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Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice.
Mosa, Rasha; Huang, Lili; Li, Hongzhuo; Grist, Michael; LeRoith, Derek; Chen, Chen.
Afiliação
  • Mosa R; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
  • Huang L; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
  • Li H; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
  • Grist M; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
  • LeRoith D; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
  • Chen C; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
Am J Physiol Regul Integr Comp Physiol ; 314(1): R71-R83, 2018 01 01.
Article em En | MEDLINE | ID: mdl-28903914
ABSTRACT
Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol 314 R71-R83, 2018. First published September 13, 2017; doi 10.1152/ajpregu.00157.2017 .-Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS-R1a) in the pancreas has raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signaling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [d-Lys3]-growth hormone-releasing peptide (GHRP)-6, on glucose homeostasis, food intake, and indirect calorimetric parameters in nonobese diabetic MKR mice. Our results showed that [d-Lys3]-GHRP-6 (200 nmol/mouse) reduced pulsatile growth hormone secretion and body fat mass as expected but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and C-peptide levels were observed in MKR mice following long-term [d-Lys3]-GHRP-6 treatment, suggesting a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin-positive cells and a decrease in insulin-positive cells in [d-Lys3]-GHRP-6-treated mice. Furthermore, [d-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of proopiomelanocortin gene expression and antagonized GH secretion via reduced growth hormone-releasing hormone gene expression in hypothalamus. These results demonstrate that [d-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Glicemia / Diabetes Mellitus Tipo 2 / Receptores de Grelina / Antagonistas de Hormônios / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Glicemia / Diabetes Mellitus Tipo 2 / Receptores de Grelina / Antagonistas de Hormônios / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article