Insulin.resistance

review

article

Diabetes, Obesity and Metabolism 12: 555–569, 2010.© 2010 Blackwell Publishing Ltdreview article

Acupuncture: is it effective for treatment of insulinresistance?F. Liang1,2 & D. Koya1

1Department of Endocrinology & Metabolism, Kanazawa Medical University, Ishikawa, Japan2Department of Acupuncture & Moxibustion, Hubei University of Traditional Chinese Medicine, Hubei, Wuhan, China

Insulin resistance (IR) is closely associated with obesity, type 2 diabetes mellitus (T2DM), hypertension, polycystic ovary syndrome (PCOS),non-alcohol fatty liver diseases (NAFLD) and metabolic syndrome and is also a risk factor for serious diseases such as cardiovascular diseases.Pharmacological treatments available for IR are limited by drug adverse effects. Because acupuncture has been practiced for thousands ofyears in China, it has been increasingly used worldwide for IR-related diseases. This review analyses 234 English publications listed on thePubMed database between 1979 and 2009 on the effectiveness of acupuncture as a treatment for IR. These publications provide clinicalevidence, although limited, in support of the effectiveness of acupuncture in IR. At this stage, well-designed, evidence-based clinical randomizedcontrolled trial studies are therefore needed to confirm the effects of acupuncture on IR. Numerous experimental studies have demonstratedthat acupuncture can correct various metabolic disorders such as hyperglycemia, overweight, hyperphagia, hyperlipidemia, inflammation,altered activity of the sympathetic nervous system and insulin signal defect, all of which contribute to the development of IR. In addition,acupuncture has the potential to improve insulin sensitivity. The evidence has revealed the mechanisms responsible for the beneficial effectsof acupuncture, though further investigations are warranted.Keywords: acupuncture, hypertension, inflammation, IR, insulin signal, obesity, PCOS, T2DM

Date submitted 31 August 2009; date of first decision 7 December 2009; date of final acceptance 9 December 2009

IntroductionInsulin resistance (IR), defined as failure of ordinary levels ofinsulin to trigger its downstream metabolic actions, is closelyassociated with obesity, type 2 diabetes mellitus (T2DM), poly-cystic ovary syndrome (PCOS), metabolic syndrome, hyper-tension and non-alcoholic fatty liver disease (NAFLD) [1,2].IR results in impaired insulin action in insulin-sensitive tis-sues, leading to abnormalities in glucose metabolism, anddysfunction in insulin secretion. Hyperinsulinemia itself isatherogenic through the induction of oxidative stress by stimu-lating sympathetic nerve activity. Ectopic fat deposition, stress,proinflammatory state and a maladaptive response of innateimmunity may together confer increased risk for glucose intol-erance that enhances the risk for the development of T2DMand the related cardiovascular disease. The IR-related diseaseshave become epidemic worldwide and predicted to increase inthe future (Table 1) [2–8], which will result in huge threatto human health. It is urgent to act now to prevent IRso as to halt the progression of comorbidities of IR-relateddiseases.

The two classes of drugs currently available with directeffects on IR are biguanides (e.g., metformin) and thiazo-lidinediones, or TZDs (e.g. pioglitazone, rosiglitazone) [9].However, pharmacological treatment has limitations related

Correspondence to: Prof. Daisuke Koya, M.D. Ph.D., Department of Endocrinology &Metabolism, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.E-mail: [email protected]

to drug adverse effects, costs and patient compliance. Forbiguanides, gastrointestinal symptoms (diarrhoea, abdomi-nal discomfort and anorexia) are the most common adverseeffects [10]. The most common adverse events of TZDsleading to discontinuation are edema, body weight (BW)gain, depressed mood disorders, nausea and dizziness. More-over, a recent multi-center, randomized trial indicated thatrosiglitazone increases the risk of heart failure and limb frac-tures [11].

Because IR is a precondition of diseases such as T2DM,hypertension and cardiovascular diseases, it is important andrecommended to intervene against IR prior to the developmentof IR-related diseases, rather than taking action after onset ofdiseases. Actually, in traditional Chinese medicine (TCM),prevention before onset of diseases is highly valued. Differentmethods of acupuncture and moxibustion have been applied toprevent and treat diseases [12]. Acupuncture means needlingat specific points (acupuncture points or acupoints), whichcan give rise to special sensation (usually described as soreness,numbness, heaviness, distension and ‘de Qi’ in Chinese or‘arrival of Qi’) to regulate Qi circulation, dredge meridiansand remove pathogens. In modern medicine, acupunctureat acupoints is believed to activate peripheral afferent nervefibres and receptors, resulting in sensory interaction atdifferent levels of the central nervous system and releaseof variety of transmitters and modulators, so as to produceanti-inflammatory signal, neuroendocrine and neuro-immunesignals [13].

review article DIABETES, OBESITY AND METABOLISM

Table 1. Prevalence of IR-related diseases worldwide.

Gender prevalence

IR-related disease Prevalence Men Women Total number year Reference

Overweight 23.2% 24.0% 22.4% 937 million 2005 61.35 billion 2030

Obesity 9.8% 7.7% 11.9% 396 million 2005 6573 million 2030

Type 2 diabetes 2.8% 171 million 2000 34.4% 366 million 2030

PCOS 7–8% of premenopausal women 6.7% 2004 2Metabolic syndrome 25.2% (Australia) 16.7% (Australia) 2004 7 (WHO definition)

41.3% (USA) 32.7% (USA)23% (France) 12% (France)

Hypertension 26.4% 26.6% 26.1% 972 million 2000 529.2% 29% 29.5% 1.56 billion 2025

NAFLD 17.1% 691 million 2004–2007 8

Acupuncture is widely applied in clinical practice forIR-related diseases such as obesity, diabetes and related com-plications, PCOS and hypertension [14–18]. Several studieshave concluded that acupuncture can improve insulin sensitiv-ity [19–21], as it is effective against metabolic disturbances suchas hyperglycemia [16,22], overweight [14], hyperphagia [14],hyperlipidemia [23], inflammation [21], altered activity ofsympathetic nerve system [24], and insulin signal defect [25],which are closely associated with the pathogenesis of IR [1,26].Is acupuncture a suitable therapeutic approach for individualswith IR so as to prevent progression to IR-related diseases? Thisreview analyses various clinical studies on acupuncture andits effects on IR-related diseases. It also explores the effects ofacupuncture on the pathogenesis of IR based on analysis of arti-cles published in English on the PubMed database. The reviewalso scrutinizes practical aspects of acupuncture in treatmentof IR-related diseases such as acupoint selection, stimulationparameters, and safety issues. Furthermore, methodologicalagenda related to the field are speculated as well.

Clinical Studies of Acupuncture in IR-relatedDiseasesObesity

A randomized controlled trial (RCT) reported a negativeeffect for acupuncture on weight loss [27], in which the highand differential attrition between groups (30% in treatmentgroup and 60% in control group) made it difficult tointerpret the negative results, although point selection andstimulation parameters may explain the discrepancy in theconflicting results. A recent systematic review of 31 RCTsof acupuncture for obesity concluded that acupuncture is aneffective treatment for obesity [14]. Acupuncture significantlyreduces BW, compared to placebo or sham treatment,resulting in improved outcomes for obesity relative toconventional medications. Several lines of evidence suggest thatacupuncture at body points or/and ear points results in weightreduction, accompanied by diverse beneficial effects in obesity(Table 2) [14,15,28–35], such as suppression of appetite [15],

reduction in BW, body-mass index (BMI), waist circumference(WC), hip circumference (HC) [14,15,28–35], regulation offat metabolism (decreases in total cholesterol, triglyceride, low-density lipoprotein (LDL), lipoprotein A and apolipoproteinB levels) [30,34], increase in IgG, insulin, C-peptide levelsand decrease in glucose levels of obesity [31,35]. Moreover,the psychological status of obese patients is improved byacupuncture [15], even in a negative report on weight loss [27].However, such evidence is not totally convincing because of thepoor methodological quality of trials reviewed [14]. Therefore,well-planned, long-term studies are needed to investigate theeffect of acupuncture in the treatment of obesity.

Diabetes Mellitus

Studies on acupuncture in the field of diabetes were publishedin China since the early 1950s. These studies concluded thatacupuncture is effective against diabetes, and patients withT2DM appear to have a better response than those with type 1diabetes [16]. Patients with diabetes treated with acupunctureshowed improved clinical manifestations as well as reduction infasting blood sugar and improvement in oral glucose tolerancetest. Other studies indicated that acupuncture improved bothhyperglycemia and IR [36–38].

Acupuncture has been used also for diabetic neuropathy,gastroparesis and bladder neural dysfunction [39–41]. A singlecase report using magnets on the ear showed complete controlof blood glucose (BG) and diabetic retinopathy [42]. Despitethe above evidences, better designed RCTs that include largepopulation samples are required to draw definitive conclusionsregarding the potential treatment of diabetes mellitus withacupuncture.

Hypertension

Acupuncture is reported to change the levels of blood pressure(BP) modulators such as endothelin-1 [43], renin [44],aldosterone and angiotensin II [45] in hypertensive patients.Most importantly, the primary end-point such as systolicblood pressure (SBP) and diastolic blood pressure (DBP)

556 Liang and Koya Volume 12 No. 7 July 2010

DIABETES, OBESITY AND METABOLISM review articleTa

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Volume 12 No. 7 July 2010 doi:10.1111/j.1463-1326.2009.01192.x 557


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DIABETES, OBESITY AND METABOLISM review articlelevels were reduced after acupuncture [43–45,47,48]. However,high-quality RCTs showed conflicting results [46–48]. Thediscrepancy in the reported effects of acupuncture treatmentmay be related to the study designs. First, two positivetrials applied anti-hypertensive drugs with acupuncturetreatment [47,48], while another well-designed RCT usedfully individualized TCM acupuncture alone without anti-hypertensive medications, reporting no meaningful reductionin SBP or DBP relative to invasive sham acupuncture [46].Secondly, the patients in the positive study may be healthierwith lower baseline BP levels than those in the negativereport (131/81 mmHg in [47], 137/84 mmHg in [48] and150/93 mmHg in [46]). Finally, maybe most importantly, theuse of different sham acupuncture protocols in these studiesmay account for the diverse results [46–48]. A recent systematicreview including 11 RCTs without language limitationconcluded that the anti-hypertensive effect of acupuncture isinconclusive [49]. Considering the demonstrable physiologicaleffects of acupuncture, it seems a bit hasty to make definiteconclusions about the ineffectiveness of acupuncture onhypertension [50], and a more rigorous methodology iswarranted at this stage.

Polycystic Ovary Syndrome

Admittedly, there are no well-designed RCTs which haveevaluated the effect of acupuncture on PCOS. However, onestudy reported that low-frequency electroacupuncture (EA)increased ovulation (38%) in PCOS women, and significantlylowered BMI, waist-to-hip circumference ratio (WHR) andserum basal insulin concentration [51]. BMI is a major riskfactor for coronary heart disease (CHD) and T2DM inwomen with PCOS [52]. Another study reported that low-frequency EA induced ovulation in non-ovulatory women(9 with PCOS). In non-ovulatory women, high plasma β-endorphin levels and low hand skin temperature, representingincreased sympathetic activity, improved after EA, probablyreflecting inhibition of the sympathetic nervous system(SNS) [53]. Increased sympathetic activity in PCOS maybe linked to hyperandrogenism, hyperinsulinemia and/orhypertension [54]. In summary, clinical studies suggest thatlow-frequency EA improves endocrine, neuroendocrine andmetabolic disturbances in PCOS without any negative side-effects, while high-quality RCTs are required to verify theseresults.

Experimental EvidenceEmerging experimental evidence suggests that acupuncturehas multi-faceted effects on IR-related pathologies such asabnormal metabolism, inflammation, sympathetic activity anddefective insulin signalling pathway. The evidence may providea potential window to understand the effect of acupuncture inIR-related diseases from a mechanistic perspective.

Effects on Metabolic Pattern

Hypoglycaemic Effect. Acupuncture is reported to regulate BGlevel. EA is applied in most studies using detailed stimulation

parameters. Application of 15-Hz EA at certain abdominalacupoint such as Guanyuan (CV4) and back acupoints suchas Weiwanxiashu (EX-B3) induces sustained hypoglycaemiceffect in diabetic Psammomys compared with EA at non-specificpoints, and such effect was independent of weight loss [55].

In alloxan-induced diabetic rabbits, EX-B3 significantlylowered BG levels and inhibited the release of plasma pancreaticglucagon (PG), while no significant changes in BG and PG werefound when acupuncture was applied at Zusanli (ST 36) pointalone. Interestingly, BG and PG contents decreased more clearlywhen EA was employed at both EX-B3 and ST 36, suggestingthat ST 36 has a marked synergetic action with EX-B3 [56].The report provides proof for the reasonability of combinationof acupoints in acupuncture theory. Whether the combinationof acupoints may reflect point specificity, a stronger sensoryinput, or both, deserves further investigation.

In another study, EA (15 Hz, 10 mA) at Zhongwan(CV 12) for 30 min reduced BG in normal rats and ratmodels of T2DM [22]. The same EA at CV 12 for 90 minimproved hyperglycemia and glucose intolerance in T2DMGoto–Kakizaki rats [57]. EA at ST 36 reduced BG, increasedlactate metabolites and decreased lactate/glucose ratio. Theincreased lactate/glucose ratio suggests increased anaerobiccellular glucose metabolism [58]. EA applied at ear points andbody points reduces serum glucose levels probably by increasingserum insulin and C-peptide levels in obese women [35].

A number of studies suggested that the effect of EA on BGregulation could be insulin-dependent [22,35,57]. EA reducesBG in T2DM and normal rats, but not in T1DM, STZ-induceddiabetic rats and genetic biobreeding/Worcester (BB/W) rats.Furthermore, the hypoglycaemic action of EA disappeared inIR rats that did not release endogenous insulin [22]. In supportof this finding, EA in normal rats increased plasma insulin-likeimmunoreactivity [22]. The underlying mechanism seems tobe associated with endogenous opioids and insulin secretion.2-Hz EA at CV 12 stimulated the adrenal glands to induceβ-endorphin, which enhanced insulin secretion, resulting inreduction of plasma glucose levels [22]. The hypoglycaemiceffect of 2-Hz EA at ST 36 is also mediated by serotonin andendogenous opioid peptides through secretion of insulin [19].Interestingly, EA stimulation at CV 12 using a higher frequency(15 Hz) produced larger reductions in BG levels than lowfrequency (2 Hz) [59]. Other more recent studies demonstratedthat EA stimulation at 15 Hz elicits secretion of endogenousopioids from site(s) other than the adrenal glands [60].

On the other hand, studies on IR diabetic fat Psammomysobesus suggest that EA at CV 12 results in long-term non-insulin-dependent hypoglycaemic effects [55]. The combinedapplication of acupoints decreased insulin levels in DM andhypertension with hyperinsulinemia [61]. It seems that theeffects of acupuncture are closely associated with the state ofinsulin secretion. In different IR states, insulin sensitivity is theend target in any improvement of insulin action.

Improvement in Insulin Sensitivity. Low-frequency EA stim-ulates glucose transport in skeletal muscles independent ofinsulin and increases the insulin sensitivity of glucose transportin rats [20,62]. EA is reported to improve insulin sensitivity in



diabetic rats and IR animal model [20,55,57,63]. The improve-ment of insulin sensitivity may be due to the amelioratedresponsiveness to insulin via excitation of somatic afferentfibres by EA [64]. The decrease in free fatty acids (FFA) andrecovery of insulin signal proteins such as IRS1 and GLUT4may also explain the improvement in insulin sensitivity [63].The EA-induced improvement in insulin sensitivity in PCOSrats was also considered to be mediated by increased plasmalevels of insulin growth factor-1 (IGF-1) [21].

BW Loss and Reduction in Food Intake. Most studies concludedthat both body acupuncture and auricular acupuncture wereeffective in reducing BW in obese subjects [14,15,29–35].Whatis the mechanism of BW reduction? Experimental studiessuggest that this effect of acupuncture is related to thefrequency-dependent stimulation of the satiety centre in thecentral nervous system. Both low- and high-frequency EAsignificantly decreased food intake and BW, and upregulatedthe expressions of α-melanocyte-stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART)in the hypothalamic arcuate nucleus of obese rats [15,65].EA at 2 Hz was demonstrated to be more effective than100 Hz EA [65]. It is possible that the effects of 2 Hz EAin reducing appetite and BW are mediated at least in partby increased expression of α-MSH and reduced expression ofneuropeptide Y (NPY) in the hypothalamic arcuate nuclei [15].In support of this, needling on ST 36 resulted in decreased NPYlevels in both the arcuate nucleus and paraventricular nucleus ofthe hypothalamus in streptozotocin-induced diabetic rats [66].Moreover, it was reported that EA-induced BW reduction wasmainly due to a decrease in food intake rather than increase inenergy expenditure [15]. A reduction in the orexigenic peptidesghrelin and NPY may be involved in this process as well [67].

Regulation of Lipid Metabolism. Several studies reported thatacupuncture could rectify dysregulated lipid metabolism indifferent pathogenic conditions [15,34]. EA application inobese women decreases the level of serum total cholesterol,triglyceride and LDL cholesterol [34]. This hypolipidemiceffect is postulated to be related to increased serum levelsof β-endorphin. The hypolipidemic effect of EA also reducesmorbidity associated with obesity by mobilizing the energystores, resulting in weight reduction [34].

A recent report showed that 15 Hz (10 mA) EA at bilateralST 36 for 60 min lowered FFA levels and decreased IR [63].EA at Fenglong (ST 40) (dense–sparse waves, 3.85–18 Hz,0.05 mA, 20 min/session for 2 weeks) reduced cholesterollevel and regulated the expression levels of various genesin the livers of hypercholesterolemic mice [68,69], while EAat non-acupoint failed to produce the same effects. Globalgene expression profiling showed that EA at ST 40 notonly regulated the expression of genes directly involved incholesterol metabolism in the liver, but also significantlyaffected the expression of genes involved in signal transduction,transcription regulation, cell cycle, cell adhesion, immunityand stress [69]. Other studies suggested that the effect of EAon cholesterol concentrations may involve promoting lipidmetabolism and suppressing inflammation by modulating themessenger RNA (mRNA) expression of adiponectin receptor 2

(Adipo R2), Lysyl-tRNA synthetase (Krs) [23]. It was alsospeculated that stimulation of sensory receptors of the deepperoneal nerve at a specific point may be involved in thecholesterol-lowering action of acupuncture, because needling atspecific points resulted in loss of its hypocholesterolemic effect,when the specific point was blocked by injection of a largerdose of novocain or severing the deep peroneal nerve [70].

Acupuncture and SNS

Studies in IR models prior to the development of obesityand T2DM have shown that early IR is associated withincreased SNS activity [71]. In IR state, hyperinsulinemia isthe initiating factor that increases sympathetic neural activity.Progression of IR could lead to downregulation of adrenore-ceptors and/or reduced sensitivity, resulting in reduced sympa-thetic responsiveness. More recent evidence demonstrates thatstress-induced SNS overactivity upregulates NPY, an orexigenichormone, and its Y2 receptor, in visceral adipose tissue, whichis strongly linked to IR and T2DM. SNS overactivity specif-ically contributes to the development of abdominal obesity,metabolic syndrome and PCOS [71,72], because SNS activ-ity induces a proinflammatory state through IL-6 production,which in turn results in an acute-phase response.

There is a close link between nerve growth factor (NGF) andSNS in the pathogenesis of steroid-induced PCO rats [73].Repeated low-frequency EA inhibited ovarian sympatheticactivity by reducing the high ovarian concentrations of NGFand endothelin-1 [74], leading to increased ovarian blood flowin estradiol valerate-induced PCO [75]. Moreover, a recentstudy demonstrated that low-frequency EA downregulatedmRNA expression of markers of sympathetic nerve activity,such as NGF, NPY, and β(3)-adrenergic receptor, in adiposetissue of dihydrotestosterone-induced PCOS [76].

Low-frequency EA (1 Hz, 5 mA and 5 ms) at ST 36can suppress sympathetic nerve activity [77] and stimulateparasympathetic activity in restrained rats [78]. In support ofthis, a recent RCT study demonstrated that low-frequencyEA at abdomen and lower limbs suppressed high musclesympathetic activity in PCOS patients [24].

It is speculated that EA inhibits sympathetic activity byregulating the expression of nitric oxide synthase (NOS) inthe central nervous system [79–81]. In this regard, the anti-hypertensive effect of EA is primarily due to vasodilation ofthe mesenteric vessels caused by inhibition of sympatheticvasoconstrictor tone [82].

In contrast, EA at Hegu (LI 4) at low- and high-frequenciescould selectively activate sympathetic [83] and simultaneouslyinhibit gastric parasympathetic nerve activity [84]. Thesereports indicate that different acupoints have different effectson SNS. Thus, one must take the diverse actions of acupointsinto consideration in the treatment of SNS overactivity in IR-related diseases, which is consistent with the combination ruleof acupoints in TCM theory.

Acupuncture and Inflammation

Obesity, IR and T2DM are closely associated with chronic‘inflammation’ characterized by abnormal cytokine produc-tion, increased acute-phase reactants and other mediators,


DIABETES, OBESITY AND METABOLISM review articleand activation of a network of inflammatory signallingpathways [85]. The finding over a decade ago of overexpressionof tumour necrosis factor-alpha (TNF-α) in the adipose tissueof obese mice provided the first clear link between obesity, dia-betes and chronic inflammation [86]. In addition to TNF-α,overexpression of several other inflammatory mediators andcytokines in adipose and other tissues have also been describedin experimental mouse models of obesity and in humans [85].Inflammatory signals disrupt insulin action and mediate IR inobesity and T2DM [87].

Several studies have described the anti-inflammatory actionsof acupuncture. The initial studies showed that calcitoningene-related peptide (CGRP) mediates acupuncture-relatedregulation of acute, sub-acute and chronic inflammation,based on the vasodilative properties of this neuropeptide [88].Substance P should be considered to counteract the release ofCGRP from the nerve endings, whereas the balance betweenmast cell-derived proinflammatory TNF-α and T-cell-derivedanti-inflammatory IL-10 could contribute to the developmentof chronic inflammation [88]. More importantly, recent studiessuggest that EA restores the expression of a multitude of adiposetissue genes such as Leptin, interleukin-6 (IL-6), uncouplingprotein 2 (UCP2) and peroxisome proliferator-activated receptorgamma (PPAR-γ ), which are associated with IR, obesity andinflammation in PCOS rats [21].

The anti-inflammatory actions of EA may be mediated alsoby stimulation of the vagus nerve, because electric stimulationof the vagus nerve attenuate systemic inflammation [89],by decreasing the release of cytokines (TNF-α, IL-1β, IL-6and IL-18). In this regard, the neural–immune interaction,the ‘cholinergic anti-inflammatory pathway’ has muchshorter response time than the humoral anti-inflammatorypathways [90], which may explain the immediate anti-inflammatory effect of acupuncture.

A recent study demonstrated that the anti-inflammatoryaction of EA was frequency dependent. The suppressiveeffects of low-frequency EA on carrageenan-induced pawinflammation are mediated by sympathetic post-ganglionicneurons, while the suppressive effects of high-frequency EA aremediated by the sympatho-adrenal medullary axis [91].

Effect on Leptin

Obesity is associated with increased levels of leptin and lowleptin sensitivity [92]. Leptin affects different key enzymesinvolved in lipogenesis, lipolysis and fatty acid oxidation [93].Consistent with the clinical effect of EA, EA is also reported toreduce serum leptin levels in parallel with its weight losseffect [94]. You et al. found that 100 Hz EA produced asignificant decrease in plasma leptin in obese rats [95]. WhereasKim et al. [96] applied 100 Hz EA to ad libitum-fed normal ratsand reported a significant increase in plasma leptin levels. Theseresults suggest that the effect of EA in modulating plasma leptinlevel depends on the energy balance state of the animal. Onthe other hand, the sensitivity to leptin should be regardedas a more important factor in determining the developmentof obesity than plasma level of leptin [95,96]. In other words,resistance to leptin is more important in the development ofobesity than inadequate supply of leptin. Further studies are

needed to characterize the effect of EA on the sensitivity ofleptin.

Effect on Insulin Signal

IR is characterized by marked reduction in insulin-stimulatedphosphatidylinositol-3 kinase (PI3K)-mediated activation ofAkt. EA was reported to modulate the expression of genesinvolved in signal transduction, cell-cycle, metabolism, stressresponse and DNA repair [23,97]. Low-intensity electriccurrent (or mild electrical stimulation; MES) influences signaltransduction and activates PI3K/Akt pathway in diabetes mousemodels, improving insulin sensitivity and fat metabolism [25].15 Hz EA on the bilateral ST 36 reversed the low expressionof insulin signal proteins (IRS1, GLUT4) in insulin resistantsteroid-background rats [63]. Further studies are required toinvestigate how EA affects the change in insulin signal.

Points SelectionIR is generally characterized by clinical symptoms such asobesity and/or excess appetite, which has been conceptualizedin a variety of ways, such as heat in the stomach andintestine [98], Qi deficiency in the spleen and stomach [98],Qi and yin deficiency [98], and yin and yang deficiency [61].Based on these concepts about the causes of obesity, T2DM andhypertension, various acupoints are targeted in the treatmentof IR, such as points of the stomach meridian of foot yangming(ST) (ST 36, ST 40), spleen meridian of foot taiyin (SP) (SP 6,SP 3), bladder meridian of foot taiyang (BL) (BL 23, BL 13),large intestine meridian of hand yangming (LI) (LI 11, LI 4),conception vessel (CV) (CV 6, CV 4) and liver meridian of footjueyin (LR) (LR 3). The frequency of acupoints used in obesity,diabetes and hypertension is shown in figures 1–3. The mostcommon acupoints used for effective acupuncture in obesity,diabetes and hypertension are ST 36, SP 6, LI 11 and BL 23,according to the results displayed in figures 1–3. However,the most frequently used acupoints for these three conditionsin clinical practice are different because there are differentsyndromes (subtypes) of the diseases due to diverse etiologies.

In IR-related experimental research, one point (bilateralwith two needles) is usually applied to study the effect ofacupuncture, which is easier to analyse. While in clinicalresearch, at least 2 points or more are used to relieve clinicalsymptoms. Further studies are needed to determine specificpoint(s) that can produce effective treatment of IR and relateddiseases and the best acupoints formula that can produce themost beneficial effects.

Stimulation ParametersInstead of manual acupuncture, EA was used in manystudies on IR-related diseases, because the parameters of EAcan be precisely characterized and therefore the results arereproducible, whereas the outcome of manual acupuncture ismainly dependent on the acupuncturist and is therefore notnecessarily reproducible. In addition, laser acupuncture withprecise intensity parameters has also been applied clinically inIR-related diseases such as hypertension and obesity [99,100].



Figure 1. Frequency of acupoints used for obesity in the English literature retrieved through search of the PubMed database spanning from 1 January1979 to 30 September 2009, using the following key words: ‘acupuncture’, ‘obesity’ and ‘human’. ST 36: Zusanli; ST 40: Fenglong; ST 25: Tianshu; ST 44:Neiting; ST 37: Shangjuxu; ST 28: Shuidao; ST 34: Liangqiu; SP 6: Sanyinjiao; SP 9: Yinlingquan; SP 3: Taibai; LI 11: Quchi; LI 4: Hegu; CV 6: Qihai; CV 12Zhongwan; CV 4: Guanyuan; CV 9: Shuifen; CV 10: Xiawan; CV 17: Shanzhong; BL 20: Pishu; BL 23: Shenshu; BL 18: Ganshu; BL 15: Xinshu; BL 17:Geshu; LR 3: Taichong; TE 6: Zhigou; GV 20: Baihui; PC6: Neiguan; HT 7: Shenmen; GB 34: Yanglingquan. ST: stomach meridian of foot yangming;SP: spleen meridian of foot taiyin; LI: large intestine meridian of hand yangming; BL: bladder meridian of foot taiyang; CV: conception vessel; LR: livermeridian of foot jueyin; TE: triple energizer meridian of hand shaoyang; GV: governor vessel; GB: gallbladder meridian of foot shaoyang.

Low frequency of 2 Hz [19,21,24,30,31,34,35,51,57,58] and15 Hz [20,22,55] and high frequency of 100 Hz [95] are used,with the former being more common [58], because EAinduces frequency-dependent release of neuropeptides [39].Interestingly, thyrotropin-releasing hormone (TRH) can bereleased by electric stimulation at a frequency of 0.5 and3 Hz [101]. Peripheral stimulation at 2 Hz produces a signif-icant increase in enkephalin-like immunoreactivity but notin dynorphin immunoreactivity, whereas 100 Hz increasesdynorphin immunoreactivity but not enkephalin immunore-activity [102]. In a follow-up double-blind study, the resultsobtained in rats were fully confirmed in humans [103]. More

importantly, low-frequency EA is used more frequently to treatIR with beneficial results [21,24,29–35,51,63], including sup-pression of inflammation, attenuation of sympathetic nerveactivity and enhancement of insulin signalling.

In addition, the different response to acupuncture inpreviously reported studies may be explained by the use ofdifferent stimulation parameters such as intensity, duration ofa single session and entire treatment, number of sessionsand number of needles. Except for C-type fibres, EA atdifferent intensities can activate A-beta and A-delta typefibres [104], while manual acupuncture activates all typesof nerve fibres, particularly C-type afferents. With regard to


DIABETES, OBESITY AND METABOLISM review article

Figure 2. Frequency of acupoints used for diabetes in the English literature retrieved through search of the PubMed database spanning from 1 January1979 to 30 September 2009, using the following key words: ‘acupuncture’, ‘diabetes’ and ‘human’. ST 36: Zusanli; CV 6: Qihai; CV 4: Guanyuan; CV 12Zhongwan; BL 20: Pishu; BL 23: Shenshu; BL 13: Feishu; LU10: Yuji; LI 11: Quchi; GV 4: Mingmen. LU: lung meridian of hand taiyin.

Figure 3. Frequency of acupoints used for hypertension in the English literature retrieved through search of the PubMed database spanning from1 January 1979 to 30 September 2009, using the following key words: ‘acupuncture’, ‘hypertension’ and ‘human’. PC 6: Neiguan; LR 3: Taichong; ST 36:Zusanli; ST 40: Fenglong; LI 11: Quchi; LI 4: Hegu; GB 20: Fengchi; SP 6: Sanyinjiao; SP 3: Taibai; BL 23: Shenshu; KI 1: Yongquan; CV 12 Zhongwan.PC: pericardium meridian of hand jueyin; KI: kidney meridian of foot shaoyin.

IR-related diseases, the duration for a single session rangesfrom 5 to 30 min in animal studies (except the study ofLin et al. [63] with 60-min duration to test insulin tolerancetest, Ishizaki et al. [57] with 90-min duration to test glucosetolerance test) [19–22,63,64,66,74–76] and 30–60 min forhuman treatment (Table 2) [24,29–48,51]. The number ofneedles used in acupuncture ranges from 1 to 18 (Table 2).Determination of the ideal stimulation parameters to be usedin acupuncture for IR-related diseases remains a challenge.

Safety Issues of Acupuncture

Compared with conventional treatment, acupuncture carriesseveral potential advantages, such as low cost, relatively fewcomplications and possibility of a personalized treatment.Complications of acupuncture can arise from inadequate ster-ilization of needles and improper delivery of treatment, whichcan cause local pain, inflammation or infection [105]. Nev-ertheless, acupuncture is a safe intervention in the hands of



competent practitioners [105,106]. Yamashita et al. prospec-tively evaluated 55,291 acupuncture treatments administeredby acupuncturists with medical training and documented only64 adverse events (0.12%). All of these adverse events wereminor, the most common being bruising, dizziness, perspira-tion, discomfort, and dermatitis [107].

More serious complications such as abscess formation, bac-teremia, cardiac tamponade, spinal lesions and pneumothoraxhave been reported in the literature [108–111], but these arelimited to elderly immunocompromised subjects and thosewith poorly controlled diabetes mellitus [108–111]. In fact,none of these complications were observed by Yamashita et al.In a sample of 1332 practitioners in Norway (1135 physiciansand 197 acupuncturists), the average rate of complications wasonly 0.21 complication per year for every year of (full-time)acupuncture practice [112].

The adverse effects of acupuncture may be avoided andrectified by using the procedure properly. In addition to betterknowledge of the anatomy, appropriate antiseptic practice bypractitioners will reduce many serious complications associatedwith acupuncture. Skilled techniques in manipulating needlesare required to avoid improper treatment. It is suggested thatneedle acupuncture should be avoided in elderly patients withdiabetes. For such individuals, auricular points’ pressing ornon-invasive laser acupuncture may be an alternative choice.

Methodological Agenda and PerspectivesUse of Appropriate Control in Research Studies

What constitutes a valid acupuncture treatment and anappropriate control is a question of much debate inthe field [113]. Methodological problems in IR-relatedacupuncture trials include difficulties in the blinding process,finding an appropriate placebo or control mechanism, andpatient expectations of the efficacy of acupuncture couldinfluence perceived or actual outcome [114].

The most commonly used control (sham) proceduresinclude non-penetrating sham needle at the same acu-point [48], identical needling at non-acupoints [47] or superfi-cial needling at non-acupoints [41,46]. Identical or superficialstimulation at non-acupoints may be challenging. When a non-acupoint (‘sham’) is used, it is possible for the treatment to beblinded by all except the acupuncturist, whereas the ‘intentionalenvironment’ created by acupuncturists has been identified asa component of acupuncture therapy [115]. This may explainwhy up to 50% of individuals treated by such ‘sham’ processesshow some physiological effect, especially in studies of paininhibition [116]. More importantly, control procedures thatare meant to be inert can in fact activate slow conductingunmyelinated (C) tactile afferents and consequently result inalleviation of the affective component of pain [117].

In comparison, the ‘placebo’ needle seems promising, whichis a non-penetrating, blunt tip needle held in place by a bandaidand plastic ring [118,119]. This placebo needle was perceived byvolunteers as similar to the true penetrating acupuncture needle(also held in place via bandaid and ring). Most importantly,the placebo was significantly less effective in pain-relief and

demonstrated to be an effective masking device for blinding inRCTs of acupuncture [119–121].

Laser acupuncture is currently being used in double-blindstudies [122–124]. In this technique, a laser needle is used,which is rather fixed onto the skin rather than pricked intothe skin, to deliver the laser power to the acupoints; theprecise power intensity can determined by using the intensitycurve [122]. In this way, the patient can hardly feel thestimulation and the operator may also be unaware of whetherthe laser needle system is active, and therefore true double-blind studies in acupuncture research can be performed. Inthis regard, previous studies indicated that laser acupunctureapplied to the placebo points did not produce marked cerebralchanges compared with that applied to the acupoints [123,124].

Mapping of Acupoints

It has been reported that acupuncturists differed by up to 25%in the acupoints they used, raising doubts and uncertaintyregarding the efficacy and safety of acupuncture treatment, aswell as causing difficulties in the fields of acupuncture researchand education [125]. In this regard, the ‘WHO StandardAcupuncture Point Locations in the Western Pacific Region(WHO Standard)’ released earlier last year set standardized86 points of the initial 92/361 controversial acupoints [126].Such standardization should enhance the reproducibility andvalidity of acupuncture studies, which in turn will lead toa better understanding of the effects of acupuncture andeventually optimize its clinical efficacy for a range of diseasesand syndromes including IR-related diseases.

Animal research studies are of great importance to identifythe underlying mechanism of acupuncture in treatment ofIR-related diseases (figure 4). Originating in China centuriesago, acupoints were described in human body rather than inanimals. Animal research of acupuncture was initiated in Chinain the early 1950s and various mammals such as monkey, horse,dog, mouse, rabbit and rat have been applied in acupuncturestudies. Although there have been standardized acupoints inhuman body [125], no such acupoints have been defined inanimals. Most animal studies applied acupoints correspondinganatomically to their original locations in humans. A recentreport on transpositional acupoint location in mice and ratsmay be supplied as a reference [127].

Mapping the precise location of needles at specific acupoints,including insertion points, depth, direction and angle willdefinitely have impact on the effect of acupuncture. Furtherstudies are needed to clearly map the site and depth of needleprick/insertion at acupoints.

Standardized Treatment

Traditional medicine in East Asia has been divided byregional groups, such as TCM, Kampo medicine (Japan),TKM (traditional Korean medicine) [126]. Correspondingly,acupuncture treatment is divided into TCM style, Japanesestyle and Korean style based on different traditions andbackgrounds. Therefore, to accurately assess any potentialbenefits of acupuncture treatment of IR-related diseases, thestudy of acupuncture must be effectively integrated with the


DIABETES, OBESITY AND METABOLISM review article

Figure 4. Proposed mechanism of the effect of acupuncture on insulin sensitivity. (i) Acupuncture reduces BW by reducing food intake and inducinglipid metabolism. (ii) Acupuncture lowers blood glucose level by inducing insulin secretion. (iii) Acupuncture ameliorates inflammation by depressinghyperactivity of SNS and regulating vagus nerve activity. (iv) Acupuncture improves insulin signal pathway by activating phosphorylation of PI3K/Aktand inducing expression of IRS1/GLUT4 in insulin-sensitive organs.

science of evaluation. Based on principles used by practitioners,it is essential to develop standard programmes, for example,criteria for selecting and combining acupoints and spacing oftreatments.

Long-term Studies

As a chronic condition, IR is probably to require longerperiods of acupuncture treatment to prevent progressionto more serious disease because it may take years for IRto progress to T2DM [1], or from PCOS to cardiovasculardiseases [128]. However, most of the studies to date havebeen of short duration, ranging from 20 days [30,31,34] to16 weeks (Table 2) (only one study lasting for 8–9 monthswith 10–14 treatments [51]). Long-term studies are needed todefine the accurate effect of acupuncture in IR-related diseases.Acupuncture may also be considered during the maintenancephase of weight loss programmes to prevent relapse. Inaddition, data at each phase of long-term treatment wouldprovide a more thorough evaluation of this complementarytreatment.

SummaryAll clinical studies on acupuncture for treatment of IR-relateddiseases are underpowered due to small sample size and limited

data. Furthermore, most of them are uncontrolled clinical trials.Among the RCTs with positive results, the effects are modest,and interpretation of these results is limited by short duration,inadequate controls and non-standard treatment. Therefore,RCT studies are required to verify these results. RCT designsare urgently needed to overcome a number of challenges suchas effective evaluation of acupuncture while meeting researchstandards required for evidence-based medicine.

Experimental studies have revealed the mechanismsresponsible for the beneficial effects of acupuncture. Inaddition, the effects of acupuncture on psychological statuscaused by IR-related diseases are beneficial [129]. Thesestudies demonstrate that low-frequency EA affects endocrine,neuroendocrine and metabolic disturbances in obesity,diabetes, hypertension and PCOS with few negative side-effects.Indeed, EA can be a suitable complement to pharmacologicalintervention in IR. In light of the evidence, we believeacupuncture is a potentially useful complementary therapeuticstrategy in IR management that deserves more careful analysis.

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