Originating from China thousands of years ago, acupuncture is now widely practiced in both Eastern Asia and Western countries for treatment of a variety of human diseases, including dental pain, fibromyalgia, and knee osteoarthritis. Recently, numerous reports have proposed its application on diseases related to insulin resistance such as obesity and diabetes [13
This study extended such previous investigations, demonstrating that low-frequency electroacupuncture could improve insulin sensitivity in db/db mice, a genetically obese diabetic animal. More importantly, this study suggested a potential molecular mechanism whereby EA treatment ameliorates insulin resistance in db/db mice. EA increased SIRT1 protein expression and upregulated PGC-1α, NRF1, and ACOX gene expression. In turn, this could enhance mitochondrial biogenesis and fatty acid oxidation and upregulate insulin-associated signal transduction with subsequent improvement in insulin resistance.
Stimulation with needles from different point locations activates muscle afferents to the spinal cord and the central nervous system. EA induces the frequency-dependent release of neuropeptides [25
]. Low-frequency EA (1–15
Hz) releases a sizeable number of neuropeptides, and this appears to be essential for inducing functional changes in different organ systems. More importantly, low-frequency EA is applied more frequently for the treatment of insulin resistance with beneficial results [14
]. Indeed, early insulin resistance in obesity is closely associated with overactivity of the sympathetic nervous system, which induces a proinflammatory state and thus contributes to the development of T2DM [26
Low-frequency EA at the points of abdomen and/or hindlimb attenuates sympathetic nerve activity [27
], whereas EA at the points of upper limbs induces sympathetic nerve activity [29
]. Therefore, this study targeted ST36 points in the hindlimb and CV4 points in the abdomen and stimulated these with low-frequency EA.
Lines of evidence have demonstrated that EA is capable of improving hyperglycemia in the fasting stage, with a marked increase in plasma insulin levels in diabetic rats [14
]. In accordance with these studies, the present work has demonstrated that eight-week EA treatment decreased FBG levels and maintained insulin levels. This supports the suggestion that the effect of EA in regulating BG may be insulin dependent.
Ameliorated insulin sensitivity after EA was established by IPITT, which may be attributed to improvement of responsiveness to insulin via excitation of somatic afferent fibers by EA [31
]. Additionally, this study indicated that EA decreased HbA1c in the absence of statistical significance, which may be ascribed to insufficient course of treatment or limited quantity of subjects. Further, long-term study is necessary to warrant the effect of EA on HbA1c in more experimental animals.
SIRT1 levels may increase in rodent and human tissues in response to calorie restriction and exercise [2
]. This increase is assumed to cause favorable changes in metabolism. Indeed, activation of SIRT1 has been implicated as potential therapy to protect against insulin resistance [6
]. The present study revealed that EA activated SIRT1, indicating that improved insulin resistance by EA may be attributed to enhanced SIRT1 expression. Further, SIRT1 can protect against insulin resistance by deacetylating the substrate PGC-1α
and increasing PGC-1α
was recently demonstrated to integrate insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle [23
]. Overexpression of PGC-1α
rescued insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupted these activities [23
]. Collectively, these studies support the possibility that EA improves insulin sensitivity, at least partially, because of increasing SIRT1/PGC-1α
in skeletal muscle.
gene expression levels of db/db mice were higher than those of db/m mice. It is possible that elevated PGC-1α
was a compensatory response to elevated fatty acid substrate availability and reactive oxygen species (ROS) stimulation under the oxidative stress of diabetes. Alternatively, the effect may reflect the posttranslational regulation of PGC-1α
, in which case gene expression may not always correlate with protein levels [34
]. To support this, db/db mice that develop hyperglycemia have recorded lower skeletal muscle PGC-1α
] and high PGC-1α
mRNA levels [20
] compared with strain-matched C57BL/6J mice. In this respect, the effect of EA on PGC-1α
protein expression requires further investigation.
is a coactivator for NRF1 expression [24
], discrepancy between induced PGC-1α
and reduced NRF1 gene levels in db/db mice may indicate that mitochondrial function was improved by EA [34
]. The resultant increase in expression of mitochondrial genes, including NRF1, may exert positive effects on insulin signaling [12
Figure 4 Schematic model of electroacupuncture on insulin resistance in skeletal muscle. SIRT1-mediated deacetylation of PGC1α is required to activate genes that are associated with mitochondrial fatty acid oxidation in response to energy demands. The (more ...)
This study has its share of limitations. There is no definite confirmation that EA improves glucose clearance and uptake into skeletal muscle to account for ITT data. Therefore, it remains a possibility that the liver, adipose tissues, or certain tissues are responsible for ITT improvement (e.g., electroacupuncture improved P-AMPK in white adipose tissue and liver; P-Akt improved P-AMPK in white adipose tissue but not in liver; data not shown).
This study suggested a preliminary mechanism of electroacupuncture. Specifically, low-frequency EA improved insulin sensitivity in a mouse model of genetic insulin resistance and diabetes, at least in part, via stimulation of SIRT1/PGC-1α in the skeletal muscle. Events involved in this mechanism are presented in . This effect leads to a net switch in the metabolic program of the organism to an adaptation that may be of benefit in the face of disorders characterized by insulin resistance. The study introduces an effective and safe activator (electroacupuncture) for SIRT1, offering a basis for applying acupuncture in clinical practice in the treatment of diseases related to insulin resistance.