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Exp Clin Endocrinol Diabetes 2020; 128(02): 125-132
DOI: 10.1055/a-0723-3544
Article
© Georg Thieme Verlag KG Stuttgart · New York

Early Growth Hormone Intervention Improves Glucose Metabolism in Adult Rats Born Small for Gestational Age

Yingmin Wang
1   Department of Pediatrics, The First Affliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
2   Department of Endocrinology, Tongde Hospital of Zhejiang Province, Hangzhou, China
,
Weifen Zhu
3   Department of Endocrinology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
,
Lianhui Chen
1   Department of Pediatrics, The First Affliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
,
Li Liang
1   Department of Pediatrics, The First Affliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
› Author Affiliations Statement of Financial Support: This work was supported by the National Science Foundation of China (Grant No. 81170733), the medicine and health science technology project of Zhejiang Province (Grant No. 2017177741), and Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ18H070001).
Further Information

Publication History

received 31 May 2018
revised   29 July 2018

accepted 29 August 2018

Publication Date:
26 September 2018 (online)

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Abstract

Background Small for gestational age (SGA) due to intrauterine malnourishment is closely related to metabolic syndrome and type 2 diabetes mellitus. Growth Hormone (GH) treatment has been demonstrated to influence metabolic parameters and islet function of SGA individuals. The present study demonstrates the effects of early GH treatment on glucose tolerance and expression of pancreatic duodenal homeobox 1 (Pdx1) of SGA rats during adulthood.

Methods SGA rat model was induced by restricting food intake during pregnancy. GH or normal saline was administered during postnatal days 21–35 of SGA rats and appropriate for gestational age (AGA) rats, respectively.

Results In early adulthood (postnatal day 70), as compared to AGA rats, SGA rats showed: (1) decreased body weight; (2) increased postprandial blood glucose; and (3) down-regulated Pdx1 with increased histone deacetylase (HDAC) and down-regulated histone H3-lysine 4 methyltransferase SET7/9. Exogenous GH administration led to a restoration of body weight and normalized glucose tolerance due to an enhanced Pdx1 expression, accompanied by decreased HDAC and up-regulated SET7/9 in SGA rats in early adulthood.

Conclusion Our results demonstrate positive effects on glucose metabolism by an early and short GH treatment in SGA adulthood.

Key words

small for gestational age - pdx1 - growth hormone

Supplementary Material

 

  • References

  • 1 Longo S, Bollani L, Decembrino L. et al. Short-term and long-term sequelae in intrauterine growth retardation (IUGR). J Matern Fetal Neonatal Med 2013; 26: 222-225
    CrossrefPubMedSearch in Google Scholar
  • 2 Jornayvaz FR, Vollenweider P, Bochud M. et al. Low birth weight leads to obesity, diabetes and increased leptin levels in adults: The CoLaus study. Cardiovasc Diabetol 2016; 15: 73
    CrossrefPubMedSearch in Google Scholar
  • 3 Liu J, Wang XF, Wang Y. et al. The incidence rate, high-risk factors, and short- and long-term adverse outcomes of fetal growth restriction: A report from Mainland China. Medicine (Baltimore) 2014; 93: e210
    PubMedSearch in Google Scholar
  • 4 Xu YP, Liang L, Wang XM. The levels of Pdx1/insulin, Cacna1c and Cacna1d, and beta-cell mass in a rat model of intrauterine undernutrition. J Matern Fetal Neonatal Med 2011; 24: 437-443
    CrossrefPubMedSearch in Google Scholar
  • 5 Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab 2009; 11 (Suppl. 04) 30-37
    CrossrefPubMedSearch in Google Scholar
  • 6 Frogne T, Sylvestersen KB, Kubicek S. et al. Pdx1 is post-translationally modified in vivo and serine 61 is the principal site of phosphorylation. PLoS ONE 2012; 7: e35233
    CrossrefPubMedSearch in Google Scholar
  • 7 Hashimoto H, Kamisako T, Kagawa T. et al. Expression of pancreatic and duodenal homeobox1 (PDX1) protein in the interior and exterior regions of the intestine, revealed by development and analysis of Pdx1 knockout mice. Lab Anim Res 2015; 31: 93-98
    CrossrefPubMedSearch in Google Scholar
  • 8 Spijker HS, Song H, Ellenbroek JH. et al. Loss of beta-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes 2015; 64: 2928-2938
    CrossrefPubMedSearch in Google Scholar
  • 9 Cardinale V, Puca R, Carpino G. et al. Adult human biliary tree stem cells differentiate to beta-pancreatic islet cells by treatment with a recombinant human Pdx1 peptide. PLoS ONE 2015; 10: e0134677
    CrossrefPubMedSearch in Google Scholar
  • 10 Chun SY, Mack DL, Moorefield E. et al. Pdx1 and controlled culture conditions induced differentiation of human amniotic fluid-derived stem cells to insulin-producing clusters. J Tissue Eng Regen Med 2015; 9: 540-549
    CrossrefPubMedSearch in Google Scholar
  • 11 Allahverdi A, Abroun S, Jafarian A. et al. Differentiation of human mesenchymal stem cells into insulin producing cells by using a lentiviral vector carrying PDX1. Cell J 2015; 17: 231-242
    PubMedSearch in Google Scholar
  • 12 Teo AK, Tsuneyoshi N, Hoon S. et al. PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells. Stem Cell Reports 2015; 4: 578-590
    CrossrefPubMedSearch in Google Scholar
  • 13 Park JH, Stoffers DA, Nicholls RD. et al. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008; 118: 2316-2324
    PubMedSearch in Google Scholar
  • 14 Pinney SE, Jaeckle Santos LJ, Han Y. et al. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia 2011; 54: 2606-2614
    CrossrefPubMedSearch in Google Scholar
  • 15 Guemes Hidalgo M, Fernandez de Larrea Baz N, Munoz Calvo MT. et al. Response to 3 years of growth hormone therapy in small for gestational age children: clinical, hormonal and metabolic parameters. An Pediatr (Barc). 2013. 78 288-296
    Search in Google Scholar
  • 16 Lebl J, Lebenthal Y, Kolouskova S. et al. Metabolic impact of growth hormone treatment in short children born small for gestational age. Horm Res Paediatr 2011; 76: 254-261
    CrossrefPubMedSearch in Google Scholar
  • 17 Saggese G, Fanos M, Simi F. SGA children: auxological and metabolic outcomes - The role of GH treatment. J Matern Fetal Neonatal Med 2013; 26 (Suppl. 02) 64-67
    CrossrefPubMedSearch in Google Scholar
  • 18 Xu Y, Ke H, Liang L. et al. PEG-rhGH Therapy for small for gestational age rats and effects on their metabolic parameters. Hormone Research in Paediatrics 2011; 76: 35-43
    PubMedSearch in Google Scholar
  • 19 Vickers MH, Hofman PL, Gluckman PD. et al. Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat. Am J Physiol Endocrinol Metab 2006; 291: E1212-E1219
    CrossrefPubMedSearch in Google Scholar
  • 20 Stull ND, Breite A, McCarthy R et al. Mouse islet of Langerhans isolation using a combination of purified collagenase and neutral protease. J Vis Exp 2012; 67:
    PubMed
  • 21 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487-1495
    CrossrefPubMedSearch in Google Scholar
  • 22 Maganti AV, Maier B, Tersey SA. et al. Transcriptional activity of the islet beta cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. J Biol Chem 2015; 290: 9812-9822
    CrossrefPubMedSearch in Google Scholar
  • 23 Sharma D, Shastri S, Sharma P. Intrauterine Growth Restriction: Antenatal and Postnatal Aspects. Clin Med Insights Pediatr 2016; 10: 67-83
    PubMedSearch in Google Scholar
  • 24 Argente J, Mehls O, Barrios V. Growth and body composition in very young SGA children. Pediatr Nephrol 2010; 25: 679-685
    CrossrefPubMedSearch in Google Scholar
  • 25 Carrascosa A, Audi L, Fernandez-Cancio M. et al. Growth hormone secretory status evaluated by growth hormone peak after two pharmacological growth hormone release stimuli did not significantly influence the two-year catch-up growth induced by growth hormone therapy in 318 prepubertal short children with idiopathic growth retardation. Horm Res Paediatr 2011; 75: 106-114
    CrossrefPubMedSearch in Google Scholar
  • 26 van Dijk M, Bannink EM, van Pareren YK. et al. Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls. J Clin Endocrinol Metab 2007; 92: 160-165
    CrossrefPubMedSearch in Google Scholar
  • 27 Horikawa R, Tanaka T, Nishinaga H. et al. The influence of a long-term growth hormone treatment on lipid and glucose metabolism: A randomized trial in short Japanese children born small for gestational age. Int J Pediatr Endocrinol 2016; 2016: 19
    CrossrefPubMedSearch in Google Scholar
  • 28 Kappelgaard AM, Kiyomi F, Horikawa R. et al. The impact of long-term growth hormone treatment on metabolic parameters in Japanese patients with short stature born small for gestational age. Horm Res Paediatr 2014; 81: 272-279
    CrossrefPubMedSearch in Google Scholar
  • 29 Zhu WF, Tang SJ, Shen Z. et al. Growth hormone reverses dyslipidemia in adult offspring after maternal undernutrition. Sci Rep 2017; 7: 6038
    CrossrefPubMedSearch in Google Scholar
  • 30 Smeets CC, Renes JS, van der Steen M. et al. Metabolic health and long-term safety of growth hormone treatment in silver-russell syndrome. J Clin Endocrinol Metab 2017; 102: 983-991
    PubMedSearch in Google Scholar
  • 31 Lebl J, Lebenthal Y, Kolouskova S. et al. Metabolic impact of growth hormone treatment in short children born small for gestational age. Hormone Research in Paediatrics 2011; 76: 254-261
    CrossrefPubMedSearch in Google Scholar
  • 32 Yamada T, Cavelti-Weder C, Caballero F. et al. Reprogramming mouse cells with a pancreatic duct phenotype to insulin-producing beta-like cells. Endocrinology. 2015; 156: 2029-2038
    CrossrefPubMedSearch in Google Scholar
  • 33 Wang W, Shi Q, Guo T. et al. PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations. Mol Cell Endocrinol 2016; 428: 38-48
    CrossrefPubMedSearch in Google Scholar
  • 34 Liang QL, Mo Z, Li XF. et al. Pdx1 protein induces human embryonic stem cells into the pancreatic endocrine lineage. Cell Biol Int 2013; 37: 2-10
    CrossrefPubMedSearch in Google Scholar
  • 35 Buffat C, Mondon F, Rigourd V. et al. A hierarchical analysis of transcriptome alterations in intrauterine growth restriction (IUGR) reveals common pathophysiological pathways in mammals. J Pathol 2007; 213: 337-346
    CrossrefPubMedSearch in Google Scholar