Growth hormone-releasing factor immunoreactivity in the hypothalamus and cortex of the rat: in vivo and in vitro studies.

Utilizing a specific RIA for rat (r) GRF, hypothalamus and cerebral cortex from adult rat and long term dissociated fetal rat hypothalamic and cerebral cortical cell cultures were investigated for the presence of rGRF immunoreactivity (IR-GRF). After homogenization in an acidic medium, tissues and cultures were extracted on octadecylsilyl-silica columns, and IR-GRF and somatostatin (IR-SS) were measured by RIA. In extracts from the hypothalamus from the adult rat the content of IR-GRF was 3.02 +/- 0.16 ng ( +/- SE) per hypothalamus. IR-GRF was identical with synthetic rGRF on gel filtration chromatography and by parallel displacement of dilutions of extract in RIA. In extracts from cerebral cortex isolated from the adult rat, no IR-GRF was detected. In extracts from long term dissociated cell cultures from fetal hypothalami, 7.3 +/- 7 pg/10(6) cells of IR-GRF were present and were identical with synthetic rGRF by chromatographic and immunological criteria. In the extracts from cerebral cortical cell cultures cross-reacting material was present which on gel filtration chromatography revealed two peaks of immunoreactivity of higher mol wt than synthetic rGRF. There was nonparallelism on dilution of the extract. The ratio of IR-SS to IR-GRF by weight (IR-SS/IR-GRF) was calculated to compare the relative abundance of IR-GRF in cultured hypothalamic cells. In the hypothalamus isolated from the adult rat the ratio of IR-SS/IR-GRF by weight was 15.8 +/- 1.4 as compared to 48.9 +/- 10.3 in hypothalamic cultures. We conclude that IR-GRF indistinguishable from synthetic rGRF is present in long term dissociated hypothalamic cell cultures, but is relatively less abundant than in the hypothalamus of the adult rat when compared on the basis of IR-SS. No IR-GRF was detectable in cerebral cortex of the adult rat. At least one cross-reacting molecular species is detected in cerebral cortical cultures by the rGRF RIA, but exhibits nonparallelism and has a higher mol wt than synthetic rGRF. The increase of the ratio of IR-SS/IR-GRF in hypothalamic cell cultures in vitro compared to hypothalamus in vivo suggests that the culture conditions change differentially the expression of IR-SS and IR-GRF.

The effects of growth hormone, prolactin, corticotropin, and thyrotropin on the production and secretion of somatostatin by hypothalamic cells in vitro.

The influence of GH and several other pituitary hormones on the secretion and intracellular content of immunoreactive somatostatin (IRS) in cultured hypothalamic cells was examined. Hypothalamic cells prepared from 17-day-old rat embryos and maintained as reaggregate monolayers for 12 days in vitro were used. Short term release of IRS from these cultures was found to be stable and relatively constant. IRS release was enhanced by 60 mM K+ in a calcium-dependent fashion and by dopamine at concentrations as low as 1 nM. GH (1 microM) increased medium IRS content above baseline 12, 24, and 48 h after the incubation was begun, but had no effect after only 4 h. Hypothalamic cell content of IRS was increased by a 24-h incubation in 0.3 and 1.0 microM GH, but not by 0.1 microM GH. TSH (1 microM) induced an increase in IRS release comparable to 1 microM GH. However, intracellular IRS content was decreased after exposure to TSH. Cosyntropin, an ACTH analog, inhibited both IRS release and cell content, whereas PRL had no effect on either medium or cellular IRS content. Our results demonstrate that developing somatostatinergic neurons in the hypothalamus have the capacity to respond to pituitary hormones, indicating that short-loop feedback pathways may exist in perinatal hypothalamic cells.

Signal transduction systems in growth hormone-releasing hormone and somatostatin release from perifused rat hypothalamic fragments.

The role of signal transduction systems was examined in the secretion of GH-releasing hormone (GHRH) and somatostatin (SS) from perifused rat hypothalamic fragments. Forskolin, an adenylate cyclase activator, stimulated the release of GHRH and SS in a concentration-dependent manner (10-100 microM) with greatest stimulation for GHRH at 100 microM (mean +/- SE, 249 +/- 14%) and for SS at 30 microM (172 +/- 18%). (Bu)2cAMP also augmented GHRH and SS release. The protein kinase-C activator phorbol 12-myristate 13-acetate did not significantly stimulate basal GHRH or SS release at concentrations of 10 nM to 1 microM. The calcium ionophore A23187 enhanced the release of GHRH and SS in a concentration-dependent manner (2-20 microM), with the greatest responses of 282 +/- 50% at 10 microM and 189 +/- 24% at 20 microM, respectively. Potentiation by phorbol 12-myristate 13-acetate of forskolin-stimulated GHRH and SS release was observed. A23187 at 10 microM did not enhance forskolin-stimulated GHRH release, but did potentiate forskolin-stimulated SS release in a more than additive response. We conclude that there is 1) cAMP stimulation of hypothalamic GHRH and SS release, 2) a modulating role of protein kinase-C on cAMP-stimulated release of GHRH and SS, 3) a stimulatory role of the calcium messenger system for GHRH and SS release, 4) interaction of the signal pathways with differences in net GHRH and SS responses, and 5) a modulatory effect of protein kinase-C in perifused hypothalamic fragments which differs from the stimulation of basal GHRH and SS release reported in fetal-derived hypothalamic cell cultures. Our observations suggest an important regulatory role of interacting signal transduction systems in the hypothalamic secretion of GHRH and SS.

Insulin receptors on cultured hypothalamic cells: functional and structural differences from receptors on peripheral target cells.

We have studied the functional and structural characteristics of insulin receptors on cultured rat hypothalamic cells. The receptors on these cells are specific for insulin, but have a lower binding affinity than that measured in nonneuronal tissues. Neither acute (2-h) nor long term (24-h) exposure of the hypothalamic cells to high insulin concentrations resulted in receptor down-regulation. However, insulin is internalized in these cells and accumulated in the presence of the lysomotropic agent chloroquine. Acute exposure to insulin does not alter initial rate of 2-deoxyglucose transport in hypothalamic cells, but does cause a stimulation of aminoisobutyric acid uptake. Photoaffinity labeling of the receptors of the hypothalamic cells with a biologically active photosensitive insulin revealed a major specifically labeled band of 115K mol wt and a minor band of 40K mol wt under disulfide-reducing conditions compared to bands of 125K and 90K mol wt seen after labeling of the insulin receptors of adipocytes. The receptor proteins in hypothalamic cells under nonreducing conditions (420K, 370K, and 310K mol wt) were also smaller than those in adipocytes. Thus, the insulin receptors of cultured hypothalamic cells differ from insulin receptors on peripheral target tissues in both functional and structural aspects.

Influence of food deprivation in the rat on hypothalamic expression of growth hormone-releasing factor and somatostatin.

Food deprivation in the rat is associated with a reduction in serum GH levels characterized by suppression of high amplitude GH bursts and a decrease in the duration of secretory episodes. The mechanism(s) mediating this response is unknown. The present studies were designed to evaluate the role of hypothalamic factors potentially responsible for abnormal GH dynamics in food-deprived rats by measuring hypothalamic prepro-GH-releasing factor (GRF) and preprosomatostatin (SRIF) mRNA and peptide levels in adult male Sprague-Dawley rats after 72 h of food deprivation or free access to food. Hypothalamic prepro-GRF mRNA was reduced 80% in food-deprived rats compared to that in fed controls (P less than 0.001), while GRF content was unchanged. Levels of prepro-SRIF mRNA in food-deprived rats were similar to those in controls, as was hypothalamic SRIF content. The time course of hypothalamic prepro-GRF mRNA reduction was determined in groups of rats food-deprived for 24, 48, or 72 h and revealed a significant (30%) reduction of prepro-GRF mRNA (P less than 0.05 vs. fed) by 24 h, with maximal reduction (80%) by 48 h. Refeeding groups of animals for up to 72 h after they had been food-deprived for 72 h resulted in restoration of prepro-GRF mRNA levels to 50% of control levels by 24 h (P less than 0.05 vs. fed) and a return to control values by 48 h. These data suggest that decreased GRF gene expression and possibly GRF release play a major role in the loss of pulsatile GH secretion seen in this model of nutrient deprivation.

Altered pituitary growth hormone (GH) regulation in streptozotocin-diabetic rats: a combined defect of hypothalamic somatostatin and GH-releasing factor.

Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 +/- 0.10 ng/hypothalamus) did not differ from that in controls (1.16 +/- 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.

Regional distribution of human growth hormone-releasing hormone in the human hypothalamus by radioimmunoassay.

The regional distribution of human GH-releasing hormone (hGHRH) in the hypothalamus was determined by RIA using a standardized microdissection technique. The antiserum used in the RIA is highly specific for human GHRH-44, and cross-reactivity to hGHRH-40 is minimal (less than 0.06%). The concentration and content of immunoreactive hGHRH-44 (IR-GHRH) were measured in extracts of 12 nuclei and areas microdissected from hypothalami from 5 autopsy subjects. Extracts of proximal and distal pituitary stalk were similarly analyzed for IR-GHRH. The highest concentration of IR-GHRH in the hypothalamus was in the infundibular nucleus, with lesser concentrations in the periventricular area and paraventricular and supraoptic nuclei. All other regions had measurable concentrations, except the mammillary nuclei. There was 56.1 +/- 12.4 (+/- SD) ng (11.1 +/- 1.2 pmol) IR-GHRH in the human hypothalamus and pituitary stalk, with 62% in the pituitary stalk. IR-GHRH in tissue extracts produced the same dose-response curve as did hGHRH in the RIA and coeluted with synthetic hGHRH-44 on gel filtration. Our results indicate the following. 1) The regional distribution of IR-GHRH in the human hypothalamus differs from the regional distributions of other neuropeptides. 2) The infundibular nucleus contains the greatest IR-GHRH regional concentration, in accord with immunohistochemical studies. 3) Appreciable concentrations of IR-GHRH are found in regions not previously identified by immunohistochemical techniques. 4) The IR-GHRH molar content in the hypothalamus-pituitary stalk is lower than that reported for other hypothalamic releasing hormones.

An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity.

Generalized resistance to thyroid hormones results from diverse mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor, and different kindreds have variable phenotypes. However, the T3-binding affinities of these mutant receptors studied in vitro have all been severely reduced compared to wild type. We report here a new kindred, CL, with a mutation further upstream than previously reported, a guanine to adenine base substitution at nucleotide 1244 in codon 315 changing an arginine to histidine. This base substitution was the only one found in codons 90-456 of genomic sequence and was formally shown to be a mutation by screening 51 random individuals. The kindred CL receptor complementary DNA was recreated, and the mutant receptor synthesized with rabbit reticulocyte lysate had a T3-binding affinity of 2.4 +/- 0.9 x 10(10) M-1 compared to the wild-type human placental receptor affinity of 5.2 +/- 1.6 x 10(10) M-1. Affected members of this kindred appeared clinically to have a relatively mild degree of resistance with mean total thyroxine of only 192 +/- 24 nmol/L and inappropriately normal TSH levels. Kindred CL is an example of mild generalized resistance to thyroid hormones correlated with a mutation in the beta-receptor that resulted in only a modest deficiency in T3-binding activity.

High sensitivity two-site immunoradiometric and immunochemiluminometric assays for rat growth hormone-releasing hormone. Development of an acridinium ester based chemiluminescence assay for the avidin-coated bead system.

High sensitivity two-site immunoradiometric and immunochemiluminometric assays were developed for the direct measurement of rat GHRH in perifusate of hypothalamic fragments and in hypophysial portal plasma. A solid phase immunoradiometric assay was developed initially using avidin-coated polystyrene beads and radioimmunoassay quality polyclonal antibodies to N-terminal and C-terminal fragments of GHRH. Immunoaffinity purification of the high affinity antibodies required a strong eluant, 1 M acetic acid with 10% dioxane. For high sensitivity, the affinity-purified C-terminal signal antibody was iodinated by the lactoperoxidase-glucose oxidase method and absorbed with avidin-BSA-IgG conjugated matrix. Conversion to an acridinium ester based immunochemiluminometric assay required substantial modifications to optimize performance. For both assays, the innovative modification of delayed addition of the bead enhanced assay performance by two-fold. By precision profile analysis the sensitivity of the immunochemiluminiometric assay (0.035 pg/tube) was two-fold better than the sensitivity of the immunoradiometric assay (0.066 pg/tube). These assays, 4-7-fold more sensitive than a highly optimized radioimmunoassay (0.26 pg/tube), were validated for direct unextracted measurement of GHRH in perifusate and in hypophysial portal plasma. They have significant advantages for biological measurements, reducing the number of hypothalami per perifusion chamber and enabling measurement of low concentrations of plasma GHRH not previously possible. The avidin-coated bead system can be flexibly used to develop high sensitivity two-site peptide assays using polyclonal antibodies. Further, this system has been extended to acridinium ester based immunochemiluminometric assays with improvement of assay performance.

Dramatic response of follicular thyroid carcinoma with superior vena cava syndrome and tracheal obstruction to external-beam radiotherapy.

We report a patient with follicular thyroid carcinoma progressing to superior vena cava (SVC) syndrome and tracheal obstruction despite multiple doses of radioactive iodine therapy but subsequently responding dramatically to external-beam radiotherapy (RT). Although RT is not considered to be the treatment of choice for follicular carcinoma, RT in our patient produced unequivocal improvement of SVC syndrome and tracheal obstruction.

Solid-phase radioimmunoassay and chemiluminoimmunoassay for somatostatin in unextracted rat plasma.

Measurement of somatostatin (SS) in small microliter volumes of rat plasma obtained from the hypophysial portal circulation would be aided by a sensitive and robust technique not dependent on extraction. We have developed radioimmunoassay (RIA) and chemiluminoimmunoassay (CIA) for SS in unextracted rat plasma from a previously described solid-phase method in human plasma. Plasma SS was captured by primary antibody bound to second antibody coated polystyrene bead. After incubation the bead was washed and [125I]Tyr1-SS added. Following overnight incubation and washing, the bead was counted. The sensitivity for 50 microliters plasma was 11 pg/ml. Parallel displacement with abdominal portal and hypophysial portal plasma was demonstrated. For direct CIA, SS was labeled with acridinium and purified using 2 sequential gradient elutions on reversed-phase HPLC. Labeled SS performed satisfactorily in solution CIA, but did not bind well in solid-phase CIA. Hence, an indirect CIA using biotinylated SS and quantitation by acridinium labeled streptavidin was established with equivalent performance to solid-phase RIA. In summary, we have developed and validated sensitive and robust solid-phase RIA and indirect CIA for SS in unextracted rat plasma. This solid-phase method could serve as a universal system for the measurement of other neuropeptides in rat plasma.

Time course of hypothalamic growth hormone-releasing hormone and somatostatin content in streptozocin diabetic rats: evidence for early changes in hypothalamic regulation.

Growth hormone secretion is markedly suppressed early in streptozocin induced diabetes mellitus of the rat. Our studies were designed to delineate early changes in hypothalamic regulation by growth hormone-releasing hormone (GHRH) and somatostatin (SS) with the aim of determining the best time period for hypothalamic secretion studies. Although hypothalamic GHRH content (ng/hypothalamus) and SS concentration (ng/mg wet weight) were unchanged at 17 to 20 days in previous studies, we anticipated changes earlier in the time course from transient imbalances in release and synthesis. We examined hypothalamic GHRH content and SS concentration in control, diabetic, and insulin treated diabetic rats (n = 5-13; streptozocin 100 mg/kg i.p.) at 0, 2, 4, 7, 10 and 21 days. In diabetic rats GHRH content was greater at day 2 (142 +/- 9% of control-same day, P < 0.05) and day 4 (139 +/- 17%, P < 0.05), but was less at day 10 (67 +/- 4%, P < 0.01). GHRH content of insulin treated diabetic rats was elevated at day 2 (158 +/- 10%, P < 0.05), but subsequently was unchanged from control. In diabetic rats SS concentration was decreased at day 4 (78 +/- 5%, P < 0.01) and at day 21 (91 +/- 3%, P < 0.05). Our results show earliest changes compared to control in GHRH content at 2 days and in SS concentration at 4 days. These findings support early changes in hypothalamic secretion, define a time period of 1 to 10 days for further studies of release and gene expression, and suggest complex relationships of gene expression, peptide synthesis, and peptide release.

Increasing incidence and characteristics of differentiated thyroid cancer in Huntington, West Virginia.

Since 1985, we have observed an increasing number of differentiated thyroid cancer cases in Huntington, West Virginia. We describe tumor incidence, patient and tumor characteristics, treatment modalities, and tumor recurrence and death. One hundred seventeen patients with differentiated thyroid cancer were identified between 1976 and 1999. Data were collected from patient records in our practice and the tumor registries at the three hospitals serving our community. The annual incidence of differentiated thyroid cancer increased significantly from fewer than 3 cases per 100,000 prior to 1996 to 9.4 cases per 100,000 in 1999. The median age at diagnosis was 49 years (range, 16-80). The median tumor size was 2.5 cm (range, 1.2-10). Forty-seven percent of the patients had bilateral disease, 28% had three or more tumors, 44% had thyroid capsular invasion, and 16% had gross extrathyroid invasion at surgery. Twenty-two percent had cervical lymph node involvement and 9% had distant metastases at diagnosis. During 1-month to 23-year follow-up, 11% had recurrence, and 5% died of thyroid cancer. In summary, differentiated thyroid cancer has increased dramatically in our community. The tumors appear to be aggressive at diagnosis as reflected by the high percentage of tumors with bilateral, multicentric, and locally invasive disease.

A post-thyroidectomy convulsion: an unusual presentation of chronic hypoparathyroidism.

A 59-year-old woman with previously undiagnosed hypoparathyroidism presented with a tonic-clonic seizure 38 years after thyroidectomy. This case is unusual because of the initial presentation, but also unique because it is the longest latency period between surgery and presentation in recent literature.

Two cases of malignant lymphoma complicating autoimmune (Hashimoto's) thyroiditis.

The occurrence of lymphoma of the thyroid in a setting of autoimmune thyroid disease is being recognized with increasing frequency. The usual presentation is a rapidly enlarging goiter. This article describes two cases of this condition and emphasizes how prompt diagnosis and treatment can yield satisfactory results.

Reversed-phase high-performance liquid chromatographic purification of 125I-labeled rat growth hormone-releasing hormone for radioimmunoassay.

Using reversed-phase high-performance liquid chromatography, an effective purification was developed for radioiodinated rat growth hormone-releasing hormone (rGHRH) with isolation of monoiodo-rGHRH. The use of this purified radio-label resulted in improvement in binding, half-maximum displacement and sensitivity in radioimmunoassay for rGHRH. The improved radioimmunoassay performance allowed the measurement of in vitro basal and stimulated the release of rGHRH from incubated hypothalamic preparations.

Developmental and sex-related changes of the growth hormone axis in lean and obese Zucker rats.

The development and sex-related changes in the hypothalamic-pituitary GH axis were examined in lean and obese Zucker male and female rats from 6 to 12 weeks of age. Pituitary GH content was not different in any phenotype/sex group at 6 weeks. GH content increased with age in male rats, but at 10 and 12 weeks content was decreased in obese male rats relative to lean rats. GH content did not increase in female rats and there was no difference in content between lean and obese female rats. Hypothalamic GHRH content was not different between the groups. Hypothalamic SS content was decreased in obese male rats compared to lean male rats (95%) and in obese female rats compared to lean female rats (78%). Individual 6-hour plasma GH profiles from rats 6-7 weeks of age showed the characteristic sexually dimorphic GH secretory patterns. However, spontaneous GH secretion was dramatically reduced in obese animals when compared to sex-matched lean rats. GH peak amplitude (25% of lean) and mean GH concentration (19% of lean) were decreased in obese male rats without a significant alteration in GH peak frequency or baseline level. In obese female rats, the number of GH peaks, peak amplitude, baseline GH, and mean GH concentration were all decreased compared to lean. The reduction in peak amplitude (14% of lean) and in mean GH concentration (20% of lean) was similar to the reduction in obese male rats. Serum IGF-I concentrations were not different among the groups at 6 weeks. IGF-I levels in male rats increased with age but were not different between lean and obese rats. IGF-I concentrations in female rats were unchanged with time and were not different between lean and obese rats. Serum insulin was increased in obese male and female rats at 6 through 12 weeks. We conclude (1) GH secretion is depressed at 6-7 weeks in obese male and female rats with the magnitude of reduction similar to previous observations in male rats 12 weeks or older; (2) pituitary GH content is depressed only in obese male rats and occurs after the defect in GH secretion; (3) hypothalamic GHRH content is unchanged and hypothalamic SS is slightly to moderately decreased in obese rats; (4) serum IGF-I is not different between lean and obese rats; (5) obese male and female rats were hyperinsulinemic.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of hypophysectomy and growth hormone administration on hypothalamic growth hormone-releasing hormone and somatostatin content: relationship to age-related growth rate.

The purpose of these studies was to evaluate the effect of age-related differences in growth rate on the hypothalamic content of growth hormone-releasing factor (GHRH) and somatostatin (SS) and on the short loop feedback regulation of GHRH and SS. Percent weight gain, GHRH content, and SS content in control adolescent (8 weeks) and adult rats (6 months) were compared in normal rats administered supraphysiologic amounts of rat growth hormone (rGH) or in hypophysectomized rats receiving thyroxine and corticosterone with or without physiologic rGH replacement. In control adolescent rats, the rate of weight gain was 5-fold higher than in adult rats. GHRH content was higher in adolescent rats, while SS content was lower. After the administration of supraphysiologic amounts of rGH, GHRH content increased in adolescent rats but did not change in adult rats. SS content was unchanged in either age group. Following hypophysectomy GHRH content declined similarly in both groups, whereas the decrease in SS content was greater in adolescent rats. With replacement rGH, weight gain was restored, GHRH content increased but not fully to control, and SS content did not change. The ratio of SS content to GHRH content (SS/GHRH) was higher in control adult rats than in adolescent rats. SS/GHRH increased following hypophysectomy and returned to control values by rGH replacement. We conclude that age-related differences in growth rate are accompanied by appropriate changes in SS/GHRH and that SS and GHRH are regulated by short loop feedback at both ages with increased responses in adolescent rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effects of retinyl palmitate on streptozotocin- and alloxan-induced beta cell toxicity and diabetes in the rat.

The cellular effects of retinoids may be relevant to protection against chemical-induced diabetes mellitus. To determine whether retinyl palmitate protects the beta cell from streptozotocin- and alloxan-induced diabetes, we injected streptozotocin, 60 mg/kg, or alloxan, 100 mg/kg, with or without varying doses of retinyl palmitate intraperitoneally or by tail vein. Plasma glucose was measured for over 4 weeks. To determine if the protective effects of retinyl palmitate were mediated through effects on superoxide dismutase, a scavenger of tissue free radicals, we determined whether retinyl palmitate affected islet superoxide dismutase activity. Retinyl palmitate, given intraperitoneally or by tail vein, protected against both streptozotocin- and alloxan-induced diabetes. The effect was dependent on the route of administration. When given intraperitoneally, the protective effect was greater than when given intravenously. When given by tail vein, the protective effect was dose dependent. Retinyl palmitate in vitro did not affect insulin secretion or islet superoxide dismutase. We conclude that retinyl palmitate treatment protects against streptozotocin- and alloxan-induced diabetes. Further studies are needed to determine whether retinyl palmitate protects against the development of diabetes in other animal models and whether this effect is relevant to diabetes in man.