David Rabin

Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man

Comparisons were made between the artery and a heated superficial hand vein (HSHV) for the measurements of amino acids, lactate, glycerol, free fatty acids, insulin and glucagon and the measurements of glucose and alanine kinetics in man. Normal subjects (n = 8) were studied after an overnight fast (12–14 hr). U-14C-alanine and 3, 3H glucose were administered by a constant infusion and blood was sampled from catheters placed in a radial artery and a superficial dorsal vein of a heated hand (68°C environment), during a control period and a period of a steady state hyperaminoacidemia achieved by a constant infusion of an L-amino acid solution. The blood concentrations of all substrates and hormones measured and the concentrations of cold and radioactive glucose and alanine were comparable in the two vessels during both study periods. In contrast, measurements obtained in a deep forearm vein (DV) showed the concentrations of plasma glucose to be lower (3% in the control period and 5% during the experimental period) and those of plasma alanine to be higher (13% and 5% during control and experimental periods respectively) than the artery or the HSHV. The difference in glucose specific activity between the artery or the HSHV and the DV were however slight but non-significant, while plasma alanine specific activity was significantly lower in the DV as compared to the artery or the HSHV (32% in the control period versus 14% in the experimental period) suggesting a process of exchange of alanine and glucose occuring during the transit of blood across the forearm. As a result blood samples obtained from a DV will overestimate the derived total body glucose and alanine turnover rates. Thus the heated superficial hand vein can adequately replace the artery for the measurements of whole blood amino acids, lactate and glycerol and for plasma FFA, insulin and glucagon; its use can obviate the risks associated with arterial catheterization and can be a suitable site for the measurements of total body glucose and alanine kinetics in man.

A luteinizing hormone-releasing hormone agonist decreases biological activity and modifies chromatographic behavior of luteinizing hormone in man.

The effect of the luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6,Pro9-NEth]LHRH (LHRHA), on luteinizing hormone (LH) bioactivity was assessed with a rat interstitial cell assay in four men during a 14-d treatment period. Biologic/immunologic (B/I) ratios were unchanged initially with treatment but by day 12 had fallen to levels lower than basal values. Frequent sampling on day 12 revealed blunted gonadotropin responsiveness to LHRHA and absence of spontaneous LH pulsations. Despite continued administration of LHRHA, human chorionic gonadotropin administration resulted in elevated B/I ratios and testosterone levels. Further characterization of the serum immunoreactive LH by Sephadex chromatography revealed a later elution profile during treatment with LHRHA. Thus, LHRHA appears to act, in part, by modification of the bioactivity of LH in man.

Isolated ACTH Deficiency: A Heterogeneous Disorder Critical Review and Report of Four New Cases

Isolated adrenocorticotropin (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. This review summarizes the clinical and laboratory features of 39 previously reported cases plus 4 new patients. The clinical manifestations of isolated ACTH deficiency are variable, nonspecific and similar to those seen in adrenocortical insufficiency of any cause. The diagnosis of isolated ACTH deficiency due to intrinsic pituitary disease is made unequivocally when all the following criteria are met: 1) low basal urinary 17-hydroxycorticosteroid (17-OHCS) levels with or without low basal plasma cortisol, 2) low or normal basal plasma ACTH, 3) stimulation of cortisol, 17-OHCS or both during prolonged ACTH administration, 4) lack of 17-OHCS elevation in response to metyrapone and 5) normal secretory indices of other pituitary hormones. Isolated ACTH deficiency secondary to suprapituitary (e.g., hypothalamic) dysfunction is also based upon the above criteria, but, in addition, is associated with stimulation of cortisol and ACTH secretion following vasopressin administration.

Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans

SummaryDichloroacetate decreases plasma glucose, lactate, and alanine concentrations in normal and diabetic subjects, and lowers lactate concentrations and increases survival in animals with experimentally induced lactic acidosis. The relationship between these effects and plasma dichloroacetate concentrations have not been previously studied in man. Dichloroacetate (1–50 mg/kg) was infused over 30 min to 16 healthy subjects and plasma drug concentrations were followed by gas chromatography over the next 8 h. Peak plasma concentrations were linearly related to the dose (r = 0.98, p<0.001) up to 30 mg/kg, above which 4 of 7 subjects had disproportionately high plasma drug concentrations. Nonlinear disposition was also indicated by the convex decreasing plasma elimination curves; levels declining less rapidly initially than later. At plasma concentrations below 10 μg/ml, elimination was monoexponential with a half-life of 32±11 min (mean±SD). Plasma drug clearance also decreased with doses greater than 20 mg/kg. Within 2 h of administration of the maximally effective dichloroacetate dose of 35 mg/kg, plasma lactate concentrations fell 75% below baseline and alanine fell 50% below baseline, while blood glucose was unaffected.

The disposal of an intravenously administered amino acid load across the human forearm

This study was designed to examine the role of the skeletal muscle in man in the disposal of an intravenously administered L-amino acid solution. Arterio-deep venous differences of amino acids, glucose and lactate, and blood flow across the human forearm were measured in 9 healthy normal male volunteers (age = 27 ± 2 yr, weight = 79 ± 4 kg and height = 180 ± 2 cms) after an overnight fast (12 hr). Glucose and alanine turnover rates were estimated using a continuous infusion of 3-3H-glucose and U-14C-alanine isotopes. All measurements were obtained during steady state conditions, basally and two hours after the start of an L-amino acid infusion (8.5% solution). During the control period there was a significant release of total alpha amino nitrogen (AAN) equal to 300 ± 97 nmole100 g forearm muscle/min with alanine and glutamine accounting for over 80% of that amount (260 ± 24 nmole100 g forearm muscle/min). The release of the branched chain amino acids (BCAA) was only significant for valine, while the release of each of the keto acids of leucine and valine, α-ketoisocaproate and α-ketoisovalerate (37 ± 12 and 36 ± 7 nmole100 ml forearm muscle/min respectively) was significant from zero and exceeded the release of the corresponding amino acids (13 ± 17 and 24 ± 7 nmole100 g forearm muscle/min for leucine and valine respectively). The infusion of the L-amino acid solution resulted in a reversal of amino acid balance across the forearm. There was a net uptake of AAN of 1195 ± 209 nmole100 g forearm muscle/min with the BCAA accounting for 513 ± 75 nmole100 g forearm muscle/min or 49 ± 6% of the uptake. The net uptake of BCAA by skeletal muscle did not exceed 35% of the amount infused. The release of α-ketoisocaproate and α-ketoisovalerate showed no significant change from basal levels. The output of alanine and glutamine persisted in response to the infusion; while alanine output dropped by 40%, glutamine output increased by 50% (68 ± 23 and 218 ± 42 nmole100 g forearm muscle/min respectively), yet the combined release of alanine and glutamine did not change significantly from basal levels. Amino acid infusion resulted in a twofold increase in insulin and glucagon. Plasma glucose fell from 5.3 ± 0.05 mM basally to 5.04 ± 0.06 mM (p < 0.05), while blood lactate increased from 0.587 ± 0.03 mM to 0.639 ± 0.025 mM (p < 0.05); similarly there was a time dependent increase in glucose uptake by muscle (from 0.857 ± 0.08 to 1.27 ± 0.07 μmole100 g forearm muscle/min, p < 0.05) and lactate release (0.226 ± 0.03 to 0.297 ± 0.045 μmole100 g forearm muscle/min, p < 0.05). These results indicate that a significant amount of the amino acids infused, and specifically the BCAA are extracted by human skeletal muscle, and mostly retained as such for later use. The data obtained under the conditions of the present study also indicate that tissues other than skeletal muscle are as important in the overall handling of these amino acids. However, it remains to be seen whether these findings can be extrapolated to other physiological conditions.

Isolated Deficiency of Follicle-Stimulating Hormone

Abstract Isolated deficiency of follicle-stimulating hormone (FSH) was found in a 22-year-old woman with primary amenorrhea. Pituitary growth hormone, ACTH and thyrotropin release, assessed either directly or indirectly, was normal. Serum luteinizing hormone levels were high, generally 50 to 90 mlU per milliliter, whereas serum follicle-stimulating hormone levels were undetectable (less than 3 mlU per milliliter). Serum estradiol-17β concentration was less than 10 pg per milliliter. Ovarian biopsy revealed primordial follicles but without maturation to the stage of antral formation. Administration of menotropins (human menopausal gonadotrophins), which contains urinary follicle-stimulating and luteinizing hormone, led to the appearance of readily detectable levels of follicle-stimulating hormone in the serum (between 10 and 20 mlU per milliliter)that fell to less than 3 mlU per milliliter 48 hours after the last injection of menotropins. Luteinizing hormone release was inhibited by intravenous injection o...

Histamine Release From a Gastric Carcinoid: Provocation by Pentagastrin and Inhibition by Somatostatin

We have previously reported that flushing associated with a gastric carcinoid tumor can be provoked by pentagastrin and inhibited by either somatostatin or combined histamine H1- and H2-receptor blockade. In this report, the effects of pentagastrin and somatostatin on histamine release in a patient with a metastatic gastric carcinoid tumor were examined. Small doses of intravenous pentagastrin (0.1-0.4 micrograms) produced a dose-dependent increase in the level of circulating plasma histamine. Graded infusions of somatostatin suppressed both basal and pentagastrin-stimulated plasma histamine levels in a dose-dependent fashion. A close correlation was found between circulating plasma histamine levels and attendant changes in blood pressure and pulse rate. This study documents that pentagastrin directly evokes the release of histamine from this patients gastric carcinoid tumor and that the release of histamine is inhibited by somatostatin. In addition, this study provides additional evidence that the primary mediator of the flushing in this patient with foregut carcinoid syndrome is histamine.

Compounding the Ordeal of ALS: Isolation from My Fellow Physicians

IT has been three years since my first symptoms suggested a diagnosis of amyotrophic lateral sclerosis (ALS). The pain and anguish of this illness are known to most physicians and are an inevitable...

Occasional notes. Compounding the ordeal of ALS: Isolation from my fellow physicians.

IT has been three years since my first symptoms suggested a diagnosis of amyotrophic lateral sclerosis (ALS). The pain and anguish of this illness are known to most physicians and are an inevitable...

Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man

SummaryThe present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220–240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7–12 μU/ml. Glucagon (1.5 ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148±37 to 228±25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132±21 to 74±15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143±31 to −72.5±39 mg/ min (p<0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137±20 vs 151±60 mg/min) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.