| ObjectiveRecent studies find that fibroblast growth factor-19,21 play important roles in glucose and lipid metabolism by combining different fibroblast growth factor receptors(FGFRs)and are defined as new metabolic hormones.Moreover,studies find that selective activation of FGFR1 improves glucose and lipid metabolism.As a first line oral drug,metformin exerts its effects by inhibiting glucose output and increasing insulin sensitivity in peripheral tissues.Our aim is to examine alterations of FGF19 and FGF21 serum levels.FGFR1 protein levels and Akt phosphorylation were also evaluated before and after metformin treatment in diabetic rats.Thus we may find new drug and organ effects of metformin.MethodsA total of 60 male Wistar rats(aged 8 weeks)were randomly assigned to control group(Con)(n=20)and high fat diet group(HFD)(n=40).Con rats were fed with normal diet,while HFD rats were fed with high fat diet.After 6 weeks of administration,HFD rats received an intraperitoneal injection of STZ(35mg/kg)in 0.1M citrate buffered saline(PH=4.2)to form type 2 diabetes mellitus(T2DM)after an overnight fast.After T2DM formation,the rats were then assigned to diabetic rats group(DM)and diabetic rats combined metformin(500 mg.kg-1.d-1)treatment group(DM+METF).At 24th weeks of the experiment,serum FGF19 and FGF21 were evaluated by ELISA kits.Pancreatic and adipose tissues were collected to assess FGFR1 protein levels by Western blot(WB)and immunochemistry(IHC).Protein levels of Akt and phospho-Akt(p-Akt)were analyzed by WB.Comparisons among three groups were analyzed by one way-ANOVA followed by Dunnett's test.Results1.General features of rats in each group:After diabetes model formation,rats in DM group had a higher food and fluid intake as well as a higher body weight gain compared to that in Con rats.After metformin treatment,fluid,food intake and body weight gain was higher than Con rats but lower than DM rats(All P<0.05).2.Biochemical parameters comparison:At the end of the experiment,diabetic rats had impaired glucose and lipid as well as bile acid metabolism.At the end of the experiment,HFD/STZ diabetic rats displayed increased blood glucose at each time point and delayed serum insulin peak.At 120 minutes,insulin concentration in DM rats was still higher than that in Con rats.After metformin treatment,FBG,FIN,TC,TG and LDL were significantly decreased in DM+METF rats compared to DM rats(All P<0.05).3.Comparison of FGF19,FGF21,FGFR1 and phospho-Akt among three group.We detected decreased levels of serum FGF19 and increased of FGF21(All P<0.05)in diabetic rats group(DM)when compared to Con rats.Besides,pancreatic FGFR1 expression and Akt phosphorylation were decreased after diabetes formation.However;after metformin treatment,serum FGF19 was decreased while FGF21 was increased when compared to DM rats.Moreover,the FGFR1 protein levels was restored in the pancreas while still higher in the visceral adipose than that in DM rats.Akt phosphorylation was significantly increased in both tissues in DM+METF rats.Conclusions:1.High fat diet combined a low dose streptozotocin(3 5mg/kg)can induce rats to type 2 diabetes model.Type 2 diabetic rats are characterized with glucose and lipid metabolic disorders.2.Metformin exhibits effects on improving glucose,lipid metabolism as well as body weight gain.Moreover,metformin promotes bile flow by decreasing total cholesterol and total bile acids.3.Diabetic rats showed impaired metabolism of FGF19 and FGF21.Besides,pancreatic FGFR1 and Akt phosphorylation were also impaired in diabetic rats.4.FGF19 serum level was reduced(P<0.05),while FGF21 was increased in DM+METF rats(P<0.05).Akt phosphorylation was restored in DM+METF rats when compared to DM rats.The above data may indicate that metformin treatment improves glucose homeostasis and this may be due to FGFs-FGFRl interactions thus affecting pancreatic and visceral adipose functions. |
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