Introduction
Type 2 diabetic mellitus (T2DM), an endocrine and metabolic syndrome with glucose metabolism disorder, has become the third high-risk chronic disease after cardiovascular diseases and tumors (Al-Rubeaan, 2015). Statistical data from the International Diabetes Federation show that 9.3% of adults aged 20-79 years, a staggering 463 million people, are living with diabetes, and the number will jump to a staggering 700 million by 2045 if the situation is uncontrolled (Saito et al., 2019). Moreover, more than half (56%) of people with diabetes remain undiagnosed and are at a higher risk of developing harmful and costly complications, which seriously reduce the quality of people’s life (Kattan et al., 2018). Thus, effective strategies to prevent and control T2DM are of utmost importance, which is a major challenge for the medical community.
The pancreas is no longer able to make insulin or the body cannot make good use of the insulin it produces is the main cause of T2DM (Bergeron et al., 2018). In the state of insufficient insulin, the resulting excess of hepatic glucose production contributes to hyperglycemia and also profoundly inhibits lipolysis in adipocytes (Xia et al., 2019). A recent study further suggests that the gut microbiota acts as an “exteriorized organ”, which plays an important impact on the onset and development of diabetes or obesity (Wei et al., 2020). For example, an increased Firmicutes/Bacteroidetes ratio is a commonly used indicator of obese and diabetic (ob/ob) mice (Fugmann et al., 2015). Other studies show that gut microbiota and microbial metabolic activities are known to affect lipid and glucose metabolism and chronic low-grade inflammation in the metabolic syndrome (Jayachandran et al., 2017). There is increasing evidence that the change of those factors plays a vital role in the evolution of insulin resistance. In addition, many treatment drugs for T2DM patients, including metformin (Wu et al., 2017) and gliclazide (van Bommel et al., 2020) have been reported to influence the gut microbiota to ameliorate T2DM. Moreover, a series of treatments, including prebiotics and antibiotics, have been evaluated for the regulation of obesity and T2DM and its related metabolic disorders. For example, antibiotic treatment alters the structure of gut microbiota, relieves metabolic endotoxemia, and improves glucose tolerance in the ob/ob diabetic mice (Lange et al., 2016). Besides, a fermentable dietary fiber (oligofructose) was reported to promote the growth of beneficial bacteria and improve intestinal barrier functions and decrease hepatic inflammation in diabetic mice (Zheng et al., 2018). Those studies indicated that gut microbiota may have important effects on T2DM and its associated metabolic disorders.
Diosmetin (3’,5,7-trihydroxy-4’-methoxyflavone, Dios), an aglycone of the natural flavonoid abundantly present in legumes, olive leaves, and citrus plants, possesses anticancer, antimicrobial, antioxidant, and anti-inflammatory properties (Yang et al., 2017). Recently, several reports have shown the anti-diabetic activity of Dios. For example, Jiang et al. (Jiang et al., 2018) found that Dios exhibited the neuroprotective effect in streptozotocin (STZ)-induced diabetic nephropathy (DN) mice, via modulating the Akt/NF-κB/iNOS signaling pathway. Moreover, based on its strong anti-oxidant property, Dios attenuates the effects of diabetes in STZ-induced diabetic rats. Until now, there was no study confirming the role of Dios in alleviating abnormal glucose metabolism and gut microbiota on T2DM. Hence, we sought to determine whether Dios could improve the disturbance in glucose metabolism and gut microbiota in KK-Ay diabetic mice. Our results implied that Dios could ameliorate glucose metabolism in KK-Ay diabetic mice by the regulation of C. glu on IRS/PI3K/AKT signaling pathway and reshaped the unbalanced gut microbiota, which demonstrated that Dios might act as a potential anti-diabetic agent to relieve T2DM and its related metabolic disorders.