4. Discussion
In
this present review, the active constituents from herbs and
nutraceuticals with anti-diabetic effects, as well as the underlying
action mechanisms, were comparatively summarized and discussed.
Generally, the active constituents mainly acted through ameliorating
metabolic abnormalities, inhibiting
chronic low-grade inflammation
and reversing gut microbiota dysbiosis, all of which were further
regulated by different signaling pathways or factors. For example,
herbs and nutraceuticals could
reduce WAT accumulation, increase BAT activity or promote WAT browning
to ameliorate lipid metabolism disorders. Also, it was also reported to
relieve IR by inhibiting inflammatory infiltration and cytokines
secretion via suppressing NF-κB, TLR4 and NLRP3 activities. Although the
mechanism by which natural herbal and nutraceutical active constituents
reverses gut microbiota dysbiosis is still largely unclear, it has been
confirmed that they could regulate gut microbiota abundance and
metabolite emission, thereby alleviating the impairments from
detrimental metabolite. In addition, herbs and nutraceuticals could also
achieve the improvement of IR by regulating miRNA expression.
Current studies usually distinguish the contributions of different
factors involved with IR, which exaggerates the individual role of a
single factor. The pathogenic underpinnings of IR, however, resemble the
chicken-and-egg cycle, making it challenging to pinpoint the initial
event that triggers IR. For example, the lipid metabolism disorder in an
obese and insulin resistant patient could trigger systemic chronic
low-grade inflammation of the whole body, further regulate the gut
microbiota abundance and affect the gastrointestinal absorption,
eventually causing the aggravation of obesity and IR. Another theory
suggests that the emergence of IR may come before obesity. One possible
explanation is that HG and HFD could affect the gut microbiota abundance
before the development of obesity. When the gut microbiota abundance
changed, the gut microbiota metabolites are able to enter the systemic
circulation and regulate the functions of the body. In other words, IR
is probably derived from hyperglycemia and
hyperinsulinemia, which subsequently
induce IR of the liver and eventually the entire body (Tang, Le-Tien,
Goldstein, Shin, Lai & Fantus, 2001; Yuet al., 2011). This process
probably skips the step of obesity, which explains the facts that some
patients with IR or T2DM are not obese.
Meanwhile, a therapeutic target, such as PPARγ, might exhibit converse
functions in different tissues. PPARγ activity is directly proportional
to the fat mass which is a pathogenic factor to induce chronic
inflammation and exacerbate IR. However, PPARγ could also improve the
insulin sensitivity of the organism (Gijs Den Besten, Rick Havinga &
Albert K. Groen, 2015). Therefore, PPARγ has a dual role in IR, and
studies on PPARγ should focus on its regulation rather than activation.
Metabolic diseases including IR and T2DM are regulated by
multi-mechanisms, multi-targets and multi-pathways. Herein, it is hard
for single-target drugs to achieve satisfying therapeutic effects.
Alternatively, natural herbal constituents have showed great potential
and significance to develop anti-diabetic medicines with multi-targets.
For illustration, resveratrol (Fig 5) has been proved to alleviate IR by
several mechanisms acted simultaneously as below: (1) Regulating
NAD/NADH ratio and SIRT1 expression to relieve ethanol-induced IR (Luoet
al., 2017); (2) Inhibiting PTP1B in a SIRT1-independent manner to
restore peripheral insulin transduction (Gonzalez-Rodriguez et al.,
2015); (3) Reducing liver ERS to improve insulin sensitivity (Zhao,
Zhang, Shu, Song & Ma, 2019); (4) Targeting duodenal SIRT1 and AMPK to
activate the gut-brain-liver neuronal axis, improve insulin sensitivity
and reduce blood glucose level (Cote et al., 2015).
Meanwhile, TCM holds that the organs
harmony keeps the body in shape, which also has guiding significance for
further researches on metabolic diseases. Traditional research
methodology on IR is also limited. Due to the various mechanisms and
organs involved in metabolic diseases, it is finite to study the impact
of a single target. A growing number of studies have been performed from
a multi-organ linkage perspective. Supporting this view, Shen et al.
focused on the skeletal muscle–adipose tissue crosstalk to investigate
the protective effects and mechanisms of myricanol against IR (Shen,
Liao, Zhang, Pan & Lin, 2019). It
was shown that the gut-brain-liver axis played a critical role in
glucose production (Wang et al., 2008). The subcutaneous adipose
tissue-liver axis was also found to control hepatic gluconeogenesis
(Reilly et al., 2015).
Active constituents from natural
products may have few side effects, however this does not make them
completely non-toxic. For instance, resveratrol inhibited normal insulin
signaling pathway by suppressing p-AKT/AKT level in ethanol-induced IR
rats (Luoet al., 2017). Besides, it was reported that resveratrol showed
negative effects on cells at higher concentrations, which encouraged ERS
and IR (Zhao, Zhang, Shu, Song & Ma, 2019). Holistically, the doses of
natural active ingredients should be taken into consideration to avoid
side effects. The therapeutic effects of natural active ingredients on
IR are a function of both their positive and negative effects, as well
as their concentrations.
Numerous constituents from herbs and nutraceuticals effectively against
IR, such as artemisinin, green tea polyphenols and berberine have been
extensively employed in clinical trials. Nevertheless, most studies
still stayed at the early stage of cell or animal studies. There is
still lack of the clinical drugs with great efficacy, few side effects
and precise action mechanisms. Here, this review also demonstrated that
most active constituents against obesity-induced IR were flavonoids or
alkaloids from herbs and nutraceuticals, which provided clues for
developing new medicines. Further studies on natural medicine resources
are moving forward to develop novel anti-diabetic drugs and clarify the
connection between obesity and T2DM.