3.4 Regulating miRNAs
miRNA, a single-stranded, small and non-coding RNA molecule, is the biomarker of multiple diseases by targeting at mRNAs transcribed from gene clusters rather than the single genes. miRNAs from different tissues can enter the internal circulation in the form of exosomes to affect the metabolic profiles of distant organs, thus promoting the crosstalk among various organs (Ji & Guo, 2019). Specifically, the exosomes from the liver, adipose tissue and macrophages-derived play a critical role in regulating glucose homeostasis and insulin sensitivity. In particular, the adipose tissue-derived miRNAs are one of the key sources of all circulating miRNAs, which are recognized as novel adipokines (Ying et al., 2021; Ying et al., 2017). Reportedly, miRNAs primarily regulated the metabolism by modulating adipocytes differentiation, cytokines secretion and inflammatory genes and proteins expression (Arner & Kulyte, 2015).
It has been discovered that miRNA-141 expression was considered as an important biomarker of IR (Faheem, Rehman, Jabeen & Akash, 2020). miRNA-690 from lean adipose tissue macrophages was confirmed as an insulin-sensitizing miRNA (Yinget al., 2021). Ying et al. demonstrated that glucose intolerance and IR occurred in the recipient lean mice when treated with adipose tissue macrophage-derived exosomal miRNAs from obese mice (Yinget al., 2017). On the contrary, adipose tissue macrophage-derived exosomal miRNAs from lean mice could enhance the glucose tolerance and insulin sensitivity of obese mice. Many miRNAs related biomolecules, such as miRNA mimics, anti-miRNA oligonucleotides and exosome containing miRNAs, are potential therapeutic targets for the treatment of IR (Ji & Guo, 2019).
Curcumin (Supporting Information Table S8) administration significantly restored fructose-induced body weight gain in rats without affecting the food and water intake (Ding et al., 2015). The serum insulin, TG, TC and uric acid levels, as well as the glucose and insulin intolerance of rats were also significantly modulated by curcumin treatment. These effects were probably achieved by activating miR-206 expression to downregulate PTP1B and then improving insulin signaling to prevent fructose-induced glomerular foot cell injury and proteinuria.
Emodin is an anthraquinone compound, mainly derived from the rhizomes ofRheum officinale Baill. The anti-diabetic capacities of emodin were demonstrated by Xiao et al. in a published study (Xiao et al., 2019). It was revealed that emodin supplementation markedly reversed hyperglycemia, dyslipidemia and glucose metabolic disorders in T2DM rats in a dose- and time-dependent manner. Further assays elucidated that emodin addition probably decreased glucose consumption by down-regulating miR-20b-mediated SMAD7 expression.
δ-Tocotrienol, a subtype of vitamin E, is a lipid-soluble vitamin with benzo-monohydropyran carbon frame structure and unique antioxidant and anti-inflammatory properties. δ-Tocotrienol intervention significantly alleviated the blood glucose, inflammation and oxidative stress of T2DM patients, contributing to the inhibition of diabetes development and its complications. Recently, the research based on 304 T2DM patients have suggested that δ-tocotrienol treatment improved IR and T2DM through up-regulating miRNA-126 and miRNA-132 expression (Mahjabeen, Khan, Mirza & Pervez, 2021).
3.5 Others
As a multifactorial metabolic disease, IR is probably associated with various signal pathways and targets that acts simultaneously. As a result, not all of the mechanisms by which naturally occurring herbal and nutraceutical active constituents modulate insulin resistance could be generalized to the above pathways and factors. For example, emodin not only acted by regulating miRNAs, but also achieved the effects by inhibiting 11 beta-Hydroxysteroid dehydrogenase type 1 (11β-HSD1, an enzyme highly expressed in liver, brain and adipose tissues) (Feng et al., 2010). In brief, emodin administration significantly improved insulin sensitivity and lipid metabolism on prednisone- or dexamethasone-induced IR mice by inhibiting 11β-HSD1 mRNA expression. Moreover, bitter gourd, the fruit of Momordica charantia L., is an herb that is utilized in TCM as a heat-clearing medicament and is regarded as a remedy for “Xiao Ke”. A recent study has shown that the soluble and insoluble fractions of bitter gourd could restore metabolic disturbance, hyperlipidemia, hyperglycemia and improve glucose tolerance by suppressing inflammation and SREBP-1c/FAS pathway (Xu, Cao, Feng & Liu, 2018).
Some naturally occurring active ingredients’ processes, however, have not been fully explained. For example, mulberry fruit polysaccharide was found to reduce blood glucose levels and body weight gain in STZ-induced mice, possibly due to its antioxidant and hypoglycemic properties, however, further studies are still needed to clarify the precise targets (Chen, Huang, Li & Fu, 2017). The mechanisms by which theaflavins treatment protected against palmitic acid-induced HepG2 cells were also unclear (Tong et al., 2018).