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.