Cholinergic control of growth hormone (GH) responses to GH‐releasing hormone in insulin dependent diabetics: evidence for attenuated hypothalamic somatostatinergic tone and decreased GH autofeedback

Ismail, I.A.; Scanlon, M. F.; Peters, John R.

doi:10.1111/j.1365-2265.1993.tb00987.x

Cited by 22 publications

(15 citation statements)

References 51 publications

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“…This hypothesis is consistent with a report showing BALB/c mice, when treated with a single i.v. injection of HI STZ (250-300 mg/kg), have elevated circulating GH levels, which was associated with hypoinsulinemia and hyperglycemia without dramatic weight loss or ketosis (Flyvbjerg et al 1999), a response similar to that reported in poorly controlled type I diabetic humans (Cohen & Abplanalp 1991, Ismail et al 1993, Krassowski et al 1988). However, from these studies it is difficult to say with certainty if the variable effects of STZ on circulating GH levels are due to the severity of catabolic condition or if the differences are more related to species or genetic background of the animal model used.…”

Section: Introductionsupporting

confidence: 63%

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

Kim¹,

Sohn²,

Lee³

et al. 2006

Journal of Endocrinology

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The impact of streptozotocin (STZ)-induced, insulinopenic diabetes on the GH axis of rats and mice differs from study to study, where this variation may be related to the induction scheme, severity of the diabetes and/or the genetic background of the animal model used. In order to begin differentiate between these possibilities, we compared the effects of two different STZ induction schemes on the GH axis of male Sprague-Dawley rats: (1) a single high-dose injection of STZ (HI STZ, 80 mg/kg, i.p.), which results in rapid chemical destruction of the pancreatic -cells, and (2) multiple low-dose injections of STZ (LO STZ, 20 mg/kg for 5 consecutive days, i.p.), which results in a gradual, autoimmune destruction of -cells. STZ-treated animals were killed after 3 weeks of hyperglycemia (>400 mg/dl), and in both paradigms circulating insulin levels were reduced to <40% of vehicle-treated controls. HI STZ-treated rats lost weight, while body weights of LO STZ-treated animals gradually increased over time, similar to vehicle-treated controls. As previously reported, HI STZ resulted in a decrease in circulating GH and IGF-I levels which was associated with a rise in hypothalamic neuropeptide Y (NPY) mRNA (355% of vehicle-treated controls) and a fall in GH-releasing hormone (GHRH) mRNA (45% of vehicle-treated controls) levels. Changes in hypothalamic neuropeptide expression were reflected by an increase in immunoreactive NPY within the arcuate and paraventricular nuclei and a decrease in GHRH immunoreactivity in the arcuate nucleus, as assessed by immunohistochemistry. Consistent with the decline in circulating GH and hypothalamic GHRH, pituitary GH mRNA levels of HI STZ-treated rats were 58% of controls. However, pituitary receptor mRNA levels for GHRH and ghrelin increased and those for somatostatin (sst2, sst3 and sst5) decreased following HI STZ treatment. The impact of LO STZ treatment on the GH axis differed from that observed following HI STZ treatment, despite comparable changes in circulating glucose and insulin. Specifically, LO STZ treatment did suppress circulating IGF-I levels to the same extent as HI STZ treatment; however, the impact on hypothalamic NPY mRNA levels was less dramatic (158% of vehicle-treated controls) where NPY immunoreactivity was increased only within the paraventricular nucleus. Also, there were no changes in circulating GH, hypothalamic GHRH or pituitary receptor expression following LO STZ treatment, with the exception that pituitary sst3 mRNA levels were suppressed compared with vehicle-treated controls. Taken together these results clearly demonstrate that insulinopenia, hyperglycemia and reduced circulating IGF-I levels are not the primary mediators of hypothalamic and pituitary changes in the GH axis of rats following HI STZ treatment. Changes in the GH axis of HI STZ-treated rats were accompanied by weight loss, and these changes are strikingly similar to those observed in the fasted rat, which suggests that factors associated with the catabolic state are critical in modify...

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Section: Introductionsupporting

confidence: 63%

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

Kim¹,

Sohn²,

Lee³

et al. 2006

Journal of Endocrinology

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“…Elevated GH levels were found in studies on Type 1 diabetic patients and Biobred (BB) rats [312][313][314]. The results, however, showed suppressed pulsatile GH secretion in STZ-induced diabetic rats, consistent with previous reports on STZ-treated rats [74,88,90].…”

Section: Discussionsupporting

confidence: 89%

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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“…Failure of T1D patients to increase their GH responses to GHRH following pyridostigmine treatment suggests a decrease in hypothalamic somatostatin release in these patients [26]. Evidence suggests that portal vein insulin deficiency contributes to GH dysregulation by downregulating hepatic GH receptors explaining the state of “GH resistance” in this population [27].…”

Section: Gh Response To Oral Glucose and To Chronic Hyperglycemiamentioning

confidence: 99%

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Hage

Kamenický

Chanson³

2019

Neuroendocrinology

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The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.

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Cholinergic control of growth hormone (GH) responses to GH‐releasing hormone in insulin dependent diabetics: evidence for attenuated hypothalamic somatostatinergic tone and decreased GH autofeedback

Cited by 22 publications

References 51 publications

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

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

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

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