bluuebunny/crossref_metadata_2025 huggingface dataset:
Cephalic-phase insulin secretion in normal and pancreatic islet-transplanted rats
Authors: Berthoud H. R. , Trimble E. R. , Siegel E. G. , Bereiter D. A. , Jeanrenaud B.
Published: December 2017

The ability of saccharin, in comparison with glucose and tap water, to elicit glycemia-independent neurally mediated insulin secretion was investigated in chronically catheterized, freely moving rats. Plasma glucose and insulin concentrations were measured continuously from venous blood with a sampling resolution of one per minute. In normal rats, 1 ml of 0.15% saccharin caused a significant rapid rise in peripheral plasma insulin levels lasting up to 5 min, without significant changes in glycemia. Tap water alone also induced a transient elevation in insulinemia but was much smaller than the saccharin-induced response. In streptozotocin diabetic rats bearing intrahepatic, presumably denervated islet isografts, these rapid insulin responses to oral saccharin and tap water stimulation were completely abolished, whereas the early insulin response to intravenous glucose was decreased by only about 30%. These results are consistent with the concept of gustatory and other oral sensory signals acting as triggers for neurally mediated insulin release.
Cause of glucose oscillations during glucose infusion: periodic variation in glucose uptake
Authors: Bowden C. R. , Bergman R. N. , Marsh D. J.
Published: December 2017

Constant infusion of glucose (10 mg . kg-1 . min-1) into conscious, intact dogs induced oscillations in the plasma concentrations of glucose and insulin. Glucose rose from basal (98 +/- 1 mg/dl) and, after 3 h, entered oscillations that persisted until the end of the 9-h glucose infusion. Between 240 and 540 min, glucose fluctuated by +/- 17 mg/dl about a mean value of 143 +/- 2 mg/dl; frequency of the glucose oscillation was 0.54 +/- 0.03 cycles/h. During the same time interval, insulin increased from basal 13 +/- 2 mu U/ml to mean 46 +/- 4 mu U/ml. Insulin oscillated at an amplitude (peak-to-peak) of 48 mu U/ml, with frequency not different from that of glucose (0.60 +/- 0.09 cycles/h). The oscillation in glucose "led" the insulin oscillation by 22 +/- 5 min. In three animals, [2-3H]glucose was infused along with unlabeled glucose during oscillations, and it was determined that almost all (98%) of the glucose appearance was from the exogenous infusion. Thus varying endogenous glucose production was ruled out as a contributory factor to the glucose oscillation. Total glucose uptake (Rd) fluctuated periodically at the same frequency as glucose and insulin (0.56 +/- 0.05 cycles/h) and with a large amplitude (Rd mean = 248 mg/min; peak-to-peak amplitude = 85 mg/min). Direct splanchnic balance measurements were made in the interval 240-540 min to determine the specific contributions of splanchnic (Rds) and peripheral glucose uptake (Rdp) to the oscillation in total Rd. Peripheral uptake oscillated in phase with plasma insulin and accounted for 80% (57.5 g) of total Rd. The splanchnic bed (presumably liver) sequestered 20% (14.1 g) of infused glucose, and Rds varied in phase with plasma glucose. The liver extracted 5.6 +/- 0.3% of the total amount of glucose presented to it in the 5-h interval of observation. It is concluded that a) large fluctuations in peripheral glucose utilization are responsible for the observed periodicities in glucose concentration; b) peripheral uptake fluctuations result from periodic bursts in insulin secretion; c) during glucose infusion, glucose is the primary moment-to-moment regulator of hepatic glucose uptake, whereas insulin is the principal regulator of peripheral glucose utilization.
Amino acid degradation and effect of leucine on pyruvate oxidation in rat atrial muscle
Authors: Tischler M. E. , Goldberg A. L.
Published: December 2017

Both left and right atria from fasted rats produced significant amounts of 14CO2 during incubation with U-14C-labeled leucine, isoleucine, valine, alanine, glutamate, glutamine, aspartate, asparagine, proline, threonine, or lysine. This pattern of amino acid metabolism resembles that of skeletal muscle. Production of 14CO2 from [1-14C]leucine was 2.5-fold greater in atria from fasted than from fed rats and was due to greater alpha-ketoisocaproic dehydrogenase activity in the tissue from fasted animals. At normal plasma concentrations, leucine reduced the oxidation of glucose and lactate in atria from fasted but not from fed rats by inhibiting pyruvate oxidation and without altering the rate of glycolysis. Leucine also reduced glucose oxidation when added in the presence of ketone bodies or other amino acids and stimulated the release of lactate into the medium. Although the leucine skeleton can be completely oxidized to CO2 and thus can serve as an alternative fuel in fasting in place of glucose, oxidation of leucine (like glucose or lactate oxidation) accounts only for a very small fraction of the total oxygen consumption of the resting atria.
Essential fatty acid deficiency and plasma triglyceride turnover in rats
Authors: Huang M. T. , Williams M. A.
Published: December 2017

Hepatic triglyceride secretion in essential fatty acid-deficient rats was examined by three separate techniques in an effort to resolve conflicting evidence on the question of whether essential fatty acid deficiency altered hepatic triglyceride secretion in vivo. First, plasma triglyceride turnover was measured by intravenous injection of [2-3H]glycerol trioleate. Equations of the kinetics were formulated based on a single, open pool model. Turnover rates and pool sizes of plasma triglyceride were calculated from these equations. Second, [2-3H]glycerol was injected, and apparent rate constants for plasma triglyceride secretion and clearance were calculated by kinetic analysis. Third, Triton WR-1339 was used to inhibit lipoprotein clearance from blood plasma, and rates of plasma triglyceride accumulation were measured. The results of these studies showed that the rate of hepatic triglyceride secretion was 2-3 times greater in essential fatty acid-deficient rats than in nondeficient controls. The increase in triglyceride secretion, as well as the higher level of liver triglyceride typical of essential fatty acid-deficient rats, could be caused by increased lipogenesis and increased mobilization of fatty acids from adipose tissues.
A model for carbon kinetics among plasma alanine, lactate, and glucose
Authors: Foster D. M. , Hetenyl G. , Berman M.
Published: December 2017

To account for the exchange of carbon atoms among alanine, lactate, and glucose in vivo, [2,3-3H]- and [U-14C]alanine or [3-3H]- and [U-14C]glucose were injected simultaneously to nonanesthetized normal dogs. The concentrations in plasma of 14C-labeled alanine, lactate, and glucose, and the injected 3H-labeled substrate were followed for 160 min after injection of the tracers. An integrated kinetic model describing the exchange of carbon atoms among substrates was developed from these data. The analysis suggests that there is a very rapid exchange of the carboxyl carbon of alanine with lactate in contrast to carbons 2 and 3. The model was used to calculate the fluxes of carbon atoms among the substrates in a steady state. In normal dogs plasma alanine and lactate contribute 14% of the carbon atoms released into the circulation as glucose.
Adrenal of male dog secretes androgens and estrogens
Authors: Santen R. J. , Samojlik E. , Demers L. , Badder E.
Published: December 2017

In the absence of functioning gonads, the adrenal is an important source of androgens and estrogens. In order to precisely quantitate the adrenal secretion rates of the sex steroids, we cannulated the adrenal veins and measured venous blood flow and arterial venous steroid gradients in adult male beagle dogs under pentobarbital anesthesia. Celite chromatography and specific radioimmunoassays were utilized to measure steroid levels. During basal conditions, the adrenal produced larger amounts of the androgens (667 ng/min of androstenedione, 5.45 ng/min of testosterone, and 3.43 ng/ min of dihydrotestosterone) than of the estrogens (1.245 ng/min of estradiol and 0.239 ng/min of estrone. These secretion rates were 20- to 50,000-fold less than that of cortisol (12,360 ng/min). Studies were also carried out during adrenal suppression with hydrocortisone to block ACTH release and with the adrenal steroidogenesis inhibitor, aminoglutethimide, plus hydrocortisone. The secretion rates of each androgen measured fell during ACTH inhibition. Significant suppression of estrone and estradiol, however, required addition of aminoglutethimide. This study provides direct evidence that the adrenal in the male dog can secrete estrogens, a previously controversial issue.
Site of enhanced insulin sensitivity in exercise-trained rats at rest
Authors: Mondon C. E. , Dolkas C. B. , Reaven G. M.
Published: December 2017

Spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin and lower plasma insulin levels after oral glucose than sedentary control rats. To assess insulin sensitivity of specific organs, glucose uptake by perfused hindlimb muscle and liver from resting exercise-trained rats was compared with perfused organs from control rats. Glucose uptake, assessed by metabolic clearance formulas, was 17% faster in hindlimbs from exercise-trained rats when perfused without added insulin and 43% faster at perfusate insulin levels of 40 microU/ml. After an overnight fast, glucose clearance in exercise-trained hindlimbs increased over controls by 57% in the basal state and by 97% at low perfusate levels. In contrast, glucose clearance by livers from both fed and fasted exercise-trained rats was less than one-half that of livers from control rats. These results suggest that skeletal muscle, and not liver, is the organ primarily responsible for the increased sensitivity to insulin-induced glucose uptake with exercise training and that this response is enhanced after overnight fasting.
Effects of diabetes on oxidative decarboxylation of branched-chain keto acids
Authors: May M. E. , Mancusi V. J. , Aftring R. P. , Buse M. G.
Published: December 2017

Oxidative decarboxylation is the first irreversible step in the degradation of leucine. The effect of streptozotocin diabetes on this reaction was studied in cell-free rat liver preparations, using [1-14C]alpha-ketoisocaproate as substrate. Diabetes increased the branched-chain ketoacid dehydrogenase (BCKD) activity (per g liver or per mg protein) of homogenates, but the ratios of homogenate BCKD activity to other mitochondrial markers remained unchanged. A cytosolic branched-chain ketoacid decarboxylase activity (15-22% of homogenate activity), which did not require NAD, CoA, or NADP, was also increased in diabetics. Insulin treatment of diabetics normalized enzyme activity in all fractions. The apparent Km of BCKD in homogenates was 43-45 microM; diabetes increased the apparent Vmax from 165 nmol x min-1 x g tissue-1 to 260 nmol x min-1 x g-1. In contrast, the Km for cytosolic alpha-ketoisocaproate decarboxylation was 270 microM in controls, and diabetes resulted in both a lower Km (210 microM) and a higher Vmax. Adrenalectomy did not affect activity in homogenates from controls, but partially reversed the diabetes-associated increase. Glucagon pretreatment of controls did not affect activity. In summary, distinct mitochondrial and cytosolic enzymes decarboxylate alpha-ketoisocaproate in liver. The increased hepatic capacity of diabetic rats to degrade the carbon skeleton of leucine is attributed mainly to a relative increase in mitochondrial mass.
Comparison of glucagon responses to 2-deoxy-D-glucose and hypoglycemia in man
Authors: Werner P. L. , Benson J. W. , Brodsky J. B. , Hollander P. M. , Asplin C. M. , Johnson D. G. , Palmer J. P.
Published: December 2017

2-Deoxy-D-glucose (2DG), by competitive inhibition of glucose utilization, produces a state of intracellular glucopenia with resultant activation of both the sympathetic and parasympathetic branches of the autonomic nervous system. We have investigated the relationship between the activation of the autonomic nervous system caused by this drug and glucagon secretion. Subjects experienced symptoms identical to those observed during true hypoglycemia and demonstrated a marked rise in both gastric acid secretion and urinary epinephrine excretion. Mean immunoreactive glucagon (IRG) levels rose only slightly post-2DG (maximal mean increment, 18 pg/ml). Insulin-induced hypoglycemia, although eliciting a similar increase in urinary epinephrine excretion, was followed by a severalfold increase in IRG. Thus, although hypoglycemia and 2DG induced similar discharge of the autonomic nervous system, the glucagon response to hypoglycemia was much greater. These observations provide strong evidence that marked increases in sympathetic and parasympathetic discharge in man are weak alpha-cell stimuli and further support the hypothesis that the rise in IRG that occurs during hypoglycemia is not mediated primarily via the autonomic nervous system.
Reevaluation of the sand rat as a model for diabetes mellitus
Authors: Rice M. G. , Robertson R. P.
Published: December 2017

The North African sand rat, Psammomys obesus, has been claimed to be a valuable model for investigating diabetes. It has been reported that, in the laboratory with free access to food, sand rats overeat, become obese, and develop hyperglycemia and ketoacidosis. We have observed that, although sand rats from our colony become obese and hyperinsulinemic, hyperglycemia is rare and ketoacidosis is virtually nonexistent. Because age, obesity, and dietary sucrose have been reported to be risk factors for diabetes, we have attempted to cause diabetes in a large group of sand rats by inducing obesity through sucrose feeding over an extended period of time. Animals fed sucrose-rich diets were compared to controls fed normal carbohydrate (starch) diets. No group of animals studied over 18 mo developed hyperglycemia and virtually all groups maintained small but significant glucose-induced acute insulin responses. Hyperinsulinemia and insulin resistance accompanied obesity, but there were no differences between dietary groups. Lean sand rats fed sucrose had higher circulating levels of triglyceride (TG) and accelerated TG secretion rates (TGSR) compared to lean controls. After a longer period of observation, all sand rats had elevated plasma TG levels, however, TGSR were normal, indicating that TG removal may have become defective. Although this animal is an excellent model in which to examine spontaneous obesity, Psammomys obesus is a poor model for the study of human diabetes mellitus.
Prostaglandin synthesis inhibitors reverse alpha-adrenergic inhibition of acute insulin response to glucose
Authors: Metz S. A. , Robertson R. P.
Published: December 2017

Prostaglandin E (PGE) has several effects on glucose homoeostasis and insulin secretion. The same events can be induced by alpha-adrenergic stimulation, which is known to stimulate PGE synthesis. To evaluate the hypothesis that PGE may be one intracellular mediator for certain alpha-adrenergic events, we examined the effects of a known PG synthesis inhibitor Sodium salicylate (SS) (40 mg/min iv) on the alpha-adrenergic effects of epinephrine (Epi) at two doses (3 and 6 micrograms/min) in normal male subjects. The lower dose of epinephrine diminished the acute insulin response (AIR) after a 20-g intravenous glucose pulse (control, 463 +/- 149; epinephrine, 97 +/- 38% of basal insulin, mean +/- SE, n = 6, P < 0.02); SS markedly augmented the AIR during epinephrine towards control values (339 +/- 137%; P < 0.02). In 12 subjects, the higher dose of Epi abolished the AIR. When similar studies were performed during a SS infusion, the AIR was partially restored (96 /+- 27% of basal insulin, n = 12, P < 0.01). Similarly, partial reversal of this alpha-adrenergic effect of Epi was observed with indomethacin, another inhibitor of PG synthesis. At both doses of Epi, SS augmented the glucose disappearance rate (KG) after the glucose pulse (P < 0.001). Sodium salicylate also increased basal glucagon levels (P < 0.05). In contrast, SS did not affect the glycemic response, the suppression of basal insulin levels, or the hemodynamic responses induced by adrenergic stimulation. We conclude that two prostaglandin synthesis inhibitors partially reverse the alpha-adrenergic inhibition of the AIR to glucose caused by Epi, without affecting other adrenergic events. The data are compatible with a role for prostaglandins in alpha-adrenergic events selectively in the pancreatic islet.
Distribution and motor effect of VIP in female genital tract
Authors: Ottesen B. , Larsen J. J. , Fahrenkrug J. , Stjernquist M. , Sundler F.
Published: December 2017

The distribution and concentration of vasoactive intestinal polypeptide (VIP) in different parts of the female genital organs from various species (cat, goat, pig, rabbit, rat, and guinea pig) were studied by means of immunohistochemistry and immunochemistry. In addition, the effect of VIP on the mechanical activity of uterine muscle was investigated in vitro. VIP immunoreactive nerve fibers innervating vessels and smooth muscle cells were fairly numerous in the genital organs of the cat and goat and less numerous in the pig, rabbit, rat, and guinea pig. In all species studied, VIP-containing nerves were most numerous in the cervix. The tissue concentration of VIP measured by immunochemistry was in agreement with the immunohistochemical findings. VIP inhibited the mechanical uterine activity in the cat, goat, pig, and rabbit, whereas only minimal effects were obtained in the rat and guinea pig. This difference between the species corresponded to the number of VIP-containing nerves in the uterine muscle. The data support the hypothesis that VIP may play a physiological role in the local nervous control of the uterine mechanical activity.
Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouse
Authors: Kaplan M. L. , Leveille G. A.
Published: December 2017

Lipogenesis and insulin sensitivity are evaluated in adipose tissue, liver, and diaphragm of ob/ob and non-ob/ob mice. In ob/ob mice, hepatic fatty acid synthesis from [U-14C]glucose is elevated by 4 wk of age, and adipose tissue fatty acid synthesis increases at approximately 7 wk. Hepatic activities in ob/ob mice of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), malate dehydrogenase (EC 1.1.1.40), and alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) are dramatically increased by 7 wk of age. Diminished insulin-stimulated glycogen synthesis is first noted in the diaphragm of ob/ob mice at 7 wk of age. Insulin-stimulated glycogen synthesis in adipose tissue of ob/ob mice is impaired at 3 wk. At 7 wk, insulin-stimulated fatty acid synthesis in adipose tissue of ob/ob mice is markedly increased. Adipose tissue glyceride-glycerol synthesis continues to increase throughout development, whereas fatty acid synthesis decreases after 7 wk. The data suggest that alterations in lipid synthesis occur very early in the development of ob/ob mouse, prior to expression to overt obesity, at which time a major contribution to lipogenesis is made by the liver. The altered de novo lipogenesis does not precede the reported diminution in energy metabolism.
Electrical stimulation of the liver cell: activation of glycogenolysis
Authors: Freude K. A. , Sandler L. S. , Zieve F. J.
Published: December 2017

To examine the role of ionic factors in the regulation of glycogen metabolism, we examined the effects of electrical stimulation on liver glycogen cycle enzymes. Passage of electric current through a suspension of rat hepatocytes caused the conversion of glycogen phosphorylase to its active (a) form and the simultaneous conversion of glycogen synthase to its inactive (D) form. The rise in phosphorylase a activity was dependent on the magnitude of current flow, was detectable after 5 s of current flow, and was rapidly reversible on cessation of stimulation. The activation of phosphorylase by shocking was completely eliminated by depletion of cellular Ca2+ and was restored by readdition of Ca2+. Cyclic AMP and cyclic GMP levels were unaffected by shocking. It is concluded that shocking, in the absence of any hormone or exogenous chemical, causes an increase in cytosol Ca2+, which in turn leads to activation of phosphorylase and inactivation of synthase. Electrical stimulation may serve as a model system for studying the role of ions in metabolic regulation.
Measurement of urea kinetics in vivo by means of a constant tracer infusion of di-15N-urea
Authors: Wolfe R. R.
Published: December 2017

We have assessed the feasibility of studying urea metabolism in vivo in both steady state and nonsteady state situations by means of the primed constant infusion of di-15N-urea and the analysis of the resulting enrichment in plasma urea. Both hepatectomized dogs with known rates of urea infusion and intact dogs were studied. The enrichment of the bistrimethylsilyl derivative of urea was determined on a gas chromatograph-mass spectrometer. Selected ion monitoring was set for m/e 189 (M - 15), m/e 190 (A + 1), and m/e 191 (A + 2), thus enabling the calculation of the rate of urea production from nonrecycled NH3 (from A + 2 data) (Ra N), the rate of recycling of NH3 into urea (Ra R) (from A + 1 data), and thus the total rate of urea production (Ra N + Ra R). When urine collections were made, the incorporation of urea-N into protein was estimated from the difference between Ra N and urea excretion. We found that, in the steady state in a hepatectomized dog, the rate of appearance of urea can be determined accurately. In the nonsteady state in both hepatectomized and intact dogs, urea appearance could be estimated within +/- 20% in most situations. The only situation in which this was not the case was when we attempted to measure rapid changes in Ra R. Thus, within limits, this can be a useful technique enabling the quantitation of various aspects of urea metabolism.
Reutilization of fatty acid carbons for lung lipid synthesis
Authors: Rabinowitz J. L. , Cardwell T. , Bassett D. J.
Published: December 2017

The utilization of glucose, palmitate, and oleate for the synthesis of lung lipids was studied in isolated rat lungs. Lungs were ventilated with 5% CO2 in air and perfused for 100 min with a Krebs-Ringer bicarbonate buffer (pH 7.4), containing 3% fatty acid-free albumin and either 5.6 mM [U-14C]glucose or 0.25 mM [1-14C]palmitate, or 0.25 mM [1-14C]-oleate. At the end of 100 min of perfusion with these precursors, between 73 and 85% of total lipid 14C was recovered as phospholipid. Glucose carbon was mainly incorporated into triglyceride fatty acids (TG-FA) and phosphatidylcholine fatty acids (PC-FA) of 16- and 18-carbon chain length. After perfusion with [14C]palmitate and [14C]oleate, only 65 and 20% of 14C was recovered as PC 16-carbon and 18-carbon FA, respectively. The remaining 14C was mainly recovered as FA shorter than the 14C precursors. Schmidt degradation analysis of lipid FA demonstrated considerable labeling of alkyl carbons on perfusion with the carboxyl-labeled precursors, indicating that FA degradation products were used for synthesis of lipid FA. This process was enhanced on addition of glucose to the perfusate.
Glucoregulatory and metabolic response to exercise in obese noninsulin-dependent diabetes
Authors: Minuk H. L. , Vranic M. , Marliss E. B. , Hanna A. K. , Albisser A. M. , Zinman B.
Published: December 2017

The metabolic response to exercise in obese postabsorptive noninsulin-dependent diabetics was compared to that of obese nondiabetics. Exercise consisted of 45 min on a cycle ergometer at 60% maximum oxygen consumption. Six diabetic subjects were studied during oral hypoglycemic therapy and four on diet alone. The sulfonylurea therapy had no effect on the response. Glycemia was elevated at rest in both diabetic subgroups (192 +/- 24 mg/dl for diet alone, 226 +/- 36 mg/dl for sulfonylurea treatment) and a similar fall (35 and 37 mg/dl, respectively) occurred with exercise. In control subjects, glycemia was 86 +/- 4 mg/dl and did not change with exercise. In the diabetics at rest, glucose production was elevated (220 +/- 25 mg/min), whereas the metabolic clearance of glucose was suppressed. During exercise the increase in glucose utilization was similar to that in controls, but glucose production failed to increase significantly, thus accounting for the decline in plasma glucose. At rest, plasma immunoreactive insulin (IRI) was elevated to 0.90 ng/ml in the controls and decreased to 0.65 ng/ml with exercise. In the diabetics IRI was similarly elevated (0.89 ng/ml) but failed to decrease normally with exercise. Lactate, pyruvate, alanine, and free fatty acids increased similarly in diabetics and controls, whereas the increase in 3-hydroxybutyrate during recovery was less in diabetics. The sustained insulinemia, the basal overproduction of glucose, and hyperglycemia itself may all contribute to the observed differences in glucose flux during exercise in noninsulin-dependent diabetics.
Hemorrhage in newborn lambs: effects on arterial blood pressure, ACTH, cortisol, and vasopressin
Authors: Rose J. C. , Morris M. , Meis P. J.
Published: December 2017

Arterial blood pressure, central venous pressure, and plasma concentrations of ACTH, cortisol, and vasopressin (AVP) were monitored in chronically prepared, unanesthetized newborn and weanling lambs at rest and during and after hemorrhage of 15% of estimated blood volume at 1.5%/min. Differences in the endocrine and blood pressure responses to hypovolemia were noted in the two groups of animals. Hemorrhage did not change arterial mean pressure, reduced central venous pressure, and caused a delayed increase in the plasma concentrations of ACTH, cortisol, and AVP in the newborn lambs. In weanling lambs, hemorrhage reduced arterial mean pressure and central venous pressure and promptly increased plasma ACTH and cortisol levels while plasma AVP concentrations again showed a delayed increase. The data indicate that certain hormonal mechanisms for the defense of blood volume are present and operational within 3 days of birth and that age-related differences in the responses to hemorrhage exist in the lamb.
The “calcium clamp”: effect of constant hypocalcemia on parathyroid hormone secretion
Authors: Fox J. , Heath H.
Published: December 2017

This report describes acute studies of parathyroid hormone (PTH) secretion and metabolism in conscious dogs, performed with a new technique, the “calcium clamp.” Bolus injections and graded infusions of either calcium (Ca) or EGTA, respectively, increase or decrease plasma Ca to desired levels in 1–2 min; rapid determination of plasma Ca permits feedback control of the infusion rates to maintain the desired Ca concentration for prolonged periods. Using this technique, we have examined the effect in five dogs of a sustained (1 h) decrease in plasma Ca from 9.6 to 7.6 mg/dl on the secretion of PTH. Plasma immunoreactive PTH (IPTH) concentration in precaval blood increased within 1 min, peaked at 4–10 min (greater than 5 times control), but thereafter declined gradually to 57% of the maximum at 60 min, despite ongoing and constant hypocalcemia. Abrupt restoration of normocalcemia caused IPTH levels to decrease with an apparent half-time of 3.0 +/- 0.3 min (mean +/- SE). Thus, external feedback-regulated control of plasma Ca is possible in experimental animals. IPTH concentrations decline from the maximum during constant hypocalcemia, a new observation that suggests that PTH secretion and/or metabolism are altered progressively by the hypocalcemia.
Norepinephrine-stimulated lipolysis in acute and chronic hypoxemia
Authors: Baum D. , Oyer P.
Published: December 2017

The effects of acute and chronic hypoxemia on norepinephrine-stimulated lipolysis were studied in dogs. Right-to-left shunts were created in experimental dogs to render them chronically hypoxemic (PaO2 37-55 torr). Control animals received sham operations (PaO2 greater than 70 torr). During air ventilation, there was no significant difference in norepinephrine-induced glycerol and free fatty acid (FFA) rises in the control and experimental groups. In control dogs, glycerol and FFA responses to norepinephrine were unaffected by acutely lowering oxygen tensions (PaO2 46-48 torr) to levels found in air-breathing experimental dogs. However, greater acute reductions in oxygen tensions (PaO2 less than 30 torr) in both control and experimental animals resulted in pronounced glycerol and FFA falls from the elevated levels produced by norepinephrine infusions during air ventilation. PaO2 levels less than 30 torr similarly decreased the glycerol and FFA elevations in control animals given phenoxybenzamine and norepinephrine. As with severe hypoxemia, propranolol suppressed glycerol and FFA increases stimulated by norepinephrine. Theophylline did not influence the hypoxemic-induced glycerol and FFA falls. These observations suggest that severity was important in the hypoxemic inhibition of norepinephrine-stimulated lipolysis; the effects of low oxygen breathing were not ameliorated by chronic hypoxemia. A beta-adrenergic receptor abnormality appears to contribute to this inhibition.
Role of Ca2+ in response of adrenal glomerulosa cells to angiotensin II, ACTH, K+, and ouabain
Authors: Schiffrin E. L. , Lis M. , Gutkowska J. , Genest J.
Published: December 2017

The effects of Na+-K+-ATPase inhibition by ouabain and blockage of Ca2+ influx into the cell by verapamil and lanthanum on the response of isolated rat adrenal glomerulosa cells to angiotensin II, ACTH, and K+ were studied. Ouabain significantly increased basal aldosterone output at a concentration of 10(-5) mol/liter, whereas at 10(-3) mol/liter basal secretion was unaffected. Steroidogenic response to angiotensin II was significantly potentiated at concentrations of ouabain of 10(-5) mol/liter, but responses to angiotensin II, ACTH, and K+ were inhibited by 10(-4) and 10(-3) mol/liter of ouabain. The Ca2+ antagonist verapamil (10(-6) to 10(-4) mol/liter) decreased basal aldosterone secretion as well as the response to angiotensin II, ACTH, and K+. The effects of ouabain (10(-5) mol/liter) on basal and stimulated steroidogenesis were abolished by verapamil (10(-4) mol/liter). Lanthanum decreased basal and angiotensin II, ACTH, and K+ induced aldosterone secretion. The effects of ouabain (10(-5) mol/liter) on basal and stimulated aldosterone biosynthesis were blocked by lanthanum. These results suggest that Ca2+ mediates the effects of angiotensin II, ACTH, K+ and Na+-K+-ATPase inhibition on aldosterone biosynthesis. Ca2+ may be the final common intracellular messenger of most aldosterone secretagogues.
Brown adipose tissue of cafeteria-fed rats
Authors: Himms-Hagen J. , Triandafillou J. , Gwilliam C.
Published: December 2017

Feeding a "cafeteria" diet for 2 wk to male Holtzman rats resulted in a weight gain that was, on average, only slightly more than that of control rats fed a regular chow diet. Wet weight, DNA, and total protein content of interscapular brown adipose tissue were more than doubled in the cafeteria-fed rats and proliferation of mitochondria paralleled tissue growth. After 2 wk of recovery from cafeteria feeding, the expanded size of the tissue had completely regressed to a normal level. Brown adipose tissue mitochondria of cafeteria-fed rats bound 3 times more purine nucleotides than mitochondria of chow-fed control rats, but no change in the proportion of polypeptides with molecular weight in the region of 32,000 could be detected. The changes in brown adipose tissue and its mitochondria in cafeteria-fed rats correspond to those seen previously in noradrenaline-treated rats, i.e., tissue growth accompanied by mitochondrial proliferation and an unmasking of proton conductance pathways. The increase in 32,000-mol-wt polypeptides seen in brown adipose tissue mitochondria of cold-acclimated rats does not occur in the cafeteria-fed rats. Control mechanisms are presumed to differ, either quantitatively or qualitatively, in the two situations, cold exposure and overeating, which both cause growth of brown adipose tissue.
Effects of gastric nutritional supplementation on fetal umbilical uptake of nutrients
Authors: Charlton V. E. , Reis B. L.
Published: December 2017

Intrauterine nutritional supplementation may be of therapeutic benefit to the malnourished, growth-retarded fetus. Using 14 chronically catheterized, third trimester fetal lambs, we evaluated the effects of gastric infusions of amino acids and glucose on umbilical uptake of alpha-amino nitrogen, glucose, lactate, and oxygen. When amino acids were infused, amino nitrogen was gained through the intestine at an average rate equal to 45% of fetal umbilical uptake of amino nitrogen. There were no consistent changes in umbilical uptake of the measured nutrients, except for a small decrease in umbilical uptake of oxygen (P less than 0.05). No relationship were found between changes in fetal amino nitrogen levels or changes in fetal-maternal amino nitrogen concentration gradients and umbilical uptake of amino nitrogen. When glucose was infused, glucose was absorbed through the intestine at an average rate equal to 42% of fetal umbilical uptake of glucose. There were no changes in umbilical uptake of amino nitrogen, lactate, or oxygen. Umbilical uptake of glucose decreased, however, in inverse proportion to both the glucose infusion rate (P less than 0.005) and the rise in fetal glucose concentration (P less than 0.025). This limited the quantity of glucose that could be gained by the fetus, via gastrointestinal supplementation. During the infusions, we also observed a change in the pattern of fetal lower body blood flow. There was a 12% decrease in the mean umbilical blood flow (P less than 0.005) and a 22% increase in mean intestinal flow (P less than 0.05).
Partial prevention of glucocorticoid-induced muscle atrophy by endurance training
Authors: Hickson R. C. , Davis J. R.
Published: December 2017

Male rats were either sham-operated (N) or castrated (C) at 65 days of age. They were further subdivided into sedentary or exercise groups that were trained by treadmill running 5 days/wk for 12 wk. During the last 10 days of training, the animals received daily subcutaneous injections of cortisone acetate (CA) (100 mg/kg) or 1% carboxymethylcellulose. Body weight decreased approximately 25% in all groups that received CA. The fast-twitch plantaris and gastrocnemius muscle weights were approximately 35% lower in CA-treated versus cortisone-free N and C sedentary animals. Exercise prevented from one-fourth to one-half of the muscle weight loss in N and C runners when compared to their respective pair weight controls. Muscle weights of the CA-treated freely eating N controls were significantly less than that of N runners that received CA. In plantaris muscles of both N and C animals that received CA, total protein concentration and citrate synthase activity, a mitochondrial marker, remained constant, but their amounts per muscle decreased in proportion to the atrophy. However, myoglobin concentration increased in plantaris muscles of CA-treated animals, although total myoglobin per muscle was reduced slightly. Myoglobin levels were increased in plantaris muscles both as a result of training and CA, but citrate synthase activity was increased only as a result of the exercise. These results show that exercise can retard the glucocorticoid-induced muscle atrophy.
Glutamate interconversions and glucogenicity in the sheep
Authors: Heitmann R. N. , Bergman E. N.
Published: December 2017

Simultaneous measurements were made of net and unidirectional glutamate metabolism by the portal-drained viscera, liver, kidneys, and hindquarters of fed, acidotic, and fasted sheep. The contribution of glutamate to glutamine and glucose production also was estimated. Of the glutamate present in whole blood, 45% was in plasma and 55% in the cellular fraction. Acidosis and fasting reduced blood glutamate concentrations, but did not change the plasma:cellular ratio. [14C]glutamate exchanged only little between plasma and blood cells. Clearly, this demonstrates a lack of the alpha-amino acid transport system in blood cells. Net rates of plasma glutamate flux by the portal-drained viscera and kidneys were less than 0.5 mmol/h, but, in fed sheep, the liver released 2--3 mmol/h into the plasma and the hindquarters removed an average of 0.9 mmol/h. Both were reduced by acidosis and fasting. Unidirectional rates were highly significant and greater than net rates. Acidosis and fasting primarily seemed to affect production by the liver, but only utilization by the hindquarters. Plasma glutamate turnover averaged 6--9 mmol/h, but interconversions with glutamine were low; only 12--25% was converted to glutamine and most of this occurred in extrarenal tissues. A similar rate of 20--26% of the glutamate was converted to glucose, which accounted for about 4% of the total glucose produced. The kidneys seemed to play an important gluconeogenic role; whereas the liver possibly could account for 100% of the glucose produced from glutamate in fed sheep, the kidneys accounted for 40--45% during acidosis and fasting.
Source and fate of circulating citrulline
Authors: Windmueller H. G. , Spaeth A. E.
Published: December 2017

Previous work has demonstrated a continuous release of citrulline from the small intestine into the circulation. To evaluate the physiologic significance of this process, we have now measured citrulline uptake and release by isolated, perfused livers and, through surgical means and arteriovenous difference measurements, by various organs of the rat in vivo. Intestinally derived citrulline, an end product of glutamine nitrogen metabolism, passes through the liver without appreciable uptake. No significant extraintestinal source of circulating citrulline was found. Contrary to earlier suggestions, the liver releases no citrulline normally, but only when supplied with unphysiological high levels of ornithine and ammonia. Renal citrulline uptake was equivalent to approximately 83% the rate of intestinal release; kidneys, in turn, released arginine equivalent to approximately 75% of the citrulline taken up. Acute experiments in which the intestine, intestine plus liver, or kidneys were excluded from the circulation indicate that additional organs may also participate in citrulline exchange, at least when the circulating citrulline level is abnormal. The intestinal-renal pathway seems to account for a large though still unmeasured portion of the citrulline turnover in the circulation.
Relation of insulin receptor occupancy and deactivation of glucose transport
Authors: Haring H. U. , Biermann E. , Kemmler W.
Published: December 2017

Kinetics of association and dissociation of 125I-insulin and of activation and deactivation of 3-O-methylglucose transport were determined in isolated rat fat cells. Equilibrium bound insulin (7.5, 25, 100 microunits/ml) dissociated with a t1/2 of 2 min (100 microunits/ml), 4 min (25 microunits/ml), and 16 min (7.5 microunits/ml). Consecutive deactivation of transport is observed only in the presence of glucose (1 mM); the t1/2 of deactivation is approximately 60 min (100 and 25 microunits/ml) and 20 min (7.5 microunits/ml). At 15 degrees C, the t1/2 of dissociation (7.5 microunits/ml) is 25 min, and deactivation is not observed. Addition of dithioerythritol (5 mM) during the association of insulin decreased the binding rapidly; however, a reduced insulin effect was only seen if the binding decreased during the early activation phase of transport. In conclusion, the maintenance of the insulin effect on transport does not require persistent receptor occupancy; dissociation and deactivation are, with respect to kinetics, temperature dependency and requirement of glucose, independent processes. Receptor occupancy probably only controls the activation of transport; deactivation seems to be controlled by postreceptor processes.
Interaction of arginine and gastric inhibitory polypeptide on insulin release in man
Authors: Elahi D. , Raizes G. S. , Andres R. , Hershcopf R. J. , Muller D. C. , Tobin J. D. , Andersen D. K.
Published: December 2017

The interrelations of the insulin secretagogues, glucose, arginine (Arg), and gastric inhibitory polypeptide (GIP) were quantified in six normal young men in five sets of experiments with the hyperglycemic clamp technique (125 mg/dl above basal glucose levels for 2 h). After 60 min of intravenous glucose alone, one of the following was added: A) oral glucose (OG) (40 g/m2); B) 15 g.m-2.h-1 Arg infusion; C) 15 g.m-2.h-2 Arg infusion and OG; D) 7.5 g.m-2.h-1 Arg; E) 7.5 g.m-2.h-1 Arg and OG. The clearance rate of Arg was similar for B, C, D, and E. In all experiments, plasma GIP levels were unchanged from the basal level during the 1st h. The increases in plasma GIP levels in experiments C and E were similar to the increase when OG alone was ingested (A). When the stimulatory effect of the secretagogue(s) alone on insulin (IRI) is computed, the increase due to OG (A) and to 7.5 g.m-2.h-1 Arg (D) were similar and additive (A + D approximately equal to E). However, the stimulatory effect of 15 g.m-2.h-1 Arg + OG (C) on IRI was not significantly greater than 15 g.m-2.h-1 alone (B). The 15 and 7.5 g.m-2.h-1 Arg infusion produced different patterns of insulin and glucagon secretions. At the lower dose, the response of both hormones to Arg decreased with time. Arg and GIP act through a similar and possibly common mechanism on the beta-cell. However, only Arg was found to be alpha-cytotropic. GIP does not appear to influence the metabolic clearance of Arg. The dose-response relationships to Arg of the beta- and alpha-cell appear similar.
State of metabolic control determines role of epinephrine-glucagon interaction in glucoregulation in diabetes
Authors: Kemmer F. W. , Lickley H. L. , Gray D. E. , Perez G. , Vranic M.
Published: December 2017

Epinephrine (0.1 micrograms.kg-1.min-1) was infused with or without somatostatin (0.1 microgram.kg-1.min-1) in six depancreatized dogs, studied under normo- and hypoinsulinemia to determine whether the participation of glucagon in epinephrine-induced hepatic glucose overproduction is governed by the degree of metabolic control. When normoglycemia was achieved by basal intraportal insulin replacement, insulin levels remained constant during the epinephrine infusion, and there was a twofold increase in extrapancreatic immunoreactive glucagon (eIRG) and glucose production (Ra). Although eIRG increments were prevented by somatostatin, the increase in Ra was undiminished, indicating that epinephrine can act independently of glucagon as in normal animals. During subbasal intraportal insulin infusion in the depancreatized dogs, insulin levels remained 35% lower than with basal replacement, and the animals were hyperglycemic. Epinephrine induced a similar twofold increase in eIRG as during normoglycemia, and again this rise was prevented by somatostatin. There was a significantly greater, threefold increase in Ra with epinephrine when the animals were hyperglycemic. This exaggerated response to epinephrine was not seen during eIRG suppression by somatostatin, suggesting that glucagon participated in the epinephrine-induced hepatic glucose overproduction when the depancreatized dogs were in poor metabolic control, as seen previously in alloxan-diabetic dogs. However, in the depancreatized, unlike in the alloxan-diabetic dogs, epinephrine-induced glucagon release was small. Thus, hypoinsulinemia appears to sensitize the liver to eIRG during epinephrine infusion. The fact that epinephrine induces hyperglycemia both in physiology and diabetes could indicate an important role in enhancing glucose transport in insulin-insensitive tissues.
Disposal of alpha-ketoisocaproate: roles of liver, gut, and kidneys
Authors: Abumrad N. N. , Wise K. L. , Williams P. E. , Abumrad N. A. , Lacy W. W.
Published: December 2017

The alpha-keto analogues of the branched-chain amino acids, and particularly that of leucine, alpha-ketoisocaproate (KIC), have been found to reduce urea synthesis and as a result have been proposed for the treatment of uremia and portal systemic encephalopathy. Because little is known about the fate of these keto acids in the intact animal, we examined the disposal of a KIC load in five conscious overnight-fasted dogs with catheters previously implanted in an artery, and in the portal, hepatic, and renal veins. During the absorptive period (54 +/- 9 min; range, 20-75 min), 62 +/- 5% of the administered load (6,358 +/- 662 mumol) of the keto acid was absorbed as KIC and 23 +/- 3% was transaminated across the gut and entered as leucine. The hepatic uptake of KIC was equivalent to 35 +/- 5% (2.316 +/- 419 mumol) of the administered load, and of that, one-third was transaminated to leucine and two-thirds were converted to ketone bodies. The splanchnic output of KIC amounted to 1,732 +/- 256 mumol of 27 +/- 2% of the administered load, half of which was transaminated across the kidneys to leucine. As a result, the amount of KIC reaching the extrahepatic extrarenal tissues as KIC carbon amounted to 15% of the load administered. We conclude that the majority of an intragastrically administered KIC load reaches the (extrarenal) peripheral tissues in the form of leucine or ketone bodies. The study also underscores the importance of the "gut," the kidneys, and the liver in metabolism of the absorbed KIC load.
TRH mobilizes membrane calcium in thyrotropic cells as monitored by chlortetracycline
Authors: Gershengorn M. C. , Thaw C.
Published: December 2017

Chlortetracycline (CTC), a probe of membrane-bound divalent cations, was used to study the action of thyrotropin-releasing hormone (TRH) in mouse pituitary thyrotropic tumor (TtT) cells in culture. Cellular fluorescence of CTC was caused by both Ca2+- and Mg2+-CTC complexes and was influenced by the concentration of these cations in the incubation medium. TRH, but not other peptides, caused a rapid, transient, and concentration-dependent decrease in the CTC fluorescence intensity; half-maximal effect occurred with 10--30 nM TRH. The decrement in fluorescence intensity caused by TRH was not due to enhanced loss of CTC from the cells. The decrease in fluorescence elicited by TRH was specific for Ca2+-CTC complexes because preincubation of the cells with 1 mM EGTA or 1 mM EDTA plus 2.05 mM Mg2+ abolished the response, whereas preincubation with 1 mM EDTA plus 2.05 mM Ca2+ permitted the usual TRH response. Antimycin A and carbonyl cyanide m-chlorophenylhydrazone decreased cellular ATP content to 37 +/- 1 and 32 +/- 1% of control, respectively, and abolished the TRH-induced decrease in CTC fluorescence. We conclude that TRH displaced Ca2+ from an energy-dependent, membrane-bound pool(s) within TtT cells and that this may be one mechanism by which the concentration of intracellular free Ca2+ is raised so that is couples stimulation by TRH to TSH secretion.
Enrichment of glycine pool in plasma and tissues by glycine, di-, tri-, and tetraglycine
Authors: Adibi S. A. , Morse E. L.
Published: December 2017

Very little information is available on metabolism of oligopeptides in vivo. The present studies were performed to investigate the metabolic fate of diglycine, triglycine, and tetraglycine when injected into a central vein in rats. These peptides disappeared rapidly from plasma without any significant loss in urine. Plasma and tissue concentrations of glycine were measured when the same amount of glycine was injected in free or peptide form. Two minutes after the injection of glycine (1.l0 mumol/g body wt), there was over a tenfold increase in plasma glycine concentration. This increase was diminished when diglycine instead of glycine was injected. Each increase in the number of glycine residues resulted in further reduction in the initial rise in plasma glycine concentration was increased by each injection. This was more pronounced in the kidney than in the liver. Injection of triglycine and tetraglycine resulted in greater glycine concentration in the kidney than injection of either glycine or diglycine. Furthermore, unlike liver and muscle, each increase in the number of glycine residues resulted in greater recovery of glycine peptides from the kidney. These results suggest that with each increase in the number of glycine residues a greater amount of injected glycine peptide is taken up by the kidney for hydrolysis to glycine.