PEG-rhGH Therapy for Small for Gestational Age Rats and Effects on Their Metabolic Parameters

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Abstract

Aims: To determine whether administration of long-acting polyethylene glycol moiety covalently linked to recombinant human growth hormone (PEG-rhGH) can be efficacious in the treatment of small for gestational age (SGA) rats and to characterize its effects on metabolic parameters. Methods: 20 pregnant rats were randomly divided into undernourished and standard nourished groups. SGA or appropriate for gestational age (AGA) offspring from each were then randomly assigned to receive either PEG-rhGH or normal saline (NS). Once-weekly subcutaneous injections of PEG-rhGH (2 µg/g/week) were administered starting at 21–42 days. Glycometabolism, blood pressure (BP), hormone and biochemical levels were analyzed at 21, 42 and 70 days. Results: SGA rats at 21 days were lighter and shorter than AGAs (34.77 ± 2.11 vs. 48.83 ± 1.78 g, 10.42 ± 0.22 vs. 12.99 ± 0.17 cm, p < 0.05). At 42 days, SGA animals experienced a greater body weight gain. BP was higher in NS-treated SGA than in the AGA group at 70 days (138.16 ± 3.02 vs. 112.26 ± 5.42 mm Hg, p < 0.05). Meanwhile, NS-treated SGA exhibited higher glucose levels at 60 and 90 min than the AGA groups. No differences in hormone levels between the SGA and AGA groups were found at the end of PEG-rhGH treatment. Conclusion: These data suggest that PEG-rhGH treatment does not increase the risk of developing metabolic syndrome in adolescent aged rats.

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Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

D Barker, C N Hales, C H D Fall … (1993)

Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".

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Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial.

José Jansen, Yvonne van Duynhoven, Paul Mulder … (2003)

The GH dose-response effect of long-term continuous GH treatment on adult height (AH) was evaluated in 54 short children born small for gestational age (SGA) who were participating in a randomized, double-blind, dose-response trial. Patients were randomly and blindly assigned to treatment with either 3 IU (group A) or 6 IU (group B) GH/m(2).d ( approximately 0.033 or 0.067 mg/kg.d, respectively). The mean (+/-SD) birth length was -3.6 (1.4), the age at the start of the study was 8.1 (1.9) yr, and the height SD score (SDS) at the start of the study -3.0 (0.7). Seventeen of the 54 children were partially GH deficient (stimulated GH peak, 10-20 mU/liter). Fifteen non-GH-treated, non-GH-deficient, short children born SGA, with similar inclusion criteria, served as controls [mean (+/-SD) birth length, -3.3 (1.2); age at start, 7.8 (1.7) yr; height SDS at start, -2.6 (0.5)]. GH treatment resulted in an AH above -2 SDS in 85% of the children after a mean (+/-SD) GH treatment period of 7.8 (1.7) yr. The mean (SD) AH SDS was -1.1 (0.7) for group A and -0.9 (0.8) for group B, resulting from a mean (+/-SD) gain in height SDS of 1.8 (0.7) for group A and 2.1 (0.8) for group B. No significant differences between groups A and B were found for AH SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.2, 0.6; P > 0.2) and gain in height SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.1, 0.7; P > 0.1). When corrected for target height, the mean corrected AH SDS was -0.2 (0.8) for group A and -0.4 (0.9) for group B. The mean (+/-SD) AH SDS of the control group [-2.3 (0.7)] was significantly lower than that of the GH-treated group (P < 0.001). Multiple regression analysis indicated the following predictive variables for AH SDS: target height SDS, height SDS, and chronological age minus bone age (years) at the start of the study. GH dose had no significant effect. In conclusion, long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of AH, even with a GH dose of 3 IU/m(2).d ( approximately 0.033 mg/kg.d).

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Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss.

Lucinda Milardo, William P Esler, J. Livingston … (2007)

Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.

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Author and article information

Journal

Journal ID (publisher-id): HRP

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2011

Publication date (Print): July 2011

Publication date (Electronic): 10 March 2011

Volume: 76

Issue: 1

Pages: 35-43

Affiliations

^aDepartment of Endocrinology, The Children’s Hospital, Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, ^bDepartment of Biochemistry and Molecular Biology, Pharmacy School of Jilin University, Changchun, and ^cDepartment of Neonatology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

Author notes

*Li Liang or Lizhong Du, Department of Endocrinology, The Children’s Hospital of, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou 310003 (China), Tel. +86 571 8706 1007, E-Mail zdliangli@163.com, dulizhon@yahoo.com.cn

Article

Publisher ID: 324566 Other ID: Horm Res Paediatr 2011;76:35–43

DOI: 10.1159/000324566

PubMed ID: 21389689

SO-VID: a4fb6827-ab5f-4362-bfca-aa4ff07d54cc

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 10 June 2010

Date accepted : 22 January 2011

Page count

Figures: 3, Tables: 4, Pages: 9

PEG-rhGH Therapy for Small for Gestational Age Rats and Effects on Their Metabolic Parameters

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Karger: Endocrinology

Most cited references 28

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial.

Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss.

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