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Biomedical subjects

J F Caro

Publications and source records attributed to J F Caro.

At least 127 records · Page 7Linked to original sources
PubMed1982

Glucocorticoid-induced insulin resistance: the importance of postbinding events in the regulation of insulin binding, action, and degradation in freshly isolated and primary cultures of rat hepatocytes.

We have recently proposed that "down regulation" of the insulin receptor may be one of the many biological responses of a cell to insulin. In an attempt to further explore this hypothesis we have studied insulin action, binding, and degradation in freshly isolated hepatocytes from rats rendered insulin resistant by the administration of dexamethasone, 1.0 mg/kg every other day, for 1 and 4 wk, and in dexamethasone-treated (0.1 muM for 24 h) primary cultures of hepatocytes from normal rats. Dexamethasone treatment for 1 and 4 wk resulted in significant hyperinsulinemia and euglycemia when compared with age- and weight-matched control animals. Freshly isolated hepatocytes from rats treated with dexamethasone for 1 wk bound less insulin than cells from control animals. This decrease in insulin binding was reflected in a decrease in the total number of cellular insulin receptors upon solubilization of the cells. Insulin action was evaluated by the ability of insulin to stimulate the uptake of alpha-aminoisobutyric acid. The basal rate of aminoisobutyrate uptake in freshly isolated hepatocytes was enhanced by 1 wk of dexamethasone treatment, and although there was an apparent shift to the right in the dose-response curve for insulin-stimulated aminoisobutyrate uptake, at no insulin concentration was there a significant difference in the uptake by hepatocytes from control and dexamethasone-treated animals. This was true whether expressed as a percentage or absolute increment above basal. Insulin degradation was enhanced in hepatocytes from animals treated with dexamethasone for 1 wk but could not account for the observed changes in insulin binding. Hepatocytes from animals treated with dexamethasone for 4 wk were resistant to insulin with regard to aminoisobutyrate uptake, yet both insulin binding and insulin degradation returned to the levels observed in hepatocytes from control animals. Primary cultures of hepatocytes from normal rats exposed to dexamethasone, 0.1 muM, in vitro for 24 h were similar to hepatocytes from rats treated with dexamethasone for 4 wk in that they were insulin resistant with regard to aminoisobutyrate uptake and had normal to increased insulin binding. Insulin degradation was also similar. These cells were resistant to the ability of insulin, 0.1 muM, to down regulate its receptor whereas parallel cultures treated with insulin in the absence of dexamethasone had a 52% decrease in insulin binding. These data indicate that hepatocytes that are insulin responsive respond to in vivo hyperinsulinemia by a decrease in the number of insulin receptors and by increased insulin degradation. Hepatocytes rendered resistant to insulin both in vivo and in vitro are resistant to these effects of insulin. These studies emphasize the importance of postbinding events in the modulation of insulin binding, action, and degradation, and support the hypothesis that down regulation of the hepatocyte insulin receptor is one of the many biological actions of insulin. They also help explain how a cell can be insulin resistant and have a normal number of insulin binding sites in the presence of hyperinsulinemia.

Aminoisobutyric Acids↗
PubMed1982

Dopamine does not affect parathyroid function in man.

There is conflicting evidence for a role of dopamine (DA) in modulating parathyroid gland function. DA stimulates parathormone (PTH) secretion in cattle in vivo and in vitro, but is without effect on dispersed human parathyroid cells from adenomatous and hyperplastic tissue. Therefore, we studied the PTH response to a 30-min infusion of DA (4 micrograms/kg . min) in five normal male volunteers. There was no change in the levels of PTH, as measured by RIA, although this infusion rate was effective in lowering PRL levels. During the infusion period, total calcium levels remained unchanged. We conclude that, unlike cattle, the parathyroid gland in humans is unresponsive to DA. Thus, the regulation of PTH secretion by biogenic amines has important species variation.

Adult↗
PubMed1982

The regulation of lipid synthesis in freshly isolated and primary cultures of hepatocytes from fasted rats: the primary role of insulin.

To determine the relative roles of insulin intermediates in the glycolytic pathway in the control of lipogenesis, we have evaluated lipid synthesis in freshly isolated and primary cultures of hepatocytes from normal ad libitum fed and 72 hr fasted rats. In freshly isolated hepatocytes from fasted rats the rate of lipid synthesis is markedly depressed and resistant to the stimulatory effects fo insulin and spermine, a post insulin binding mimicker of insulin action. This is true whether lipid synthesis is evaluated from 3H2O or from (14C)-acetate. These characteristics are retained in primary cultures of these hepatocytes. This cell system, therefore, is suitable to evaluate the effects of insulin and substrates on the recovery of lipid synthesis in hepatocytes from fasted rats. Glucose, fructose, glycerol, pyruvate, and acetate in the incubation medium for 20 hr were without effect on the rate of lipid synthesis and insulin responsiveness in the primary cultures from fasted rats. However, when the cells were incubated for 20 hr with insulin, 10(-9) M, the rate of lipid synthesis and insulin responsiveness were comparable to that of primary cultures of hepatocytes from fed rats. The present studies demonstrate the unique role for insulin in restoring lipid synthesis and insulin responsiveness in mammalian liver from fasted animals.

Acetates↗
PubMed1981

Increased absolute calcium binding to albumin in hypoalbuminaemia.

The amount of calcium bound to protein was measured in 30 patients with differing diseases and varying degrees of hypoalbuminaemia. Total serum calcium increased directly with both serum albumin and ultrafilterable calcium concentrations. The estimated amount of calcium bound per gram of albumin varied inversely with the albumin concentration, decreasing from 2.1 to 1.0 mg calcium/g albumin as albumin concentration increased from 1.7 to 3.1 g/dl. Circulating parathyroid hormone (PTH) concentrations varied inversely with measured ultrafilterable calcium concentrations. The frequency of raised PTH concentrations decreased as serum albumin increased. Use of a conventional correction factor for albumin binding (0.88 mg calcium bound per gram of albumin) to calculate corrected total calcium led to major errors in estimating ultrafilterable calcium in these patients. The PTH concentrations in turn correlated with the degree of deviation between estimated and measured ultrafilterable calcium concentrations. Ionised calcium was low in seven of ten additional hypoalbuminaemic patients studied whereas correction of total calcium for albumin indicated normocalcaemia in all. Thus correction of total calcium in patients with hypoalbuminaemia by formulae which use a fixed binding ration of calcium to albumin may give an erroneous impression of normocalcaemia. The increase in calcium binding ratio during hypoalbuminaemia needs to be considered during assessment of calcium status in these patients.

Calcium↗
PubMed1981

Evidence for modulation of insulin action and degradation independently of insulin binding.

The interrelationships between insulin binding, action, and degradation were investigated in isolated hepatocytes with the aid of an insulin-receptor antibody (IRA) preparation that does not affect insulin binding. These IRA have insulin-like effects as determined by their ability to stimulate [14C]acetate incorporation into lipids. However, this effect is less than that of insulin; and in the presence of insulin and IRA, the effects of insulin are partially inhibited. The IRA have no effect on lipogenesis stimulated by postreceptor insulin "mimickers." The IRA also significantly inhibit insulin degradation. However, they do not affect insulin degradation in the presence of a large excess of unlabeled hormone. Taken together these data demonstrate that insulin action and degradation can be modulated independently of binding and suggest that the IRA partially inhibit insulin action and degradation through a portion of the insulin receptor that is not a determinant of insulin binding. It is possible, however, that there exist in the antiserum heterogeneous antibodies that bind to nonreceptor sites on the plasma membrane and mediate some of the phenomena observed.

Animals↗
PubMed1981

Suppression of secondary hyperparathyroidism by propranolol in renal failure patients.

Renal osteodystrophy in part due to secondary hyperparathyroidism, is one of the major unresolved problems affecting patients on chronic hemodialysis. In addition, evidence has shown that parathyroid hormone (PTH) is toxic to other organ systems besides bone. The results of a prospective study on the effect of propranolol in reducing PTH levels in chronic renal failure patients on hemodialysis are reported. Propranolol administration reduced PTH levels by over 50-75%. The levels of calcium, phosphorus, alkaline phosphatase and hematocrit were variable, but patients with severe derangements in these measurements also seemed to benefit from propranolol. It should now be determined by larger and longer studies whether these biochemical improvements can be translated into clinical benefits.

Alkaline Phosphatase↗
PubMed1980

Osteomalacia and weakness from excessive antacid ingestion.

A 60-year-old woman was evaluated for bone pain and incapacitating weakness. Initial laboratory studies showed a serum calcium level of 10.1 mg/dL, severe hypophosphatemia (1.1 mg/dL), and an elevated alkaline phosphatase level. X-ray films showed changes consistent with osteomalacia. Further studies revealed hypercalciuria (448 mg/24 hr) but absent urinary phosphorus. These data indicated phosphate malabsorption. Excessive use of an aluminum hydroxide-containing antacid was the cause of this patient's failure to absorb dietary phosphate. The features of this syndrome are reviewed to increase physicians' awareness of this illness, which occurs particularly in the elderly and is easily treated.

Alkaline Phosphatase↗
PubMed1980

Insulin receptors in hepatocytes: postreceptor events mediate down regulation.

Down regulation of the insulin receptor of primary cultures of rat hepatocytes occurs in the presence of insulin and several agents with insulin-like activity, which act through or distal to the insulin receptor. These findings indicate that the interaction of insulin with its specific binding site is not in itself sufficient to down-regulate this receptor and that one or more steps subsequent to this interaction are necessary. Thus, down regulation may be a complex biological response to insulin, and if a cell were resistant to this effect of insulin, our data may explain how target cells from a patient or animal can have a normal number of receptors in the presence of increased concentrations of circulating insulin.

Animals↗
PubMed1980

Functional relationships between insulin binding, action, and degradation. A reassessment.

We have evaluated the interrelationships between insulin binding, action, and degradation in primary cultures of isolated rat hepatocytes. In this cell system, over 99% of insulin degradation is cell-mediated. Whereas the Km value of insulin degradation in disrupted cells is approximately 10(-7) M, the Km value of insulin degradation in intact cells increases with increasing concentrations of insulin and parallels the Kd value of total insulin binding at all insulin concentrations. The dose-response relationship for insulin action differs from that of insulin degradation and specific insulin binding. However, when the portion of specific insulin binding which is degraded insulin is subtracted, the dose-response relationship for the remaining "specific-intact" insulin bound correlates with that of insulin action. These data indicate that the interpretation of relationships between insulin action, binding, and degradation depends on the biological system and the fraction of insulin binding utilized for analysis. In addition, our data derived in primary cultures of hepatocytes suggest that high affinity insulin binding sites may mediate insulin action, that insulin binding is rate-limiting for insulin degradation, and that all insulin binding sites, including "nonspecific" sites, may mediate insulin degradation.

Animals↗
PubMed1980

Insulin action and binding in isolated hepatocytes from fasted, streptozotocin-diabetic, and older, spontaneously obese rats.

Insulin binding and basal and insulin-stimulated uptake of alpha-aminoisobutyric acid were measured in isolated hepatocytes from young control rats as well as from older spontaneously obese, 72h-starved, and nonketotic streptozotocin-diabetic rats. Isolated hepatocytes from older spontaneously obese rats are similar to those from younger smaller rats in size, maximal insulin responsiveness, the dose-response relationship for insulin-stimulated aminoisobutyrate uptake, and the number and affinity of insulin receptors. Hepatocytes from 72h-fasted rats have similar numbers of insulin receptors per cell as cells from young control animals, but are significantly smaller, have an enhanced basal rate of aminoisobutyrate uptake, and are insulin resistant with regard to maximal insulin-stimulated uptake of aminoisobutyrate at 0.1mm-aminoisobutyrate. Because of the decreased maximal response to insulin, the concentration of insulin that elicits a half-maximal response of aminoisobutyrate uptake is decreased. Hepatocytes from diabetic animals, like those from starved rats, have significantly greater basal rates of aminoisobutyrate uptake; whereas the maximal absolute insulin response is the same as control cells, the percentage response is smaller. These cells bind significantly more insulin than do control cells. The increase in insulin binding is reflected in a shift to the left of the dose-response curve for insulin-stimulated uptake of aminoisobutyrate. These studies indicate that there is no insulin resistance with regard to uptake of aminoisobutyrate in hepatocytes from older obese rats. Furthermore, the insulin resistance observed in hepatocytes from starved rats occurs despite an increase in the number of receptors per unit surface area and cannot be explained by alterations in the interaction between insulin and its receptor. The enhanced insulin binding per unit surface area, however, is reflected in the shift to the left of the dose-response curve for insulin. This is also true for hepatocytes from diabetic animals, in which insulin binding per cell is increased.

Age Factors↗
PubMed1980

Hyperthyroidism with normal serum total T4, T3, and thyroid binding protein concentration.

A 60-year-old woman, free of other disease, with severe clinical hyperthyroidism had normal total serum T4 with elevated free T4 concentration and T3 resin uptake characteristic of hyperthyroidism, with thyroid binding globulin (TBG) deficiency. However, serum TBG concentration as determined by immunoassay was normal, suggesting that the biochemical defect affecting the T4 binding sites did not affect is antigenicity. Her total and free serum T3 levels were low-normal with a markedly elevated reverse T3 concentration. These findings, in the presence of clinical hyperthyroidism, are consistent with an impairment in peripheral conversion of T4 to T3, apparently, in this case, due only to long-standing severe hyperthyroidism.

Female↗
PubMed1980

Effects of parathyroid hormone infusion and primary hyperparathyroidism on serum prolactin in man.

Serum PRL, parathyroid hormone (PTH), and Ca levels were measured in 14 patients (8 women and 6 men) with primary hyperparathyroidism. Six normal volunteers (3 men and 3 women) received a 1-h control infusion of 5% glucose containing 2% human serum albumin, a 1-h infusion of the same fluid containing 450 U bovine PTH, and a repeated 1-h infusion of glucose and albumin. Serum PRL was measured during these infusion periods and showed a peak within 30 min of the start of bovine PTH infusion; PRL levels declined therafter in spite of continued PTH infusion. Serum PRL levels returned to normal within 1 h of discontinuance of bovine PTH infusion. The serum PRL levels in patients with primary hyperparathyroidism were within the normal range, and there was no correlation between serum PTH and PRL levels. These results suggest that the PRL response to PTH infusion is a pharmacological rather than a physiological or pathophysiological effect of PTH.

Adult↗
PubMed1979

Prostaglandin E and hypercalcemia in breast carcinoma: only a tumor marker? A need for perspective.

Prostaglandin E concentrations were measured in a patiet with breast carcinoma, hypercalcemia, undetectable parathyroid hormone (PTH) and no evidence of bone metastases. Catheterization of the drainage bed of her tumor documented production of E series prostaglandins. Treatment with the largest recommended doses of indomethacin for 10 days failed to lower her plasma prostaglandin E (PGE) concentrations or to correct the hypercalcemia, but it normalized urinary excretion of PGE. Subsequent chemotherapy reduced prostaglandin concentrations toward normal values concomitant with a reduction of clinically estimated tumor burden. During this period of time, serum calcium concentrations had no consistent relationship to the plasma PGE levels. We suggest that PGE merely reflected the tumor burden of this patient and did not directly contribute to the genesis of her hypercalcemia. The pertinent literature relating PGE and hypercalcemia is reviewed.

Antineoplastic Agents↗