bluuebunny/crossref_metadata_2025 huggingface dataset:
A multiresponse parathyroid hormone assay: an inhibitor has agonist properties in vivo
Authors: Horiuchi N. , Rosenblatt M. , Keutmann H. T. , Potts J. T. , Holick M. F.
Published: December 2017

Vitamin D-deficient rats subjected to thyroparathyroidectomy (TPTX) were used to evaluate in vivo the biological properties of native bovine parathyroid hormone (bPTH) and chemically synthesized fragments and analogues of the hormone on several parameters of hormone action: calcium and phosphorus fluxes, generation of cyclic adenosine 3',5'-monophosphate (cAMP), and the metabolism of 25-hydroxyvitamin D3 [25(OH)D3]. Vitamin D-deficient rats, after TPTX or sham operation, were intravenously infused with a nutrient containing 7.5 mM CaCl2 for 30 h. During the last 7 h, PTH or one of its analogues was infused intravenously at rates between 0.04 and 20 nmol/h. One hour after the start of the peptide infusion, tritiated 25(OH)D3 was injected. Urine was collected hourly for phosphate and cAMP determinations and, at the end of the experiment, blood was obtained to determine the relative accumulation of tritiated 1,25-dihydroxyvitamin D3 ([3H]1,25(OH)2D3). Infusion of bPTH-(1--84), bPTH-(1--34), human (h)PTH-(1--34), or [Nle8, Nle18, Tyr34]bPTH-(1--34) amide was accompanied by a comparable dose-dependent decrease in plasma phosphate and a dose-dependent increase in plasma calcium and [3H]-1,25(OH)2D3, and urinary excretion of phosphate and cAMP. An evaluation of [Nle8, Nle18, Tyr34]bPTH-(3--34) amide, a potent inhibitor of PTH action in vitro in the renal adenylate cyclase assay, revealed that the analogue possessed weak agonist properties in vivo. The analogue increased excretion of both cAMP and phosphate in the urine, decreased plasma phosphate levels, and increased the accumulation of [3H]-1,25(OH)2D3 in the plasma. This multiparameter model system should aid in the elucidation of the in vivo biological effects of PTH and its analogues.
Effect of changes in thyroid status on tissue respiration in fetal and newborn sheep
Authors: Klein A. H. , Reviczky A. , Padbury J. F. , Fisher D. A.
Published: December 2017

The effect of both exogenous and endogenous changes in thyroid status on in vitro tissue respiration and thermogenic enzymes (sodium-potassium-adenosine triphosphatase and alpha-glycerophosphate dehydrogenase) was studied in fetal and newborn sheep. Oxygen consumption of liver and brain increased from 25 +/- 4.1 and 58.5 +/- 2.8 microliters O2 X 100 mg-1 X h-1, respectively, in tissues from unthyroidectomized fetal animals at 136-140 days gestation to 60 +/- 4.2 and 72 +/- 1.5 microliters O2 X 100 mg-1 X h-1 in tissues from unthyroidectomized newborn lambs between birth and 7 days of age. The physiological changes in thyroid function that normally occur at birth resulted in a mean (+/- SE) plasma triiodothyronine (T3) concentration of 563 +/- 39 ng/dl in the newborn lambs compared with 39 +/- 8 ng/dl in the fetal animals. Kidney respiration and thermogenic enzyme activities in the several tissues studied did not change. Liver, kidney, and brain respiration and thermogenic enzymes from T3-treated thyroidectomized fetal and newborn lambs were not increased (compared with untreated thyroidectomized animals) despite a marked increase in plasma T3 concentrations. Conclusions are that 1) liver, kidney cortex, and frontal brain cortex in the fetal and newborn lamb are relatively insensitive to the calorigenic effect of thyroid hormones, and 2) a perinatal increase in hepatic and cerebral respiration occurs in newborn animals (compared with fetal animals) but is probably not due solely to perinatal increases in thyroid hormones.
Dissociation of membrane potential and hormone secretion in bovine parathyroid cells
Authors: Morrissey J. J. , Klahr S.
Published: December 2017

An increase in the calcium ion concentration of the medium from 0.5 to 2.0 mM is associated with a 65% decrease in the secretion of parathyroid hormone from dispersed parathyroid cells. This maneuver also depolarized the cell membrane from -55 to -21 mV as measured by the distribution of [3H]tetraphenylphosphonium ion between cells and medium. An increase in the potassium ion concentration of the medium to 50 mM caused a 67% increase in hormone secretion at 0.5 mM calcium and depolarized the cell to -31 mV. The high potassium did not significantly change hormone secretion or the membrane potential at 2.0 mM calcium. Chlorpromazine inhibited hormone secretion by 40% and depolarized the cell to -30 mV at 0.5 mM calcium in the medium. Chlorpromazine did not change hormone secretion or membrane potential in cells incubated at 2.0 mM calcium. These results suggest that depolarization of the cell by calcium cannot account by itself for the inhibition of hormone secretion and chlorpromazine mimics the effect of an increase in calcium on parathyroid cell function.
Effect of phenobarbital treatment on metabolism of vitamin D by rat liver
Authors: Baran D. T.
Published: December 2017

Phenobarbital has been postulated to impair hepatic conversion of vitamin D to 25-hydroxyvitamin D [25(OH)D] either by accelerating the conversion of vitamin D to biologically inactive products or by directly inhibiting 25(OH)D production. The effect of a dose of phenobarbital documented to decrease circulating 25(OH)D levels on hepatic vitamin D metabolism has been investigated in rachitic rats with a recycling in vitro hepatic perfusion system. Phenobarbital (75 mg/kg/day) administered intraperitoneally to D-replete rats increased circulating 25(OH)D blood levels after 4 wk of therapy but was attended by decreased levels after 6 and 8 wk. Rachitic rats were then injected daily with phenobarbital for either 4 or 8 wk and the livers removed and perfused at a rate of 15 ml/min for 3 h. The concentrations of [3H]25(OH)D in the hepatic perfusate at 3 h was decreased after both 4 and 8 wk of phenobarbital. Although total [3H]-25(OH)D production (hepatic plus perfusate) was unaffected by phenobarbital, the efficiency of hepatic production was decreased after 8 wk of treatment and the release of [3H]-25(OH)D from the liver into the perfusate was inhibited after both 4 and 8 wk. The data indicate that chronic phenobarbital therapy decreases both the release of [3H]25(OH)D from the liver into the perfusate and the efficiency of hepatic [3H]-25(OH)D production. Phenobarbital-induced inhibition of 25(OH)D release from the liver may be another mechanism for the low 25(OH)D levels noted in humans after long-term phenobarbital therapy.
Insulin regulation of fat cell ribosomes, protein synthesis, and lipoprotein lipase
Authors: Vydelingum N. , Drake R. L. , Etienne J. , Kissebah A. H.
Published: December 2017

Ribosomes of high purity were isolated from fat cells by discontinuous sucrose gradient centrifugation. Approximately 23% of the ribosomes were membrane bound. A reproducible fraction of ribosomes was recovered as polysomes capable of incorporating [3H]leucine into peptides in a cell-free system. Insulin (0.1-1.0 mU/ml) produced an increase in polysomal activity. Linear sucrose gradient profiles also revealed an increase in the ratio of polysomes to total ribosomes. Coincident with this effect, insulin increased the lipoprotein lipase activity fraction inhibitable by cycloheximide (0.01 mg/ml), and the immunotitratable enzyme activity. Insulin also enhanced the incorporation of labeled amino acids into adipose tissue immunoprecipitable lipoprotein lipase and total fat cell proteins. Cordycepin (0.1 mg/ml) or alpha-amanitin (10 micrograms/ml) partially inhibited insulin effects on ribosomes and protein synthesis but not on lipoprotein lipase. EGTA (1mM) prevented all of the insulin effects, whereas the calcium ionophore A-23187 (2 microM) augmented the hormone actions. The ionophore alone partially mimicked the insulin effects. In adipocytes, insulin increased the size of the protein-synthesizing polysomal pool by a mechanism which, in part, requires nuclear mRNA processing. Insulin, however, increased lipoprotein lipase synthesis independent of nuclear events. Calcium ions may be important for the expression of these insulin effects.
Diminished sympathetic nervous system activity in genetically obese (ob/ob) mouse
Authors: Young J. B. , Landsberg L.
Published: December 2017

The genetically obese (ob/ob) mouse exhibits defective thermoregulatory responses to cold exposure. Pathophysiological explanations for this phenomenon have focused on abnormalities in intracellular metabolism or insensitivity of peripheral tissues to the thermogenic effects of catecholamines. Because the sympathetic nervous system (SNS) is subject to feedback regulation, a peripheral impairment in thermogenesis should be associated with a compensatory increase in SNS activity. To examine SNS activity in the ob/ob mouse, norepinephrine (NE) turnover was measured in heart and interscapular brown adipose tissue (IBAT) of ob/ob and lean mice. The results from studies utilizing radiolabeled NE or inhibition of NE biosynthesis with alpha-methyl-p-tyrosine to measure NE turnover demonstrated reductions in SNS activity of 33-56% in heart and of 45-73% in IBAT in ob/ob mice at ambient temperature (22 degrees C) compared with measurements in lean controls. During cold exposure (4 degrees C) NE turnover increased in heart and IBAT to a similar extent in both ob/ob and lean mice, but NE turnover rates in heart, and probably in IBAT as well, remained lower in the obese mice than in the lean despite the gradual development of hypothermia in the ob/ob mice during this period. Administration of naltrexone, a long-acting opiate antagonist, failed to reverse the suppression of SNS activity observed in the ob/ob mice. These data indicate that diminished SNS activity in ob/ob mice may be an additional factor contributing to the defective thermogenesis characteristic of these animals.
Hyperinsulinemia of obesity is due to decreased clearance of insulin
Authors: Meistas M. T. , Margolis S. , Kowarski A. A.
Published: December 2017

The hyperinsulinemia of obesity could result from a decrease in the metabolic clearance rate of insulin (MCR-I), an increase in the secretory rate of insulin (SR-I), or a combination of both these processes. Because C-peptide and insulin are secreted in an equimolar ratio, the plasma concentrations of C-peptide (C) and insulin (I) are inversely proportional to their rates of metabolic clearance (C/I = MCR-I/MCR-C). We obtained 24-h integrated concentrations (IC) of insulin (IC-I) and C-peptide (IC-C) in 23 obese and 45 nonobese subjects over a period of normal activity and food intake. The IC-I was 69% higher in the obese subjects (P less than 0.0001). A 13% increase in the IC-C (P = 0.04), with a constant rate of C-peptide clearance, indicates a proportionate increase in SR-I. A 33% decrease in the IC-C/IC-I in the obese group (P less than 0.005) reflects a decrease in MCR-I; hence, 75% of the hyperinsulinemia is due to a decrease in the clearance of insulin. Because peripheral MCR-I (pMCR-I) is similar in obese and nonobese subjects, the decrease in MCR-I may be due to a decrease in the hepatic clearance of insulin. This conclusion was supported by our comparison of 24-h IC-C/IC-I ratios in the obese and nonobese subjects. Whereas the 24-h IC-C/IC-I of the nonobese resembled the fasting state, the 24-h IC-C/IC-I of the obese resembled the postprandial state, when insulin removal by the liver is known to be suppressed. These data are consistent with a decreased 24-h hepatic MCR-I (hMCR-I) as the cause of the hyperinsulinemia of obesity.
Role of insulin in thermogenic responses to refeeding in 3-day-fasted rats
Authors: Rothwell N. J. , Saville M. E. , Stock M. J.
Published: December 2017

Refeeding 3-day-fasted rats with 40 kJ carbohydrate (CHO; corn flour) or protein (gelatin) caused a rise in plasma insulin levels 3 h later, but refeeding fat or injection of norepinephrine (400 micrograms/kg) had no effect. Injection of insulin (0.25 U) caused a 15% rise in metabolic rate 24 h later in fasted rats that could be inhibited by treatment with propranolol. Refeeding rats with a single CHO meal produced an increase in oxygen consumption (15%) 24 h later that was inhibited by injection of diazoxide or 2-deoxy-D-glucose given at the time of the meal. The thermogenic response to insulin injection was unaffected by treatment with diazoxide or 2-deoxy-D-glucose. Genetically obese Zucker rats failed to increase metabolic rate after insulin or CHO. In normally fed lean rats, maintained on a stock diet or a palatable cafeteria diet, insulin (4 U) enhanced the thermogenic response to norepinephrine and stimulated resting metabolic rate (16%) in the cafeteria-fed rats. These data suggest that insulin is involved in the thermogenic responses to food and catecholamines.
Further observations of aldosterone response in barnacle muscle fibers
Authors: Tallitsch R. B.
Published: December 2017

Work with single muscle fibers from the barnacle Balanus nubilus has revealed that these fibers can be rendered sensitive to external application of aldosterone by preexposing the barnacle in vivo to the steroid for 16 h. Experiments investigating the dose-response relationship, glucocorticoid sensitivity of the preparation, and the role of the mitochondria in the aldosterone response in this preparation are presented. It is demonstrated that saturation kinetics may be seen in the dose-response curve if care is taken to isolate only fibers from animals that are in midmolt cycle. Data is presented that demonstrated a specific mineralocorticoid response to aldosterone in this preparation rather than a combined mineralocorticoid-glucocorticoid response, as has been demonstrated in other preparations. Experiments investigating the role of the mitochondrial inhibitors and substrates suggest that aldosterone modulates Na efflux in barnacle muscle fibers by altering mitochondrial function, presumably at the level of succinic hydrogenase.
Endocrine basis for weight gain after fasting or VMH lesion in rats
Authors: Penicaud L. , Larue-Achagiotis C. , Le Magnen J.
Published: December 2017

To study some hormonal and metabolic factors contributing to the regulation of body fat mass, food intake, and the circadian lipogenesis-lipolysis pattern, insulin and glucose responses to intravenous glucose loads were measured in both phases of the light-dark cycle in two groups of rats considered to be below their level of body fat mass regulation [rats with lesion of the ventromedial hypothalamus nuclei (VMH) in the "dynamic" phase of obesity and food-restricted rats during the refeeding phase] compared with the responses of two other groups at this level (VMH-lesioned rats in "static" phase and normal rats). Glucose tolerance and insulin release were greater during the dynamic phase and to a lesser degree during refeeding than during the static phase and normal feeding. The differences between night and day found in normal rats disappeared in dynamic and refed animals and reappeared at the level of static phase. Thus the normal circadian hormonal metabolic patterns responsible for increased lipogenesis and relative hyperphagia during the night and lipolysis with hypophagia during the day were lost in rats below their level of body fat mass regulation and were reinstated in animals on returning to this level.
Increase in pituitary dopaminergic receptors after monosodium glutamate treatment
Authors: Heiman M. L. , Ben-Jonathan N.
Published: December 2017

We investigated whether a decrease in arcuate nucleus dopamine (DA) levels resulting from neonatal treatment with monosodium glutamate (MSG) affects the anterior pituitary DA receptors in adult male rats. MSG treatment resulted in a significant reduction in medial basal hypothalamic (MBH) DA levels, no change in its norepinephrine (NE) and epinephrine (E) concentrations, and a marked increase in circulating prolactin (PRL). Scatchard analyses of DA binding characteristics to anterior pituitary membranes using [3H]spiperone revealed linear plots, suggesting a single class of high-affinity, low-capacity binding sites. The DA binding capacity was significantly higher in MSG-treated rats than in controls with no change in affinity. The data indicate that anterior pituitary DA receptors change in accordance with altered physiological conditions. The increase in the number of DA receptors following destruction of the arcuate nucleus is probably a direct effect of reduced DA levels reaching the anterior pituitary gland.
Partition of maternal glucose production between conceptus and maternal tissues in sheep
Authors: Hay W. W. , Sparks J. W. , Wilkening R. B. , Battaglia F. C. , Meschia G.
Published: December 2017

Experiments were conducted in late-gestation, conscious, pregnant ewes to measure maternal glucose production and the net glucose uptake by the uterus, fetus, uteroplacenta, and nonuterine maternal tissues. Glucose concentration in the ewes varied naturally or decreased in response to fasting. Normoglycemic ewes (63.8 +/- 8.7 mg/dl) had a glucose production rate of 178.7 +/- 44.5 mg/min compared with a rate of 76.9 +/- 20.6 mg/min for hypoglycemic ewes (34.7 +/- 7.4 mg/dl). Uterine glucose uptake (56.5 +/- 16.8 mg/min), fetal glucose uptake (15.7 +/- 5.2 mg/min), uteroplacental glucose uptake (40.8 +/- 13.4 mg/min), and nonuterine maternal glucose uptake (122.2 +/- 27.7 mg/min) in the normoglycemic ewes were significantly greater than in the hypoglycemic ewes (28.7 +/- 5.4, 7.5 +/- 4.4, 21.2 +/- 6.6, and 48.2 +/- 15.2 mg/min, respectively). The fractional distribution of maternally produced glucose among nonuterine maternal tissues, the fetus, and the uteroplacenta was not altered markedly by hypoglycemia despite a 57% reduction in maternal glucose production.
Glucagon suppression improves glucoregulation in moderate but not chronic severe diabetes
Authors: Lickley H. L. , Kemmer F. W. , Doi K. , Vranic M.
Published: December 2017

To determine the effectiveness of glucagon suppression in improving glucose homeostasis in diabetes, tracer-determined glucose kinetics were measured during a 6-h somatostatin infusion in six alloxan-diabetic dogs (moderately severe diabetes) and five depancreatized dogs deprived of insulin treatment for 3 days (prolonged severe diabetes). Plasma immunoreactive glucagon (IRG) decreased 70 +/- 9% in the alloxan-diabetic and 80 +/- 4% in the depancreatized dogs. Portal vein levels of plasma immunoreactive insulin (IRI) fell (17.0 +/- 2.3 to 4 micro.5 +/- 0.4 microU/ml) as did peripheral vein IRI levels (6.7 +/- 0.9 to 4.7 +/- 0.5 microU/ml) in the alloxan-diabetic dogs. In the depancreatized dogs plasma IRI levels were undetectable. Plasma glucose concentrations fell (278 +/- 17 to 169 +/- 12 mg/dl) during IRG suppression in the alloxan-diabetic dogs due to a rapid and sustained decrease in glucose production (Ra) (6.0 + 0.9 to 3.6 + 0.3 mg X kg-1 X min-1). Glucose disappearance (Rd) decreased gradually (5.9 + 0.6 to 3.9 + 0.2 mg X kg-1 X min-1). In contrast, in the depancreatized dogs, IRG suppression did not alter glucose concentrations or kinetics. Thus, glucagon suppression decreased glycemia by decreasing Ra only in moderately severe diabetes. However, this was associated with decreased rather than improved glucose utilization. The ineffectiveness of glucagon suppression during prolonged severe diabetes could relate to the degree and duration of the metabolic derangement and/or indicate that the continuous presence of some insulin is necessary for glucagon suppression to improve glucose homeostasis.
[LeuB24]insulin is an insulin agonist at the liver in vivo
Authors: Figlewicz D. P. , Best J. D. , Tager H. S. , Taborsky G. J.
Published: December 2017

A mutant insulin isolated from the plasma of a diabetic patient has been reported to antagonize insulin action in vitro and was thought to be [LeuB24]insulin. This study examines the ability of [LeuB24]insulin to antagonize insulin action at the liver in vivo in anesthetized dogs. Antagonism of insulin action was first simulated by decreasing the intraportal insulin infusion 50%. This resulted in a significant increase in both glucose production (Ra) (delta = + 0.30 +/- 0.08 mg X kg-1 X min-1) and the glucose level in arterial plasma (delta = +6.5 +/- 2.8 mg/dl), validating the responsiveness of the preparation to partial insulin antagonism. [LeuB24]insulin was infused intraportally, at molar ratios of 1:1, 1:2, 1:4, and 1:10 (50, 25, 12.5, and 5 ng/min, respectively) with insulin (54 ng/min). Infusion at all but the lowest dose resulted in a significant drop in glucose production (delta = -0.44 +/- 0.07, -0.35 +/- 0.06, and -0.28 +/- 0.08 mg X kg-1 X min-1 for4 analogue infusions of 50, 25, and 12.5 ng/min, respectively) and plasma glucose levels (delta = -7 +/- 3 and -3 +/- 1 mg/dl for analogue infusions of 50 and 25 ng/min, respectively). No change in Rd (glucose disposal) was observed for either insulin withdrawal of [LeuB24]insulin infusion. We conclude that, at the liver in vivo, [LeuB24]insulin does not antagonize insulin action but rather acts as an insulin agonist. Its hepatic effects would not contribute to a diabetic hyperglycemia.
Autonomic nervous control of pancreatic somatostatin secretion
Authors: Holst J. J. , Jensen S. L. , Knuhtsen S. , Nielsen O. V.
Published: December 2017

We studied the autonomic nervous control of pancreatic somatostatin secretion using isolated perfused pig pancreases prepared with either intact vagal or splanchnic nerve supply. Electrical stimulation of the vagus nerves increased pancreatic protein output 59-fold, whereas somatostatin output decreased to 57% of prestimulatory secretion. Acetylcholine mimicked the somatostatin response to vagal stimulation, and atropine abolished the inhibition. Splanchnic nerve stimulation increased perfusion pressure up to threefold, whereas somatostatin output decreased to 68%. Phenoxybenzamine abolished the pressure response to splanchnic nerve stimulation and reversed the inhibition to a 20% increase in somatostatin output. Propranolol did not influence the inhibitory effect of splanchnic stimulation but abolished the increase seen after phenoxybenzamine. It is concluded that both divisions of the autonomic nerve supply to the pancreas are inhibitory to somatostatin secretion, but increased secretion may be brought about by a beta-adrenergic mechanism.
Effect of PTH and 1,25(OH)2D3 on renal 25(OH)D3 metabolism, adenylate cyclase, and protein kinase
Authors: Armbrecht H. J. , Wongsurawat N. , Zenser T. V. , Davis B. B.
Published: December 2017

The purpose of these studies was to characterize the action of PTH and 1,25(OH)2D3 on the renal metabolism of 25(OH)D3 to 1,25(OH)2D3 and 24,25(OH)2D3. Renal metabolism of 25(OH)D3, adenylate cyclase, and protein kinase activity were measured using isolated renal slices from rats fed a vitamin D-deficient, low-calcium diet and thyroparathyroidectomized. PTH added to renal slices for 4 h in vitro maximally increased 1,25(OH)2D3 production by 67% and decreased 24,25(OH)2D3 production by 24% over the concentration range 0.05-5.0 U/ml. Parathyroid hormone (PTH) (0.05 U/ml) added to renal slices for 5 min produced a significant increase in tissue cAMP and a near-maximal increase in cAMP-dependent protein kinase activity. Preincubation of renal slices with 50 nM 1,25(OH)2D3 decreased renal 1,25(OH)2D3 production by 26% and increased 24,25(OH)2D3 production by 55%. 1,25(OH)2D3 also blocked the effect of PTH (5.0 U/ml) on renal 25(OH)D3 metabolism. However, PTH-stimulated adenylate cyclase and protein kinase activity was not blocked by preincubation with 1,25(OH)2D3. These studies demonstrate that PTH may act directly on the kidney to modulate renal 25(OH)D3 metabolism and that this action can be inhibited by 1,25(OH)2D3. This inhibition by 1,25(OH)2D3 occurs at a site distal to or separate from PTH-stimulated protein kinase activity.
Modeling glucose disposal in diabetic dogs fed mixed meals
Authors: Yamasaki Y. , Tiran J. , Albisser A. M.
Published: December 2017

We have utilized a previously described mathematical model to study glucose disposal in fed, conscious, ambulatory, diabetic dogs. The model was applied to estimate the daily disposition of ingested glucose in the periphery, liver, and urine following a regular mixed meal containing 130 g of carbohydrate. Experimental data was obtained from 11 pancreatectomized animals. Both the portal and peripheral routes were used for intravenous insulin infusion and the daily profiles of peripheral plasma glucose and insulin concentrations measured. Total calories in mixed meals derived from carbohydrates (37%), fat (30%), and protein (30%). When judged according to the root-mean-square differences, agreement was excellent between model-predicted and experimentally observed glucose as well as insulin concentrations. This agreement occurred whether or not, in addition to basal insulin, meal insulin was also given. Using the model, we then predicted in detail the rates of glucose uptake in peripheral tissue, liver, and kidneys. With portally infused insulin resulting in diurnal glycemic normalization, the net daily hepatic glucose balance was physiological, being close to zero. Remarkably, with peripheral insulin infusions there was an unphysiological net negative hepatic glucose balance of 10 g/day.
Renin-angiotensin system in hypophysectomized rats. I. Control of blood pressure
Authors: Simon C. D. , Honeyman T. W. , Fray J. C.
Published: December 2017

The mechanisms whereby the pituitary gland maintains arterial pressure were investigated in rats. The arterial pressure in hypophysectomized rats was 30 mmHg below normal. Saralasin or captopril caused a further fall of 25 and 30 mmHg, respectively, suggesting that the renin-angiotensin system plays a role in blood pressure maintenance in hypophysectomized rats. Growth hormone administration to hypophysectomized rats increased the arterial pressure, but pretreatment with captopril prevented the effect. Plasma renin activity and basal renin secretion (in vitro) was normal in hypophysectomized rats despite a twofold greater renal renin content. Secretory responsiveness to isoproterenol and calcium omission was lower in hypophysectomized rats. It is concluded that the renin-angiotensin system plays a role in maintaining arterial blood pressure in hypophysectomized rats although the responsiveness of the system may be decreased.
Sex difference in insulin-stimulated glucose transport in rat and human adipocytes
Authors: Foley J. E. , Kashiwagi A. , Chang H. , Huecksteadt T. P. , Lillioja S. , Verso M. A. , Reaven G.
Published: December 2017

In an effort to determine whether differences in basal and maximum insulin-stimulated glucose transport by isolated adipocytes are a function of donor sex, we measured glucose transport rates in the absence and presence of 8 nM insulin in adipocytes isolated from the abdominal subcutaneous fat tissue of nine male and ten female subjects with varying degrees of obesity and in adipocytes isolated from the abdominal subcutaneous and retroperitoneal fat tissue of (180-220 g) male and female rats. Because maximal insulin-stimulated glucose transport rate per cell of adipocytes isolated from subcutaneous abdominal tissue of male and female subjects was constant in each sex, the data have been normalized on the basis of transport per cell. The results demonstrated that basal and maximal insulin-stimulated glucose transport per cell was 53-75% higher per cell in the females versus males in adipocytes from human subcutaneous abdominal adipose tissue (P less than 0.01). A similar difference in glucose transport rate between males and females (P less than 0.001) was also found in rat abdominal subcutaneous adipose tissue. Adipocytes isolated from rat retroperitoneal adipose tissue had higher transport rates (approximately three-fold) and smaller sex differences (35% higher in females) than found in adipocytes from rat and human subcutaneous tissue. These results indicate that basal and maximum insulin-stimulated glucose transport is higher by adipocytes isolated from females and that this difference is independent of adipose cell size and species.
Glucagon and glucose dynamics in sheep: evidence for glucagon resistance in the fetus
Authors: Devaskar S. U. , Ganguli S. , Styer D. , Devaskar U. P. , Sperling M. A.
Published: December 2017

We compared the effects of glucagon infused at 5 and 50 ng X kg-1 X min-1 on glucose turnover (GT), production (Ra), and utilization (Rd) in the fetal (F; n = 5, gestation 129 +/- 3 days, term approximately 150 days) and nonpregnant adult (A; n = 5 and 6) sheep. Infusion of glucagon at 5 ng X kg-1 X min-1 raised fetal glucagon levels (IRG) from a basal of 168 +/- 27 to a mean sustained level of 863 +/- 160 pg/ml but had no effect on basal levels of glucose (G) of 12 +/- 3 mg/dl, insulin (IRI) of 16 +/- 3 microU/ml, GT of 21 +/- 1.3 mg/min, and Rd of 15 +/- 2 mg/min; Ra remained negligible. When fetal IRG was raised to a mean sustained level of 1,809 +/- 210 pg/ml by infusion of glucagon at 50 ng X kg-1 X min-1, G doubled to 23 +/- 1.5 mg/dl, IRI rose to 21 +/- 0.9 microU/ml, GT rose to 60 +/- 5 mg/min, Rd to 30 +/- 4.8 mg/min, and Ra to 41 +/- 6 mg/min (P less than 0.01 for each) indicating induction of F glucose production so that GT was now derived from endogenous sources. By contrast, when IRG levels were raised from 109 +/- 10 to 538 +/- 43 pg/ml by infusion of 5 ng X kg-1 X min-1 to A, basal G rose from 56 +/- 2 to 88 +/- 6 mg/dl, IRI from 24 +/- 2 to 45 +/- 6 microU/ml, GT and Ra from 93 +/- 7 to 173 +/- 17 mg/min, and Rd from 93 +/- 7 to 148 +/- 12 mg/min (P less than 0.01 for each). No further increments of these indexes occurred in A when IRG was raised to a mean sustained level of 2,275 +/- 135 pg/ml by infusion of 50 ng X kg-1 X min-1. These results indicate a relative resistance in F to the glycemic effects of glucagon, consistent with previously demonstrated decreases of hepatic glucagon receptors and glucagon-stimulated cAMP production in fetal liver.
Impaired energy utilization and Na-K-ATPase in diabetic peripheral nerve
Authors: Greene D. A. , Lattimer S. A.
Published: December 2017

Recent electrophysiological and biochemical evidence implicates altered peripheral nerve Na-K-ATPase activity in the nerve conduction impairment of acute experimental diabetes. Composite in vitro nerve energy utilization is seriously impaired by experimental diabetes, yet is not modulated directly by insulin action on peripheral nerve. Therefore, we hypothesized that the reduction in diabetic nerve energy utilization reflects impaired nerve Na-K-ATPase activity. The reduction in steady-state energy utilization in diabetic peripheral nerve is shown to be quantitatively equal to the ouabain-inhibitable fraction of respiration, a measure of Na-K-ATPase activity in peripheral nerve. Na-K-ATPase activity in diabetic (but not nondiabetic) endoneurial preparations is influenced by medium solute concentration. Furthermore, diabetic nerve Na-K-ATPase activity and sodium-dependent myo-inositol uptake are similarly affected by medium solute changes, suggesting that the nerve sodium gradient may limit intracellular myo-inositol uptake in diabetic nerve. Conversely, because reduced diabetic nerve myo-inositol content impairs nerve Na-K-ATPase, a possible pathophysiological cycle of progressively deranged myo-inositol metabolism and Na-K-ATPase function may exist in diabetic peripheral nerve.
Hepatic extraction of exogenous insulin in depancreatized conscious dogs
Authors: Ishida T. , Chap Z. , Chou J. , Lewis R. M. , Hartley C. J. , Entman M. L. , Field J. B.
Published: December 2017

Hepatic and mesenteric extraction of exogenous insulin and glucose appearance and clearance were compared in conscious depancreatized and normal dogs after intraportal or peripheral intravenous insulin infusion. Portal vein insulin levels were higher, whereas arterial insulin levels were lower after intraportal compared with intravenous peripheral infusion of insulin. During the intraportal infusion of 1 and 2 mU X kg-1 X min-1 insulin, 40 +/- 3% of the insulin presented to the liver was extracted by that organ in the diabetic dogs, similar to the value obtained in normal dogs (39 +/- 5%). Hepatic extraction of insulin after intravenous peripheral infusion of that hormone was similar in normal and diabetic dogs and was not significantly different from intraportal infusion. Mesenteric extraction of insulin in the diabetic dogs (13 +/- 2%) was similar to the 19 +/- 3% in the normal animals. The blood sugar changes were similar after both routes of insulin infusion. Suppression of glucose appearance in diabetic dogs was also similar during both routes of infusion. Glucose clearance during the peripheral intravenous infusion of insulin in diabetic dogs was greater than during intraportal insulin. These findings indicate that hepatic extraction of exogenous insulin was similar in normal and depancreatized dogs and was not influenced by the different infusion routes. Suppression of glucose appearance in diabetic dogs was similar after both routes despite different portal vein insulin levels. The peripheral action of intravenous peripheral infused insulin in diabetic dogs was greater than that of intraportal insulin reflecting the higher arterial insulin levels.
Adaptation of B and A cell function during prolonged glucose infusion in human subjects
Authors: Ward W. K. , Halter J. B. , Beard J. C. , Porte D.
Published: December 2017

States of insulin resistance are characterized by hyperinsulinemia that often appears to be out of proportion to the minimal degree of hyperglycemia. One possible explanation for these findings is that mild hyperglycemia per se can cause an adaptive increase in islet sensitivity to glucose, leading to increased insulin output at a given glucose level. To test this hypothesis, we compared acute insulin responses (AIR) and acute glucagon responses (AGR) to 5-g arginine injections before and after 20-h glucose infusions (200 mg X m-2 X min-1) in 11 healthy men of varying age and degree of adiposity. The 20-h glucose infusion caused an increase in fasting plasma glucose (PG) in all subjects (95 +/- 2 vs. 130 +/- 3 mg/dl). PG was clamped at three levels (approximately 95, 165, and 235 mg/dl) before and after the 20-h glucose infusion. Despite matching of PG levels, consistent increases of AIR were observed after the 20-h glucose infusion: 86 +/- 10 vs. 57 +/- 8 at PG = 95 (P = 0.002); 241 +/- 20 vs. 192 +/- 22 at PG = 165 (P = 0.02); and 508 +/- 59 vs. 380 +/- 50 microU/ml at PG = 235 mg/dl (P = 0.009). In addition, the slope of the relationship between AIR and PG level (potentiation slope), a measure of B cell sensitivity to glucose, increased consistently from 2.28 +/- 0.35 (control) to 3.07 +/- 0.45 (P = 0.004) after the 20-h infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Maternal-fetal glucose exchange: necessity of a three-pool model
Authors: Hay W. W. , Sparks J. W. , Battaglia F. C. , Meschia G.
Published: December 2017

Tracer glucose was infused simultaneously into mother ( [6-3H]glucose) and fetus ( [U-14C]glucose) in pregnant sheep in the last month of gestation to study the exchange of glucose molecules between maternal and fetal blood. Net rates of entry and exit of tracer glucose via the uterine and umbilical circulations were measured by application of the Fick principle under steady-state conditions. The net flux of fetal tracer to the uteroplacenta from the fetus was 53.4 +/- 3.1% of the fetal tracer infusion. The net flux of fetal tracer into maternal blood was 43.8 +/- 5.0% of the net flux of fetal tracer to the uteroplacenta from fetal blood. The net flux of maternal tracer to the uterus from the mother was 31.7 +/- 2.8% of the maternal tracer infusion. The net flux of maternal tracer into fetal blood was 40.5 +/- 4.4% of the net flux to pregnant uterus from maternal blood. This evidence demonstrates that the uteroplacental tissue mass constitutes a glucose pool that is interposed between the maternal and fetal glucose pools and rapidly metabolizes glucose molecules derived from both maternal and fetal blood. Calculations based on a three-pool model show that the fetal glucose pool contributes approximately 40% of the glucose that is metabolized by the placenta. The comparison of the three-pool model with a previously proposed two-pool reversible model shows that the latter lumps the placental utilization of fetal glucose with fetal glucose utilization and overestimates the rate of fetal glucose metabolism by approximately 60%.
Glucocorticoid sites in skeletal muscle: adrenalectomy, maturation, fiber type, and sex
Authors: DuBois D. C. , Almon R. R.
Published: December 2017

The glucocorticoid receptor population in skeletal muscle of the rat was examined. Data are included that address the following: tissue preparation, receptor stabilization, method of assay and analysis, cross-reactivity of a large variety of steroids, time to equilibrium, and the effect of adrenalectomy on the number of sites as well as the apparent binding affinity. In addition, we have observed the following: 1) an exponential decline in the concentration of sites from 27 to 160 days after birth; 2) a significantly higher concentration of sites in muscle from male animals as compared with female animals; and 3) a significantly higher concentration of sites in the slow-fiber soleus muscle as compared with the fast-fiber extensor digitorum longus muscle.
GTP and Na+ modulate receptor-adenyl cyclase coupling and receptor-mediated function
Authors: Limbird L. E.
Published: December 2017

Activation and inhibition of adenylate cyclase activity is mediated via two distinct GTP-binding proteins. In both stimulatory and inhibitory systems, receptor occupancy by a hormone or agonist drug stabilizes receptor interactions with its functionally associated GTP-binding protein and, as a consequence, facilitates GTP occupancy of the regulatory protein. Activation of cyclase proceeds until GTP is hydrolyzed to GDP. Although hormonal inhibition of cyclase is elicited by a sequence of molecular events seemingly parallel to those for activation of cyclase, it is not known whether hormonal inhibition of cyclase involves the direct interaction of the GTP-occupied inhibitory regulatory protein with the catalytic subunit or results indirectly from destabilization of the interaction of the stimulatory GTP-binding protein with the catalytic moiety. Sodium ion also modulates receptor-mediated inhibition of adenylate cyclase, although apparently via a component distinct from the GTP-binding subunit of the inhibitory GTP-binding protein. Sodium also influences the physiological functions elicited by receptors that mediate inhibition of cyclase, at least for alpha 2-adrenergic-promoted platelet secretion. The relationship between sodium effects on hormonal attenuation of cAMP accumulation and elicited physiological effects is discussed.
Changes in plasma zinc content after exercise in men fed a low-zinc diet
Authors: Lukaski H. C. , Bolonchuk W. W. , Klevay L. M. , Milne D. B. , Sandstead H. H.
Published: December 2017

For 30 days five healthy men aged 23-57 yr consumed a diet adequate in zinc (8.6 mg/day); they ate a low-zinc diet (3.6 mg/day) for the next 120 days and then received a zinc-supplemented (33.6 mg/day) diet for 30 days. Copper intake was constant at 1.8 mg/day. Aerobic capacity was determined periodically during each diet period. Relative zinc balance (% of control) declined during depletion (r = -0.28, P less than 0.009). Pre- and postexercise zinc concentrations decreased when dietary zinc was restricted (r = -0.61, P less than 0.0001 and r = -0.78, P less than 0.0001) and increased with supplementation (r = 0.61, P less than 0.008 and r = 0.76, P less than 0.0003, respectively). Both plasma zinc and hematocrit increased (P less than 0.01) after maximal exercise. To minimize the effect of hemoconcentration during exercise, the van Beaumont quotient (J. Appl. Physiol. 34: 102-106, 1973) was calculated using pre- and postexercise hematocrit and plasma zinc. The initial quotient of 1.8 +/- 1.8% (mean +/- SE) declined (P less than 0.05) to -7.4 +/- 2.3% during depletion. With zinc repletion, the quotient increased to 6.9 +/- 3.6%, which was greater (P less than 0.05) than the quotient in depletion but similar to the initial quotient. The quotient was a strong predictor (r = 0.71, P less than 0.0005) of the change in relative zinc balance during zinc depletion. In contrast, no changes were found in plasma copper content. These data suggest that zinc mobilization from tissues is impaired during zinc depletion, and they validate the use of the van Beaumont quotient as an index of change in body zinc stores.
Sympathoadrenal system and regulation of thermogenesis
Authors: Landsberg L. , Saville M. E. , Young J. B.
Published: December 2017

The sympathetic nervous system (SNS) plays a critical role in the regulation of mammalian thermogenic responses to cold exposure and dietary intake. Catecholamine-stimulated thermogenesis is mediated by the beta-adrenergic receptor. In the rat brown adipose tissue is the major site of metabolic heat production in response to both cold (nonshivering thermogenesis) and diet (diet-induced thermogenesis). Measurements of norepinephrine turnover rate in interscapular brown adipose tissue of the rat demonstrate increased sympathetic activity in response to both cold exposure and overfeeding. In adult humans, a physiologically significant role for brown adipose tissue has not been established but cannot be excluded. It appears likely that dietary changes in SNS activity are related, at least in part, to the changes in metabolic rate that occur in association with changes in dietary intake.
Defective glucose counterregulation limits intensive therapy of diabetes mellitus
Authors: Santiago J. V. , White N. H. , Skor D. A. , Levandoski L. A. , Bier D. M. , Cryer P. E.
Published: December 2017

Defective recovery from insulin-induced hypoglycemia, due to combined deficiencies of glucagon and epinephrine secretory responses to plasma glucose decrements, occurs in some patients with insulin-dependent diabetes mellitus (IDDM). Patients with IDDM determined to have inadequate glucose counterregulation during an insulin infusion test (40 mU X kg-1 X h-1) with bedside plasma glucose monitoring and clinical observation have been found to have a 25-fold greater risk of severe hypoglycemia during subsequent intensive therapy than patients with adequate glucose counterregulation. Thus, the efficacy of the glucose counterregulatory systems determines the limits of intensive therapy of IDDM.
Alterations in rat epidermis provoked by chronic vitamin D deficiency
Authors: Pavlovitch J. H. , Galoppin L. , Rizk M. , Didierjean L. , Balsan S.
Published: December 2017

Long-term effects of vitamin D deficiency on epidermis were studied using histometric techniques, [3H]thymidine incorporation into DNA (labeling index), estimation of epidermal acid phosphatase activity, and one-dimensional gel electrophoresis of keratin proteins. The decrease in epidermal thickness due to a reduced number of granular cell layers and a lower level of epidermal acid phosphatase activity were observed in vitamin D-deficient rats. The number of nuclei in the basal layer was increased. No changes in labeled index due to chronic vitamin D deficiency or to 'single injection of 1,25-dihydroxycholecalciferol to vitamin D-deficient rats were observed. A comparative study of the keratin composition revealed differences in the keratin polypeptide pattern: vitamin D-deficient epidermis specifically lacked two low-molecular-weight components and presented several quantitative differences among other keratin polypeptides. The changes in epidermal morphology and metabolism that took place with vitamin D deficiency were independent of plasma calcium levels because similar modifications were present in vitamin D-deficient but normocalcemic rats (fed a diet rich in calcium and supplemented with lactose). These findings suggest that vitamin D may be one of the important factors for maintaining normal epidermal structure and metabolism through an effect on cell differentiation and formation of granular cell layers. They offer the possibility of using epidermal modification as an additional marker of vitamin D deficiency.
Effect of testosterone on gonadotropin response to DBcAMP, cAMP binding, and cAMP production in pituitary cultures
Authors: Tang L. K. , Martellock A. C. , Tang F. Y.
Published: December 2017

The role of testosterone (T) in the modulation of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) sensitivity to DBcAMP was examined in the pituitary monolayer cultures prepared from intact young female rats. Hormone contents in media and cell homogenates were determined by radioimmunoassays. Incubation with 8 and 4 mM DBcAMP for 4 h consistently induced a significant (P less than 0.05) increase in FSH and LH release, respectively. Pretreatment with 10 nM T for 4 days reduced the minimal dose of DBcAMP required to stimulate FSH release (2 vs. 8 mM) but had no effect on the DBcAMP-induced LH release. Data indicate that T treatment for 4 or 7 days stimulated total FSH contents (sum of hormone contents in medium and cells). Similarly, incubation with 10 mM DBcAMP for 4 h significantly increased total FSH content per dish in both the T-treated and non-T-treated cultures. Neither T nor DBcAMP had any effect on LH production under these conditions. Intracellular cAMP was significantly increased to three- to eightfold of control after T treatment for 3 or 6 h, respectively. Furthermore, cAMP-binding activities were significantly increased after T treatment for 1 or 4 days (174 or 422% of control). Our previous data indicate that estrogen increases LH production, cAMP binding, cAMP production, and LH sensitivity to DBcAMP, and these data indicate that T exerts stimulatory effects on FSH in a similar fashion. These results support the concept that the two gonadotropins are regulated independently via different gonadal steroids.
Measurement of glycerol turnover by infusion of nonisotopic glycerol in normal and injured subjects
Authors: Carpentier Yvon A. , Jeevanandam Malayappa , Robin Arnold P. , Nordenström Jorgen , Burr Robert E. , Leibel Rudolph L. , Hirsch Jules , Elwyn David H. , Kinney John M.
Published: December 2017

A new technique for measuring glycerol turnover in human subjects is presented using a staged infusion of unlabeled glycerol. A total of 105 measurements was made in normal subjects and postoperative or acutely ill patients. The relation between glycerol turnover rate (Rt) and concentration (C) (Rt = 31 + 2.07C) from 80 staged infusion measurements in 21 normal subjects did not differ significantly from observations of others made by isotope dilution. In 11 patients, glycerol turnover was also measured by dilution of isotopic glycerol. Mean values did not differ significantly between the two methods. The average difference, regardless of sign, for individual values was 17%. This agreement tends to validate the assumptions of both methods. Advantages of the staged infusion method are that it is quicker and easier to perform and does not entail a risk due to administration of radioactive materials. Evidence obtained in this study from a three-stage procedure indicates that satisfactory information may be obtained from a two-stage infusion at successive rates of 250 and 600 μmol/min for 70 min each, with a prime of 2 mmol given as a bolus at the start of each stage.

isotope dilution; glycerol clearance; glycerol concentration; lipolysis; futile cycle

Submitted on December 27, 1983

Accepted on April 18, 1984