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.