Impact Of Early Growth Hormone Intervention On Metabolic Parmeters Of SGA Rats And Regulatory Of Pdxl Gene Expression

Background The rapidly increasing prevalence of metabolic syndrome (MS) and type2diabetes mellitus (T2DM) is one of the most challenging problems, which has caused serious harm to human health. Small for gestational age (SGA) due to intrauterine malnourishment is closely related to the incidence of MS and T2DM for the high prevalence of these diseases when SGA children through to adulthood. Among the complex and diverse pathogenesis, pancreatic islet dysfunction is a very important element that links SGA with adult metabolic diseases. However, it is unclear how pancreatic islet dysfunction developed in SGA. Pancreatic duodenal homeobox1(Pdxl) is a transcription factor that plays a central role in pancreatic β-cell function and survival. Chronic hyperglycemia and dyslipidemia, which are major features of type2diabetes, cause β-cell dysfunction via reduced Pdx1expression. Decrease of Pdx1gene expression plays an important role in SGA pancreas development, which induces later islet dysfunction. By researches based on human studies, Growth Hormone Treatment influences SGA metabolic parameters. Yet the mechanism between GH treatment and metabolic improvement remains unclear.Objective SGA permanently alters pancreatic beta cells function leading to the development of diabetes in adulthood, and reduced expression of the pancreatic homeobox transcription factor Pdxl plays an important role during this development. To determine whether early administration of GH may affect metabolic parameters and β-cell function in the SGA rats.Methods SGA neonatal rat model was created by reducing in maternal total food intake to50%of ad-lib during pregnancy in mother rat. SGA or control (AGA) offspring were randomly assigned to receive GH (5mg/kg/d, SGA+GH, n=8) or normal saline (SGA+NS, n=8). Daily subcutaneous injections of GH were administered at21days untill offsprings achieve catch-up body weight, that is35days. Body weight, length, IPGTT, fasting insulin levels were analyzed at21d,35d and70d. Pdxl mRNA level and protein level from pancreas of each groups are measured at0d,21d,35d and70d. Islets Set7/9protein level and HDACs activity are measured at21d,35d and70d.Results At21d, SGA rats were lighter and shorter than that of the controls (P＜0.01), and has higher fasting glucose than that of the controls (P＜0,05), while has lower fasting insulin (P＜0.05). SGA received GH achieved catch-up growth at35d, and no significance has found among each groups. At day70, IPGTT shows SGA+NS exhibiting higher glucose levels at30min and60min than the AGA+NS group (P<0.05), while SGA+GH group shows no significance in glucose level compared with AGA+NS group (P＞0.05). Pdx1mRNA expression is remarkably reduced in SGA neonatal rats, but rescued in GH treated SGA rats after GH treatment,and lasting to rat adulthood. Before recieving GH treatment, Set7/9protein level in SGA rat islet is lower compared to AGA rats (P＜0.05). After the treatment, Set7/9level remarkably increased in SGA rats. Day21, SGA rats appears higher HDAC activity than that of AGA rats. GH treatment can lower HDAC activityin SGA rat islets at Day35(P＜0.05).Conclusion These data suggests that GH treatment benefit blood glucose metabolism in SGA rats, and increases transcription factor Pdxl expression via epigenetic modification.