الفهرس 
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Abstract
The use of the traditional antidiabetic drugs is no more sufficient alone due to the development of insulin resistance and impaired of glucose tolerance. The pancreatic islet cells can initially respond to the increase insulin resistance by increasing insulin secretion to maintain normal glycemic control. With time the disease progress leads to loss of islet function which leads on the long run to development of many complications including retinopathy, end stage renal disease, neuropathy and cardiovascular disease. So it was a must to have new agents (DPP-4 inhibitors) to be used parallel with these traditional classes. DPP-4 inhibitors act to increase the number of the pancreatic islet cells through cell proliferation. The uses of combination therapies including DPP-4 inhibitors and traditional anti-diabetic agents (metformin, glimepiride, pioglitazone) produce a better effect to improve glycemia and preserve pancreatic islet cells. In addition, this new agent delays the rising of the diabetes complication. This study was conducted to investigate the effect of the combination therapies on glycemic control and beta cell mass in type 2 diabetic rats.
Material and method:
Seventy two rats were used in the current study. Rats were randomly divided into nine groups, eight rats per each group. At the beginning eight rats were assigned to healthy group fed with basal diet and diabetic groups (sixty four rat) fed with high fat diet for four weeks followed with interprotenial injection of low dose of STZ (30 mg/kg) so as to induce type 2 diabetes. The diabetic groups switched to basal diet and re-assigned again the diabetic groups into sitagliptin (10 mg/kg, p.o), metformin (60 mg/kg, p.o), glimepiride (0.5 mg/kg, p.o), pioglitazone (10 mg/kg, p.o) and three combination group (combination 1 (sitagliptin/metformin), combination 2 (sitagliptin/glimepiride), and combination 3 (sitagliptin/pioglitazone) with same doses to be take once daily for 28 day. The body weights were monitored through the treatment period to record the percentage change in body weight as well as the percentage of mortality was reported. OGTT was done then the rats were sacrificed. Lipid profile and liver enzymes activities analysis were done. Morphometric analysis was performed using hematoxylin and eosin stains to measure the pancreatic islet diameters. Immunohistochemical analyses were performed for insulin and for Ki-67 (a proliferation marker) to determine the optical density of insulin-positive area as well as and the number of ki-67 positive nuclei.
Result:
High fat diet followed with single low dose of STZ induced type 2 diabetes mellitus in rats. This was evident by the marked elevation in fasting blood glucose. The AUC calculated from the OGTT was greater than that calculated from all the treated groups. The diabetic group showed high serum level of liver enzymes and lipid profile. These results were accompanied by reduction in the size of the pancreatic islet cells and spread of vacuoles as well as reduction in optical density for insulin positive nuclei and number of Ki-67 immunpositive nuclei. Administration of sitagliptin, metformin, glimepiride, pioglitazone and their combination therapies alleviated most of the abnormalities in the above mentioned parameter induced type 2 DM.
Conclusion:
Monotherapies of sitagliptin, metformin, glimepiride, pioglitazone and their combination therapies are promising as therapeutic options for treatment of type 2 diabetes mellitus. The combination therapies showed better glycemic control and greater cell proliferation compared to monotherapies. Consequently, it is concluded that the combination therapy of sitagliptin/glimepiride has greater effect than other treatment regimen. The use of combination therapies showed a synergistic action regards to the action of sitagliptin on the pancreatic islet mass through beta cell replication which lead to increase the effect of this traditional agents. The use of sitagliptin/glimepiride combination shows better effect on the beta cell diameter than other treatment regimens. The combination therapies made a marked glycemic control than the use of monotherapies.