Hyperinsulinaemia and trace metals.
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Animals↗
Biomedical subjects
J N Clore
Publications and source records attributed to J N Clore.
Thyrotropin-induced hyperthyroidism: evidence for a common progenitor stem cell.
A 36-year-old woman with hyperthyroidism, elevated blood thyroid-stimulating hormone (TSH) and alpha-subunit levels, amenorrhea, hyperprolactinemia and no evidence of acromegaly, was found to have a pituitary adenoma containing TSH, alpha-subunit and growth hormone by immunohistochemistry. Preoperative testing revealed elevated TSH and alpha-subunit with no response to thyrotropin-releasing hormone (TRH) but a normal response in prolactin to TRH. Culture of the pituitary cells showed release of TSH, alpha-subunit and prolactin. In vitro, TRH failed to cause TSH discharge; however, it increased prolactin concentrations in the culture medium. Triiodothyronine, added to the pituitary cell culture, resulted in no inhibition of TSH and prolactin discharge. By electron microscopy, the adenoma cells showed features of thyrotrophs. However, some adenoma cells contained fibrous bodies characteristic of some growth hormone cell tumors and acidophil stem cell adenomas, suggesting that the adenoma originated in a common progenitor cell.
Adenoma↗
Reduced insulin clearance in normal subjects due to extreme hyperinsulinemia.
Insulin clearance was assessed in five normal subjects infused with insulin at a rate of 10 mU.kg-1.min-1 for 12-16 hours, which produced insulin levels of 1500-2000 microU/ml (approximately 10(-8) M). This level approximates the Kd of low affinity insulin binding sites, whereas previous clearance studies had been performed at insulin concentrations of 10(-9) M or less, approximating the Kd of the high affinity insulin receptor. The metabolic clearance rate for insulin during the infusion averaged 214 +/- 29 ml.min-1.m-2, which is half of that reported previously when lower insulin levels were achieved. Upon termination of the insulin infusion, the disappearance of insulin was markedly prolonged with an average "half-life" of 62 minutes. The rapidity with which hyperinsulinemia altered clearance suggested that down-regulation of insulin receptors was probably not the explanation for the reduced clearance. To elucidate the cause for the observed decrease in insulin clearance, five additional subjects were studied. If insulin was infused for 3.0-4.5 hours, the half-life of insulin disappearance was intermediate between that for an insulin bolus dose and that for a 12-16 hour insulin infusion. Administration of an insulin bolus dose at the end of a 12-hour infusion, while the insulin concentration was still approximately 10(-8) M, or 140 min later, when the insulin concentration was 10(-9) M, was followed by rapid disappearance with half-lives of 1.5 and 6-8 minutes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men.
To assess the effects of dehydroepiandrosterone (DHEA) on body fat mass, serum lipid levels, and tissue sensitivity to insulin, five normal men were given placebo and five normal men were given oral DHEA [1600 mg/day (554.7 mmol/day)] for 28 days in a randomized, double blind study. In the DHEA group serum DHEA-S levels rose 2.5- to 3.5-fold, and mean (+/- SEM) serum androstenedione rose from 4.3 +/- 0.6 to 8.6 +/- 1.2 nmol/L (P less than 0.004, by paired t test), but serum total testosterone, free testosterone, sex hormone-binding globulin, estradiol, and estrone levels did not change. In the DHEA group the mean percent body fat decreased by 31%, with no change in weight. This suggests that the reduction in fat mass was coupled with an increase in muscle mass. DHEA administration also resulted in a fall in mean serum total cholesterol concentration (4.82 +/- 0.21 vs. 4.48 +/- 0.29 nmol/L; P less than 0.05), which was due almost entirely to a fall of 7.5% in mean serum low density lipoprotein cholesterol (3.21 +/- 0.11 vs. 2.97 +/- 0.14 nmol/L; P less than 0.01). No changes in anthropometric parameters or serum lipid levels occurred in the placebo group. Tissue sensitivity to insulin, assessed by the hyperinsulinemic-euglycemic clamp technique, did not change in either the placebo or DHEA groups. These results suggest that in normal men DHEA administration reduces body fat, increases muscle mass, and reduces serum low density lipoprotein cholesterol levels. Tissue sensitivity to insulin was unaffected by short term DHEA administration.
Adipose Tissue↗
Effect of chronic adrenocorticotropin stimulation on the excretion of 18-hydroxycortisol and 18-oxocortisol.
The human adrenal gland can metabolize cortisol to yield steroids oxygenated at the 18 position in a series of reactions similar to those by which corticosterone is converted to 18-hydroxycorticosterone and aldosterone and perhaps catalyzed by the same enzyme. These analog steroids, 18-hydroxycortisol and 18-oxocortisol, are produced in small quantities normally, but can be produced in excess by aldosterone-producing adrenal adenomas and in glucocorticoid-suppressible aldosteronism. Chronic ACTH administration has been reported to produce a transient increase in aldosterone production. We studied the effect of chronic ACTH administration on the excretion of aldosterone-18-oxoglucuronide and its relationship to the excretion of 18-hydroxycortisol and 18-oxocortisol. Five normal men collected 24-h urine samples for 3 control days and 5 days while receiving ACTH (40 U, im, twice daily). Urinary excretion of tetrahydrocortisol, tetrahydrocortisone, aldosterone 18-oxo-glucuronide, 18-hydroxycortisol, and 18-oxo-cortisol was measured by RIA. Urinary tetrahydrocortisol and tetrahydrocortisone excretion increased 7- to 10-fold during ACTH administration. Urinary aldosterone 18-oxoglucuronide excretion increased to a peak on the second day (6-fold increase) and decreased to basal levels by the fifth day of continuous ACTH administration. The excretion of 18-hydroxycortisol increased about 6-fold and remained elevated throughout the period of ACTH administration. The excretion of 18-oxocortisol increased from an average of 3.7 nmol/day to a peak of 176.7 nmol/day (a 47-fold increase) on the third day and decreased to 107.9 nmol/day on the fifth day of ACTH administration. These results are consistent with the hypothesis that the decrease in aldosterone production after 2 days of ACTH administration is the result of induction of 17-hydroxylase by ACTH, resulting in the biosynthesis of cortisol in these cells. Since the cells have the cytochrome P-450-dependent corticosterone methyl oxidase enzyme, cortisol becomes its predominant substrate, resulting in the increase in 18-hydroxycortisol and 18-oxocortisol production. We have called these cells transitional cells because they have enzymatic systems of the zona glomerulosa and the zona fasciculata.
Adrenal Glands↗
Adrenocorticotropin and cortisol-induced changes in urinary sodium and potassium excretion in man: effects of spironolactone and RU486.
The role of the glucocorticoid (type II) receptor in the Na+ retention induced by cortisol is not known. The relative contribution of mineralocorticoid (type I) and type II receptor activation to changes in urinary Na+ and K+ excretion in man was studied using spironolactone and RU486 to inhibit type I and II receptors, respectively. Normal men eating a constant daily diet received either ACTH or cortisol for 5 days. Spironolactone (400 mg/day) inhibited ACTH (80 U/day)-induced kaliuresis, but not the Na+ retention produced by ACTH or cortisol (240 mg/day) and only blunted the modest Na+ retention induced by cortisol (120 mg/day). RU486 (1200 mg/day for the first 2 day) inhibited the first day kaliuresis and carbohydrate intolerance produced by cortisol, but did not affect the Na+ retention. Thus, the kaliuresis produced by cortisol and ACTH can be attributed to type II and type I receptor activation, respectively. The failure of RU486 to inhibit the Na+ retention induced by cortisol with evidence of adequate blockade of type II receptors indicates that the Na+ retention produced by cortisol is not mediated by type II receptor activation, but is, at least in part, mediated by the type I receptor.
Adrenocorticotropic Hormone↗
Prolonged insulin resistance following insulin-induced hypoglycaemia.
Nineteen normal male volunteers underwent a 10-h glucose clamp study to examine the duration and mechanism of insulin resistance after hypoglycaemia. Dextrose delivery by the Biostator to maintain the target blood glucose level fell below baseline 2 h after induction of hypoglycaemia and remained suppressed for at least 7 h after insulin hypoglycaemia. Insulin secretion as manifested by C-peptide levels remained suppressed for 3-4 h after insulin hypoglycaemia despite return of blood glucose to baseline by 90 min. Glucose kinetic data (3-3H-glucose) performed in six of the subjects indicated that the prolonged insulin resistance was due to significantly increased hepatic glucose production and to suppressed glucose utilisation, persisting for at least 4 h after counterregulatory hormone levels had returned to normal. Post-hypoglycaemic insulin resistance as determined by dextrose delivery was markedly attenuated and the rise in hepatic glucose output totally eliminated in five hypopituitary subjects without growth hormone or cortisol responses to hypoglycaemia. We conclude that post-hypoglycaemic insulin resistance occurs in non-diabetic subjects and persists for at least 7 h following hypoglycaemia. This prolonged insulin resistance is largely related to release of growth hormone and cortisol.
Adult↗
The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans.
Insulin may mediate the hyperandrogenism that frequently occurs in patients with insulin-resistant states. To test this hypothesis, we studied five normal women and one woman with hyperandrogenism, insulin resistance, and acanthosis nigricans with the hyperinsulinemic-euglycemic clamp technique. Each woman received a 0.1 U/kg insulin bolus dose, followed by a 10 mU/kg X min insulin infusion for 12-16 h. In the normal women, an average insulin level of 1832 +/- 292 (+/- SEM) microU/ml was achieved; serum glucose was clamped at 116 +/- 5 mg/dl. At this level, insulin may bind to the insulin-like growth factor I receptor as well as to its own receptor. Contrary to our working hypothesis, a rise in serum testosterone did not occur in any women during insulin infusion, and in one women, serum testosterone levels decreased. When analyzed as a percentage of the basal value, serum progesterone levels fell 20% in the normal women within the first 2 h of insulin infusion, but did not change thereafter. Dehydroepiandrosterone sulfate (DHEA-S) levels, however, uniformly and progressively decreased by 39% after 12 h of insulin infusion in the normal women and by 31% at 14 h in the woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. The fall in serum DHEA-S levels was not due to diurnal rhythmicity, as the changes in serum DHEA-S levels did not correlated with those in serum cortisol. Suppression of PRL release also was excluded as a cause of the fall in DHEA-S levels. These results indicate that acute hyperinsulinemia of 12- to 16-h duration does not increase serum testosterone or DHEA-S concentrations and, indeed, can cause a decline in serum DHEA-S levels in both normal women and the single woman studied with hyperandrogenism, insulin resistance, and acanthosis nigricans.
Acanthosis Nigricans↗
Effects of extreme hyperinsulinaemia on serum levels of trace metals, trace metal binding proteins, and electrolytes in normal females.
In order to assess the possible effects of insulin on serum concentrations of trace metals (iron, copper, zinc) and trace metal binding proteins (ferritin, transferrin, coeruloplasmin), five normal females were studied with the hyperinsulinaemic-euglycaemic clamp technique. A 0.1 U/kg insulin bolus was administered, followed by an insulin infusion at a rate of 10 mU/kg/min for 12-16 h. Insulin levels of 1500-2000 microU/ml (9.21-12.28 nmol/l) were attained. When iron levels in serum were assayed colorimetrically, there appeared to be a progressive rise in the mean concentration during the course of the insulin infusion. Direct analysis of serum samples by atomic absorption spectrophotometry also showed that the level of non-haeme iron increased 3-fold in the serum of the subject with the lowest concentration of this metal at the start of the study. In contrast with the results for serum iron, the levels of ferritin, total iron binding capacity (transferrin), zinc, copper and coeruloplasmin were not altered in any subject during the insulin infusion or at 24 h following discontinuation of the infusion. Within 4 h of institution of the hyperinsulinaemic clamp significant reductions in serum levels of potassium, phosphorus, cholesterol, total protein and albumin were noted. As the insulin infusion progressed, the urea nitrogen, uric acid and bicarbonate levels fell as well. These observations suggest that supraphysiologic hyperinsulinaemia of 12-16 h duration may alter serum levels of iron, but not serum levels of zinc, copper or trace metal binding proteins in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Quantitative assay of types I and III collagen synthesized by keloid biopsyes and fibroblasts.
Molecular sieve column chromatography was used to determine the amount of type I and III collagen synthesized by normal dermis and keloid biopsies and fibroblasts derived from these tissues. After incubation with radioactive proline, the collagen was extracted and separated into types I and III and then quantitated. There was no significant difference in the percent type III collagen synthesized by fresh keloid biopsies compared to normal dermis. Likewise, there was no significant difference in the percent type III collagen synthesized by keloid fibroblasts compared to normal dermal fibroblasts. However, fibroblasts from both keloid and normal dermis synthesized a lower percentage of type III collagen in cell culture compared to the original biopsies. These findings demonstrate that keloid collagen has the same type distribution as normal dermis and suggest that increased collagen synthesis in these lesions is not related to altered collagen types.
Adolescent↗
Quantitation of collagen types I and III during wound healing in rat skin.
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Animals↗
Source of error in operative cholangiography.
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Cholangiography↗
Absorption characteristic of breakfast determines insulin sensitivity and carbohydrate tolerance for lunch.
To test the hypothesis that prolonging absorption of breakfast might improve the glucose tolerance of the subsequent meal served at lunch, normal male volunteers were administered the same carbohydrate in either a rapidly absorbed (sucrose, S) or slowly absorbed (sucrose with guar, S + G) form for breakfast (0800) and lunch (1145). Area under the curve (AUC) for glucose did not differ for S at breakfast vs. S + G at breakfast, although AUCinsulin for S at breakfast was greater than that for S + G at breakfast (3389 +/- 608 vs. 1523 +/- 246 microU.min.ml-1, P less than .002). Plasma glucose and insulin profiles for the two breakfast meals differed markedly. Once S was ingested, plasma glucose and insulin returned to baseline after 120 and 160 min, respectively. However, once S + G was ingested, plasma glucose and insulin were still significantly above baseline values after 180 min. When S was eaten for breakfast, AUCglucose for lunch was similar to that for breakfast, regardless of whether lunch consisted of S or S + G. However, if S + G was eaten for breakfast, AUCglucose for S + G or S at lunch was 44% (P less than .005) and 75% of that for breakfast, respectively. Only one of five subjects who ingested S + G for breakfast failed to exhibit a fall in AUCglucose when S was eaten for lunch. The beneficial effect of prolonged absorption of breakfast on the glucose tolerance of lunch was not observed if the timing of lunch was delayed by 2 h (i.e., served at 1345).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗