Loss of insulin response to ingested amino acids after jejunoileal bypass surgery for morbid obesity.

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.

The role of alanine and glutamine in steroid-induced nitrogen wasting in man.

1. Administration of dexamethasone, 8 mg/day (0-02 mmol/day), for 5 days to normal subjects produced negative nitrogen balance, due to early and sustained increases in urinary urea nitrogen excretion 2. In eight subjects ingesting 0-9--1-6 g of protein day-1 kg-1 body weight the cumulative increment in urea nitrogen excretion averaged + 12-5 g (SEM 2-8, P less than 0-01) over the 5 days of glucocorticoid administration. 3. Increases in urinary urea nitrogen excretion could be related to both plasma alanine and blood glutamine changes by using a multiple regression equation. 4. These results suggest that corticosteroids induce increased release of alanine and glutamine by peripheral tissues, which may augment urea formation and negative nitrogen balance. 5. The correlation between increments in urea nitrogen excretion and increases in plasma arginine remains unexplained.

Effect of oral amino acid supplementation on liver disease after jejunoileal bypass for morbid obesity.

Previous work in our laboratory and others suggests that protein malnutrition plays an important role in the pathogenesis of hepatic steatosis and dysfunction which characteristically appears after jejunoileal bypass for morbid obesity. Postoperative protein-calorie malnutrition is at least in part a consequence of diminished intestinal absorption of free amino acids. In an attempt to prevent liver disease, six morbidly obese patients were orally supplemented with essential amino acids for 4 months after surgery. Oral amino acid supplementation only partially influenced protein malnutrition and had no effect on deterioration of hepatic morphology and dysfunction. Although this mode of therapy appears to be ineffective in preventing postoperative liver abnormalities, other studies suggest that oral oligopeptide supplementation and parenteral administration of amino acids are beneficial. In addition to protein deificiency, other factors which may contribute to the development of liver disease are reviewed.

Metabolism of forearm tissues in man. Studies with glucagon.

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

Effects of brief starvation on muscle amino acid metabolism in nonobese man.

A reduction in the release of substrate amino acids from skeletal muscle largely explains the decrease in gluconeogenesis characterizing prolonged starvation. Brief starvation is associated with an increase in gluconeogenesis, suggesting increased release of amino acids from muscle. In the present studies, accelerated amino acid release from skeletal muscle induced by brief starvation was sought to account for the accompanying augmentation of gluconeogenesis. To do this amino acid balance across forearm muscles was quantified in 15 postabsorptive (overnight fasted) subjects and in 7 subjects fasted for 60 h. Fasting significantly reduced basal insulin (11.3-7.5 muU/ml) and increased glucagon (116-134 pg/ml). Muscle release of the principal glycogenic amino acids increased. Alanine release increased 59.4%. The increase in release for all amino acids averaged 69.4% and was statistically significant for threonine, serine, glycine, alanine, alpha-aminobutyrate, methionine, tyrosine, and lysine. Thus, with brief starvation, muscle release of glycogenic amino acids increases strikingly. This contrasts with the reduction of amino acid release characterizing prolonged starvation. The adaptation of peripheral tissue metabolism to brief starvation is best explained by the decrease in insulin.

Interaction of secretin and insulin on human forearm metabolism.

The effect of secretin on forearm metabolism (muscle compartment) was examined in the presence of low and high concentrations of insulin. Continuous infusions (30 min. duration) of secretin 12 ng/min. (SEC), insulin 160 ng/min. (INS) or these doses of insulin and secretin together (INS + SEC) were delivered into the brachial arteries of normal volunteers. SEC alone was without significant effect on forearm metabolism. INS as previously reported, stimulated glucose and potassium uptake and inhibited the output of some amino acids from the deep venous bed. The two hormones together (INS + SEC) increased maximum lactate (p less than 0.025) and alanine output (p less than 0.005) beyond that observed with INS alone. A marked calcium output occurred (p less than 0.001) with the combined infusion which was not observed with either hormone alone. Potassium metabolism with INS + SEC was similar to that observed with INS alone. These results suggest that these two hormones, acting in concert, stimulate glycolysis and net calcium efflux. This joint action of insulin and secretin may have a physiological role in the immediate postprandial period.

Insulin secretion and glucose tolerance in adults with protein-calorie malnutrition.

Glucose tolerance, insulin secretion, and responses to arginine infusion were studied in 17 adults with severe protein-calorie malnutrition (PCM) in Calcutta, India. Patients were selected for the severity of their malnutrition and for absence of other diseases. After 2-4 mo of refeeding there was complete clinical recovery, and control studies were performed. Glucose tolerance, as assessed by intravenous glucose-tolerance test (IVGTT), was reduced in PCM. Insulin response, both to glucose and to arginine infusion, was clearly reduced. The K value of the IVGTT correlated well with the ratio of mean to basal serum insulin during the first 40 min of the test. Basal serum insulin was nearly unchanged in PCM as compared with after recovery, although one patient studied serially showed a temporary drop in basal insulin during the first week of refeeding. In PCM, plasma amino acid levels failed to fall in response to arginine-induced insulin secretion as they did in the control studies. It appears that insulin secretory response is severely reduced in PCM and that a degree of insulin resistance in relation to body weight is present. These changes result in diminished glucose tolerance and probably in a reduced rate of tissue utilization of amino acids. Such alterations may be of adaptive significance in chronic PCM.

Regional differences in fatty acid oxidation by the adult rabbit myocardium.

Differences in coronary perfusion and tissue oxygenation between the epicardium and endocardium have been shown. Thus, intrinsic capacity for substrate oxidation may also exhibit regional variation. Accordingly, homogenates of left ventricular papillary muscle ("endocardium") and left ventricular free wall trimmed of endocardium ("epicardium") were compared for their capacity to oxidize palmitic acid-1-14C (PA) and octanoic acid-1-14C (OcA). Homogenates from one to three rabbits were combined for each study; 18 studies were performed using PA, and 10 using OcA. The protein content of endo- and epicardial homogenates was the same (Biuret method). At ambient PA concentrations of 0.2 mM, oxidation of PA by "endocardium" was 64 +/- 6.3% that of the "epicardium" (p less than 0.001). At ambient concentrations of 1.0 mM, oxidation of OcA by "endocardium" was not different from that of "epicardium" (118 +/- 10.5%; p greater than 0.1). Thus, the oxidative capacity for long chain FFA by the endo- and epicardial homogenates are at variance. Differences in carnitine-mediated transmitochondrial transport of long chain fatty acids may be the explanation. Such regional metabolic differences could play a role in regional alterations in myocardial function under adverse hemodynamic and metabolic circumstances.

Nitrogen sparing induced by a mixture of essential amino acids given chiefly as their keto-analogues during prolonged starvation in obese subjects.

11 normal obese subjects were fasted for 33 days. In five, who served as controls, urine urea nitrogen excretion remained constant for 2 wk thereafter. The other six were given seven daily infusions containing 6-8 mmol each of the alpha-keto-analogues of valine, leucine, isoleucine, phenylalanine, and methionine (as sodium salts) plus 3-4 mmol each of the remaining essential amino acids (lysine, threonine, tryptophan, and histidine). Rapid amination of the infused ketoacids occurred, as indicated by significant increases in plasma concentrations of valine, leucine, isoleucine, alloisoleucine, phenylalanine, and methionine. Glutamine, glycine, serine, glutamate, and taurine fell significantly. Blood glucose, ketone bodies, plasma free fatty acids, and serum immunoreactive insulin concentrations were unaltered. Urine urea nitrogen fell from 1.46 to 0.89 g/day on the last day of infusions; 5 days later it was still lower (0.63 g/day) and in two subjects studied for 9 and 17 days postinfusion it remained below preinfusion control values. Urine ammonia, creatinine, and uric acid were unaltered. Nitrogen balance became less negative during and after infusions. The results indicate that this mixture of essential amino acids and their keto-analogues facilitates nitrogen sparing during prolonged starvation, in part by conversion of the ketoacids to amino acids and in part by altering mechanisms of nitrogen conservation. The latter effect persists after the ketoacids are metabolized.

Insulin sensitivity of forearm tissues in prediabetic man.

In genetic prediabetic subjects (the glucose tolerant offspring of two diabetic parents or the identical twin of a known diabetic) serum insulin concentrations after glucose administration are subnormal. Maintenance of glucose tolerance in this setting is apparently paradoxical, suggesting increased tissue insulin sensitivity. Accordingly, forearm tissue insulin sensitivity in nine genetic prediabetic males was compared with that of seven males without familial diabetes. Diabetes was excluded in all subjects by preliminary oral glucose tolerance testing. On the preliminary 3 h oral glucose tolerance test (OGTT) the sum of increments in blood glucose above fasting was greater in prediabetic than in control subjects. Conversely, the sum of increments in serum insulin was subnormal for the first 2 h. The insulin index (the sum of increments in insulin divided by the sum of increments in glucose) was significantly lower in prediabetics throughout the test. High physiologic levels of insulin were produced in the forearm by intrabrachial arterial insulin infusion (100 muU/kg per min for 26 min). Balances of glucose and amino acids across forearm muscle became more positive, as did balances of glucose and free fatty acids across adipose tissue plus skin. There were no differences in response between prediabetic and normal subjects.Hence, the insulin sensitivity of peripheral tissues is normal in genetic prediabetes. Increased tissue insulin sensitivity is not essential to explain coexisting euglycemia and insulinopenia in prediabetes because blood glucose values on the OGTT are, in fact, elevated although still within the range considered normal.

Effects of intrabrachial arterial infusion of pyruvate on forearm tissue metabolism. Interrelationships between pyruvate, lactate, and alanine.

Postabsorptive release of alanine from forearm skeletal muscle is large relative to other amino acids, suggesting new synthesis by transamination of pyruvate. This hypothesis was tested and the pathway quantified in six subjects, each given two 30 min intrabrachial arterial pyruvate infusions. The first (12 mumoles/min) supplied approximately that amount of pyruvate produced endogenously by glycolysis in resting muscle. The second (36 mumoles/min) approximated endogenous pyruvate production by glycolysis during moderate exercise. Changes in balance across forearm tissues of pyruvate, glucose, lactate, and amino acids were measured. The time-course of pyruvate equilibration across fore-arm muscles was detailed in three additional subjects. The two infusions increased arterial pyruvate from 64 to 674 and 1776 mumoles/liter respectively. Muscle consumed 72% of the exogenous pyruvate during both infusions. Outputs of lactate and alanine increased, accounting respectively for 30.3 and 6.7% of the pyruvate at the low infusion rate, and 17.1 and 3.8% at the high rate. The remaining pyruvate probably was oxidized. Muscle release of valine, isoleucine, and leucine decreased during the high dose infusion. Additionally, adipose tissue plus skin released more alanine and lactate during the high dose infusion. Other metabolies were unchanged.Thus, both muscle and adipose tissue plus skin synthesize alanine from pyruvate. Lactate production considerably exceeds that of alanine. In muscle, increased availability of intracellular pyruvate serving as a nitrogen acceptor may facilitate branched chain amino acid oxidation. Muscle consumption of infused pyruvate is rapid, and detailed studies of its equilibration suggest that passage across the muscle cell membrane is rate limiting.

Muscle and splanchnic glutmine and glutamate metabolism in postabsorptive andstarved man.

Arterio-venous differences across forearm muscle in man in both prolonged starvation and in the postabsorptive state, show an uptake of glutamate and a relatively greater production of glutamine. Splanchnic arteriovenous differences in the postabsorptive state show a net uptake of glutamine and lesser rate of glutamate production. These data suggest that muscle is a major site of glutamine synthesis in man, and that the splanchnic bed is a site of its removal. The relative roles of liver and other tissues in the splanchnic circuit were not directly assessed, only the net balance. These data in man are in conflict with most previous studies in other species attributing the major proportion of glutamine production to the liver and, pari passu, to the splanchnic bed.

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.