Influence of physical training on the fuel-hormone response to prolonged low intensity exercise

The effects of physical training on the fuel-hormone response to prolonged (3 hr), low intensity cycle ergometer exercise (40% maximal aerobic power) which in the untrained state fails to produce a rise in blood lactate, was examined in six healthy male subjects. The training program consisted of one hour cycle ergometer exercise performed 4 times weekly for 6 weeks and resulted in a 19% increase in maximal aerobic power. Prior to training, prolonged low intensity exercise resulted in a 20% decline in plasma glucose, a 2.5-fold rise in plasma free fatty acids (FFA), a 7-fold rise in plasma epinephrine, a 3-fold elevation in plasma norepinephrine, and a 2.5-fold rise in plasma glucagon. Following training, the exercise-induced decline in glucose was 60% less than before training, the elevations in plasma FFA and norepinephrine were respectively, 45% and 90% less than before training and no significant increment in plasma norepinephrine and glucagon was observed. Training also blunted the exercise-induced elevations in circulating ketones and growth hormone and resulted in a lower respiratory exchange ratio during exercise. The data indicate that training markedly diminishes the fuel-hormone perturbations associated with low intensity exercise and in the face of a lessened increment in plasma FFA results in a greater utilization of fat and less dependence on carbohydrate during the exercise.     

Insulin binding to monocytes and insulin sensitivity in anorexia nervosa

In six female patients with anorexia nervosa, we examined specific binding of ¹²⁵I-insuIin to monocytes and in vivo sensitivity to insulin before and after treatment. Insulin sensitivity was determined by the rate of glucose disappearance during an intravenous insulin tolerance test (K_ITT).In the untreated state, the patients with anorexia nervosa were 26 to 41 per cent below ideal weight and amenorrheic. Fasting plasma glucose and insulin levels were, respectively, 20 per cent and 55 per cent below those observed in healthy controls. Insulin binding to monocytes was 70 per cent greater than that in controls. Scatchard analysis of the insulin binding data revealed an increase in binding capacity with no change in binding affinity. During the insulin tolerance test, K_ITT (9.7 ± 0.7 per cent · min^?1) was 50 per cent greater in untreated patients than in healthy controls.Following treatment with behavior modification, there was a gain in body weight to within 2 to 11 per cent of ideal body weight, and menstrual function returned. Plasma glucose and insulin levels rose to values similar to those in healthy controls. Insulin binding declined by 40 per cent to values comparable to those in the controls. The decrease in insulin binding was due to a reduction in binding capacity. The plasma glucose response to the insulin tolerance test (K_ITT) fell 50 per cent below pretreatment values to levels comparable to those in healthy controls.Both before and after treatment, an inverse correlation was observed between plasma insulin concentration and insulin binding to monocytes whereas a direct correlation was demonstrable between insulin binding to monocytes and k_ITT.The data indicate that in anorexia nervosa insulin binding to monocytes and in vivo sensitivity to insulin are increased. The increase in insulin binding may be a consequence of a decrease in plasma insulin and may, in turn, be responsible for the increase in insulin sensitivity. The increases in insulin binding and insulin sensitivity return to normal following regain of body weight.     

Biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes

Oral glucose tolerance was examined in five maturity-onset diabetics during the infusion of somatostatin or saline. Somatostatin inhibited glucose-stimulated insulin release and reduced plasma glucagon by 50%--65%. The rise in plasma glucose after glucose ingestion was initially (at 30--120 min) reduced by somatostatin. However, beyond 3 hr, plasma glucose levels were 50--200 mg/100 ml higher, with somatostatin reaching concentrations at 6 hr that were twofold higher than those observed with saline ( p less than 0.005). The degree of late glucose intolerance was inversely related to postglucose plasma insulin concentrations (p less than 0.01). These findings demonstrate a biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes. The exaggerated later hyperglycemia is related to suppression of insulin secretion. The initial blunting of postprandial hyperglycemia may reflect decreased carbohydrate absorption and/or hypoglucagonemia-mediated enhancement of glucose disposal.     

The role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man

In order to express in equivalent terms seemingly divergent results obtained with isotopic tracer studies as compared to hepatic venous catheter studies on the role of the liver in the metabolism of oral glucose, our previously published studies using the hepatic venous catheter technique in normals and diabetics given intravenous and/or oral glucose were analyzed with respect to the splanchnic fractional extraction of glucose, total splanchnic glucose influx, and the proportion of total glucose metabolism accounted for by net splanchnic glucose uptake. In normal subjects during extreme hyperinsulinemia (plasma insulin, 500–1,200 μU/ml) induced by i.v. insulin while maintaining the blood glucose concentration at basal levels (insulin clamp), total glucose metabolism rose to 10.5 ± 0.9 mg/min · kg, while splanchnic fractional extraction of glucose was 4.2 ± 1.1%, and net splanchnic glucose uptake accounted for only 5 ± 2% of total glucose turnover. During hyperglycemic (blood glucose, 200 mg/dl) hyperinsulinemia induced by i.v. glucose, net splanchnic glucose uptake was twice that observed with euglycemic hyperinsulinemia, and the proportion of total glucose metabolism occurring in the splanchnic bed rose to 14 ± 4%. These increments were due entirely to a rise in splanchnic glucose influx since the fractional extraction (3.4 ± 0.5%) remained unchanged from that observed with euglycemic hyperinsulinemia. After oral glucose (100 g), splanchnic glucose influx was comparable to hyperglycemic hyperinsulinemia induced with i.v. glucose, but splanchnic fractional extraction rose to 13.1 ± 1.9% (p < 0.001 versus i.v. glucose), a value comparable to that observed with isotopic studies of oral glucose metabolism. Total glucose turnover was, however, 30% lower than after i.v. insulin (p < 0.01), so that net splanchnic glucose uptake accounted for 54 ± 5% of total glucose metabolism. In maturity-onset diabetics, after 100 g oral glucose splanchnic glucose influx was 69% greater than in controls (p < 0.001), but net splanchnic glucose uptake was 44% below controls (2.3 ± 0.5 versus 4.1 ± 0.5 mg/min · kg, p < 0.02). This reduction in glucose uptake could be accounted for by a splanchnic fractional extraction ratio (4.7 ± 1.4%) that was 64% lower than in controls given oral glucose (p < 0.001). It is concluded that: (1) in normal subjects, the ability of the splanchnic area to extract circulating glucose (as reflected by the splanchnic fractional extraction) is 2–3-fold greater after oral glucose than after intravenous glucose; (2) the rise in splanchnic fractional extraction to levels of 13% in association with only moderate increases in total glucose turnover fully accounts for the predominance of the splanchnic area in the metabolism of oral as compared to intravenous glucose; and (3) in maturity-onset diabetics, oral glucose fails to induce a rise in splanchnic fractional extraction of glucose comparable to that observed in normal subjects.     

Effects of ethanol ingestion on glucose tolerance and insulin secretion in normal and diabetic subjects

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were $\text{30–80 mg}\text{100 ml}$ lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.     

Effect of somatostatin on the plasma amino acid response to ingested protein in man.

To evaluate the effect of somatostatin on the plasma amino acid response to ingested protein and amino acids, normal subjects received a 6-hr intravenous infusion of somatostatin or saline initiated 2 hr before consuming a lean beef meal (3 g/kg) or oral leucine (5 g). The effect of somatostatin on intravenous leucine disposal was also examined. In the saline control study, the branched-chain amino acids exhibited the largest elevations in plasma concentration after protein ingestion. Somatostatin markedly reduced the protein-induced increments in plasma branched-chain amino acids by 50%–75% (p < 0.001) throughout the study period. This effect was not attributable to augmented systemic disposal of these amino acids since somatostatin exaggerated by 70%–75% the rise in plasma leucine produced by intravenous leucine (p < 0.05). Somato-statin also blunted by 40%–80% the elevations in most other amino acids after protein feeding. When leucine alone was ingested, somatostatin delayed the peak rise in plasma leucine by 1 hr, but did not alter the total area under the plasma leucine response curve. We conclude that somatostatin causes a sustained reduction in the systemic availability of amino acids contained in ingested protein, while availability of free leucine is only transiently delayed. These findings raise the possibility that somatostatin reduces systemic availability of protein-derived amino acids primarily by interfering with the digestive process.     

Hepatic and extrahepatic splanchnic glucose metabolism in the postabsorptive and glucose fed dog

In awake dogs we measured the glucose balance across the liver and extrahepatic splanchnic tissues in the postabsorptive state and during two hours of IV infusion of glucose or for three hours following ingestion of oral glucose and during four hours of sequential intraportal followed by oral glucose. The IV glucose infusion rate was adjusted to maintain a steady state glucose concentration of either euglycemic levels (insulin clamp, group 1, N = 4), 125 mg/100 mL above the postabsorptive glucose concentration (+125 mg glucose clamp, group 2, N = 3) or 200 mg/100 mL above basal glucose levels (+200 mg glucose clamp, group 3, N = 7). Oral glucose was given at a dose of either 1.5 g/kg (group 4, N = 7) or 2.5 g/kg (group 5, N = 12). In dogs that received IV glucose, basal gut glucose uptake (0.5 +/- 0.1 mg/min X kg) was stimulated by hyperglycemia (1.5 +/- 0.5 and 1.4 +/- 0.1 mg/min X kg for group 2 and 3, respectively, P less than 0.05). In these same animals basal hepatic glucose output (-2.7 +/- 0.3 mg/min X kg) was promptly suppressed and net hepatic glucose uptake occurred (2.8 +/- 0.2 and 2.4 +/- 0.5 mg/min X kg in group 2 and 3 respectively). Euglycemic hyperinsulinemia (group 1) suppressed postabsorptive hepatic glucose release but did not enhance glucose removal by either the liver or gut tissues. After oral glucose gut tissues released absorbed glucose into portal blood. Over three hours following the glucose meal 74% and 59% of the ingested glucose was absorbed in group 4 and 5, respectively. As with IV glucose, postabsorptive hepatic glucose production was suppressed and over the first two hours after feeding the liver took up glucose (3.4 +/- 1.0 and 3.1 +/- 0.7 mg/min X kg groups 4 and 5, respectively) at a rate similar to that seen with IV glucose. To further examine the effect of the route of glucose administration on liver glucose handling, hepatic glucose balance was measured serially over four hours in three dogs that received IV glucose into a mesenteric vein to produce portal hyperglycemia (+125 mg/dL portal glucose clamp N = 3). Oral glucose (2.5 mg/kg) was given at two hours, and the rate of the mesenteric glucose infusion adjusted to maintain portal glycemia constant. The hepatic glucose balance averaged 5.5 mg/min X kg over the 0 to 2 hour period and 4.2 +/- 1.0 mg/min X kg over the 2 to 4 hour time.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of physiologic hyperglucagonemia on urinary glucose,nitrogen, and electrolyte excretion in diabetes

To evaluate the effect of physiologic hyperglucagonemia on nitrogen and glucose metabolism and on urinary electrolyte excretion, pancreatic glucagon was administered as a continuous 3-day infusion to three adult-onset non-insulin-dependent diabetics and two insulin-treated juvenile diabetics while on a constant dietary intake. The glucagon infusion resulted in increases in plasma glucagon which were 4–6-fold greater than control values. Despite prolonged hyperglucagonemia, urinary glucose excretion was unchanged. Similarly, urinary urea nitrogen and total nitrogen excretion were not altered by glucagon administration. Urinary sodium tended to rise, albeit not significantly (P < 0.1), on the first infusion day, but later declined to control values despite increasing plasma glucagon concentrations. Urinary chloride, potassium, calcium, and phophorus excretion remained unchanged. We conclude that continuous physiologic increments in plasma glucagon do not enhance glycosuria or increase protein catabolism and ureagenesis in diabetes when insulin is available. The augmented protein catabolism and gluconeogenesis that accompany diabetic ketoacidosis can not be explained primarily on the basis of hyperglucagonemia.     

The plasma amino acid response to cafeteria feeding in the rat: Influence of hyperphagia,sucrose intake,and exercise

The plasma amino acid response to voluntary hyperphagia was evaluated in rats fed a “cafeteria” diet for 4 to 8 weeks and compared to chow-fed controls. The influence of the sucrose content of the cafeteria diet was examined by studying rats given a low-sucrose, highly palatable, liquid diet (Magnacal). In a second series of studies the cafeteria diet was fed to rats housed in wheel cages and who ran 2.0 ± 0.1 milles per day and compared with a sedentary cafeteria-fed group housed in standard cages. As expected, the cafeteria diet resulted in hyperphagia (45% to 55%) and in increased weight gain (35% to 50%). In response to cafeteria feeding there was an increase in plasma threonine, serine, proline, citrulline, α-amino butyric acid (ABA), and tyrosine. Significant decreases were observed in the branched chain amino acids (BCAA), valine and leucine. All of these changes were also observed when hyperphagia was induced with the low-sucrose diet, with the exception of the rise in ABA. In the exercised cafeteria-fed rats, excessive weight gain did not occur. Nevertheless, the amino acid response to the cafeteria diet was the same as in sedentary rats with excessive weight gain. The plasma amino acid pattern in those rats that developed glucose intolerance during cafeteria feeding and those that maintained normal glucose tolerance was similar. We conclude that hyperphagia induced by cafeteria feeding in the rat results in a specific plasma amino acid profile characterized by elevations in some amino acids (threonine, serine, proline, citrulline, ABA, and tyrosine) and reductions in the BCAA. These changes (other than the rise in ABA) are not dependent on an increased sucrose intake and occur in the face of increased exercise, in the absence of excessive weight gain and in the presence of normal or impaired glucose tolerance. The plasma amino acid changes may, thus, primarily be a consequence of hyperphagia.     

Metabolic, endocrine, and drug-induced interference with pituitary function tests: a review.

Data are summarized concerning some common disease-induced and drug-induced alterations of pituitary function tests. These factors must be kept in mind in order to avoid errors in the diagnosis and treatment of pituitary disease.     

A rise in ambient temperature augments insulin absorption in diabetic patients

The absorption rate of ¹²⁵I-Actrapid insulin (6 U) from a subcutaneous injection site was examined in six insulin-dependent diabetic patients at ambient temperatures of 20°C and 35°C. During a 4-hr observation period, the insulin disappearance rate at 35°C was 50%–60% greater than at 20°C (p<0.01). Despite the small dose of insulin used, plasma glucose levels tended to be 1 to 2 mmole/liter lower at 35°C than at 20°C. These findings indicate that a rise in ambient temperature augments insulin absorption, in insulin-treated diabetic patients.     

Effect of insulin and glucose on feeding behavior

Four experimental groups of human subjects, in whom plasma glucose and insulin were independently raised or lowered, were tested for perceptions of hunger, taste, bodily state, and food intake. The data showed that hyperinsulinemia, unrelated to change in plasma glucose concentration, resulted in increased hunger, heightened palatability of sucrose or sweetness, and greater food intake.     

Urinary 3-methylhistidine/creatinine ratio as a clinical tool: Correlation between 3-methylhistidine excretion and metabolic and clinical states in healthy and stressed premature infants

We have investigated the role of the urinary 3-methylhistidine (3MH) excretion, a measure of protein catabolism, in the evaluation of the metabolic state of premature infants. Two-hundred and twenty-two 24 hr urine collections and $\text{3}\text{MH}\text{Cr}$ ratio determinations (expressed as μmoles of 3MH per mg creatinine) were carried out in 36 infants (average gestational age 32.7 ± 0.7 wk, weight 1640 ± 120 grams) and the relationship between the $\text{3}\text{MH}\text{Cr}$ ratios and the metabolic and clinical state has been investigated. Five or more $\text{3}\text{MH}\text{Cr}$ measurements were carried out on each of 19 infants and serial determinations on four of those babies are presented. The urinary $\text{3}\text{MH}\text{Cr}$ ratio of healthy infants with adequate caloric intake and normal growth curve was .148 ± .039 (S.D.) μmol/mg, about 35% higher than the $\text{3}\text{MH}\text{Cr}$ ratio in healthy adults. As long as the premature infants were healthy the degree of prematurity had no effect on the $\text{3}\text{MH}\text{Cr}$ ratio. The relationship between $\text{3}\text{MH}\text{Cr}$ ratio and nitrogen balance was highly significant (p < .001). $\text{3}\text{MH}\text{Cr}$ ratio also correlates very well with the metabolic status of the infants: in the group with normal $\text{3}\text{MH}\text{Cr}$ ratios ≤.175 (.148 + 1 S.D., n = 90) there were four clinically stressed infants (4.4% false negative rate) while in the group with elevated $\text{3}\text{MH}\text{Cr}$ ratios >.225 (.148 + 2 S.D.; n = 79) there were only three clinically well infants (3.8% false positive rate). In comparing the clinical status and $\text{3}\text{MH}\text{Cr}$ ratios, we found that in the group of infants who could not be clearly defined as clinically well or stressed (n = 108) the $\text{3}\text{MH}\text{Cr}$ ratio was more useful than clinical judgment in the prediction of metabolic status. It can be concluded that $\text{3}\text{MH}\text{Cr}$ ratio is a potentially useful clinical tool which describes with high accuracy the clinical and metabolic status of premature infants. This conclusion is further supported by the data of serial $\text{3}\text{MH}\text{Cr}$ determinations.     

Urinary 3-methylhistidine excretion in juvenile-onset diabetics: Evidence of increased protein catabolism in the absence of ketoacidosis

Urinary 3-methylhistidine excretion (an indicator of protein catabolism) was measured in ten diabetic patients and in age and weight matched control subjects. The diabetic group, while receiving their usual insulin dose, excreted 42% more 3-methylhistidine than the control group (2.7 versus 1.9 μmole/kg body weight/24 hr). When the insulin dose of the diabetic subjects was reduced by 15% or 25%, the concentrations of blood and urinary glucose were significantly increased but the rate of urinary 3-methylhistidine excretion was not increased further. These findings demonstrate augmented protein catabolism in diabetics even in the absence of ketoacidosis. It appears that blood and urine glucose levels are more sensitive to changes in insulin availability than protein catabolism.     

Four-valve polymicrobial endocarditis caused by pseudomonas aeruginosa and serratia marcescens

This report describes what is believed to be the first case of mixed Pseudomonas and Serratia endocarditis, of probable nosocomial etiology, with involvement of all four heart valves in a 56 year old nonaddicted patient. Although both organisms were recovered in culture, infection and tissue invasion were documented by light and electron microscopy. The clinical course in this patient differed from more typical patterns of Pseudomonas or Serratia endocarditis that have been observed as complications of narcotic addiction or compromised cardiac status. Our patient had the rare occurrence of endocarditis with two organisms and four-valve involvement. Clinically, however, this presented as a right-sided endocarditis and behaved as though only a single organism were present.     

Effect of parathyroid hormone on renal tubular reabsorption of amino acids

We have examined the effect of endogenous and exogenous parathyroid hormone (PTH) on renal tubular reabsorption of free amino acids. In four normal volunteers, acute infusion of purified bovine PRH (2.5-5 U/kg/15 min) increased urinary phosphate excretion by 40%–220% and urinary excretion of several amino acids by 25%–175%. Sustained infusion of purified PTH (1–2 U/kg/hr) in two of these volunteers produced both increased renal clearances of several amino acids and a decreased renal tubular maximum for L-proline (T_mPro). In one of two patients with primary hyperparathyroidism, the T_mPro was distinctly reduced before, and was restored to normal after extirpation of a parathyroid adenoma. These changes in T_mPro correlated significantly (r = 0.80; p < 0.01) in both groups of subjects with reduction in fractional tubular reabsorption of phosphate (TRP). The mechanism of this PTH-modulated reduction in renal tubular reabsorption of free amino acids remains to be determined.     

Uptake and metabolism of free cyanocobalamin by cultured human fibroblasts from controls and a patient with transcobalamin II deficiency

We have investigated the uptake and metabolism of free cyanocobalamin (CN-Cbl; vitamin B₁₂) by intact cultured human skin fibroblasts. Monolayers of control fibroblasts take up free CN-[⁵⁷Co]Cbl via a saturable, calcium-independent process that is inhibited by sulfhydryl reagents, inhibitors of protein synthesis, and inhibitors of electron transport, but not by inhibitors of glycolysis. CN-Cbl taken up in this manner is converted to active cobalamin (Cbl) coenzymes (adenosylcobalamin and methylcobalamin) and becomes associated with intracellular Cbl-dependent apoenzymes (methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase). Since fibroblasts from controls were also found to synthesize transcobalamin II (TC II), a plasma protein shown previously to facilitate the cellular uptake of Cbl, it seemed possible that the observed uptake of free CN-Cbl was TC II-mediated. This thesis was rejected by demonstrating that cells from a patient with complete TC II deficiency took up free CN-Cbl as well as control cells did. Finally, we propose a mechanism by which an uptake process for free Cbl might serve a function in intracellular metabolism of Cbl.     

Prolonged benefit of nitroglycerin ointment on exercise tolerance in patients with angina pectoris.

The effect on exercise tolerance of 2 per cent nitroglycerin ointment and placebo was studied on the bicycle ergometer in 10 patients with angina pectoris, a positive exercise test, and documented coronary artery disease. After a control stress test sufficient to produce angina pectoris and > 1 mm. horizontal or downsloping ST segment depression, nitroglycerin ointment or placebo was administered in a random, double-blinded manner and stress tests were repeated at 1 hour and 3 hours. End points for the exercise stress test were angina and 1 mm. ST segment depression. Forty-eight hours later, stress tests were again performed at 1 hour and 3 hours after administration of the alternate preparation. Work load (watts) plus duration of exercise (minutes) were calculated for each stage of the bicycle ergometer protocol and exercise tolerance was expressed as the sum of this product for all stages completed.Nitroglycerin ointment produced a significant increase in exercise tolerance from a control value of 877 ± 129 watt-minutes to 1165 ± 173 watt-minutes at 1 hour and 1040 ± 137 watt-minutes at 3 hours. Duration of exercise also increased significantly after nitroglycerin ointment from 13.7 ± 1.4 minutes in the control stress test to 16.8 ± 1.4 minutes at 1 hour and 16.3 ± 1.2 minutes at 3 hours. Exercise induced ST segment depression decreased significantly at 1 hour and 3 hours after nitroglycerin ointment but not after the placebo.The placebo produced a small, but statistically significant, increase in exercise tolerance and duration of exercise at 1 hour after its application. However, these increases were significantly smaller than the one observed after nitroglycerin ointment. No changes were observed 3 hours after application of the placebo. Double product at peak exercise was unchanged after nitroglycerin or placebo ointments at 1 hour and 3 hours.These data indicate that nitroglycerin ointment is capable of producing an improvement in exercise tolerance and a reduction in the magnitude of exercise-induced ST segment depression up to 3 hours in patients with coronary artery disease and angina pectoris.     

Double aortic arch system producing obstruction to left ventricular outflow

The occurrence of a double aortic arch system with intracardiac defects is unusual. Clinical recognition may be difficult in the absence of upper airway obstruction. This report describes the diagnosis and surgical management of an infant with Interruption of the ventral left arch and hypoplasia of the dorsal right arch who presented with evidence of pulmonary and systemic venous congestion caused by obstruction to left ventricular outflow and a large left to right ventricular shunt.