| The experiments were designed to study pharmacodynamic action and mechanism of the shorter glucagon like peptide-1 (sGLP-1) on type 2 diabetes treatment. GK type 2 diabetes rats were divided randomly according to the requirement for experiments, and treated with sGLP-1, rhGLP-1 and saline solution respectively, then we analyzed the pharmacodynamic action of sGLP-1 on type 2 diabetes treatment by compared with rhGLP-1. In addition, we studied the mechanism of sGLP-1 on type 2 diabetes treatment through investigated the effect of sGLP-1 on pancreaticβ-cell proliferation, apoptosis and insulin-secretion. The main contents and results were as following:1. The treatment action of sGLP-1 on type 2 diabetes1) The fasting blood glucose of the BALB/c mice had no significant change at 15min after they were treated with sGLP-1(140, 70 or 35μg·kg-1) or rhGLP-1(35μg·kg-1) (P>0.05, 140, 70 or 35μg·kg-1 sGLP-1 or 35μg·kg-1 rhGLP-1 vs. saline).2) The blood glucose of the BALB/c mice, which was treated with 35μg·kg-1 sGLP-1 or 35μg·kg-1 rhGLP-1 by hypodermic injection, decreasing conspicuously compared with that of the mice were treated with saline solution by the same way at 0, 30, 60 and 120 min after intraperitoneal injection of glucose (P<0.01), but it had no apparent change compared with that of the mice were only treated with saline solution by intraperitoneal injection (P>0.05).3) The fasting blood glucose of GK rats, which were subjected to continuous infusion of sGLP-1 or rhGLP-1, decreased conspicuously compared with only injection of saline group (p<0.05) at the third week of the treatment.4) The fasting blood glucose of GK rats, which were subjected to intermittent infusion (2 times a week) of 25μg·kg-1 sGLP-1, decreased conspicuously compared with that of controls (p<0.05) at the third week. Interestingly, the fasting blood gluose of GK rats which were treated with25μg·kg-1 rhGLP-1 by the same way had no significant change compared with that of controls.5) The infusion of 25μg·kg-1 sGLP-1 or 25μg·kg-1 rhGLP-1 to type 2 diabetic rats had a significant positive effect on glucose tolerance, as demonstrated by an intraperitoneal glucose tolerance testing (IPGTT) performed at 4 weeks from the beginning of the infusion (P<0.01, 25μg·kg-1 sGLP-1 or 25μg·kg-1 rhGLP-1 vs. saline solution treated rats).6) At the end of continuous infusion for 3 weeks, the insulin level of all the experimental groups have no distinguished change compared with that of the controls (P<0.05).7) Compared with the controls, sGLP-1 treatment had no distinguished effect to GK rats on weight for 4 weeks continuous infusion (p>0.05).2. The effect of sGLP-1 on pancreaticβ-cell proliferation and apoptosis1) The culturedβTc3-cell had shown a notable proliferation by the treatment with sGLP-1 or rhGLP-1, but hadnot shown dose-effect relationship. 2) Treatment with sGLP-1 induced marked increased in the size of islet as well as the formation of new isletlike aggregates of insulin-positive cells. In sGLP-1-treated rats, there was also an enhanced irregularity of the margins of those large islets, with the presence of an extensive branching out of cells from the periphery of the islets. This budding of cells appeared as developing branches of cells reaching and connecting the islets to neighboring ductal structures. This irregularity of the margins of the islets could be seen also in controls; however, it appeared significantly more represented after treatment with GLP-1.3) By immunofluorescence, we observed that the Caspase-3 was expressed both in controls and sGLP-1 treated rats. However, in controls, the signal for Caspase-3 was stronger in intensity and more widely distributed than in sGLP-1 treated rats. Characteristically, all the insulin positive cells were costained with Caspase-3 in controls, but there was some of insulin positive cells were not costained with Caspase-3 in sGLP-1 treated rats.4) By immunofluorescence, we also observed that the Ki-67 antigen was expressed both in controls and sGLP-1 treated rats. However, in sGLP-1 treated rats, the signal for Ki-67 was stronger in intensity and more widely distributed throughout the pancreatic parenchyma than in controls. The Ki-67 positive cells never costained for insulin. Characteristically, in sGLP-1-treated rats, the insulin-positive cells appeared to surround aggregates of Ki-67 positive cells. This was different from the appearance of the rare Ki-67-positive cells that were detected in control.In this study, sGLP-1 was investigated in pharmacodynamic action and mechanism on type 2 diabetes treatment. The results indicate that sGLP-1 has the similar pharmacodynamic action to rhGLP-1 on blood glucose decrease; sGLP-1 not only can promote pancreaticβ-cell proliferation but also can inhibit pancreaticβ-cell apoptosis, and that maybe one of the mechanisms of sGLP-1 on type 2 diabetes treatment. |
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