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Evaluation of Pharmacological Modification of Growth Hormone

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Evaluation of Pharmacological Modification of Growth Hormone Evaluation of Pharmacological Modification of Growth Hormone Secretagogue Receptor in a Mouse Model of Non-Obese Type 2 Diabetes Mellitus Rasha Mosa Master of Medicine A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2017 School of Medicine Abstract While it appears that obesity is associated with the higher incidence of type 2 diabetes mellitus (T2DM), recent findings that T2DM affects non-obese people are becoming more noticeable. Many of those who are not obese by traditional weight measurements have an increased percentage of body fat distributed predominately in the abdominal and visceral regions. Disorders of lipid metabolism play a major role in the pathogenesis of this non- obese diabetic phenotype. For examples, lipodystrophic patients develop insulin resistance due to insufficient adipose tissue and aged lean people with diabetes have defects in mitochondrial lipid oxidative mechanisms. Such non-obese diabetic patients are at increased risk of developing cardiovascular (CVD) complications. The management of non-obese T2DM should focus not only on life style modifications or blood glucose control but also strategies for correction of lipid metabolic aberrations. Growth hormone (GH) exerts powerful influences on growth and body composition. In obese animal models and human, GH is known to correlate inversely with insulin concentrations. Some studies suggest that insulin may have a direct inhibitory effect on GH secretion, whereas others showed that insulin inhibits GH secretion via suppression of growth hormone releasing hormone (GHRH) or stimulation of somatostatin (SST). Although GH-insulin relationship is well documented in obesity, studies of this GH-insulin relationship in non-obese diabetes are sparse and contradictory. Thus, this study aimed to investigate the pulsatile GH profile and its regulatory factors in MKR mice which are non-obese diabetic mice generated by igf-1 receptor mutation in skeletal muscle. Our observations demonstrated that unlike obese mice, MKR mice had normal to higher pulsatile GH secretion at different age groups. Nevertheless, there were no detectable changes in gene expressions of hypothalamic GHRH and SST. Interestingly, hypothalamic orexigenic NPY gene expression was increased that might affect GH secretion. These findings suggest that the relationship between GH and insulin was altered in MKR mice, leading to higher GH concentrations despite hyperinsulinaemia. Given that MKR mice exhibited postnatal growth retardation, we anticipated that endogenous GH levels would increase to facilitate rapid linear growth and promote muscle development that assist nutrient uptake and utilization. Therapy using growth hormone secretagogues (GHS) that increase endogenous GH secretion through binding to the ghrelin receptor (GHS-R1a) might have beneficial effects on lipid metabolism with less adverse effects on glucose metabolism than exogenous GH administration. Recent studies have provided some interesting avenues for further exploration on how Hexarelin, one of synthetic peptide GHS, enhanced fat metabolism of white adipose tissue (WAT) via CD36 activation independently of GHS-R1a. To address the effects of Hexarelin in non-obese diabetes, MKR were received daily intraperitoneal (I.P.) injection of Hexarelin (200ug/kg body weight) for 12 days. Remarkably, MKR mice displayed improved glucose and insulin tolerance with Hexarelin treatment due to enhanced fat metabolism associated with increased adipocyte differentiation and up- regulation of fatty acid uptake and oxidation related genes of WAT. Moreover, our results showed that Hexarelin increased pulsatile GH secretion, reduced fat mass and improved the lipid profile without compromising glucose metabolism. Ghrelin, the natural ligand of GHS-R1a is an appetite-stimulating hormone inducing food intake and adiposity. Due to the observed association between plasma ghrelin and insulin levels, it was suggested that inhibition of ghrelin secretion and/or blockade of GHS-R1a could be useful targets for treatment of T2DM. In this respect, the current study also examined the possible effects of repeated injections of ghrelin antagonist [D-Lys3]-GHRP- 6 (200 nmol/mouse) for 12 days in MKR mice. [D-Lys3]-GHRP-6 reduced pulsatile GH secretion and body fat mass as expected, but unexpectedly worsened glucose and insulin intolerance and increased cumulative food intake. In addition, current observations demonstrated a significant decrease in glucose stimulated insulin secretion, an increase in blood glucose and a decrease in plasma insulin in MKR mice following long-term [D-Lys3]- GHRP-6 treatment, indicating a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets of long-term [D-Lys3]-GHRP-6 treated mice showed a proportional increase in SST areas with a decrease in insulin areas. Furthermore, observations showed that [D-Lys3]-GHRP-6 stimulated food intake via reduction of proopiomelanocortin (POMC) gene expression and antagonized GH secretion via reduced GHRH gene expression in hypothalamus. In conclusion, the inverse relationship between GH and insulin is not apparent in this non- obese diabetic model. Balance of these two important hormones under different metabolic conditions is critically important in the pathophysiology of metabolic disorders and could provide therapeutic approaches to control diabetes with or without obesity. Our results also raise the possibility that Hexarelin may be a novel drug candidate for correcting the lipid disorders associated with non-obese T2DM and open many avenues for future use in clinical trials. However, the effects of long-term [D-Lys3]-GHRP-6 treatment are not completely opposite to ghrelin and may not be a target as an anti-diabetic drug. Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. Publications during candidature Peer-reviewed papers: First- authored papers Mosa RM, Zhang Z, Shao R, Deng C, Chen J, Chen C. Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases. Endocrine 2015; 49:307- 323. Mosa R, Huang L, Wu Y, Fung C, Mallawakankanamalage O, LeRoith D, Chen C. Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice. Endocrinology 2017; 158:3174-3187. Mosa R, Huang L, Li H, Grist M, LeRoith D, Chen C. Long-term treatment with the ghrelin receptor antagonist, [D-Lys3]-GHRP-6 does not improve glucose homeostasis in non- obese diabetic MKR mice. American Journal of Physiology 2017. R-00157-2017R1. Co-authored papers Webster JA, Yang Z, Kim YH, Loo D, Mosa RM, Li H, Chen C. Collagen beta (1-O) galactosyltransferase 1 (GLT25D1) is required for the secretion of high molecular weight adiponectin and affects lipid accumulation. Biosci Rep. 2017 May 17; 37(3). Conference abstracts Rasha Mosa, Jiezhong Chen, Chao Lin, Chen Chen. Protective roles of Hexarelin, a synthetic growth hormone secretagogue on pancreatic beta cells in vitro and in type 2 diabetes MKR mice. SBMS Postgraduate Symposium, The University of Queensland, 2014. Rasha Mosa, Lili Huang, Chung Fung, Michael A. Grist, Derek LeRoith and Chen Chen. Investigating GH-IGF-1 axis in a non-obese mouse T2DM model and the therapeutic applications. SBMS Postgraduate Symposium, The University of Queensland, 2015. Rasha Mosa, Lili Huang, and Chen Chen. Effects of growth hormone secretagogue receptor agonist and antagonist in non-obese type 2 diabetic MKR mice. Asia Pacific 11th Diabetic conference, Brisbane, 2016. Rasha Mosa, Lili Huang, and Chen Chen. Effects of growth hormone secretagogue receptor agonist and antagonist in non-obese type 2 diabetic MKR mice. The Annual Scientific Meeting of the Endocrine Society of Australia, Gold Coast, 2016 (Received travel grant). Rasha Mosa, Lili Huang, and Chen Chen. Effects of growth hormone secretagogue receptor agonist and antagonist in non-obese type 2 diabetic MKR mice. SBMS Postgraduate Symposium, The University of Queensland, 2016. Publications
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