GABA Effectively Improves Blood Glucose Level Of Diabetic Rabbits Through Intestinal Beneficial Flora

?-aminobutyric acid(GABA)is a non-protein amino acid with good edible safety,which is largely enriched in human pancreas.Current research shows that GABA has functions of preventing neurological diseases,anti-hypertension,anti-oxidation,anti-inflammatation,anti-bacteria and protecting intestine.Recent studies showed that GABA has a significant regulatory function in diabetes therapies,but such statement remains controversial and the mechanism is unclear.To identify the regulatory function of GABA in fasting blood glucose(FBG))and of pancreatic cell transdifferentiation.Healthy mice were divided into wild type(WT)control group,GABA-administration group,and repaglinide-positive group.Drugs were delivered per os continuously for 28 days.The results showed that the FBG of both GABA administration group and positive group showed a downward trend,however,the hypoglycemic action in GABA group was slightly lower than that of the positive group.Moreover,no pancreatic cell transdifferentiation was detected in GABA group.To further clarify the therapeutic effect of GABA on diabetes,we verified the hypoglycemic ability of GABA in diabetes rabbit model that exhibits young-onset adult diabetes(MODY)type diabetes,which was constructed previously via CRISPR/Cas9 mediated GCK knock-out.Rabbits were divided into four groups: wild type(WT)control group,wild type GABA administration group,diabetes model group and diabetes model GABA administration group.Oral administration was performed continuously for 12 weeks.The results showed that the FBG level was decreased in the all administration groups.However,though the level of blood glucose of model administration group reduced,rabbits in such group still maintained hyperglycemia state while no evidence indicates the trend of islet cell transdifferentiation.It has been reported that the intestinal flora can decompose short-chain fatty acids(SCFAs),affect insulin secretion and sensitivity,and therefore participate in the pathogenesis of diabetes.To identify whether GABA can affect the changes of intestinal flora,16 s rDNA and short-chain fatty acid tests were performed to mice and rabbits in both control and administration group.The reduction of Firmicutes and the increase of Bacteroidetes were detected in both mice and rabbits from GABA administration group.Notably,after GABA administration of diabetic rabbits,their intestinal flora changed significantly compared to the WT control group at the level of class;intestinal flora that can improve blood glucose regulation like Ackermania,Rocheella,Mycobacterium,and A.viscera increased significantly,indicating that the intestinal flora of rabbits in model administration group tend to be healthier;Bacterial flora that related to the metabolic decomposition of intestinal content like Intestinimonas and Lactobacillus also increased significantly.The results of serum assay of short-chain fatty acid levels showed that the content of acetic acid,propionic acid,n-butyric acid,and isobutyric acid in rabbits increased after GABA administration,indicating that the intestinal tract tend to have accelerated rate of carbohydrates decomposition,promoted level of short-chain fatty acid production,and can therefore regulate the level of blood glucose.In summary,oral administration of GABA can reduce FBG and promote insulin secretion in both healthy and diabetic animals.In addition,this experiment proves that the intestinal flora of diabetic model rabbits is significantly different to that of the normal rabbits.Positive adjustment of intestinal flora was detected in both healthy and model GABA-administered rabbits,indicating that GABA can promote short-chain fatty acids production by regulating intestinal flora and can lower the blood glucose by regulating energy absorption,leading the homeostasis of physiological status.