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).