Showing papers in "Metabolism-clinical and Experimental in 1974"

Mechanism of action of glucocorticoids.

Abstract: The mechanism of action of glucocorticoids is reviewed from the standpoint of seeing how far current concepts of the molecular action of steroids go towards explaining the varied physiologic and metabolic effects induced. The role of plasma binding to transport proteins in modifying steroid action is considered. The interactions between glucocorticoids and other hormones, particularly those mediated by cAMP are considered along with a discussion of the mechanism of “permissive” effects. Various proposals concerning the way in which glucocorticoids induce their effects including direct interactions with enzymes, nucleic acids, lysosomes, and receptor proteins are considered in detail, and an attempt is made to consider how far each of these mechanisms can go in explaining steroid action. Those biologic effects that cannot be accounted for by currently available mechansims are mentioned. Effects of glucocorticoids on growth, differentiation, and the inflammatory response are discussed from a mechanistic point of view. Catabolic or inhibitory effects of glucocorticoids as well as enzyme induction are examined using several exemplary systems. Finally an attempt is made to summarize the current state of knowledge concerning glucocorticoid and genome interaction.

Relevance of free tryptophan in serum to tissue tryptophan concentrations.

Abstract: The consumption of a carbohydrate diet by fasted rats is followed by major decreases in serum nonesterified fatty acids (NEFA) and nonalbumin-bound tryptophan (unbound tryptophan), but by increases in serum total tryptophan and brain tryptophan; the tryptophan concentrations of liver and small intestine are unchanged, while that of skeletal muscle falls slightly. The addition of 15% or 30% fat to a protein-carbohydrate diet results in dose-related increases in serum NEFA and serum unbound tryptophan, but no significant changes in serum total tryptophan or brain tryptophan. The observation that diet-induced changes in serum unbound tryptophan does not correlate with brain tryptophan concentrations is independent of the method used to separate free from albumin-bound serum tryptophan. These studies confirm that, in the rat, a major physiologic regulator of the extent to which serum tryptophan binds to albumin is the concentration of NEFA in serum. These studies also provide additional evidence that the concentration of tryptophan in the brain is not necessarily determined by the size of the unbound pool of tryptophan in blood as measured in serum.

Lactate inhibition of lipolysis in exercising man

Abstract: The role of rising lactate levels on substrate mobilization in exercising man is unclear. To define the role of increasing lactate levels, D,L-sodium lactate, 6 meq/kg, was infused into six exercising normal males. A mild work load was chosen that increased arterial free fatty acids (FFA) and glycerol, but did not increase lactate significantly. Infused sodium bicarbonate and sodium chloride of equal volume and osmolality served as controls. The marked rise in arterial lactate and pyruvate to 8.8 ± 0.31 μM/ml and 0.328 ± 0.023 μM/ml (mean ± SEM), respectively, resulted in a significant inhibition of the increase of plasma FFA and glycerol, which occurred during the control studies. The decreased release of these constituents could not be attributed to an “insulin effect”, since the concentration of arterial insulin decreased during exercise and was similar during each infusion period. It appears that an increase in plasma lactate or pyruvate, or both, results in a direct inhibition of exercise-mediated lipolysis in man.

Differential tissue sensitivity to elevated endogenous insulin levels during experimental peritonitis in rats

Abstract: Disturbances of glucose metabolism consequent to experimental peritonitis in rats were studied by measurement of insulin-related metabolism of isolated tissues in correlation with blood insulin and substrate levels. Blood insulin concentrations were threefold higher in infected fasting rats than in normal fasting controls, despite approximately equal blood glucose concentrations, suggesting resistance to the hypoglycemic action of insulin. The increased circulating insulin was associated with a threefold elevation of the insulin-sensitive adipose tissue pyruvate dehydrogenase enzyme complex, and a threefold increase in the rate of conversion of glucose to CO2 by fragments of epididymal fat pads. Fasting infected animals also had reduced circulating nonesterified fatty acids and relatively less depletion of epididymal adipose tissue, when compared to fasted controls presumably due to the potent action of insulin in opposing lipid mobilization. In contrast, diaphragm pyruvate dehydrogenase was not elevated, nor was diaphragm glucose conversion to CO2 stimulated in response to the elevated circulating insulin. It is proposed that reduced fat mobilization without concomitantly accelerated glucose oxidation by muscle may result in insufficient metabolic fuel for muscle and this may, in turn, promote amino acid combustion by muscle to meet cellular energy requirements. This suggested mechanism may provide a hypothetical biochemical explanation for the excessive protein catabolism associated with severe infection.

Regulation of gonadal function in uremia.

Abstract: Gonadal function and its neuroendocrine control were studied in seven uremic men on chronic hemodialysis. Testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in plasma or serum by established radioimmunoassay techniques. The metabolic clearance rate (MCR) of testosterone was also determined by constant infusion of 3H testosterone, and blood production rates were then estimated from the AM plasma level and the metabolic clearance rates. Predialysis, plasma testosterone in these uremic men were subnormal, measuring only 289 ng 100 ml ± 60 SE (normal male values are 660 ± 70). The blood production rate of testosterone was also subnormal, averaging 2.7 mg/day in the two individuals studied, since the metabolic clearance rates were normal. However, after dialysis testosterone levels rose to 408 ± 49 ng 100 ml (p

Effects of age, sex, and clinical conditions on adipose tissue cellularity in man.

Abstract: Methods for measurements of fat cell size in man are now available. Total fat cell number is more difficult to measure, and the numbers reported should probably so far be regarded as estimates of fat-containing fat cells. The first years of life seem to be critical for adipose tissue development in man. Nonobese adult women probably have more fat cells than men. Fat cell size increases with age. Obese children and adults show increases in both fat cell size and number. Division of obese subjects into different subgroups according to adipose tissue cellularity must take into consideration the age and sex variations in the nonobese population. Attempts to such subdivision seem to give one group with an increased number of fat cells, early debut of obesity, and increased body cell mass. These patients are difficult to treat successfully by conventional methods. Adult onset obesity seems to be characterized by enlarged fat cells. All data presently available are transsectional and do not allow any definite conclusions about possible fat cell division. Thus, there might well be adult obese subjects who, like certain genetically obese rodents, have fat cells which multiply during an abnormally long period of life. Fat cell size has been found to correlate with plasma insulin and triglyceride concentrations. Patients with endogenous hypertriglyceridemia and possibly adult onset diabetes mellitus before debut of the diabetes have enlarged fat cells, while patients with juvenile, insulin-requiring diabetes mellitus have small fat cells. Thus, the subgrouping of obesity according to the cellularity of adipose tissue has given associations with clinical observations such as age at debut of obesity, disturbances of carbohydrate and lipid metabolism, and with prognosis for treatment. These relationships seem to justify the adipose cellularity measurements as they are now performed, although only a fairly rough estimate of the total cell number is obtained.

A prolidase deficiency in man with iminopeptiduria.

Abstract: A deficiency in the enzyme, prolidase (EC 3.4.3.7), is described in a patient with iminopeptiduria and clinical findings that suggest a defect in collagen metabolism. The massive iminopeptiduria is unique to this disorder, with daily proline excretion rates of 1.76 g. Fifteen peptides were characterized and quantitated from a deproteinized, amino-acid-free, 24-hr urine collection using column chromatographic procedures. Amino acid analysis revealed the peptides to be di- and tri-peptides containing proline plus another amino acid, “X.” Dansylation revealed “X” to be amino-terminal in each case. Prolidase, an enzyme known to cleave X-proline bonds, was measured by two separate methods. Enzyme activity in the patient's red and white cells was absent to markedly decreased as compared to age-matched controls. Furthermore, the activity of the enzyme in the mother's and maternal grandfather's white cells was less than that found in adult controls, suggesting a heterozygous condition. The maternal grandmother's enzyme activity was normal. The enzyme data is suggestive of an autosomal recessive disorder. This patient represents the first direct demonstration of a prolidase deficiency in man.

Alpha- and beta-cell interrelationships in health and disease

Abstract: The variations in secretory responses of the pancreatic alpha and beta cells in response to variations in nutrient supply and demand in health and disease are demonstrated. The biologic capability of insulin and glucagon to control on a moment-to-moment basis the disposition of exogenous and endogenous fuels is considered. An appropriate insulin-glucagon response ensures the most efficient storage of ingested nutrients, while maintaining fuel requirements from endogenous sources when food is not available. The glucose supply, both present and past, seems to influence the insulin-glucagon response to all other nutrients, to hormones, and to neural influences more than any other factor. The intracellular entry and metabolism of glucose appears to be required to suppress alpha cell secretion below the basal level and to prevent its hyperresponsiveness to various stimuli. An inappropriately low concentration of insulin and/or high level of glucagon relative to fuel availability is observed in genetic diabetes, and in a variety of stressful illnesses such as severe infection, trauma, burns, fetal distress, and other conditions, all of which are characterized by a negative nitrogen balance. The use of amino acids to produce glucose and urea at the expense of protein synthesis is presumably promoted by a low insulin: glucagon ratio and may be a factor in the catabolic manifestations of these diseases.

Biliary lipid outputs in young women with cholesterol gallstones

Abstract: Hepatic secretions of biliary lipids were determined in eight young women with cholesterol gallstones and 14 white women without gallstones. All of the gallstone patients were non-Indian; seven were white and one was black. Hourly outputs of biliary cholesterol were significantly greater in gallstone patients than in white controls. This increased cholesterol output was a major factor in the production of lithogenic bile. The greater cholesterol output in gallstone patients was apparently related to obesity. Despite an increased hepatic secretion of cholesterol, secretion rates of bile acids were relatively low in gallstone patients. However, there was considerable overlap between secretion rates of bile acids in subjects with and without stones, and it was not demonstrated that an absolute deficiency of bile acids existed in gallstone patients. Nevertheless, the contribution of an increased output of biliary cholesterol to the formation of lithogenic bile was clearly evident in our patients.

Methionine metabolism in mammals: the biochemical basis for homocystinuria.

Abstract: Three genetic disorders result in “homo-cystinuria”. Of these, cystathionine synthase deficiency is the most common. Impairment of N 5 -methyltetrahydrofolate-homocysteine methyltransferase, due to either deficient coenzyme synthesis (derangement of B 12 metabolism) or to reduced substrate availability (methylenetetrahydrofolate reductase deficiency), is the basis for the other two forms. Analyses of the pathobiochemistry caused by these defects is essential for the development of rational and appropriate therapy. Such studies have the additional benefit of illuminating the pattern of methionine metabolism in the normal human.

Hypocalcemia in magnesium-depleted dogs: evidence for reduced responsiveness to parathyroid hormone and relative failure of parathyroid gland function.

Abstract: The effect of magnesium depletion on serum calcium and magnesium and on the response to the infusion of parathyroid extract (PTE) was evaluated in nine adult mongrel dogs during a control period, magnesium depletion, and following magnesium repletion. Magnesium depletion was associated with a fall in serum magnesium and calcium, and both returned to normal with magnesium repletion. There was a significant direct correlation between the serum concentration of calcium and magnesium in the magnesium-deficient state. During magnesium depletion, there were significant calcemic and phosphaturic responses to PTE, but these effects were reduced; the impaired responsiveness of the skeleton and the kidney to PTE returned to normal after magnesium repletion. Serum levels of immunoreactive parathyroid hormone, measured in two animals during the control and magnesium depletion state, remained stable during magnesium depletion, despite the hypocalcemia present. These results indicate that both impaired responsiveness of the skeleton to parathyroid hormone and reduced secretion of the hormone in response to hypocalcemia exist in dogs with magnesium depletion. Each of these factors probably contributes to a reduced level of serum calcium in magnesium depletion, and they may compound each other and hence aggravate the degree of hypocalcemia.

Hormone dependence in breast cancer

Abstract: Both prolactin and estrogen are involved in regulating the growth and functions of the mammary gland, and many mammary tumors retain their dependence on these hormones. Specific binding of prolactin to mammary gland can be shown in vivo. Binding of estrogen in vivo and in vitro depends on the presence of a cytoplasmic receptor protein that acts in the nucleus after binding estrogen molecules. This estrogen receptor is present in both rat and human hormone-dependent mammary tumors, but is usually missing in autonomous mammary tumors. The presence or absence of estrogen receptor may thus be an indicator of the retention or partial loss of the complete endocrine regulatory unit, which mediates the interacting effects of many hormones including prolactin and estrogen on the normal mammary gland. In agreement with preliminary case series, presence of the estrogen receptor in breast tumors would therefore be expected to correlate with hormone dependence and a favorable response to hormone manipulation.

A mechanism for hyporeninemic hypoaldosteronism in chronic renal disease.

Abstract: Selective aldosterone deficiency in chronic renal disease has been attributed to damage to the renin-producing mechanism. Four patients with selective aldosterone deficiency and chronic renal diseases were studied. These patients had hypertension, increased extracellular fluid volume, and increased total exchangeable sodium, unlikely concomitants of a clinical syndrome in which primary reduction in angiotensin generation led to deficient aldosterone secretion. In two patients who were treated with furosemide to produce sustained diminution in extracellular fluid volume, the gradual increase in plasma renin activity and plasma aldosterone indicated that physiologic suppression, not disease-induced damage, had been preventing elaboration of renin by juxtaglomerular apparatus. Salt and water retention associated with renal disease is proposed as the initial physiologic aberration.

Effect of interaction between insulin and glucagon on glucose turnover and FFA concentration in normal and depancreatized dogs

Abstract: We showed previously that arginine increased glucose production (Ra) and utilization (Rd) synchronously in normal dogs and suggested that this was due to concurrent insulin and glucagon release. In order to investigate the metabolic effects of coincidently elevated insulin and glucagon levels on Ra and Rd, glucagon was infused (1.55 μg/kg/hr) into normal dogs and into depancreatized dogs coincident with graded amounts of insulin (250–3000 μU/kg/min) until the metabolic response of the normal dog was achieved in depancreatized dogs. Main observations: Concurrent insulin and glucagon elevations increased glucose turnover (100%) in normal and depancreatized dogs while maintaining normoglycemia. Glucagon had no appreciable effect on peripheral glucose clearance in depancreatized dogs maintained on basal insulin. The effect of glucagon on Ra was not inhibited by concurrent insulin infusion at rates up to 3000 μU/kg/min. The effect of glucagon on Ra waned with time, indicating that a given insulin/glucagon ratio did not have a sustained effect. Near normal metabolic effects with respect to glucose turnover and FFA concentration were achieved in depancreatized dogs when the normal IRI response to glucagon was reproduced, indicating that the spike pattern of insulin release reflects not only the inherent secretory characteristic of β cells, but also serves an important glucoregulatory function. Glucagon induced an increase in 14C-glucose recycling, suggesting that it enhanced gluconeogenesis.

Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation.

Abstract: The possibility that altered central nervous system (CNS) metabolism is reflected by changes in the constituents of the cerebrospinal fluid (CSF) was investigated. From eight obese subjects undergoing total starvation for weight reduction, overnight and 21-day fasting specimens of venous blood and lumbar CSF were obtained nearly simultaneously to determine the concentrations of glucose, beta-hydroxybutyrate (β-OHB), acetoacetate (AcAc), and immunoreactive insulin (IRI). After 21 days of starvation, the glucose concentration fell in both blood and CSF. The decrease in blood glucose was greater than the decline in CSF glucose, resulting in a diminished blood-CSF difference. Concentrations of β-OHB and AcAc in blood and CSF were elevated after prolonged fasting, but blood levels exceeded those in CSF, producing an increased blood-CSF ketone body difference. After an overnight and 21-day fast, the IRI levels in CSF were about one-half of the serum levels. These data suggest that metabolic alterations in CNS metabolism during prolonged starvation are reflected in substrate concentrations observed in CSF, and demonstrate that insulin is presented in the CSF of man.

Effect of age and role of kidneys and liver on thyrotropin turnover in man

Abstract: In order to determine the role played by the kidneys and liver in TSH catabolism, plasma TSH concentrations, total and free T 4 , plasma disappearance of 131 I-hTSH, its distribution volume, pituitary secretion and plasma clearance rate, have been measured in nine healthy subjects (five young and four elderly subjects), in four patients suffering from chronic renal disease, and in six others with hepatic diseases. Normal young subjects displayed a T 1 2 of 56 min ± 3.0, a distribution volume of 2.4 I, a clearance rate of 31.1 ml/min and a secretion rate of 179 mU 24 hr , with a mean plasma TSH level of 3.6 ± 1.4 μU/ml. The T 1 2 values in young and old subjects were not significantly different, but in the elderly subjects, plasma TSH concentrations and secretion rates were increased (resp. 6.5 μU/ml and 277 mU 24 hr ). Besides, the TSH response to TRH decreased with advancing age. In hepatic insufficiency, the two patients suffering from viral hepatitis showed values quite similar to those found in healthy young subjects. Patients with cirrhosis, however, displayed increased plasma TSH levels, a TSH T 1 2 of 64 min ± 5, a marked increase in the volume of distribution (6.11), in the clearance (97 ml/min) and in the secretion rates ( 595 mU 24 hr ), a normal total T 4 but an increased free T 4 concentration. In patients with chronic renal diseases, the T 1 2 was significantly extended to 163 min, as was the distribution volume (4.31), while clearance (17 ml/min) and secretion rates ( 102 mU 24 hr ) were decreased. The TSH response to TRH was lower than in the control group. These findings show the different roles played by the kidneys and the liver in TSH catabolism and distribution in man. In some cases, they can be responsible for increased plasma TSH levels in the presence of an euthyroid clinical state.

Familial homozygous hypobetalipoproteinemia

Abstract: An apparently new form of abetalipoproteinemia, homozygous hypobetalipoproteinemia, was studied in progeny of a mating of two parents each heterozygous for familial hypobetalipoproteinemia, which was characterized by three-generation vertical transmission on both maternal and paternal sides of the family. The two children, with an apparent homozygous form of hypobetalipoproteinemia, had, in addition to abetalipoproteinemia, acanthocytosis, intestinal etpithelial and hepatic steatosis and steatorrhea. No low desity lipoprotein (LDL) was detected by immunodiffusion with antisera to LDL or apoLDL. The defects in apolipoproteins in these two children were the same as those reported in children with abetalipoproteinemia inherited as an autosomal recessive trait. The genetic defect of hypobetalipoproteinemia, when homozygous, can lead to all of the known clinical and biochemical features of abetalipoproteinemia.

Nitrogen and amino acid metabolism in adults with protein-calorie malnutrition.

Abstract: Nitrogen balance, plasma amino acidlevels, and amino acid balance across forearm tissues were studied in 17 adult patients with severe protein-calorie malnutrition in a Calcutta hospital. Patients were selected for the severity of their malnutrition and for absence of other diseases. During 2–4 mo of refeeding there was complete clinical recovery, including resolution of all signs of protein depletion. Plasma essential amino acids were very low in malnutrition and rose to normal during refeeding. Plasma glycine was high initially and after refeeding. Alanine and several other nonessential amino acids were normal in malnutrition and rose to high levels during refeeding. These results in adult malnutrition are similar to many of those reported in kwashiorkor, but they differ from results of studies of experimental starvation. The long duration of protein deprivation and the persistence of significant carbohydrate intake in malnutrition but not experimental starvation are probably factors that have important bearing on the differences between amino acid levels in these two conditions. Nitrogen balance was −2.4 g/day on a 2 g/day nitrogen intake initially and +6.6 g/day on a 24.7 g/day intake after refeeding. Both in malnutrition and after refeeding, postabsorptive plasma arteriovenous differences for several amino acids were small compared with values in normal Americans. These small differences reflected reduced net release of amino acids from forearm tissues in malnutrition and probably also after refeeding. Persistently subnormal amino acid release from peripheral tissues probably restricted the supply of amino acids to the liver for gluconeogenesis and thus played a role in overall nitrogen conservation. However, the presence of normal or greater postabsorptive plasma levels of alanine and other amino acids despite decreased release from peripheral tissues suggests that hepatic fractional extraction was diminished and that this was also important in the conservational adaptation to protein depletion.

Role of the thyroid in the development of the obese-hyperglycemic syndrome in mice (ob ob).

Abstract: Some aspects of thyroid activity in obese mice were investigated. Protein-bound iodine (PBI), hormonal iodine (HI), total thyroxin (TT4) in plasma, 131I uptake and release from the thyroid and apical cell width, and nuclear volume of the thyroid epithelial cells were determined in various age groups in obese and nonobese mice. On the basis of the results of the comparison between the obese and nonobese mice, it was concluded that the genetically obese mouse is hypothyroid. This conclusion is supported by the finding that body temperature that is low in obese mice, can be raised by thyroxin injections to normal values. An increased sensitivity for exogenous thyroxin can be shown also in the induction of liver mitochondrial α-glycerophosphate dehydrogenase. The possibility that hypothyroidism is one of the causes of the obese-hyperglycemic syndrome is discussed.

Benign symmetric lipomatosis: functional sympathetic denervation of adipose tissue and possible hypertrophy of brown fat.

Abstract: Levels of lipolytic hormones (growth hormone, cortisol, and glucagon), insulin, and free fatty acids were measured in a patient with benign symmetric lipomatosis during a 5-hr glucose tolerance test, an insulin tolerance test, a 24-hr fast, and an epinephrine infusion. Although there was no abnormality in insulin dynamics or impairment in lipolytic hormone secretion, there was a failure of free fatty acid concentrations to rise to expected levels during fasting and after glucose. Insulin hypoglycemia and epinephrine infusion resulted in normal and excessive free fatty acid responses, respectively. This pattern of free fatty acid release is consistent with functional sympathetic denervation of adipose tissue. The lipomatous fat in benign symmetric lipomatosis is similar in distribution to the brown fat of human newborns and rodents that may hypertrophy after denervation. It is suggested that the lipomas in this disorder may represent such brown adipose tissue.

Effect of subacute administration of human growth hormone on various serum lipid and hormone levels of hypercholesterolemic and normocholesterolemic subjects

Abstract: Six hypercholesterolemic and five normocholesterolemic subjects were injected twice daily with human growth hormone for 7 days. During HGH administration, the average serum cholesterol of both types of subjects fell significantly, and their serum triglyceride levels increased. Peak insulin responses to glucose also increased. However, no change occurred in the serum phospholipid, FFA, cortisol, or thyroxine concentrations during HGH treatment.

Dicarboxylic aminoaciduria: An inborn error of glutamate and aspartate transport with metabolic implications, in combination with a hyperprolinemia

Abstract: A defect in renal transport of the two acidic amino acids, glutamic and aspartic acids, is described in a 2-yr-old child. The high clearance values, several times in excess of the creatinine clearance, indicated renal secretion. A study of the intestinal absorption of L-glutamic acid suggested defective intestinal transport in the patient. The patient also had moderate hyperprolinemia. One clinical feature of the child appears to be related to the dicarboxylic aminoaciduria, namely, a marked tendency towards hypoglycemia.

Clinical and Metabolic Studies of Chemically Defined Diets in the Management of Obesity

Abstract: Five severely obese subjects were treatedfor up to 1 yr, under metabolic study, with chemically defined diets of 60–360 kcal containing appropriate L-amino acids (or protein), carbohydrates, vitamins, and minerals. Acceptance of the diets was excellent, and the patients rarely complained of hunger. The optimum daily formulation contained 15 g amino acids and 30–45 g carbohydrate which achieved nitrogen balance, only moderate ketosis, normal serum electrolytes and uric acid, and a mean weight loss of 4.1 Ib (1.8 kg)/week. Clinical abnormalities observed were alopecia, symptomless normochromic anemia, postural hypotension, and hypercholesterolemia. All these findings reverted to normal subsequent to resuming a normal diet. Low-calorie, chemically defined diets of approximately 60–360 kcal offer an acceptable and safer form of weight reduction than complete starvation in the severe and refractory obese patient.

Studies on cholesterol metabolism in the diabetic rat.

Abstract: Plasma and hepatic cholesterol levels were determined in rats with severe alloxan diabetes. Significant hypercholesterolemia and elevated hepatic cholesterol content were found, suggesting an expansion of the cholesterol pool in this experimental model. To elucidate the mechanisms leading to cholesterol accumulation, the biliary excretion of cholesterol and bile salts, the pool size and turnover of the trihydroxycholanic acid fraction, and the rate of cholesterol absorption were studied in alloxan diabetic rats. The results of this study indicate that in these animals (1) the biliary excretion of cholesterol and bile salts was significantly increased, and this penomenon was corrected by the administration of insulin; (2) the pool of the trihydroxycholanic acid fraction was expanded, and its rate of daily synthesis was higher than in control animals; and (3) cholesterol absorptive rates were significantly increased. These observations demonstrate that cholesterol conversion into bile salts is enhanced in the alloxan diabetic rat, and suggest that the expansion of its cholesterol pool can be partly due to an increased rate of cholesterol absorption.

Effect of long-term thiazide therapy on intestinal calcium absorption in patients with recurrent renal calculi.

Abstract: Recurrent calcium-containing renal calculi are a common and poorly understood problem. Thiazide diuretics decrease urinary calcium excretion but their effect on other parameters of calcium metabolism is not established. The purpose of this study was to determine the effect of chronic administration of thiazide diuretics on intestinal calcium absorption, skeletal calcium turnover, and urinary calcium excretion, and to use this information to attempt to clarify the pathogenesis of idiopathic hypercalciuria. Forty-one patients with recurrent calcium-containing renal calculi were studied; 73% had hypercalciuria, 44% had increased intestinal absorption, and 7% had increased bone turnover. Thiazide diuretics given to 22 patients for 3–16 mo resulted in a consistent reduction in urinary calcium excretion, while calcium absorption was unchanged (

Modulation of prolactin release by altered levels of thyroid hormones

Abstract: In an attempt to delineate the effect of thyroid hormones on prolactin release, serum concentrations of prolactin in response to synthetic thyrotropin-releasing hormone (TRH) administration in subjects with normal and altered levels of thyroid hormones were determined by a heterologous radioimmunoassay for human prolactin. In 16 male and 19 female control subjects, an intravenous administration of TRH elicited a definite elevation in prolactin levels having a peak at 15 min after injection. This response of prolactin was markedly attenuated in all of the ten untreated hyperthyroid patients but was restored in eight subjects after the treatment. In contrast, TRH-mediated prolactin release was enhanced in most cases of primary hypothyroidism. Replacement of thyroid hormones in these patients resulted in a decrease in prolactin response to TRH. Treatment of six euthyroid subjects with triiodothyronine, on the other hand, unequivocally suppressed the release of prolactin. These results suggest that thyroid hormones per se are responsible for the blunted response of prolactin secretion to TRH administration.

Enlargement of epididymal adipocytes in relation to hyperinsulinemia in obese hyperglycemic mice (ob-ob).

Abstract: The diameters of epididymal fat cells of 12–17-day-old obese and normal littermates were compared following operative removal of the epididymal fat body. The animals were kept alive and checked for obesity at an age of 6 wk. Fat cells of the genetically obese mice began their fast growth between day 12 and day 14. At this age, it is possible to identify on the basis of fat-cell diameters three classes, representing +/+, ob/+, and ob ob , respectively, which shows that the ob allel is incompletely dominant. Measurements of the plasma-insulin concentration revealed that hyperinsulinemia, which is characteristic for the obese hyperglycemic syndrome, is not manifested before the beginning of the fourth week. Since hyperinsulinemia becomes evident at a later stage in development than the rapid increase in growth rate of the fat cells, it seems that the insulin resistance and the hyperinsulinemia cannot be the primary cause of the enlargement of the epididymal adipocytes.

Effects of carbohydrates on uric acid metabolism

Abstract: The rapid infusion of fructose, but not of glucose or galactose, to normal male volunteers produced a 30% rise in serum uric acid. All three hexoses increased the renal excretion of uric acid, phosphate, bicarbonate, and glucose. While only fructose clearly increased uric acid production, all three hexoses appeared to diffusely inhibit renal proximal tubular function. Data are presented that suggest that fructose infusions may concomitantly stimulate the conversion of preformed adenine nucleotides to uric acid while inhibiting de novo uric acid synthesis. Chronic ingestion of a fructose-rich diet did not alter serum or urinary uric acid.

Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Abstract: Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of 104 ± 6 mg100 ml to 75 ± 5 mg100 ml (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of 78 ± 5 mg100 ml, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to 46 ± 3 mg100 ml, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.

Maple syrup urine disease: coenzyme function and prenatal monitoring.

Abstract: A pregnancy at high risk for “cofactor resistant” Maple Syrup Urine Disease (MSUD) was monitored by quantitating valine, leucine, and isoleucine concentrations in maternal 24-hr urines, maternal plasma, and amniotic fluid. The fetal genotype was determined by assaying the conversion of radiolabeled branched-chain amino acids to 14 CO 2 by intact cultured amniotic fluid cells. Although branched-chain amino acid concentrations in maternal fluids were similar to control values, cells cultured from the high-risk pregnancy produced 14 CO 2 at one-half the rate of control cells. This finding suggested that the unborn 46 XY fetus was heterozygous for the MSUD gene. To test this hypothesis and to study normal and mutant branched-chain α-keto-acid dehydrogenase and co-factor interaction, a broken-cell system was developed that decarboxylated branched-chain α-keto-acids only when reconstituted with required cofactors. In control systems reduced coenzyme A (CoASH), β-nitotinamide adenine dinucleotide (NAD), thiamine pyrophosphate (TPP), and magnesium chloride (Mg 2+ ) stimulated 14 CO 2 production from α-ketoisocaproic acid-I- 14 C (KIC), α-ketoisovaleric acid-I- 14 C (KIV), and L-α-keto-β-methylvaleric acid-I- 14 C (KMV) by five to fifteen times base line over a 2-hr time course. TPP and Mg 2+ alone failed to increase either KIC or KIV decarboxylase, but reconstituted 30% of KMV decarboxylase. This “TPP-reconstituted” KMV decarboxylase was also present in mutant cells homozygous for this MSUD gene. KIV decarboxylase activity was essentially absent in the homozygous-affected line and partially impaired in heterozygous lines. Cells from the newborn male off-spring had partial impairment of KIV and KMV decarboxylase. These studies indicated that the MSUD mutation in this family resulted in the production of a defective subunit of the branched-chain α-keto-acid dehydrogenase complex that was common to all three branched-chain α-keto-acids, that a “TPP-reconstituted” KMV decarboxylase was present and under separate genetic control, and that a heterozygote for this MSUD gene was predicted before birth.