[Correlation between growth hormone/insulin-like growth factor-1 resistance and insulin resistance in non catch-up growth rats born small for gestational age].
OBJECTIVE
To investigate the post-receptor signaling mechanism responsible for insulin resistance-induced growth hormone (GH) resistance in non-catch-up (NCU) growth rats born small for gestational age (SGA).


METHODS
Twenty pregnant female SD rats were fed with restricted food (40% of normal intake, 9 g/d) throughout the pregnancy so as to develop NCU-SGA rats. The rats with their length and body weight < or = -2SD were out into the NCU-SGA group, and those with their length and body weight > -2SD were out into the catch-up (CU) growth group. Rats born to normally-fed pregnant rats were set as normal control (control Group, C Group, n = 17). The body weight and length were measured every 2 weeks. At the age of 4 weeks, 24 h urine was collected to measure the urine GH (U-GH). Then blood samples were collected to measure the serum insulin-like growth factor-1 (IGF-1), fasting insulin (FINS), and glucose levels, and the liver was taken out to detect the expression of STAT5 signal. Twelve 3-week NCU-SGA rats were divided into 2 equal groups: P13K blocking group, undergoing intraperitoneal injection of LY294002, blocker of P13K twice every 3 days, and solvent control group, undergoing intraperitoneal injection of DMSO. At the age of 4 weeks, blood samples were collected and then the liver was taken out to detect the IGF-1 mRNA and STAT5 signal.


RESULTS
(1) The body weight and length at birth of the NCU-SGA group were (4.4 +/- 0.5) g and (4.5 +/- 0.2) cm, both significantly lower than those of Group C [(6.8 +/- 0.6) g and (5.3 +/- 0.2) cm respectively], and the body weight and length at 4 weeks of age of the NCU-SGA group were (63 +/- 12) g and (13.2 +/- 1.0) cm respectively, both significantly lower than those of the C group [(88 +/- 12) g and (15.3 +/- 0.5) cm respectively, all P < 0.01]. The serum IGF-1 level, IGF-1 mRNA expression, and total and phosphate STAT5 level in liver of the NCU-SGA group were (248 +/- 58) ng/ml, (6.1 +/- 0.3) copies, and (61 +/- 22)% respectively, all significantly lower than those of the C group [(383 +/- 62) ng/ml, (6.6 +/- 0.4) copies, and (91 +/- 29)%, all P < 0.01]. There was no statistic difference in 24 h U-GH between the NCU-SGA and C groups (P > 0.05). The FINS and glucose level of the NCU-SGA group were (24.7 +/- 9.6) mU/ml and (5.4 +/- 0.3) mmol/L respectively, both significantly higher than those of the C group [(9.8 +/- 2.8) mU/ml and (4.5 +/- 1.7) mmol/L respectively, both P < 0.05]. The level of 24 h U-GH was positively correlated with FINS (r = 0.680, P = 0.000). No correlation was found between IGF-1 and fasting insulin level. (2) After the PI3K pathway was chronically blocked, the NCU-SGA rats lost weight and developed a more severe insulin resistance, decreased serum IGF-1 level and the IGF-1 mRNA expression level of the PI3K inhibitor group were (218 +/- 60) ng/ml and (6.1 +/- 0.3) copies respectively, both significantly lower than those of the solvent control group [(286 +/- 45) ng/ml and (6.3 +/- 0.3) copies, both P < 0.05]. No statistically significant difference in total and phosphate STAT5 levels in liver between the P13K blocker and solvent groups.


CONCLUSIONS
GH resistance is closely associated with insulin resistance in the NCU-SGA rats. GH resistance-induced failure of catch-up growth is related to the impairment of JAK2-STAT5 pathway. Insulin resistance exacerbates growth axis resistance and growth retardation in NCU-SGA rats via a non-STAT5 dependent pathway.
Huang
Ting-Ting
TT
Department of Pediatrics, 1st Affiliated Hospital, Sun Yet-sen University, Guangzhou 510080, China.
Du
Min-Lian
ML
Ma
Hua-Mei
HM
Su
Zhe
Z
Gu
Yu-Fen
YF
D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002867:Chromones / Q000494:pharmacology; D005260:Female; D005865:Gestational Age; D013006:Growth Hormone / Q000652:urine*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001786:Blood Glucose; D002867:Chromones; D007328:Insulin; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone