Recent studies have revealed that altered mineral and vitamin D metabolism is observed in diabetic patients with the complication of osteopenia. In order to elucidate the role of parathyroid hormone-related peptide (PTHrP) on calcium homeostasis in diabetes, we have measured the serum level and urinary excretion of PTHrP as well as other serum calcium-regulating hormones in 106 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 43 control subjects. The serum concentration of intact PTH was 2.34 +/- 0.13 (mean +/- SEM) pmol/l in NIDDM patients, which is significantly lower than the value of 3.11 +/- 0.14 pmol/l in the controls (p < 0.01). Both serum calcium and calcitonin, however, were not statistically different from controls. On the other hand, circulating PTHrP in NIDDM was 40.1 +/- 1.4 pmol/l, which is significantly elevated when compared to 27.3 +/- 1.3 pmol/l in the controls (p < 0.01). Moreover, urinary excretion of PTHrP also was significantly higher in NIDDM (p < 0.01). In the present study, the circulating calcium level was well preserved in NIDDM patients, although the PTH levels were shown to be decreased. The elevated serum PTHrP might, therefore, have a physiologically compensatory role on the calcium regulatory systems in NIDDM. Furthermore, this elevation is most likely due to the excess production of this peptide and not to the decrease in urinary excretion.

Pancreatic A-cell function in the newly developed Otsuka Long Evans Tokushima Fatty (OLETF) strain of non-insulin-dependent diabetes mellitus (NIDDM) rats was examined in relation to the morphological changes in their islets and the plasma glucagon responses to insulin-induced hypoglycemia and an arginine test by chronological studies in seven male OLETF and seven male non-diabetic control Long Evans Tokushima Otsuka (LETO) rats each at 10, 16 and 24 weeks of age and eight male OLETF rats that were placed in a cage with a wheel for exercising from 5 to 24 weeks of age. The hormonal contents and morphological features of the pancreas of these rats were examined. After iv injection of insulin, the plasma glucagon level rose significantly from the basal level in OLETF rats at 10 weeks old, but little if at all in those of 16 and 24 weeks old. The pancreatic A cells of LETO rats of all age groups responded equally well to glucopenia. The areas under the response curves of plasma glucagon (sigma delta IRG) during the 90 min of insulin-induced hypoglycemia were 14496 +/- 7860 vs 9588 +/- 3930, 2257 +/- 3018 vs 9235 +/- 5447 (p < 0.05) and 826 +/- 985 vs 9707 +/- 2510 (p < 0.01) ng.min-1.l-1 in OLETF rats vs LETO rats of 10, 16 and 24 weeks old, respectively. The plasma glucagon responses during the arginine test were higher in OLETF rats than in LETO rats at 10 and 16 weeks but not at 24 weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Secretion of the anterior pituitary hormones adrenocorticotropin (ACTH), beta-endorphin and prolactin (PRL) is complex and involves a variety of factors. This review focuses on the involvement of arginine-vasopressin (AVP) in neuroendocrine regulation of these anterior pituitary hormones with special reference to receptor involvement, mode of action and origin of AVP. Arginine-vasopressin may act via at least two types of receptors: V1- and V2-receptors, where the pituitary V1-receptor is designated V1b. The mode of action of AVP may be mediating, i.e. anterior pituitary hormone secretion is transmitted via release of AVP, or the mode of action may be permissive, i.e. the presence of AVP at a low and constant level is required for anterior pituitary hormones to be stimulated. Under in vivo conditions, the AVP-induced release of ACTH and beta-endorphin is mainly mediated via activation of hypothalamic V1-receptors, which subsequently leads to the release of corticotropin-releasing hormone. Under in vitro conditions, the AVP-stimulated release of ACTH and beta-endorphin is mediated via pituitary V1b-receptors. The mode of action of AVP in the ACTH and beta-endorphin response to stress and to histamine, which is involved in stress-induced secretion of anterior pituitary hormones, is mediating (utilizing V1-receptors) as well as permissive (utilizing mainly V1-but also V2-receptors). The AVP-induced release of PRL under in vivo conditions is conveyed mainly via activation of V1-receptors but V2-receptors and probably additional receptor(s) may also play a role.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to detect somatic and psychomotor disturbances in children and adolescents residing in areas of iodine deficiency, schoolchildren from three areas with different degrees of iodine deficiency were studied. In Randan, the prevalence of severe endemic goiter was accompanied by alteration in thyroid function, increased thyrotropin levels and retardation of both bone and psychomotor age and decreased intellectual quotient. In Tehran, where iodine deficiency is mild, visible goiter was present in 15% of schoolchildren but no alterations in thyroid function, serum thyrotropin, somatic or psychomotor development could be detected. In Zagoon, where the prevalence and severity of goiter was less than Randan but more than Tehran, thyroid function was normal but slightly decreased as compared to Tehran; somatic development was unaltered, but retardation in psychomotor development was evident and the mean intellectual quotient was less than that of Tehranian schoolchildren. These findings indicate the occurrence of physical and psychomotor disturbances in apparently normal schoolchildren from areas of iodine deficiency. Alteration in psychomotor development may occur in children with normal physical growth, due to iodine deficiency.

Neuron density, volume of the area and total neuron number were measured in the medial preoptic area, anterior hypothalamic area and arcuate nucleus of the hypothalamus of young (6-month-old), middle age (14-month-old) and old (22-month-old) male and female rats. Intact male rats did not show neuron loss even in old age, while intact female rats manifested neuron loss in the medial preoptic area, anterior hypothalamic area and arcuate nucleus in old age. Long-term administration of estradiol benzoate to castrated male rats induced neuron loss in the anterior hypothalamic area and arcuate nucleus of the middle age group and in all three areas of the old age group. However, long-term ovariectomy could not prevent neuron loss in these hypothalamic areas in old age. The results suggested that estradiol can have a cumulative impact on the degree of neuron damage and simulate female-type age-related neuron loss in male rats and that there may be the possibility of an intrinsic aging process inducing neuron loss in female rats.

The characteristics of the human serum growth hormone-binding protein (GHBP) were compared with those of a water-soluble GH-binding site prepared by incubating cultured IM-9 lymphocytes in assay buffer with 25 mmol/l iodoacetamide. High-performance liquid chromatography gel filtration of the water-soluble GH-binding site incubated with 125I-labeled human GH ([125I]hGH) revealed a large peak of bound [125I]hGH eluting at the same position as the peak of [125I]hGH bound to the GHBP in serum. The estimated M(r) of the peak was 120,000, presumably representing one [125I]hGH bound to two binding sites. The binding specificities of the serum GHBP, the water-soluble GH-binding site and the GH receptor on IM-9 lymphocytes were identical. The binding affinities for 22,000 hGH and for 20,000 hGH of the serum GHBP were similar to the binding affinity of the water-soluble GH-binding site but lower than those of the cellular GH receptor. These findings show that the characteristics of the serum GHBP are comparable to those of the water-soluble GH-binding site released from IM-9 cells and support the hypothesis that in man the serum GHBP is produced by proteolytic cleavage of the cellular GH receptor.

Lectin-stimulated sheep and cow lymphocytes were used to test whether inhibitors of classical steroid receptors block suppressive effects of progesterone and whether effects of progesterone vary with physiological status. Neither RU 38486 nor RU 43044 blocked the inhibitory effects of progesterone on lymphocyte proliferation. Rather, these antagonists were themselves inhibitory. Effects of progesterone and antagonists were additive: the percentage inhibition caused by progesterone was similar whether antagonists were present or not. The degree of lymphocyte proliferation and the inhibitory effects of progesterone were of the same magnitude for pregnant/lactating cows, pregnant/non-lactating cows, postpartum/lactating cows and cyclic/non-lactating cows. In conclusion, progesterone does not appear to inhibit lymphocyte proliferation through actions that involve classical steroid receptors. There was no evidence that lymphocyte proliferation in the cow is suppressed during pregnancy or that the inhibitory effects of progesterone increase during pregnancy.

We investigated the effects of FK506, a novel immunosuppressive agent, on the phytohemagglutinin (PHA) or interferon-gamma (IFN-gamma)-induced expression of HLA-DR antigen, accessory cell function and proliferation of primary cultured human thyroid cells. Primary cultured thyroid cells from patients with Graves' disease were incubated for 3 days with PHA in concentrations in the range 1-50 mg/l or with 200 kU/l of IFN-gamma, in the presence or absence of FK506. The surface expression of HLA-DR antigen was measured by flow cytometry. Accessory cell function of thyroid cells was assessed by the incorporation of [3H]thymidine to T cells in the presence of 0.1-1.0 micrograms/l staphylococcus enterotoxin B (SEB). The proliferation of thyroid cells was determined from [3H]thymidine incorporation assays. FK506 inhibited the induction of HLA-DR antigen expression by PHA on thyroid cells in a dose-dependent manner, but did not inhibit that by IFN-gamma. Polyclonal anti-IFN-gamma antibody partly inhibited the PHA-induced HLA-DR antigen expression on thyroid cells. Phytohemagglutinin enhanced the SEB-mediated accessory cell function of thyroid cells. FK506 inhibited the accessory cell function induced by PHA. FK506 alone did not directly affect the thyroid cell proliferation, although it ameliorated the thyroid cell growth suppressed by PHA. Our data suggest that FK506 suppresses the HLA-DR antigen expression induced by PHA and the subsequent accessory cell function on thyroid cells via the inhibition of T lymphocytes present in the primary culture.

Recent data suggest that the plasma concentration of insulin-like growth factor binding protein 3 (IGFBP-3) is useful as a screening test for growth hormone (GH) deficiency. In this study, we measured by radioimmunoassay the levels of IGFBP-3 in a group of 20 subjects (12 males) of 5 years and 7 months to 16 years of age undergoing standard GH testing following cranial irradiation. The patients had received 1800 to > 6000 cGY of radiation to the hypothalamic-pituitary region, a median of 2.7 years (range 2-7 years) prior to testing. The IGFBP-3 concentrations were discordant with the results of GH testing 60% (12/20) of the time. Although IGFBP-3 levels were below the mean for age in 14 of 15 GH-deficient (peak GH < 10 micrograms/l) patients, only three of 15 GH-deficient patients had IGFBP-3 concentrations that fell below age-adjusted norms. In contrast, the IGFBP-3 levels were within the normal range in all five patients with normal GH responses. The low sensitivity (20%) of IGFBP-3 in predicting the subjects with abnormal responses was not improved by adjusting the values for bone age or stage of puberty. We concluded that a single plasma determination of IGFBP-3 is not a useful screening test for GH deficiency among patients previously treated with cranial irradiation.

The intracellular localization of Cu/Zn- and Mn-superoxide dismutase (SOD), which catalyze the dismutation of superoxide radicals (O2-) to O2 and H2O2, was studied in the thyroid tissue of various thyroid disorders by an immunohistochemical technique. The concentrations of both SODs in those tissues were measured also by a sandwich enzyme immunoassay technique. Copper/zinc-SOD in thyroid tissues were identified by immunocytochemical staining in most cases of papillary carcinoma and in some cases of other thyroid disorders. In normal follicular cells this enzyme is localized in the perinuclear cytoplasm, whereas in thyroid tumor or hyperplastic follicular cells it exists homogeneously in cytoplasm. Manganese-SOD stained strongly in papillary carcinoma and papillary-growing cells in the thyroid tissue of adenoma and Graves' disease. The concentrations of Cu/Zn-and Mn-SOD in thyroid tumor tissues and hyperplastic follicular disorders were significantly higher than those in normal thyroid tissue when they were compared as a function of protein or deoxyribonucleic acid contents. The ratio of Mn-SOD to Cu/Zn-SOD was significantly higher only in papillary carcinoma, except for other thyroid disorders as compared with that in the normal thyroid. In conclusion, SOD seems to be related to cell proliferation and differentiation in the thyroid follicular cell because Cu/Zn-SOD changes its localization in tumor and hyperplastic follicular cells and because the Mn-SOD concentration is increased in papillary carcinoma or papillary-growing cells.