line, whereas glucose uptake remained unchanged. Plasma levels of counterregulatory hormones showed no change from basal throughout the insulin infusion. In the diabetic group (plasma glucose levels 227+/-7 mg/dl in the basal state), the initial rate of decline in plasma glucose (1.01+/-0.15 mg/dl) and the plateau concentration of plasma glucose (59+/-5 mg/dl) were comparable to controls receiving the same insulin dose. However, the initial fall in plasma glucose was almost entirely a result of suppression of glucose output, which showed a twofold greater decline (60+/-6%) than in controls (27+/-5%, P <0.01) and remained suppressed throughout the insulin infusion. In contrast, the late stabilization in plasma glucose was a result of a fall in glucose uptake to values 50% below basal (P < 0.001) and 39% below that observed in controls at termination of the insulin infusion (P < 0.01). Plasma norepinephrine and glucagon failed to rise during the insulin infusion, whereas plasma epinephrine, cortisol, and growth hormone rose to values comparable to controls receiving the same insulin dose. It is concluded that (a) in normal and diabetic subjects, physiologic hyperinsulinemia results in an initial decline followed by stabilization of plasma glucose despite ongoing infusion of insulin; (b) in the normal subjects, a rebound increase in glucose output is the initial or principal mechanism counteracting the fall in plasma glucose and occurs (with an insulin dose of 0.25 mU/kg per min) in the absence of a rise in circulating counterregulatory hormones; (c) in diabetics, although the changes in plasma glucose are comparable to controls, the initial decline is a result of an exaggerated suppression of glucose output, whereas the stabilization of plasma glucose occurs primarily as a consequence of an exaggerated fall in glucose uptake; and (d) failure of plasma norepinephrine as well as glucagon to rise in the diabetics may contribute to the exaggerated suppression of glucose output.

Turnover and splanchnic metabolism of free fatty acids in hyperthyroid patients.

The arterial concentration and turnover rate and the splanchnic exchange of FFA were examined after an overnight fast in a group of 11 female patients with clinical and laboratory evidence of hyperthyroidism. [14C]oleic acid was infused intravenously and the hepatic venous catheter technique was used. As compared with healthy control individuals, the arterial concentrations of FFA and oleic acid were elevated by 30--40% in the hyperthyroid group. Both the turnover rate and the fractional turnover of oleic acid were significantly increased. The turnover rate correlated directly with arterial concentration of oleic acid in both the control and the patient group but the slope was steeper in the patients. The splanchnic uptake of oleic acid was three times higher than in the control group. The augmented uptake was a consequence of elevated arterial concentrations and increased hepatic plasma flow, whereas fractional splanchnic uptake remained unchanged. Ketone body production was four- to fivefold greater in the patients and could be largely accounted for by increased splanchnic FFA uptake. In six patients studied after treatment resulting in a return to normal thyroid function, a significant reduction was observed in arterial FFA, estimated hepatic blood flow, oleic acid turnover, and ketone body production. It is concluded that hyperthyroidism is characterized by increased turnover and splanchnic uptake of FFA and augmented ketogenesis. These findings can be explained on the basis of elevated arterial FFA concentrations and increased blood flow, particularly to the splanchnic bed.

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.

Splanchnic glucose and amino acid metabolism in obesity.

Arterial concentrations and splanchnic exchange of glucose, lactate, pyruvate, glycerol, free fatty acids, and individual acidic and neutral amino acids were determined in obese and nonobese control subjects in the basal state and during a 45 min infusion of glucose. Glucose was administered to the controls at a rate (2 mg/kg/min; 144 +/- 4 mg/min) known to inhibit splanchnic glucose output without influencing peripheral glucose utilization. The obese subjects received glucose at two dose levels (75 and 150 mg/min) which simulated either the rise in insulin or the inhibition in splanchnic glucose production observed in the controls. In the basal state splanchnic glucose production did not differ significantly between obese and control subjects. However splanchnic uptake of lactate, glycerol, alanine, free fatty acids, and oxygen was 50-160% greater in obese subjects. Splanchnic uptake of glucose precursors could account for 33% of hepatic glucose output in the obese group as compared to 19% in controls. The increase in alanine and lactate uptake was due in part, to a 50% increase in splanchnic fractional extraction. Administration of glucose to the control subjects 144 +/- 4 mg/min) resulted in a 50-60% increment in arterial insulin and a 75% reduction in splanchnic glucose output. In the obese group, infusion of glucose at a rate of 75 mg/min resulted in an equivalent rise in arterial insulin, but was accompanied by a less than 40% inhibition in splanchnic glucose output. Glucose infusion at a rate of 150 mg/min in the obese resulted in a 75% reduction in splanchnic glucose output which was equivalent to that observed in controls, but was accompanied by a significantly greater rise (100-200%) in arterial insulin. It is concluded that in obesity (a) despite basal hyperinsulinemia, splanchnic uptake of glucose precursors is increased, the relative contribution to total glucose release attributable to gluconeogenesis being 70% higher than in controls; (b) infusion of glucose at rates causing equivalent increases in arterial insulin induces a smaller inhibition in splanchnic glucose output than in controls; (c) infusion of glucose at rates causing comparable inhibition in splanchnic glucose output is accompanied by a disproportionately greater increase in endogenous insulin than in controls. These data are compatible with hepatic resistance to insulin in obesity.

Glucose metabolism during leg exercise in man.

Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Rising arterial glucose levels and small decreases in plasma insulin concentrations were found during heavy exercise. Significant arterial-femoral venous differences for glucose were demonstrated both at rest and during exercise, their magnitude increasing with work intensity as well as duration of the exercise performed. Estimated glucose uptake by the leg increased 7-fold after 40 min of light exercise and 10- to 20-fold at moderate to heavy exercise. Blood glucose uptake could at this time account for 28-37% of total substrate oxidation by leg muscle and 75-89% of the estimated carbohydrate oxidation. Splanchnic glucose production increased progressively during exercise reaching levels 3 to 5-fold above resting values at the heavy work loads. Close agreement was observed between estimates of total glucose turnover during exercise based on leg glucose uptake and splanchnic glucose production. Hepatic gluconeogenesis-estimated from splanchnic removal of lactate, pyruvate, glycerol, and glycogenic amino acids-could supply a maximum of 25% of the resting hepatic glucose production but could account for only 6-11% of splanchnic glucose production after 40 min of moderate to heavy exercise. IT IS CONCLUDED THAT: (a) blood glucose becomes an increasingly important substrate for muscle oxidation during prolonged exercise of this type: (b) peripheral glucose utilization increases in exercise despite a reduction in circulating insulin levels: (c) increased hepatic output of glucose, primarily by means of augmented glycogenolysis, contributes to blood glucose homeostasis in exercise and provides an important source of substrate for exercising muscle.

Effect of ketone infusions on amino acid and nitrogen metabolism in man.

To evaluate the role of hyperketonemia in the hypoalaninemia and decreased protein catabolism of prolonged starvation, Na dl-beta-hydroxybutyrate was administered as a primed continuous 3-6-h infusion in nonobese subjects and in obese subjects in the postabsorptive state and after 3 days and 3-5 1/2 wk of starvation. An additional obese group received 12-h ketone infusions on 2 consecutive days after 5-10 wk of fasting. The ketone infusion in nonobese and obese subjects studied in the postabsorptive state resulted in total blood ketone acid levels of 1.1-1.2 mM, a 5-15 mg/100 ml decrease in plasma glucose, and unchanged levels of insulin, glucagon, lactate, and pyruvate. Plasma alanine fell by 21% (P smaller than 0.001) in 3 h. In contrast, other amino acids were stable or varied by less than 10%. Infusions lasting 6 h reduced plasma alanine by 37%, reaching levels comparable to those observed in prolonged starvation. Equimolar infusions of NaC1 and/or administration of NaHCO3 failed to alter plasma alanine levels. During prolonged fasting, plasma alanine, which had fallen by 40% below prefast levels, fell an additional 30% in response to the ketone infusion. In association with repeated prolonged (12 h) infusions in subjects fasted 5-10 wk, urinary nitrogen excretion fell by 30%, returning to base line after cessation of theinfusions and paralleling the changes in plasma alanine. Ketone infusins resulted in two- to fourfold greater increments in blood ketone acids in fasted as compared to postabsorptive subjects. It is concluded that increased blood ketone acid levels induced by infusions of Na DL-beta-hydroxybutyrate result in hypoalaninemia and in nitrogen conservation in starvation. These data suggest that hyperketonemia may be a contributory factor in the decreased availability or circulating alanine and reduction in protein catabolism characteristic of prolonged fastings9

Amino acid metabolism during starvation in human pregnancy.

To evaluate the factors regulating gluconeogenesis in pregnancy, plasma amino acid levels were determined during the course of an 84-90 hr fast in physically healthy women studied during wk 16-22 of gestation (before undergoing therapeutic abortion), and in nonpregnant controls. The effect of pregnancy on the glycemic response to exogenous alanine administration during starvation was also investigated. In the nonpregnant group fasting resulted in a 2- to 3-fold increase in the levels of plasma valine, leucine, isoleucine, and alpha-aminobutyrate, while the concentration of alanine and glycine fell. In the pregnant group, the levels of most amino acids were significantly reduced in the postabsorptive state. With starvation, the plasma concentration of alanine fell more rapidly in the pregnant group and was significantly below that of the nonpregnant subjects for the first 60 hr of the fast. In contrast, a significant elevation in plasma glycine, serine, and threonine was observed in the pregnant group after 84 hr of fasting, whereas similar increments were not demonstrable until after 10 days of fasting in previously studied nonpregnant obese subjects. Paralleling the changes in maternal plasma, amniotic fluid levels of valine, leucine, and isoleucine increased while that of alanine fell during the fast. Although the plasma glucose concentration was lower in the pregnant group at termination of the fast, intravenous alanine administration (0.15 g/kg), resulted in a prompt, comparable increase (20-25 mg/100 ml) in plasma glucose in both groups of subjects. It is concluded that (a) pregnancy accelerates and exaggerates the hypoalaninemic and hyperglycinemic effects of starvation; (b) lack of key endogenous substrate rather than altered intrahepatic processes may limit hepatic gluconeogenesis in pregnancy and contribute to gestational hypoglycemia; (c) maternal caloric deprivation profoundly alters the levels of amino acids in amniotic fluid.