Medical Therapy Mimic RYGB Surgery Effect In HFD-STZ Induced T2DM In C57BL/6J Mice

Objective:Diabetes has become a global epidemic with a rising rate in the incidence. Type 2 Diabetes mellieus (T2DM) which closely related to obesity comprises 90% of people with diabetes mellieus. Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments on diabetes combined with morbid obesity for long-term weight loss and diabetes remission. There are numerous researches on the mechanisms underlying the merits, however the precise mechanisms are not clearly elucidated. The aim of our study was to mimic RYGB surgery effect in diabetic mouce using drugs chosen by analyzing gene profiles, and expore effective therapeutic methods to control metabolic syndrome in diabetic mice. Methods:We integrated gene expression signatures from RYGB and gene expression datum in Cmap yielding candidate drug to mimic RYGB effect. We experimentally validated a prediction for the immunosuppressant Srolimus (SRL) and antibiotic Aztreonam (AZT) as candidate drugs on the HFD-STZ induced T2DM mice to mimic the beneficial improvements of weight gain and hyperglycemia. Considering the known hyperlipidemia induced by Srolimus and the role of distal bile diversion postgastric bypass surgery, we take Colestyramine (CO) into regimen. We administrated SRL and AZT at doses of 1 mg/kg, 10mg/kg respectively and CO mixed with HFD at doses of 20mg/g on HFD-STZ C57BL6 mice for ten weeks. Results:We find that SRL treatment compared with controls leads to reduction of weight gain and epididymal fat size, slightly improvement of insulin resistance and blood glucose with no significance, decrease of serum TG levels and islet β-cells mass, augment of serum TCHO levels and glucose intolerance. AZT treatment compared with controls leads to weight increasement and epididymal fat accumulation accompanied by increased serum TG and TCHO levels, hyperglycemia and hyperinsulinemia. CO treatment attenuates weight gain, hyperglycemia, hyperlipidemia and insulin resistance, conducts pharmacal synergism combined with SRL, reduces adverse effects of AZT in the cocktail treatment of AZT and CO. The cocktail treatment of SRL and CO leads to more robust decline of blood glucose from 23.42±1.39mmol/l to 14.42±1.90mmol/l (p<0.01) and significant improvement of HOMA-IR compared with controls(p<0.01)but less weight loss. The cocktail treatment of SRL and CO leads to pronounced weight decline 2.38±0.26g(;?<0.01) at first week and weight change 0.84±0.44g(p>0.1) at ten weeks. The trigeminy therapy of AZT, SRL and CO leads to metabolic improvement similar to combination of SRL and CO, with decline of blood glucose from 25.18±1.00mmol/l to 16.4±1.65mmol/l (p=0.014) and weight decline 1.30±0.55g at first week and weight gain 1.38±0.42g at ten weeks with no significance. HOMA-IR of trigeminy therapy group reduces 45.5% when compared with control group. Conclusion:In our present study, we find a potential therapeutic strategy of mimicking RYGB effect by reconfiguration of small intestine with drug administration, although the optimal composition of regimen needs to be further carried out and the underlying mechanisms of microbiotic should be globally considered as well.