Hypothalamic Regulation of Impaired Growth Hormone Secretion in Diabetic Rats

Ndon, J A; Giustina, Andrea; Wehrenberg, William B.

doi:10.1159/000126163

Cited by 24 publications

(33 citation statements)

References 24 publications

(53 reference statements)

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“…Our study is the first report to show a direct effect of high glucose on GHRH-R, indicating that it can contribute to a regulation of GHRH-R expression and functionality and contribute to decrease GHRH sensitivity in somatotrophs, leading to a decline of GH secretion in vitro (45) and in vivo (35,38,53,55). These results may reconcile some of the divergent reports on in vivo and in vitro somatotroph sensitivity to GHRH from a large variety of single time point evaluations, ranging from 2-to 60-day post-STZ administration and exclusively analyzing GHRH-R mRNA but not functional protein levels.…”

Section: Discussionmentioning

confidence: 59%

“…In spontaneous diabetic rats and in the streptozotocin (STZ)-induced diabetic rat (STZ rat), a widely used model of type 1 diabetes, pulsatile GH secretion and GHRH-induced GH release are decreased (35,38,53,55), and declines of pituitary GH and hypothalamic GHRH mRNA levels are observed (8). In addition, hypothalamic GHRH content rises 2-4 days post-STZ administration, returns to normal after 7 days, and declines thereafter (25).…”

mentioning

confidence: 99%

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Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity

Bédard

Strecko²,

Thériault³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity. Am J Physiol Endocrinol Metab 294: E740-E751, 2008. First published February 19, 2008 doi:10.1152/ajpendo.00141.2007.-The present study investigated the effects of diabetes and high glucose on GHRH receptor (GHRH-R) mRNA and protein levels in the pituitary of diabetic rats 2, 21, and 60 days post-streptozotocin (post-STZ) administration. Two days post-STZ, the 2.5-kb GHRH-R mRNA transcript was increased. Twenty-one days post-STZ, both the 2.5-and 4-kb transcripts and a 72-kDa 125 I-GHRH-GHRH-R complex were elevated. Sixty days post-STZ, the 4-kb transcript remained increased and the 45-kDa 125 I-GHRH-GHRH-R complex (functional receptor) was decreased. Hypothalamic GHRH mRNA and serum total IGF-I levels were reduced at all three time points. To better understand the role of high glucose on GHRH-R regulation, time-course effects of 33 compared with 6 mM D-glucose (DG) were examined in cultured anterior pituitary cells from 2-mo-old healthy rats. Membrane lipoperoxidation was present in 33 mM DG, and GHRH-R mRNA levels were diminished after 24 h, Fluo-GHRH internalization was marginal after 16 -24 h, and GHRH-induced cAMP levels were decreased after 24 and 48 h. Altogether, these results indicate that the increase of the 2.5-kb GHRH-R mRNA transcript in vivo could be a consequence of a decrease of hypothalamic GHRH mRNA levels in STZ rats. Since it does not affect primarily functional GHRH-R levels, the initial diminution of circulating IGF-I levels could result from a decreased GHRH-R stimulation by GHRH. Thus, the effect of glucotoxicity would be related to a decrease of functional GHRH-R protein, as observed in rats 60 days post-STZ and in cultured pituitary cells from healthy rats exposed to a high-glucose environment.insulin-like growth factor I; oxidative stress; hypothalamus; cyclic adenosine monophosphate SPECIFIC BINDING of hypothalamic growth hormone-releasing hormone (GHRH) to the anterior pituitary somatotroph GHRH receptor (GHRH-R) (1,24,30,48) induces intracellular cAMP production (3), leading to GH secretion (2, 54), synthesis (2), and proliferation (4). In addition to protein kinase A (10, 58), protein kinase C (10), and mitogen-activated protein kinase (44, 59), pathways can be activated by GHRH. GHRH-R, a member of the subfamily B-III of G protein-coupled receptors, has been cloned in the anterior pituitary of several mammalian species (14,17,18,19,26,30,52). The presence of Ϸ2.5-and Ϸ4-kb GHRH-R mRNA transcripts has been reported (26,30) in the rat and mouse pituitary. Although the short and most abundant transcript generates the functional 423-amino acid GHRH-R (30, 33), the structure of the 4-kb transcript remains to be elucidated. Correlative evidence (15) suggests that an increased ratio of 4/2.5-kb transcript levels may reflect a shift of high-to low-affinity GHRH binding sites. Chemical crosslinking with 125 I-GHRH(1-44)NH 2 identified the ...

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity

Bédard

Strecko²,

Thériault³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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show abstract

“…Although GH may be increased or decreased, depressed IGF-1 activity is consistently demonstrated, indicating disassociation of GH/IGF-1 axis in diabetes [68][69][70][71][72][73][74]. In T1D patients, the hypersecretion of GH was observed with 8 decreased IGF-1, where increased GH was unable to stimulate IGF-1 release [75][76][77] It is important to note that GH studies in experimental models produced a converse result from observations in diabetic patients, where depressed GH levels were associated with decreased IGF-1 [72][73][74]. Suppression of GH release in a diabetic animal model was characterized by reduction of basal GH and loss of GH pulsatility, which might be a result from lack of GH synthesis and storage [87][88][89].…”

Section: Growth Hormone (Gh) In Diabetesmentioning

confidence: 99%

“…Suppressed GH pulsatility was observed in STZ-induced diabetic rats and this inhibitory effect was abolished by SRIF antiserum [74]. Decreased levels of GH in the diabetic model were correlated with increased content of somatotropin and reduced GH response to GHRH [72,[90][91][92].…”

Section: Growth Hormone (Gh) In Diabetesmentioning

confidence: 99%

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The effect of hexarelin in streptozotocin (STZ)-induced rat model through protective actions on islet beta cells and cardiomyocytes

Zhang¹

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Diabetes mellitus (DM) is a major chronic disease, affecting over 300 million people worldwide.Pancreatic islet β-cell dysfunction is known as the major cause of glucose metabolism disorder, which leads to hyperglycemia and eventually DM. Inside the cell, mitochondria perform a crucial role in coupling glucose metabolism to insulin secretion by the β-cell and on other cell functions requiring normal energy balance. Abnormal activity of mitochondria, such as increased apoptosis, contributes to β-cell dysfunction and diabetes related pathological changes in other cell types, for example, depressed growth hormone (GH) secretion was observed in the diabetic state. Cardiac complications of diabetes, also named diabetic cardiomyopathy, account for over 70% of the mortality among diabetic patients, which is characterized as cardiac systolic and diastolic dysfunctions. There are currently no effective targeted treatments. GH secretagogues (GHS) stimulate insulin secretion and GH release in the diabetic rodent model, and protect cardiomyocytes from ischemia/reperfusion injury. To further clarify the mechanism of GHS on diabetes and its cardiovascular complications, the present study employed mouse a β-cell line (MIN6) and streptozotocin (STZ)-induced diabetic rat model treated with the synthetic GHS, hexarelin (Hex), to investigate β-cell function, pulsatile GH secretion and cardiomyocyte contractility.Diabetes was induced by a single dosage of STZ (65mg/kg) IP injection in male Wistar rats with vehicle control group. After 4 weeks of disease development, animals received Hex (100μg/kg) treatment for 2 weeks. In vitro cell study mimicked the in vivo treatment regime; MIN6 cells were exposed to STZ (1mM) for 4 hours followed by a 2 hour Hex (1μM) incubation. Cell viability and mitochondrial function were measured by MTS and Rhodamine assay. Immunohistochemistry of rat pancreas sections was performed to determine islet morphology and apoptosis signaling pathways.ELISA was conducted to examine pulsatile GH and circulating levels of insulin, insulin-like growth factor-1 (IGF-1) and free fatty acids (FFA). Rat cardiomyocyte contractility and intracellular Ca 2+ concentration were investigated by cell shortening and Ca 2+ transient measurement after cardiomyocyte isolation. Whole-cell patch clamp was performed to study membrane potential and transient outward potassium current (I to ). The expression of the GHS receptor, GHS-R, was determined by Western blot. Apoptotic markers were also assessed by protein expression determination in both MIN6 cells and rat cardiomyocytes.II STZ-treated MIN6 cells showed a decrease in cell proliferation and impaired mitochondrial function with increased expression of apoptotic markers, such as caspase-3, caspase-9 and the ratio of Bax/Bcl-2, while incubation of Hex recovered these parameters towards control levels.STZ-induced diabetic rats showed evidence of symptoms of clinical diabetes such as hyperglycemia, polyphagia, polydipsia and polyuria. Body weight gain was decreased in STZ-t...

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Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats

et al. 2005

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Diabetes mellitus of both type I (insulin-dependent) and type II (noninsulin-dependent) has adverse effects on male sexual and reproductive functions in adolescent boys and men, which include impairment of spermatogenesis, reduced sperm count, serum testosterone and seminal fluid volume, impotency, and loss of libido. Streptozotocin (STZ)-induced diabetes in rats provides a relevant model to study reproductive dysfunction under diabetic conditions, as they exhibit a number of deficits in reproductive function that resemble those seen in human diabetics. Therefore, the present investigation is aimed to understand the effects of STZ diabetes on the structure and development of ventral prostate during the critical period of sexual maturation in rats. Prepubertal (40-days-old) male Wistar rats were made diabetic by single injection of STZ (120 mg/kg body weight, intraperitoneally). Induction of diabetes was confirmed by serum insulin titer, hyperglycemia, and polyuria. To another set of STZ-diabetic rats, after 3 days of diabetes induction, insulin was replaced at a dose of 3 U/100 g body weight, subcutaneously in two equally divided doses at 8:00 AM and 6:00 PM. Diabetes caused regression of prostate, leading to a decrease in the absolute weight. Histologically, glandular epithelium has undergone shrinkage with transformation of acinar cells into low cuboidal type with less prominent secretory granules and blebs. Nevertheless, the secretory activity was not totally abolished. Interstitial space was increased due to shrinkage of glandular epithelium. Histomorphometric studies on the tubular diameter, volume and surface density of acinar epithelium, lumen, and stroma also support regressive changes in prostate. Insulin replacement prevented the detrimental effects of diabetes partially. These findings implicate the adverse effects of STZ diabetes on the differentiation of ventral prostate during sexual maturation.

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Hypothalamic Regulation of Impaired Growth Hormone Secretion in Diabetic Rats

Cited by 24 publications

References 24 publications

Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity

Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity

The effect of hexarelin in streptozotocin (STZ)-induced rat model through protective actions on islet beta cells and cardiomyocytes

Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats

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