bluuebunny/crossref_metadata_2025 huggingface dataset:
Acidosis-induced glucose intolerance is not prevented by adrenergic blockade
Authors: Adrogue H. J. , Chap Z. , Okuda Y. , Michael L. , Hartley C. , Entman M. , Field J. B.
Published: December 2017

The determinants of the altered glucoregulation in acidosis were investigated in anesthetized dogs. Because CO2 rapidly equilibrates and its effects are mediated by pH changes, CO2 inhalation was examined. Plasma acid-base composition, glucose, insulin, glucagon, and blood flows were evaluated before and after an intravenous glucose load (1.2 +/- 0.1 g/kg body wt) in normal and acidotic dogs with flow probes and catheters chronically implanted in the portal circulation. A simultaneous infusion of phentolamine (5 micrograms.kg-1.min-1), propranolol (3.5 micrograms.kg-1.min-1), both, or none was used. All acidemic dogs had lower hepatic extraction of insulin and greater hyperglycemia after the glucose challenge; thus the adrenergic system is not critical for these responses. Because arterial insulin levels were either normal (propranolol) or increased (all others) in acidosis, insulin resistance was likely. Insulin infusion (2 and 4 mU.kg-1.min-1) with euglycemic clamp and [3-3H]glucose documented that acidemia decreases peripheral glucose utilization and the insulin suppression of hepatic glucose production. Acidemia also enhances plasma glucagon levels, yet this effect plays a limited role in the observed hyperglycemia.
Naloxone attenuates development of hypertension in two-kidney one-clip Goldblatt rats
Authors: Chen M. , Lee J. G. , Malvin R. L. , Huang B. S.
Published: December 2017

The present experiments were designed to determine if an opiate antagonist affects blood pressure in two-kidney one-clip Goldblatt rats. Male Sprague-Dawley rats were divided into three groups. Group 1 received an infusion of saline intraperitoneally via an osmotic pump and left renal artery constriction (RAC). In group 2, rats were treated the same as group 1, except that they received an intraperitoneal infusion of naloxone (100 micrograms/h). Group 3 received the same infusion of naloxone without RAC. Naloxone-infused Goldblatt rats showed a significantly lower systolic blood pressure (SBP) than saline-infused Goldblatt rats (132 +/- 7 vs. 160 +/- 9 mmHg at day 14), but a higher SBP than control (132 +/- 7 vs. 106 +/- 1 mmHg). Infusion of naloxone did not significantly change SBP in normotensive rats. Renal renin activity in the clipped kidney was higher than in the nonclipped kidney in groups 1 and 2. Plasma renin activity (PRA) in both groups of Goldblatt rats was higher than in group 3, but no significant difference was found between the two groups of Goldblatt rats (groups 1 and 2). Naloxone (1.5 microM) did not affect the basal secretion of renin by isolated cortical slices from untreated rats. The present data demonstrate that naloxone significantly attenuates the development of hypertension in two-kidney one-clip rats. The attenuation of blood pressure was not associated with the changes in PRA, renal renin activity, or plasma aldosterone concentrations. The data support the hypothesis that the endogenous opioid system may be involved in the development of renovascular hypertension.
Whole body and regional fuel metabolism during early postexercise recovery
Authors: Devlin J. T. , Barlow J. , Horton E. S.
Published: December 2017

We studied whole body and regional fuel metabolism 1-4 h after cycle exercise [70% maximum O2 consumption (VO2max)], using the insulin clamp technique (40 mU.M-2.min-1) with indirect calorimetry. Substrate fluxes were determined in nonexercised (forearm) muscle tissues. Total glucose utilization was not increased by exercise, either in the preinsulin or insulin-stimulated state. Glucose oxidation tended to decrease, and lipid oxidation was increased after exercise. Forearm glucose uptake (FGU) was increased 5 times by insulin in the resting state, due largely to increased fractional extraction (P less than 0.05). After exercise, FGU was not increased by insulin. Forearm alanine and lactate release was doubled 2 h after exercise. Branched-chain amino acid (BCAA) concentrations were increasing after exercise (P less than 0.01) at a time when forearm muscle was taking up these amino acids. Insulin infusion suppressed the elevated release of gluconeogenic precursors from the forearm and suppressed the elevated concentrations of BCAAs, free fatty acids, and glycerol present after exercise. In summary, basal and insulin-stimulated glucose utilization is not augmented by prior high-intensity exercise, partly because nonexercised muscle is insulin resistant. Insulin infusion attenuates the altered metabolic milieu seen during early recovery.
alpha-Glycerophosphate shuttle in a clonal beta-cell line
Authors: Meglasson M. D. , Smith K. M. , Nelson D. , Erecinska M.
Published: December 2017

It has been proposed that the alpha-glycerophosphate (alpha-GOP) shuttle plays a crucial role in regulation of glycolysis in beta-cells by linking reoxidation of cytosolic NADH to formation of ATP in the electron transport chain (J. Biol. Chem. 265: 8287, 1981). Direct evidence for this suggestion is still lacking, however. In this work the operation of the alpha-GOP shuttle was investigated in the insulin-secreting cell line HIT-T15. The constituent enzymes of the pathway were found to be present in HIT cells. Flavin-linked alpha-GOP dehydrogenase was associated with the mitochondrial fraction, whereas NAD+-dependent alpha-GOP dehydrogenase was localized in the cytosol. In the presence of amobarbital (used to preserve the function of the alpha-GOP shuttle under conditions where oxidation of NADH by the respiratory chain was blocked), glucose increased insulin secretion, O2 consumption, and the cell [ATP]/[ADP] when compared with amobarbital alone. These results indicate that the alpha-GOP shuttle contributes to ATP generation in HIT cells and that its activation may be necessary for the initiation of insulin secretion by glucose.
Regulation of branched-chain 2-oxo acid dehydrogenase activity during exercise
Authors: Kasperek G. J.
Published: December 2017

The levels of the branched-chain amino and oxo acids were measured in muscle and plasma after exercise and 10 min postexercise. Leucine was increased in both muscle and plasma after exercise and 10 min postexercise. The muscle levels of the branched-chain oxo acids were not increased immediately after exercise but were increased 10 min postexercise. Exercise caused a large increase in the plasma levels of the oxo acids of leucine and isoleucine that was further increased 10 min postexercise. The activity of branched-chain 2-oxo acid dehydrogenase (BCOAD) was increased immediately after exercise but returned to the control value by 10 min postexercise. The lack of correlation between the muscle and plasma levels of the branched-chain amino and oxo acids and BCOAD activity suggests that these amino and oxo acids are not the primary physiological regulators of BCOAD activity during exercise. On the other hand, an excellent correlation was found between the muscle ATP level and BCOAD activity, with the ATP content decreasing in tandem with an increase in BCOAD activity during exercise and decreasing during the recovery period after exercise.
Ca2+ concentration influences the hepatic extraction of bioactive human PTH-(1-34) in rats
Authors: D'Amour P. , Huet P. M.
Published: December 2017

The regulation of bioactive human parathyroid hormone [hPTH-(1-34)] hepatic extraction was studied in vitro by means of an isolated rat liver perfusion system. A standard buffer containing 20% red blood cells, 2% albumin, and variable concentrations of hPTH-(1-34) and Ca2+ was used in nonrecirculation experiments. Hepatic blood flow was kept constant at approximately 1.8 ml.g liver-1.min-1. hPTH in portal and hepatic veins was measured by a radioimmunoassay specific for hPTH-(1-34), and the results obtained were validated by gel chromatography analysis of the hormone measured. Results are expressed as mean +/- SD of five to six different experiments. In normocalcemic conditions (Ca2+ approximately 1.2 mmol/l), the hepatic extraction ratio of hPTH remained stable at 0.357 +/- 0.011 and 0.370 +/- 0.010 for hPTH-(1-34) concentrations of 0.156 +/- 0.002 and 1.314 +/- 0.014 pmol/ml; it decreased to 0.145 +/- 0.013 (P less than 0.001) for a hPTH-(1-34) concentration of 5.817 +/- 0.167 pmol/ml. Kinetics analysis of the normocalcemic data disclosed a Vmax of 1.971 +/- 0.18 pmol.min-1.g liver-1 and a Km of 1.410 +/- 0.39 pmol/ml. When hPTH-(1-34) concentration was kept stable with varying Ca2+ concentrations, elevated (1.62 +/- 0.01 mmol/l) Ca2+ gave an hepatic extraction ratio similar to normocalcemic conditions (0.335 +/- 0.014 vs. 0.357 +/- 0.011 mmol/l), whereas it significantly decreased in hypocalcemia (0.78 +/- 0.01 mmol/l) to 0.219 +/- 0.014 mmol/l (P less than 0.001). Kinetics were similar to normocalcemic conditions when Ca2+ concentration was elevated but appeared modified by hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypothalamic monoamines associated with the cephalic phase insulin response
Authors: Holmes L. J. , Storlien L. H. , Smythe G. A.
Published: December 2017

This study elucidated the hypothalamic monoamine systems associated with the cephalic phase insulin release. Male Wistar rats conditioned to drink a glucose solution were killed 2 min after the onset of their scheduled feeding; control rats were killed at the same time. The ventromedial (VMH) and lateral (LH) portions of the hypothalamus were analyzed for the monoamines and their principal metabolites. Serum was assayed for insulin and glucose. The results showed that the experimental animals had significantly higher serum insulin levels than did the control animals, although glucose levels were unchanged. In the LH, there were increased levels of norepinephrine, its metabolite dihydroxyphenylethylene glycol (DHPG), and serotonin [(5-hydroxytryptamine (5-HT)]. In the VMH, 5-HT, its metabolite 5-hydroxyindoleacetic acid, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were all higher in the conditioned animals. 5-HT levels in the LH and DOPAC levels in the VMH were closely associated with serum insulin (r = 0.80 and 0.71, respectively). This study has defined, in the normal animal, changes in monoamines in specific areas of the hypothalamus associated with the cephalic phase insulin release.
Insulin sensitivity and responsiveness during lactation and dry period in goats
Authors: Debras E. , Grizard J. , Aina E. , Tesseraud S. , Champredon C. , Arnal M.
Published: December 2017

To investigate the role of insulin in partitioning nutrients between the mammary gland and other tissues during lactation in ruminants, euglycemic-hyperinsulinemic clamps were performed in goats during early lactation (15-26 days postpartum), midlactation (78-91 days postpartum), and dry period (169-194 days postpartum). Insulin was infused at 0.4, 0.7, 1.9, 4.4, and 10 micrograms/min. Basal plasma glucose was constant during all periods despite the fact that basal glucose utilization was approximately 3 times higher during lactation than dry period. Basal plasma insulin was similar during early lactation and dry period but increased during midlactation. Insulin infusion resulted in a dose-dependent stimulation of glucose utilization. The insulin-stimulated glucose utilization above basal was greatly impaired during early lactation when compared with dry period, but this only occurred at very high plasma insulin. Insulin infusion also resulted in a decrease in glucose production; the maximal insulin effect is achieved at the lowest insulin infusion rate. The ability of insulin to decrease glucose production was significantly improved during early lactation when compared with dry period. This phenomenon may provide a mechanism to save gluconeogenic substrates during early lactation. In contrast, midlactation did not result in any significant change in insulin action with both glucose utilization and glucose production.
Fetal glucose utilization in response to maternal starvation and acute hyperketonemia
Authors: Leturque A. , Hauguel S. , Revelli J. P. , Burnol A. F. , Kande J. , Girard J.
Published: December 2017

The effects of maternal hypoglycemia and/or hyperketonemia on glucose utilization by individual fetal rat tissues have been studied in vivo. To decrease blood glucose and to raise fetal blood ketone body concentrations, 19-day pregnant rats were submitted to 48 or 96 h of starvation. To differentiate between the effects of decreased blood glucose and increased ketone body concentrations, fed pregnant rats were infused for 2 h with DL-beta-hydroxybutyrate. After 96 h of maternal starvation, fetal 2-deoxy-D-glucose (2DG) uptake decreased from 13.6 +/- 0.5 to 8.6 +/- 1.15 micrograms.min-1.g-1. This was mainly due to a decrease in 2DG uptake by fetal hindlimb muscles and heart. By contrast, 2DG uptake in fetal liver and brain was not affected by maternal starvation. Acute hyperketonemia in fed pregnant rats induced a 23% decrease in 2DG uptake by the whole fetus mainly as the result of a lowered 2DG uptake in fetal hindlimb muscles. These data suggest that fetal 2DG uptake does not simply depend on lowered blood glucose level during maternal starvation but that other hormonal, cardiovascular, or metabolic adaptations are implicated. In the rat, most of the fetal tissues including brain are protected against maternal hypoglycemia.
Modification of glycosylation of renin in sodium-depleted and captopril-treated rats
Authors: Kim S. , Hosoi M. , Hiruma M. , Ikemoto F. , Yamamoto K.
Published: December 2017

Concanavalin A (con A) chromatography of rat plasma revealed the presence of three differently glycosylated forms of renin, including the con A unbound form (renin C), the loosely bound form (renin A), and the tightly bound form (renin B). Rat renal cortical slices in vitro secreted all these forms. They had a different half-life in the plasma after ligation of both renal artery and vein (half-life of 21 +/- 1, 14 +/- 3, and 35 +/- 4 min for renin A, B, and C, respectively). Thus differently glycosylated forms of renin are released from the kidney into the blood circulation and disappear, with a different half-life. Rats were sodium-depleted and captopril-treated (40-60 mg.kg-1.day-1) for 2 wk, and the effects of these treatments on relative proportions of renin A, B, and C were investigated. These treatments elevated plasma renin concentration approximately 60-fold (from 24 +/- 3 to 1,406 +/- 128 ng angiotensin I.h-1.ml-1; P less than 0.01), in association with an increase in the relative percent of renin C in the plasma from 22 +/- 2 to 39 +/- 3% (P less than 0.01). Moreover, the relative proportion of renin C released from the renal cortical slices was significantly higher in the treated than in the control rats (42 +/- 9 vs. 16 +/- 3% of secreted renin, respectively; P less than 0.02). These results show that the predominant release of renin C, with the longest half-life (35 min) in the plasma, contributes to the increased plasma renin concentration in sodium-depleted and captopril-treated rats.
Total and myofibrillar protein degradation in isolated soleus muscles after exercise
Authors: Kasperek G. J. , Snider R. D.
Published: December 2017

The effect of exercise on the rate of total and myofibrillar protein degradation was determined by measuring the rate of release of tyrosine and 3-methylhistidine, respectively, from isolated rat soleus muscle strips after exercise. The rate of tyrosine release was 30–50% greater from the muscles of the exercised rats, whereas the rate of 3-methylhistidine release was unchanged. Thus the exercise-induced increase in the rate of protein degradation is due to increased breakdown of nonmyofibrillar proteins. The rate of protein degradation increases as a function of exercise duration and rapidly returns to the preexercise level during recovery. The exercise-induced increase in the rate of protein degradation is not inhibited by chloroquine. Together these observations suggest that the increase in the rate of protein degradation observed immediately after exercise is due to the breakdown of nonmyofibrillar proteins and occurs via the nonlysosomal pathway of protein degradation.
Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work
Authors: Wasserman D. H. , Spalding J. A. , Lacy D. B. , Colburn C. A. , Goldstein R. E. , Cherrington A. D.
Published: December 2017

The effects of the exercise-induced rise in glucagon were studied during 2.5 h of treadmill exercise in 18-h fasted dogs. Five dogs were studied during paired experiments in which pancreatic hormones were clamped at basal levels during a control period (using somatostatin and intraportal hormone replacement), then altered during exercise to stimulate the normal exercise-induced fall in insulin, while glucagon was 1) increased to mimic its normal exercise-induced rise (SG) and 2) maintained at a basal level (BG). Six additional dogs were studied as described with saline infusion alone (C). Gluconeogenesis (GNG) and glucose production (Ra) were measured using tracers [( 3-3H]glucose and [U-14C]alanine) and arteriovenous differences. Glucose fell slightly during exercise in C and was infused in SG and BG so as to mimic the response in C. Glucagon rose from 60 +/- 3 and 74 +/- 5 pg/ml to 118 +/- 14 and 122 +/- 17 pg/ml with exercise in C and SG and was unchanged from basal in BG (67 +/- 6 pg/ml). In C, SG, and BG, insulin fell during exercise by 5 +/- 1, 6 +/- 1, and 6 +/- 1 microU/ml. Ra rose from 3.3 +/- 0.2 and 3.0 +/- 0.2 mg.kg-1.min-1 to 8.6 +/- 0.8 and 9.5 +/- 1.5 mg.kg-1.min-1 with exercise in C and SG, but from only 3.0 +/- 0.2 to 5.5 +/- 0.8 mg.kg-1.min-1 in BG. GNG increased by 248 +/- 38 and 183 +/- 75% with exercise in C and SG but by only 56 +/- 21% in BG. Intrahepatic gluconeogenic efficiency was also enhanced by the rise in glucagon increasing by 338 +/- 55 and 198 +/- 52% in C and SG but by only 54 +/- 46% in BG. The rise in hepatic fractional alanine extraction was 0.38 +/- 0.04 and 0.33 +/- 0.04 during exercise in C and SG and only 0.08 +/- 0.06 in BG. Ra was increased beyond that which could be explained by effects on GNG alone, hence hepatic glycogenolysis must have also been enhanced by the rise in glucagon. In conclusion, in the dog, the exercise-induced rise in glucagon 1) controls approximately 65% of the increase in Ra, 2) increases hepatic glycogenolysis and GNG, and 3) enhances GNG by stimulating precursor extraction by the liver and precursor conversion to glucose within the liver.
Rapid assessment of average ratios: application to turnover studies
Authors: May M. E. , Collins J. C.
Published: December 2017

The calculation of a set of ratios from two sets of paired experimental data is a common practice. The ratio of the averages of two sets is in general not equal to the average of the ratios of individual pairs, and there is no predictable relation if both sets of data are unspecified real numbers. However, we prove here that the ratio of averages is the minimum bound for the average of ratios if the numerators of each ratio are identical. This is the practice for many steady-state turnover experiments, and thus summary data can be reliably utilized in this case.
Desensitization of rabbit myometrium to oxytocin and prostaglandin F2 alpha
Authors: Eiler H. , Armstrong-Backus C. S. , Lyke W. A.
Published: December 2017

The desensitizing effects of oxytocin (OT) and prostaglandin F2 alpha (PGF2 alpha) were investigated in the uteri of rabbits. Uterine motility was measured in anesthetized rabbits infused intravenously with either PGF2 alpha (50 micrograms/min) or OT (100 mU/min) alternately. The treatment sequence was saline (30 min), first drug (OT or PGF2 alpha, 90 min), second drug (OT if PGF2 alpha was first drug and vice versa, 90 min), and first drug (repeated) 60 min. Both OT and PGF2 alpha infusions increased motility approximately 200% within 5–10 min. Thereafter, motility decreased linearly to base-line value. Fifty percent desensitization was completed at 35-45 min and 100% at 90 min. A tenfold increase in the infusion rate caused no further increase in motility. However, OT infusion into a PGF2 alpha desensitized uterus (and vice versa) elicited an immediate uterokinetic response. Oxygen consumption and glucose oxidation rate of uterine slices measured at different stages (preinfusion, maximal motility, and desensitized) of uterine motility showed no difference (P greater than 0.05) between the two experimental treatments. It was concluded that either OT or PGF2 alpha infusions specifically desensitized the uterus.
Impaired production of nerve growth factor in the submandibular gland of diabetic mice
Authors: Kasayama S. , Oka T.
Published: December 2017

The production of nerve growth factor (NGF) in submandibular glands was examined in two kinds of diabetic mice. In genetically diabetic (C57BL/KsJ db/db) mice, which manifest marked insulin resistance and hyperglycemia, the concentration of NGF in the submandibular gland was less than one-tenth that of the nondiabetic controls. In streptozotocin-induced diabetic C57BL/KsJ mice, which show pancreatic insulitis leading to insulin deficiency and hyperglycemia, the glandular NGF concentration fell in a time-dependent manner to 26% of control level at 5 wk after the streptozotocin injection. A daily administration of insulin to the streptozotocin-induced diabetic mice restored the NGF concentration to almost the control level. The molecular size of NGF (13 kDa) in the glandular extracts of the genetically diabetic (db/db) mice in Western blots was indistinguishable from that of the control mice, but its level was reduced in the glands of the diabetic (db/db) animals. Although plasma NGF concentrations were normally below the sensitivity of the assay (less than 0.80 ng/ml) in both the control and the diabetic (db/db) mice, administration of cyclocytidine, which stimulates NGF release from the submandibular gland into the blood circulation, increased the plasma NGF level to 5.95 ng/ml in the control mice, but it failed to do so in the diabetic (db/db) mice. These findings suggest that, in diabetic mice, NGF production in the submandibular gland and its capacity to release NGF into the circulation are decreased.
Blood glucose turnover during high- and low-intensity exercise
Authors: Cooper D. M. , Barstow T. J. , Bergner A. , Lee W. N.
Published: December 2017

We hypothesized that whole body glucose uptake (Rd) during exercise is not related in a simple, linear manner to O2 uptake (VO2). To test this, seven healthy male subjects (age range 23-34 yr) were studied in the postabsorptive but not glycogen-depleted state. Three conditions were examined: 1) rest, 2) 40 min of constant exercise in which the work rates were carefully chosen to consist of low-intensity exercise (no elevated blood lactate, a mean of 40% maximal VO2), and 3) 40 min of high-intensity exercise (markedly elevated blood lactate, 79% maximal VO2). Gas exchange was measured breath by breath, and glucose uptake and production were measured using [6,6-2H2]glucose. Low-intensity exercise (n = 7) resulted in a small but not statistically significant increase in mean Rd [3.06 +/- 0.37 (SE) mg.min-1.kg-1] compared with resting values (2.87 +/- 0.39 mg.min-1.kg-1) despite a fourfold increase in the production of CO2 and VO2. By contrast, the high-intensity exercise Rd (n = 5, 6.98 +/- 0.67 mg.min-1.kg-1) was significantly greater than the resting value (3.03 +/- 0.56 mg.min-1.kg-1). Results of glucose production were virtually the same. Similarly, mean levels of epinephrine and norepinephrine increased significantly above resting values during high- but not low-intensity exercise. Our data demonstrate that whole body glucose dynamics and regulation during 40 min of exercise do not change in a simple linear manner with respect to metabolic rate.
Hyperosmolality elevates plasma atrial natriuretic factor in the ovine fetus
Authors: Cheung C. Y. , Miner L. K. , Brace R. A.
Published: December 2017

This study was designed to explore the effect of hyperosmolality on fetal plasma atrial natriuretic factor (ANF) concentrations in chronically catheterized sheep fetuses averaging 133 days gestation. An isotonic solution of 0.9% NaCl or hypertonic solution of 2.5% NaCl, 13% mannitol, or 7% NaCl was infused intravascularly into the fetuses at 20 ml/kg over 10 min and simultaneously into their mothers. Fetal plasma osmolality changed by -2 +/- 1 (SE) mosmol/kg in the isotonic group and by 16 +/- 2, 20 +/- 4, and 56 +/- 3 mosmol/kg in the 2.5% NaCl, 13% mannitol, and 7% NaCl groups, respectively (P less than 0.00001). Preinfusion fetal ANF levels were similar in all four groups and averaged 145 +/- 7 (SE) pg/ml. With infusion, fetal plasma ANF increased significantly in the isotonic group by 28 +/- 6%. In the 2.5% NaCl and 13% mannitol groups, the increment in plasma ANF was four times, whereas in the 7% NaCl group it was eight times that in the isotonic group (P less than 0.01). Blood volume and venous pressure changes were similar in all groups. In the hypertonic groups, plasma ANF and venous pressure returned to control levels within 1 h after the start of the infusion, whereas plasma osmolalities remained elevated. Thus infusions of hypertonic solutions into the ovine fetus caused much greater increases in plasma ANF concentrations compared with those seen with isotonic infusion. The return of plasma ANF levels to control despite maintained hyperosmolality suggests that hyperosmolality stimulated ANF release either by a direct but transient mechanism or by potentiating the effects of vascular volume expansion.
Adenine nucleotides mobilize cellular Ca2+ and inhibit parathyroid hormone secretion
Authors: Nemeth E. F. , Kosz L. M.
Published: December 2017

Measurements of the concentration of intracellular free calcium [( Ca2+]i) were used to screen for the presence of Ca2+-mobilizing receptors on dissociated and purified bovine parathyroid cells loaded with fura-2. Among a wide variety of agents known to mobilize cellular Ca2+ in other cells, only ATP and certain other nucleotides were capable of altering [Ca2+]i in parathyroid cells. The addition of ATP or adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) (10-200 microM) to parathyroid cells evoked a rapid and transient increase that was followed by a small, steady-state increase in [Ca2+]i. Cytosolic Ca2+ transients elicited by ATP or ATP gamma S persisted in the absence of extracellular Ca2+ and presence of a mitochondrial uncoupler but were blocked by pretreatment with ionomycin or fluoride. Cytosolic Ca2+ transients elicited by ATP were inhibited by increased concentrations of extracellular Ca2+, Mg2+, or Sr2+. Conversely, ATP depressed increases in [Ca2+]i elicited by these extracellular divalent cations. Parathyroid hormone (PTH) secretion was inhibited by ATP gamma S but not by those nucleotides that were without effect on [Ca2+]i. Loading cells with 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and fura-2 blocked cytosolic Ca2+ transients elicited by ATP gamma S but did not block the inhibitory effects of ATP gamma S on PTH secretion. The results show that the activation of a calcium-mobilizing receptor, in this case by ATP gamma S, is sufficient to inhibit PTH secretion. This favors the view that extracellular Ca2+ acts via a Ca2+-mobilizing receptor to regulate PTH secretion.
Energy expenditure during normo- and overfeeding in peripubertal children of lean and obese Pima Indians
Authors: Freymond D. , Larson K. , Bogardus C. , Ravussin E.
Published: December 2017

We investigated the hypothesis that peripubertal children born to obese parents have a lower 24-h energy expenditure during "weight maintenance" and/or in response to overfeeding when compared with children born to normal-weight parents. Sixteen Southwestern American Indians (12.4 +/- 1.4 yr, 55.5 +/- 14.1 kg, 30 +/- 8% body fat), eight offspring from obese parents [body mass index (BMI) = 40 +/- 6 kg/m2], and eight offspring from thin parents (BMI = 24 +/- 3 kg/m2) were admitted for 8 days to our metabolic ward. The 24-h energy expenditure was measured under eucaloric conditions and on the 3rd day of progressive overfeeding of a mixed diet, i.e., 150, 200, and 200% of weight maintenance on day 1, 2, and 3 of overfeeding. At base line, offspring of obese parents were heavier (64 +/- 15 vs. 47 +/- 6 kg, P less than 0.05) and tended to be fatter (34 +/- 8 vs. 26 +/- 9% body fat, P = 0.07), with a higher absolute fat mass (22 +/- 9 vs. 13 +/- 4 kg body fat, P less than 0.05) when compared with offspring of thin parents. During both normo- and over-feeding, the larger part of the variance in 24-h energy expenditure in the conditions of a respiratory chamber was accounted for by differences in fat-free body mass (54 and 68%, respectively), whereas differences in the level of spontaneous physical activity accounted for another 19 and 21%.(ABSTRACT TRUNCATED AT 250 WORDS)
Modeling thyroxine transport to liver: rejection of the "enhanced dissociation" hypothesis as applied to thyroxine
Authors: Mendel C. M.
Published: December 2017

Three models for the hepatic uptake of thyoxine (T4) from human plasma were considered: 1) uptake occurs exclusively via the pool of free T4 after spontaneous dissociation of T4-plasma-protein complexes, 2) uptake occurs primarily via the pool of bound T4 by the interaction of one or more binding proteins with the cell-surface membrane, and 3) uptake occurs primarily by "enhanced dissociation" of T4 from one or more of its binding proteins within the sinusoids. Each of these models was examined in relation to well-accepted unidirectional uptake and steady-state kinetics data that indicate that 1) between 4 and 24% of the T4 in normal human serum is taken up unidirectionally by the liver in a single pass, and 2) the in vivo disposal rate of T4 is unaffected by primary changes in the plasma concentration of thyroid hormone-binding globulin. Both analytical and numerical techniques were used. The first two models were found to be compatible with both the steady-state kinetics data and the unidirectional uptake data, given certain assumptions in each of the models. Although theoretically distinguishable on the basis of unidirectional uptake data, uncertainty over the true uptake (influx) rate constant for free T4 prevented resolution between these two models. In contrast, the third model, that of enhanced dissociation [W. M. Pardridge, Am. J. Physiol. 252 (Endocrinol. Metab. 15): E157-E164, 1987], was found, as currently formulated with respect to T4, to be incompatible with both the steady-state kinetics data and the unidirectional uptake data.(ABSTRACT TRUNCATED AT 250 WORDS)
Response of serum triglycerides of endogenous origin to the administration of triglyceride-rich lipid particles
Authors: Robins S. J. , Fasulo J. M. , Robins V. F. , Patton G. M.
Published: December 2017

Studies were performed in rats to quantitate the changes in the concentration of serum triglycerides (TGs) of endogenous and exogenous origin after the acute intravenous injection of TG-rich emulsion particles. Emulsions were prepared to approximate chylomicrons and to contain a TG with a single fatty acid that could be traced during its clearance from the serum. After injection of emulsions, there was a rapid increase of not only the emulsion TG but TGs that contained a variety of other fatty acids of endogenous origin. Endogenous TGs were cleared from the serum at a slower rate than the emulsion TG and accounted for the major increase in serum TGs, especially during the latter phase of the clearance period. The increase in endogenous TGs was completely abolished by hepatectomy, which had no effect on the clearance of the emulsion TG. Results thus show that TGs of hepatic origin accumulate in the serum in response to the introduction of new TG-rich lipoproteins. Feeding rats a specific TG produced a similar result, with a pronounced rise in endogenous TGs that, like the changes after emulsion administration, was particularly evident once the TG that was fed was largely cleared from the serum. These findings are consistent with a process in which the preferential clearance of chylomicron TGs interrupts the clearance of very low density lipoprotein TGs that are produced by the liver. Consequently, the composition of serum TGs that accumulate after a meal may not reflect the composition of the meal itself.
Role of the gamma-glutamyl cycle in the regulation of amino acid translocation
Authors: Vina J. R. , Palacin M. , Puertes I. R. , Hernandez R. , Vina J.
Published: December 2017

Amino acid translocation was studied in the mammary gland of lactating rats and in the placenta of pregnant rats. The uptake of amino acids by the mammary gland is maximal on days 10-14 of lactation and is minimal on days 19-21. However, on day 19 maximal uptake can be restored by injection of 1) small amounts of gamma-glutamyl amino acids, 2) 5-oxoproline, and 3) an inhibitor of 5-oxoprolinase. A severe decrease in uptake of amino acids at the peak of lactation is provoked by anthglutin, an inhibitor of gamma-glutamyltranspeptidase (GGT). Simultaneous injection of 5-oxoproline blocks these effects of anthglutin. In pregnant rats, inhibition (79%) of placental GGT activity by acivicin results in a 50% decrease of placental L-[U-14C]-alanine transfer and 70-80% decrease in its incorporation into the placental and fetal proteins. Infusion of 5-oxoproline to mothers previously treated with acivicin restored the L-[U-14C]-alanine transfer. Acivicin or 5-oxoproline did not modify the transfer and metabolism of D-[U14C]glucose by the fetal placental unit. These results show that the gamma-glutamyl cycle should not be considered a mechanism for amino acid transport but rather a generator of extracellular signals, gamma-glutamyl amino acids, that are converted intracellularly to 5-oxoproline, which activates uptake and/or metabolism of amino acids.
Mechanisms underlying enhanced glycogenolysis in livers of 3,5,3'-triiodothyronine-treated rats
Authors: Nebioglu S. , Wathanaronchai P. , Nebioglu D. , Pruden E. L. , Gibson D. M.
Published: December 2017

Rats trained on a diurnal controlled meal-feeding schedule and injected with a single dose of 3,5,3'-triiodothyronine (T3) failed to accumulate liver glycogen and incorporated less D-[6-3H]glucose into glycogen than normally observed during the feeding period. In the experimental group, the concentration of liver adenosine 3',5'-cyclic monophosphate (cAMP) did not fall during feeding and the pattern of activities of glycogen phosphorylase, glycogen synthase, and phosphorylase kinase remained conductive to glycogenolysis. Liver lysosomal alpha-glucosidase activity normally fell during feeding periods. After T3 treatment the activities of alpha-glucosidase and two lysosomal cathepsins (B1 and D) were elevated. The evidence suggests that T3 may induce both liver phosphorylase kinase and lysosomal alpha-glucosidase. This outcome of T3 excess, in concert with previously described T3-inducible systems, provides a plausible explanation for the failure of glycogen accumulation in this experimental model.
Dissociation of the effects of epinephrine and insulin on glucose and protein metabolism
Authors: Castellino P. , Luzi L. , Del Prato S. , DeFronzo R. A.
Published: December 2017

The separate and combined effects of insulin and epinephrine on leucine metabolism were examined in healthy young volunteers. Subjects participated in four experimental protocols: 1) euglycemic insulin clamp (+80 microU/ml), 2) epinephrine infusion (50 ng.kg-1.min-1) plus somatostatin with basal replacement of insulin and glucagon, 3) combined epinephrine (50 ng.kg-1.min-1) plus insulin (+80 microU/ml) infusion, and 4) epinephrine and somatostatin as in study 2 plus basal amino acid replacement. Studies were performed with a prime-continuous infusion of [1-14C]leucine and indirect calorimetry. Our results indicate that 1) hyperinsulinemia causes a generalized decrease in plasma amino acid concentrations, including leucine; 2) the reduction in plasma leucine concentration is primarily due to an inhibition of endogenous leucine flux; nonoxidative leucine disposal decreases after insulin infusion; 3) epinephrine, without change in plasma insulin concentration, reduces plasma amino acid levels; 4) combined epinephrine-insulin infusion causes a greater decrease in plasma amino levels than observed with either hormone alone; this is because of a greater inhibition of endogenous leucine flux; and 5) when basal amino acid concentrations are maintained constant with a balanced amino acid infusion, epinephrine inhibits the endogenous leucine flux. In conclusion, the present results do not provide support for the concept that epinephrine is a catabolic hormone with respect to amino acid-protein metabolism. In contrast, epinephrine markedly inhibits insulin-mediated glucose metabolism.
Catecholamines increase lymphocyte beta 2-adrenergic receptors via a beta 2-adrenergic, spleen-dependent process
Authors: Van Tits L. J. , Michel M. C. , Grosse-Wilde H. , Happel M. , Eigler F. W. , Soliman A. , Brodde O. E.
Published: December 2017

We investigated the mechanisms underlying the increase in mononuclear leukocyte (MNL) beta 2-adrenergic receptor (AR) number and responsiveness after acute infusion of catecholamines. Infusion of isoproterenol and epinephrine, but not of norepinephrine, acutely increased MNL beta-AR density, and this was blocked by the beta 2-selective antagonist ICI 118,551 but not by the beta 1-selective antagonist bisoprolol, suggesting a beta 2-AR-mediated effect. Infusion of isoproterenol but not of norepinephrine also induced a lymphocytosis, with an increase in the number of circulating suppressor/cytolytic T (Ts/c)- and natural killer (NK)-cells but a decrease in helper T (Th)-cells, leading to a decreased Th-Ts/c-cell ratio. beta-AR density was higher in Ts/c-cells than in Th-cells. After isoproterenol infusion, beta-AR density was elevated in all lymphocyte subsets but not in monocytes or platelets, suggesting a lymphocyte-specific phenomenon. Infusion of isoproterenol in splenectomized patients did not alter lymphocyte subset composition and only slightly increased beta 2-AR density. In healthy subjects lymphocyte proliferation in response to various mitogens was attenuated after infusion of isoproterenol but not of norepinephrine; this effect was abolished in splenectomized patients. We conclude that the elevated MNL beta-AR density after acute exposure to beta-adrenergic agonists is caused by a release of lymphocyte subsets from the spleen into the circulation and/or by an exchange of lymphocyte subsets between the spleen and the circulation, whereby freshly released splenic lymphocytes appear to carry more beta-AR than those found in the circulation. This appears to impair immune responsiveness in a dual manner, by decreasing the Th-/Ts/c-cell ratio and by rendering lymphocytes more sensitive to the antiproliferative effects of catecholamines via a higher beta-AR density.
Mechanism of sympathetic neural regulation of insulin, somatostatin, and glucagon secretion
Authors: Kurose T. , Seino Y. , Nishi S. , Tsuji K. , Taminato T. , Tsuda K. , Imura H.
Published: December 2017

The effects of electrical stimulation of the left splanchnic nerve on insulin, somatostatin, and glucagon secretion from the isolated perfused rat pancreas were investigated. Electrical splanchnic nerve stimulation (SNS), performed by square-wave impulses, produced a 25% decrease in effluent flow and a 10-fold increase in perfusate norepinephrine. Both insulin and somatostatin output in the presence of 16.7 mM glucose were inhibited during SNS by 85 and 56% of the basal value, respectively. Glucagon output in the presence of 5.5 mM glucose was stimulated 20-fold by SNS. Perfusion with 10(-6) M propranolol further decreased insulin and somatostatin output during SNS, when expressed as the total decrement beneath basal during stimulation. The glucagon response to SNS tended to be enhanced, although not significantly, by simultaneous infusion of 10(-6) M propranolol. However, 10(-6) M phentolamine (Phe) attenuated the SNS-induced inhibition of insulin and somatostatin output by 50 and 40%, respectively. However, insulin output remained decreased after SNS with Phe. The SNS-induced glucagon response was completely abolished by 10(-6) M Phe alone or by 10(-6) M Phe plus 10(-6) M propranolol. With 10(-6) M Phe plus 10(-6) M propranolol, insulin and somatostatin output remained decreased after SNS. These results suggest that insulin and somatostatin secretions induced by glucose are inhibited during SNS through the alpha-adrenergic mechanism and also that the beta-adrenergic mechanism exerts a stimulatory action. SNS-induced glucagon secretion occurs mainly through alpha-adrenergic activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools
Authors: Ritchie D. G.
Published: December 2017

Cytokines, derived from a wide variety of cell types, are now believed to initiate many of the physiological responses accompanying the inflammatory phase that follows either Gram-negative septicemia or thermal injury. Because hypoglycemia (after endotoxic challenge) and hyperglycemia (after thermal injury) represent well-characterized responses to these injuries, we sought to determine whether hepatic glycogen metabolism could be altered by specific cytokines. Cultured adult rat hepatocytes were prelabeled with [14C]glucose for 24 h, a procedure that resulted in the labeling of hepatic glycogen pools that subsequently could be depleted (with concomitant [14C]glucose release) by either glucagon or norepinephrine. After the addition of a highly concentrated human monocyte-conditioned medium (MCM) or various cytokines to these prelabeled cells, [14C]glucose release was stimulated by MCM and recombinant human interleukin 6 (IL-6) but was not stimulated by other cytokines tested. Furthermore, only antisera to IL-6 were capable of reducing the glucose-releasing factor activity found in MCM. These data therefore suggest a novel glucoregulatory role for IL-6.
Effects of epidermal growth factor on bone formation and resorption in vivo
Authors: Marie P. J. , Hott M. , Perheentupa J.
Published: December 2017

The effects of mouse epidermal growth factor (EGF) on bone formation and resorption were examined in male mice. EGF administration (2-200 ng.g-1.day-1 ip for 7 days) induced a dose-dependent rise in plasma EGF levels that remained within physiological range. Histomorphometric analysis of caudal vertebrae showed that EGF (20 and 200 ng.g-1.day-1) reduced the endosteal matrix and mineral appositional rates after 5 days of treatment as measured by double [3H]proline labeling and double tetracycline labeling, respectively. This effect was transitory and was not observed after 7 days of EGF administration. EGF administered for 7 days induced a dose-dependent increase in the periosteal osteoblastic and tetracycline double-labeled surfaces. At high dosage (200 ng.g-1.day-1) EGF administration increased the osteoclastic surface and the number of acid phosphatase-stained osteoclasts, although plasma calcium remained normal. The results show that EGF administration at physiological doses induces distinct effects on endosteal and periosteal bone formation and that the effects are dependent on EGF dosage and duration of treatment. This study indicates that EGF at physiological dosage stimulates periosteal bone formation and increases endosteal bone resorption in the growing mouse.
Insulin-like growth factor I receptors in adult rat liver: characterization and in vivo regulation
Authors: Venkatesan N. , Davidson M. B.
Published: December 2017

Although the presence of significant amounts of insulin-like growth factor (IGF)-I receptors in fetal tissues is well documented, adult liver has been reported to contain little or no IGF-I binding activity. In the present investigation, substantial amounts of specific IGF-I receptors were detected in crude membrane fractions and in partially purified receptor preparations of female adult rat liver. Insulin was 100 times less potent than IGF-I in competing for 125I-IGF-I binding. IGF-I binding activity was much less than that of insulin binding in both the microsomal fraction and partially purified receptor preparations. Affinity cross-linking of 125I-IGF-I to purified receptors and microsomal fractions followed by electrophoretic analysis under nonreducing conditions revealed labeling of proteins with relative molecular weight (Mr) of 350,000 and 210,000-220,000, corresponding to the molecular mass of the intact tetramer and alpha-beta dimers, respectively. Under reducing conditions, the labeling of proteins with Mr of 130,000 and 260,000, corresponding to the alpha-subunit of IGF-I receptor and its dimer, respectively, was observed. Treatment of microsomes as well as partially purified receptors with 0.5-1 mM dithiothreitol resulted in decreased IGF-I binding, and this correlated with structural changes in the receptor as detected by affinity labeling and electrophoretic analysis. Hepatic IGF-I binding activity was significantly diminished in female rats exposed to chronic growth hormone excess, suggesting down-regulation of IGF-I receptors by the enhanced circulating levels of IGF-I in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate
Authors: Blondel O. , Simon J. , Chevalier B. , Portha B.
Published: December 2017

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity.