Growth hormone (GH) is produced in a select population of cells, somatotropes, located in the anterior pituitary gland. GH is released into the general circulation where it interacts with multiple peripheral tissues through its receptor, GH receptor, to regulate growth and metabolic function. GH-releasing hormone (GHRH) and somatostatin are the primary positive and negative regulators of GH secretion, respectively. More recently, ghrelin has emerged as an additional stimulatory hormone for GH release. In humans, GH levels decrease in states of nutrient excess, such as obesity, and increase in response to nutrient deprivation, such as fasting, type 1 diabetes, and anorexia nervosa. Considering that GH regulates metabolism of carbohydrate, lipid, and protein, clarifying the mechanisms by which metabolic changes alter pituitary GH synthesis and secretion will increase our knowledge on the pathophysiology and treatment of metabolic diseases. In this review, the effect of nutrient excess and nutrient deficiency on GH-axis function in humans and other mammals will be summarized, with particular emphasis on studies exploring the direct effects of systemic signals, including insulin-like growth factor 1 (IGF-1) and insulin, on somatotrope function. Additionally, new mouse models with somatotrope-specific knockout of IGF-1 and insulin receptors generated by using the Cre/loxP system will be discussed.
Animals ; Anorexia Nervosa ; Fasting ; Ghrelin ; Growth Hormone ; Humans ; Insulin ; Insulin-Like Growth Factor I ; Mammals ; Metabolic Diseases ; Mice ; Obesity ; Pituitary Gland, Anterior ; Receptor, Insulin ; Somatostatin

No abstract available.
Ghrelin

BACKGROUND: Fasting has a profound impact on GH synthesis, and is released in all mammalian species that have been studied. The male rat has long been used as a model to determine the mechanism on how fasting mediates these changes. However, many aspects of GH synthesis, release and function are known to be gender-dependent. This study was conducted in order to determine if changes in the GH-axis, in response to fasting, differs between the sexes. METHODS: Male and female rats (8~9 weeks; n=5/group) were fasted for 72h, or supplied food ad libitum. The mean circulating serum GH and IGF-I concentrations were measured by radioimmunoassay. The levels of hypothalamic GH-releasing hormone (GHRH), somatostatin (SRIF), neuropeptide Y (NPY) and pituitary GH mRNA were measured using an RNase protection assay. The levels of pituitary GHRH receptor (GHRH-R), GH secretagogue (GHS) receptor (GHS-R) and SRIF receptor (sst1-5) mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Fasting resulted in a comparable weight loss in both the males and the females, (18.0+/-0.9%) and (17.0 0.8%), respectively. In the fasted males, there was a characteristic decrease in the serum GH (98 60 vs. 7 4 ng/mL) and IGF-I (367 35 vs 152 12 ng/mL), associated with a decrease in the hypothalamic GHRH, and an increase in the NPY mRNA, levels of 52 6% and 138 6%, respectively, compared to those of the fed controls (p<0.05). In spite of the reduction in the GHRH, fasting did not alter the levels of the pituitary GH mRNA, and in fact increased the expression of the pituitary receptors, GHRH-R and GHS-R, to 185 15 and 169 25%, respectively, to those of the fed controls. In contrast to the positive impact of fasting on the GH-stimulatory receptors, fasting led to a dramatic decrease in the expressions of the somatostatin receptor subtypes, sst2 (29+/-5% of Fed) and sst4 (60+/-7% of Fed). Fasting had comparable effects on the GH-axis of the female rats, with two notable exceptions; first, fasting did not suppress the mean circulating GH levels (16 3 vs. 38 28 ng/mL) and second, did not alter the sst2 and sst4 expressions. CONCLUSION: These results corroborate the other reports regarding the effects of fasting on the expressions of hypothalamic neuropeptides, pituitary GHRH-R and sst2, in male rats. This is the first report demonstrating that fasting stimulates the expression of pituitary GHS-R in both sexes. This is of great interest given the fact that ghrelin, the putative GHS-R ligand, is also elevated by fasting. We propose that the upregulation of both ghrelin and GHS-R may play important roles in increasing the sensitivity of the pituitary to GHRH, in that these GH-stimulatory systems work synergistically. These changes may compensate for the fasting-induced suppression of hypothalamic GHRH input. We might speculate that such compensatory mechanisms are dominant in the female rat, in that circulating GH levels are not suppressed by fasting.
Animals ; Axis, Cervical Vertebra* ; Fasting* ; Female* ; Ghrelin ; Growth Hormone ; Humans ; Hypothalamus ; Insulin-Like Growth Factor I ; Male* ; Neuropeptide Y ; Neuropeptides ; Radioimmunoassay ; Rats* ; Receptors, Somatostatin ; Ribonucleases ; RNA, Messenger ; Somatostatin ; Up-Regulation ; Weight Loss

The regulation of growth hormone (GH) secretion is, to a larger extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin, and ghrelin. Each binds to G protein-linked membrane receptors through which signaling occurs. We used a series of genetic and transgenic animal models with perturbations of individual compounds of the GH regulatory system to study somatotrope signaling. Impaired GH signaling is present in the lit mouse, which has a GHRH receptor (GHRH-R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired response to GH secretagogues (GHS), implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect GHRH on GHRH-R and GHS-R, and somatostatin receptor type 2 (sst2) expression and an inhibitory effect on sst5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. In the absence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor stimulation of GH synthesis and release. However, in the presence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor suppression of GH synthesis and release. Loss of liver insulin-like growth factor I (IGF-I) feedback on the hypothalamic-pituitary system increases GH secretion, which, in turn, stimulates liver growth. Depletion of liver-derived IGF-I increases the expression and sensitivity of pituitary GHRH-R and GHS-R. The major site of action of liver-derived IGF-I in the regulation of GH secretion is at the pituitary level. Neuropeptide Y (NPY) is not required for basal regulation of the GH axis. NPY is required for fasting-induced suppression of GHRH and SRIH expression. NPY is also required for fasting-induced augmentation of pituitary GHS-R mRNA. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role.
Animals ; Animals, Genetically Modified ; Axis ; Ghrelin ; Growth Hormone ; Hypothalamus ; Insulin-Like Growth Factor I ; Liver ; Membranes ; Mice ; Neuropeptide Y ; Rats ; Receptors, Neuropeptide ; Receptors, Pituitary Hormone-Regulating Hormone ; Receptors, Somatostatin ; RNA, Messenger ; Somatostatin

No abstract available.
Receptors, Somatostatin* ; Somatostatin*

BACKGROUND: AVP (arginine vasopressin) shows unique hemodynamic characteristics, as a vasopressor. AVP has been tried in many cathecholamine refractory vasodilatory situations, and sometimes resulted in effective hemodynamic improvement. In this study, we hypothesized that low dose AVP infusion could recover the decreased SVR (systemic vascular resistance) induced by milrinone infusion with minimal effect on PVR (pulmonary vascular resistance). METHODS: Sixteen patients undergoing OPCAB participated in this study. After a loading dose milrinone was infused, low dose vasopressin infusion was started and titrated until the systemic blood pressure increased by 20%. During the study, hemodynamic factors including pulmonary capillary wedge pressure and cardiac output were measured using a continuous thermodilution technique with a Swan-Ganz catheter. RESULTS: Milrinone infusion reduced both SVR and PVR. And vasopression infusion increased SVR, but show relatively less effect on PVR. CONCLUSIONS: Low-dose vasopressin infusion could be used to recover the SVR decrease caused by milirinone infusion with little effect on PVR.
Blood Pressure ; Cardiac Output ; Catheters ; Hemodynamics* ; Humans ; Milrinone* ; Pulmonary Wedge Pressure ; Thermodilution ; Vasopressins*

Trimethyltin chloride (TMT) has been used as a neurotoxin for inducing brain dysfunction and neuronal death. Neuronal death in the hippocampus by TMT may generate excessive nitric oxide, but there are few studies about nitric oxide synthase enzyme involved in the synthesis of nitric oxide. The purpose of present study is to analyze the TMT toxicity in each region of rat hippocampus. To evaluate the involvement of nitric oxide, we analyzed the effects of aminoguanidine known as a selective inhibitor for inducible nitric oxide synthase on behavioral changes and the hippocampus of rat by TMT toxicity. 6-week-old male Sprague-Dawley rats were administered with a single dose of TMT (8 mg/kg b.w., i.p.) and the control group was similarly administered with distilled water. TMT + aminoguanidine-treated groups were administered with aminoguanidine (10 mg/kg or 100 mg/kg b.w., i.p.) for 3 days prior to TMT injection. The rats were sacrificed 2 days after TMT administration. In the TMT-treated group, a number of cell losses were seen in CA1, CA3 and the dentate gyrus. In the TMT + aminoguanidine-treated group, neuronal death was seen in CA1 and CA3, but reduced in the dentate gyrus compared to the TMT-treated group. Western blot analysis showed that cleaved caspase-3 expression was increased in the TMT-treated group compared to the control group. However, the expression significantly declined in the TMT + aminoguanidine-treated group. The present findings suggest that inducible nitric oxide synthase is involved in neuronal death induced by TMT.
Animals ; Blotting, Western ; Brain ; Caspase 3 ; Dentate Gyrus ; Guanidines ; Hippocampus ; Humans ; Male ; Neurons ; Nitric Oxide ; Nitric Oxide Synthase ; Nitric Oxide Synthase Type II ; Rats ; Rats, Sprague-Dawley ; Trimethyltin Compounds ; Water

We investigated the effect of alpha-subunit of the stimulatory GTP-binding protein (Galphas) gene mutation on the expression of the thyrotropin-releasing hormone (TRH) receptor (TRH-R) gene in GH3 cells and in growth hormone (GH)-secreting adenomas of acromegalic patients. In the presence of cycloheximide, forskolin and isobutylmethylxanthine, cholera toxin, and GH-releasing hormone (GBRH) decreased rat TRH-R (rTRH-R) gene expression by about 39%, 43.7%, and 46.7%, respectively. Transient expression of a vector expressing mutant-type Galphas decreased the rTRH-R gene expression by about 50% at 24 h of transfection, whereas a wild-type Galphas expression vector did not. The transcript of human TRH-R (hTRH-R) gene was detected in 6 of 8 (75%) tumors. Three of them (50%) showed the paradoxical GH response to TRH and the other three patients did not show the response. The relative expression of hTRH-R mRNA in the tumors from patients with the paradoxical response of GH to TRH did not differ from that in the tumors from patients without the paradoxical response. Direct PCR sequencing of GALPHAs gene disclosed a mutant allele and a normal allele only at codon 201 in 4 of 8 tumors. The paradoxical response to TRH was observed in 2 of 4 patients without the mutation, and 2 of 4 patients with the mutation. The hTRH-R gene expression of pituitary adenomas did not differ between the tumors without the mutation and those with mutation. The present study suggests that the expression of TRH-R gene is not likely to be a main determinant for the paradoxical response of GH to TRH, and that Galphas mutation may suppress the gene expression of TRH-R in GH-secreting adenoma. However, a certain predisposing factor(s) may play an important role in determining the expression of TRH-R.
Acromegaly ; Adenoma ; Alleles ; Animals ; Cholera Toxin ; Codon ; Colforsin ; Cycloheximide ; Gene Expression ; Growth Hormone ; GTP-Binding Proteins ; Humans ; Pituitary Neoplasms ; Polymerase Chain Reaction ; Rats ; Receptors, Thyrotropin-Releasing Hormone* ; RNA, Messenger* ; Thyrotropin-Releasing Hormone ; Transfection

To directly test if elevated glucocorticoids are required for fasting-induced regulation of growth hormone (GH)-releasing hormone (GHRH), GHRH receptors (GHRH-R) and ghrelin receptors (GHS-R) expression, male rats were bilaterally adrenalectomized or sham operated. After 7 days, animals were fed ad libitum or fasted for 48 h. Bilateral adrenalectomy increased hypothalamic GHRH to 146% and decreased neuropeptide Y (NPY) mRNA to 54% of SHAM controls. Pituitary GHRH-R and GHS-R mRNA levels were decreased by adrenalectomy to 30% and 80% of sham-operated controls. In sham- operated rats, fasting suppressed hypothalamic GHRH (49%) and stimulated NPY (166%) mRNA levels, while fasting increased pituitary GHRH-R (391%) and GHS-R (218%) mRNA levels. However, in adrenalectomized rats, fasting failed to alter pituitary GHRH-R mRNA levels, while the fasting-induced suppression of GHRH and elevation of NPY and GHS-R mRNA levels remained intact. In fasted adrenalectomized rats, corticosterone replacement increased GHRH-R mRNA levels and intensified the fasting-induced decrease in GHRH, but did not alter NPY or GHS-R response. These data suggest that elevated glucocorticoids mediate the effects of fasting on hypothalamic GHRH and pituitary GHRH-R expression, while glucocorticoids are likely not the major determinant in fasting-induced increases in hypothalamic NPY and pituitary GHS-R expression.
Adrenalectomy ; Animals ; Corticosterone ; Fasting ; Glucocorticoids ; Growth Hormone ; Humans ; Male ; Neuropeptide Y ; Rats ; Receptors, Ghrelin ; Receptors, Neuropeptide ; Receptors, Pituitary Hormone-Regulating Hormone ; RNA, Messenger ; Salicylamides

BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with type 2 diabetes mellitus (T2DM). Rebamipide is an effective gastric cytoprotective agent, but there are few data on its usefulness in T2DM. The aim of this study is to evaluate the improvement of GI symptoms after rebamipide treatment in patients with T2DM. METHODS: Patients with T2DM and atypical GI symptoms were enrolled. They took rebamipide (100 mg thrice daily) for 12 weeks and filled out the diabetes bowel symptom questionnaire (DBSQ) before and after rebamipide treatment. The DBSQ consisted of 10 questions assessing the severity of GI symptoms by a 1 to 6 scoring system. Changes in the DBSQ scores before and after rebamipide treatment were analyzed to evaluate any improvements of GI symptoms. RESULTS: A total of 107 patients were enrolled, and 84 patients completed the study. The mean age was 65.0±7.8, 26 patients were male (24.8%), the mean duration of T2DM was 14.71±9.12 years, and the mean glycosylated hemoglobin level was 6.97%±0.82%. The total DBSQ score was reduced significantly from 24.9±8.0 to 20.4±7.3 before and after rebamipide treatment (P<0.001). The DBSQ scores associated with reflux symptoms, indigestion, nausea or vomiting, abdominal bloating or distension, peptic ulcer, abdominal pain, and constipation were improved after rebamipide treatment (P<0.05). However, there were no significant changes in symptoms associated with irritable bowel syndrome, diarrhea, and anal incontinence. No severe adverse events were reported throughout the study. CONCLUSION: Rebamipide treatment for 12 weeks improved atypical GI symptoms in patients with T2DM.
Abdominal Pain ; Constipation ; Diabetes Mellitus, Type 2* ; Diarrhea ; Dyspepsia ; Gastrointestinal Diseases ; Hemoglobin A, Glycosylated ; Humans ; Irritable Bowel Syndrome ; Male ; Nausea ; Peptic Ulcer ; Vomiting