Natural product cycloastragenol: a promising anti-diabetes candidate
with therapeutic effects on its related complications in rats
Abstract
BACKGROUND AND PURPOSE Type II Diabetes mellitus (T2DM) is a worrying
chronic metabolic disorder accompanied by multiple serious
complications, makes threaten public health. In the present study, we
evaluated the therapeutic effects against T2DM of the cycloastragenol
(CAG), a key metabolite of astragaloside IV (AST) isolated from
traditional Chinese plant Astragalus membranaceus and revealed its
molecular mechanism. EXPERIMENTAL APPROACH The plasma glucose-decreasing
effects of AST and CAG were monitored in KunMing mice by performing an
OGTT test. Furthermore, the effect of CAG on the metabolism of Zuker
diabetic fat (ZDF) rats was demonstrated after treatment for 5 weeks, as
well as on diabetes-relevant clinical symptoms and glucose absorbance.
The underlying molecular mechanism of the therapeutic effects of CAG was
explored in both wild-type and sodium/glucose co-transporter 2
(SGLT2)-overexpressed HEK293 cells. KEY RESULTS CAG showed stronger
effects in lowering plasma glucose and enhancing glucose tolerance than
AST in KM mice and ZDF rats. In the ZDF rats, the potential antidiabetic
properties of CAG were associated with amelioration in hyperglycemia,
dyslipidemia, myocardial and kidney fibrosis. Interestingly, glucose
reuptake was inhibited in the kidneys of mice treated with CAG, while
urine glucose and sodium levels were elevated. The underlying mechanism
might be that CAG reduced the expression of SGLT2 in the kidney and
inhibited glucose transport as well. CONCLUSIONS AND IMPLICATIONS CAG
can ameliorate the T2DM-related metabolic syndromes of ZDF rats by
acting on the SGLT2, which provides a certain references for the
application of CAG in T2DM therapy.