Pharmacodynamics Evaluation Of The Fusion Protein GGH In Mice

In the earlier stage of studies, our research group built long-lasting fusion protein(GLP-1A2G)2-HSA(GGH) using molecular biology techniques. It can well promotethe primary cell proliferation activity of the rat islets in vitro and revealed obviousdose-dependent relationship in normal mice. In this case, our paper focused onexperimental therapeutics of fusion protein GGH in mouse models with β-cell minorinjury and type2diabetic model db/db mice, which supplied pharmacologicalefficacy datas for the declaration of new drug.Firstly, by the screening of the blood glucose and islet tissue structure observedwith HE staining, we find that male C57BL/6mice which were injected a single doseof STZ120mg/kg before14days can successfully have been reliable and sensitivemouse models with β-cell minor injury. The molding rate is88%, the recovery rate is86%. The blood glucose of this model slowly increased to reach a steady state in twoweeks after islets damaged. High blood glucose levels were maintained for two weeksand returned to normal after next week. We gave GGH treatment in the second weekwhen the blood glucose levels rised and evaluated its effects on promoting theproliferation of islet cells and the recovery time of high blood glucose.Secondly, we evaluated the therapeutic effects of GGH subcutaneous injectionevery day for two weeks on the treatment of mouse models with β-cell minor injury.The results were that the treatment groups promoted the proliferation of islet cells,The proliferation rate of model group was (5.2±1.8)%while GGH2mg/kg,6mg/kg,18mg/kg group were (6.2±1.5)%,(8.2±0.8)%and (11.6±2.3)%; It increased thesecretion of fasting serum insulin, GGH6mg/kg,18mg/kg group insulin values were(10.8±1.3) mIU/L,(11.9±1.9) mIU/L which showed higher levels compared with themodel group (8.5±1.11) mIU/L (P <0.05); It reduced high blood glucose levels, thevalues of GGH6mg/kg,18mg/kg group fasting blood glucose were (7.6±1.03)mmol/L,(6.5±0.77) mmol/L which showed decreases compared with the model group(9.3±1.83) mIU/L (P <0.01); Meanwhile, GGH can shorten one week of returning tonormal blood glucose level in mice whose islets had been partly damaged, improvethe level of diet, drinking water and urine volume.Finally, we evaluated the effects and mechanisms in the spontaneous type2diabetes model db/db mice through GGH subcutaneous injection every day for six weeks. The results were that GGH promoted the synthesis and secretion of insulin,GGH18mg/kg group insulin value (9.47±0.83) mIU/L showed a higher level than themodel group (7.90±0.90) mIU/L (P <0.05); It promoted the proliferation of islet cells,the proliferation rate of GGH6mg/kg,18mg/kg group were (8.8±1.71)%,(12.8±2.50)%and revealed higher level than the model group (3.5±1.29)%(P <0.01);It inhibited the apoptosis of islet cells, the inhibitory rate of GGH2mg/kg,6mg/kg,18mg/kg group were (5.3±1.48)%,(5.0±0.71)%and (3.8±0.83)%whichshowed obvious decreases compared with the model group (9.3±1.83) mIU/L (P <0.01); In addition, the GGH also alleviated insulin resistance by promoting glycogensynthesis and improving lipid metabolism. So, this study indicates that the GGH havetherapeutic effects on the two central aspects of the pathogenesis of type2diabetes.