Discussion
Previous studies have shown that gut microbiota and its metabolic
products are vital for many metabolic diseases, including obesity
(Turnbaugh et al., 2006), insulin resistance (Cani et al., 2007),
metabolic syndrome (Vijay-Kumar et al., 2010) and liver steatosis
(Spencer et al., 2011). Increasing data indicate that diabetic metabolic
disorders are closely related to changes in
gut
microbiota composition,
gut
microbiota affects host metabolism by altering gluconeogenesis,
glycogenolysis, lipogenesis, inflammation and hormone action (Federico
et al., 2017, (Muñoz-Garach et al., 2016). Hence, reverse gut dysbiosis
may represent a novel strategy to treat or prevent diabetes. In this
study, we demonstrated that Dios treatment remarkably ameliorated
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.
Glycogen is supposed to be the principal storage form of glucose and its
metabolisms are primarily in the liver and skeletal muscle.
The concerted regulation of the
rate of glycogen synthesis and the rate of glycogenolysis is one of the
principal methods in the maintenance of
glycogen homeostasis. Defects in
these two processes can be major contributors to hyperglycemia and
insulin resistance (Petersen et al., 2017). Thus, glycogen homeostasis
plays an important role in the development of T2DM. Insulin is the main
hormone proteins produced by the β cells of pancreatic islets and
regulates many important biological functions, which control the
metabolism and storage of the three
major nutrients (Niswender, 2011). Insulin mainly stimulates
lipogenesis, glycogen and protein synthesis and inhibits lipolysis and
protein breakdown, to stimulate cell growth and differentiation, and
promote the storage of substrates in fat, liver and muscle (Edgerton et
al., 2006). When insulin resistance or insulin deficiency occurs, it
will cause a serious imbalance of these processes and metabolic
disorders, which will lead to the destruction of body homeostasis (Tzeng
et al., 2012). The IR and
related
IRS, the PI3K heterodimer, and AKT are three well-defined and essential
mediators of the insulin signaling pathway. Insulin binds to the insulin
receptor tyrosine kinase and activates the receptor and then
phosphorylates the insulin receptor
substrate (IRS), phosphorylated IRS then activates PI3K, and
subsequently phosphorylates Akt, leading to Akt activation. When AKT is
activated, it participates in the metabolic pathways of glucose
transport and glycogen synthesis (Beale, 2013). In our study, through
transcription analysis, we predicted that the potential mechanism of
Dios ameliorated T2DM may be through regulating glucose metabolism and
insulin resistance. As would be
predicted, we found that Dios could predominantly up-regulating
IRS/PI3K/AKT signaling pathway to promoting glycogen synthesis and GLUT4
translocation to regulate the balance of glucose level.
In recent years, several studies have shown that
gut
microbiota dysbiosis has been suggested as a prominent feature of T2DM
(Ahmad et al., 2019, (Sabatino et al., 2017). In diabetic mice, an
obvious shift betweenFirmicutes and Bacteroidetes when compared with
non-diabetic mice, which indicates that these major phyla may play a
role in T2DM, as reported previously (Qin et al., 2012). In our study,
we found that Dios effectively reversed gut microbiota dysbiosis when
compared to untreated diabetic mice. Moreover, Dios treatment restored
the Firmicutes/Bacteroidetes ratio close to that observed in
non-diabetic mice. Intriguingly, the ratio ofActinobacteria phylum was
also significantly higher in the H-Dios group than in the other groups.
TheActinobacteriaphylum represents one of the largest groups of bacteria. It is well
known that theActinomycetes ,
a potentially beneficial bacteria,
are a diverse phylum of Gram-positive bacteria found in the human
intestinal tract and soil (Bhatti et al., 2017). Thus, we want to
further explore the impact of Dios on the relative abundance of the gut
microbiota at the species level. In our study, the C._glu is
markedly increased by Dios (60 mg/kg) treatment compared with KK-Ay
diabetic mice. Numerous studies have indicated that C. glu is a
Gram-positive soil bacteria belonging to the orderCorynebacteriales within the Actinobacteria (Becker et
al., 2018). Meanwhile, C. gluis an important industrial metabolite producer, and has been widely used
for the industrial production of various amino acids, vitamins, and
nucleotides (Lee et al., 2016). Previous studies suggested that C.
glu plays a crucial role in the process of glycogen synthesis. At the
same time, by encoding the glg C gene of C. glu, a key enzyme in
glycogen synthesis, and studying its correlation with ADP-glucose
pyrophosphorylase, it was found that the cells of C. glu grown in
a medium containing glucose, sucrose or fructose as glycolytic
substrates showed rapid glycogen accumulation in the early exponential
growth phase (Seibold et al., 2007). Therefore, we hypothesized thatC. glu may be a potential beneficial bacteria in the development
of T2DM. To test this hypothesis, KK-Ay diabetic mice were treated withC.
glu , Dios or C. glu +Dios for 4 weeks. We found that the addition
of C. glu alone can remarkably reduce
HFD-induced body weight and blood
glucose gain and significantly ameliorated lipid accumulation compared
with KK-Ay diabetic mice group. However, when treatment with C.
glu and Dios together, the body weight and blood glucose gain
down-regulated more significantly. Besides, we found that treatment withC. glu and Dios together
can markedly ameliorate glucose
metabolism by up-regulating IRS/PI3K/AKT signaling pathway to promoting
glycogen synthesis and GLUT4 translocation compared with KK-Ay mice.
In summary, in the present study,
we demonstrated for the first time 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. Collectively, our results suggested that Dios may function
as potential anti-diabetic agent to effectively play a positive role in
the management of T2DM patients.