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Effects of acupuncture on the insulin signaling pathway and mitochondrial AMPK pathway in an animal model of type 2 diabetes mellitus: systematic evaluation and meta-analysis

Diabetology & Metabolic Syndrome volume 17, Article number: 146 (2025) Cite this article

Abstract

Background

Previous studies of acupuncture for type 2 diabetes mellitus (T2DM) have focused on lowering blood glucose and improving symptoms; however, the mechanisms underlying these effects have not been systematically reviewed. Acupuncture can improve impaired glucose-lipid metabolism and correct insulin resistance (IR) by modulating relevant pathway cytokines, which are both key process in T2DM pathogenesis.

Objectives

The aim of this study was to quantitatively assess the efficacy of acupuncture in an animal model of T2DM.

Methods

Three researchers identified animal studies of acupuncture intervention in T2DM by searching nine databases, including PubMed, Scopus, Embase, the Cochrane Library, Web of Science, Ovide Medline, BIOSIS Previews , Wan Fang, CNKI, and VIP. Literature that met the inclusion criteria was screened, required data were extracted, and meta-analysis was performed using RevMan 5.4 and Stata 17.0.

Results

A total of 31 studies with 619 animals were included—309 in the acupuncture group and 310 in the model group—all of which were male rodents. The mean quality score of the studies was 3.7, which indicated low quality. Meta-analysis showed that first acupuncture led to a significant reduction in body weight gain and hematological factors, and reduced food intake and water intake in T2DM animals. Second acupuncture significantly reduced blood glucose and serum insulin, increased insulin sensitivity, and decreased IR index in T2DM animals. Finally acupuncture had the following beneficial effects on the insulin signaling pathway and mitochondrial AMPK pathway: (1) insulin signaling pathway: Acupuncture can balance the phosphorylation levels of IRS-1 tyrosine 895 and IRS-1 serine/threonine 307 and promote the expression of all factors of the insulin signaling pathway, namely, IRS-1 mRNA, p-IRS-1, PI3K p85, PI3K mRNA, AKT, p-AKT, GLUT 4, and GLUT 4 mRNA—promoting glucose uptake, alleviating IR, and ameliorating impaired glucose metabolism. (2) Mitochondrial AMPK pathway: acupuncture significantly promoted AMPK, AMPK mRNA, p-AMPK, SIRT1, SIRT1 mRNA, PGC-1α, PGC-1α mRNA and NRF1, improved mitochondrial dysfunction, enhanced glucose metabolism, and alleviated T2DM symptoms.

Conclusion

Acupuncture can improve glucose-lipid metabolism, enhance insulin sensitivity, and correct IR, likely by promoting the expression of signaling factors in the insulin and mitochondrial AMPK pathways. These findings offer potential explanations for the mechanism of action and clinical effects of acupuncture in the treatment of T2DM.

Introduction

Type 2 diabetes mellitus (T2DM) is one of the most serious and fastest-growing diseases of the 21st century, with persistent chronic hyperglycaemia and severe complications leading to a reduced quality of life. The World Health Organization predicts that there will be 439 million people with diabetes globally in 2030, representing a huge burden on the world economy [68].The pathological mechanism of T2DM is a relative impairment of insulin secretion, or insulin resistance (IR) , resulting in increased blood glucose [68]. The insulin signaling pathway plays an important role in maintaining glucose metabolic homeostasis in T2DM. And the insulin signaling pathway is activated by insulin binding to the insulin receptor, resulting in the inhibition of gluconeogenesis, promotion of glucose uptake, and completion of the glucose metabolic process [29]. In addition, mitochondrial dysfunction is closely related to the occurrence of T2DM through affecting the insulin signaling pathway and reducing insulin secretion from pancreatic β-cells [43]. Currently, T2DM is treated with medication and lifestyle interventions, with medication having significant side effects and lifestyle interventions being difficult to adhere to [3]. Therefore, alternative treatments without such side effects are necessary.

Acupuncture is an ancient Chinese therapeutic method that has positive effects on T2DM by lowering blood glucose, improving IR, and inhibiting or delaying complications [12]. The World Health Organization has acknowledged acupuncture as an indispensable modality in the treatment of diabetes [2]. In 2015, Meijun Liu [38]—through a study in which 640 patients were treated—found that acupuncture could significantly reduce blood glucose and body fat in patients with T2DM, with an overall effectiveness rate as high as 86.09%. Furthermore, a large number of studies [10, 17, 18] have proved that acupuncture can alleviate or even prevent complications such as peripheral neuropathy, retinopathy, and diabetic nephropathy in T2DM. Meanwhile, animal studies have also shown that acupuncture not only induces a significant immediate reduction in blood glucose [5], but also produces a sustained hypoglycemic effect and does not lead to side effects such as hypoinsulinemia and weight loss [47]. Electroacupuncture can repair pancreatic β-cell damage, improve IR, increase insulin signaling, balance glucose homeostasis, and lower blood glucose by regulating relevant nerve signaling pathways [58]. In addition, acupuncture can alleviate oxidative stress, ameliorate IR, repair T2DM mitochondrial morphology and functional damage, and promote glucose metabolism by reducing ROS production and increasing ATP generation [32, 65]).

The therapeutic mechanisms of acupuncture are complex; in T2DM, acupuncture may be involved in slowing down the progression of disease by modulating the relevant pathways involved in its pathogenesis. When T2DM occurs, the body’s response to insulin is reduced and IR occurs in vivo. IR causes impairments in insulin signaling and mitochondrial pathways, leading to reduced glucose uptake in skeletal muscle and adipose tissue, decreased hepatic glycogen synthesis, and ultimately to glucose accumulation that damages the corresponding target organs and tissues [37]. The insulin signaling pathway is a central pathway in the regulation of glucose metabolism [29]. Under physiological conditions, insulin activates IRS-1 in target cells. IRS-1 tyrosine phosphorylates and binds to the PI3K p85 site to activate PI3K,this further activates AKT, which regulates the translocation of GLUT4 to the plasma membrane, and GLUT4 regulates glucose metabolism [37]. When insulin sensitivity is reduced, the insulin signaling pathway is disrupted, which ultimately leads to the development of T2DM. Mitochondrial dysfunction, which is closely related to the occurrence of T2DM, can be ameliorated by regulating the mitochondrial AMPK pathway, which increases the expression of GLUT4, improves insulin signaling, and stimulates the pancreatic β-cells to secrete insulin [46].

Acupuncture can improve T2DM by modulating the insulin signaling and mitochondrial AMPK pathways [57], however, its specific effects have not been systematically analyzed. In this review, we quantitatively analyze the effects of acupuncture on insulin signaling pathway factors and mitochondrial AMPK pathway factors. We do so by reviewing the effects of acupuncture on T2DM in animal models of T2DM to provide a scientific basis for future clinical diagnosis and treatment.

Materials and methods

Database search

In this systematic review, we followed the latest guidelines published by PRISMA 2020 [42]. Two authors (Luo F and Li ZX) independently searched PubMed, Scopus, Embase, Cochrane Library, Web of Science, Ovide Medline, BIOSIS Previews , Wan Fang, CNKI, and VIP databases. The search was completed in October 2023, no time restrictions on searching. Using Scopus as an example, the specific search formula was: ((TITLE-ABS-KEY(acupuncture) OR TITLE-ABS-KEY(*acupuncture) OR TITLE-ABS-KEY(moxibustion) OR TITLE-ABS-KEY(moxabastion) OR TITLE-ABS-KEY(pharmopuncture) OR TITLE-ABS-KEY(electroacupuncture) OR TITLE-ABS-KEY(laser acupuncture) OR TITLE-ABS-KEY(needl* therapy) OR TITLE-ABS-KEY(needl*treat*))) AND ((TITLE-ABS-KEY("Type 2 Diabetes Mellitus") OR TITLE-ABS-KEY("Maturity Onset Diabetes Mellitus") OR TITLE-ABS-KEY("Diabetes, Maturity-Onset") OR TITLE-ABS-KEY("Diabetes Mellitus, Type II") OR TITLE-ABS-KEY(t2dm) OR TITLE-ABS-KEY("Non-Insulin-Dependent Diabetes Mellitus") OR TITLE-ABS-KEY("Noninsulin Dependent Diabetes Mellitus") OR TITLE-ABS-KEY("Maturity-Onset Diabetes Mellitus") OR TITLE-ABS-KEY("Diabetes Mellitus, Noninsulin"))) AND ((TITLE-ABS-KEY("animal model") OR TITLE-ABS-KEY(rat*) OR TITLE-ABS-KEY(mouse) OR TITLE-ABS-KEY(mice) OR TITLE-ABS-KEY(dog*) OR TITLE-ABS-KEY(monkey*) OR TITLE-ABS-KEY(pig*) OR TITLE-ABS-KEY(rabbit*) OR TITLE-ABS-KEY(cat*))).

Inclusion and exclusion criteria

In this study, we designed the following inclusion and exclusion benchmarks that were fully compliant with the Cochrane Library’s PICOS (participant type, intervention type, comparison type, outcome type, study type) principles:

Participant type (P): All animal studies on T2DM were considered, irrespective of species, sex, age in months or model method, site of sampling, criteria for modeling success (fasting blood glucose ≥ 7.0 mmol/ml, postprandial glucose ≥ 11.1 mmol/ml, or ≥ 11.1 mmol/L after two hours of the oral glucose tolerance test (OGTT) [8], provided that measurements were made of insulin signaling pathway factors (the main purpose of which is to regulate the insulin signaling pathway) and mitochondrial AMPK signaling pathway factors. Non-animal type 2 diabetes studies were excluded.

Intervention type (I): The intervention group was treated with acupuncture for T2DM, and there were no restrictions on the method of intervention, duration of intervention, duration of intervention sessions, or site of needling. If there were multiple acupuncture groups, choose the one with a significant effect size. Studies in which non-acupuncture interventions or acupuncture was not the primary intervention were excluded.

Comparison type (C): The model group was modeled only, without any treatment.

Outcome type (O): (1) Primary outcome markers: blood glucose indicators (including fasting blood glucose (FBG), postprandial blood glucose (PBG), and area of decrease in oral glucose tolerance (OGTT-AUG)); insulin indicators (including serum insulin (INS), insulin sensitivity index (ISI), and index of insulin resistance (HOMA-IR)); and factors of the insulin signaling pathway (IRS-1, P-IRS-1, IRS-1 mRNA, IRS-2, GLUT 4, GLUT 4 mRNA, PI3K, PI3K mRNA, AKT, p-AKT); and cytokines of the AMPK pathway (including AMPK, P-AMPK, SIRT1, PGC-1α, NRF1, TFAM); and (2) secondary outcome indices: weight, water intake, urinary output, food intake, urine output, food intake; lipid factors (including total cholesterol (TC), triglyceride (TG), LOW-density lipoprotein cholesterol (LDL-C), High-density lipoprotein (HDL), free fatty acid (FFA), very low-density lipoprotein (vLDL), High-density lipoprotein cholesterol (HDL-C)). There was no restriction on the site of testing.

Study type (S): Randomized controlled trials of all acupuncture interventions in T2DM animal trials. Clinical studies, systematic evaluations, conference reports, and scientific and technical results were excluded. No restriction on country and language to ensure comprehensiveness of the study.

Data extraction

Two authors (Luo F and Feng JJ) extracted data from studies that met the inclusion criteria. The extracted data were title, first author’s name, date of publication, animal species, animal sex, number of animals in each group, modelling method, acupoint selection, intervention method, duration of intervention, duration of the intervention session, tissue harvested, and outcome indicators. When the included literature did not have specific data, or the data were only presented in graphs, an attempt was made to contact the first author by email to obtain the raw data. If the authors did not respond, then the values in the graphs were extracted using the Engauge Digitizer graphical number converter software.

Quality assessment

Two researchers (Luo F and Chen HH) assessed the quality of the 31 included studies with an evaluation scale based on the SYRCLE’s risk of bias tool [20]. It is the only tool to evaluate the intrinsic authenticity of animal experiments at present. The tool contains 10 entries and 22 sub-items. The tool addresses the following types of biases: random sequence generation, baseline characteristics, allocation concealment, random housing, blinding, random outcome assessment, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias [35]. The evaluation results of 10 entries in the evaluation tool are ultimately "yes", "no" and "uncertainty", where “Yes” indicates low risk of bias,“no” indicates high risk of bias,and “unclear” indicates an unclear risk of bias. If one of the relevant signaling questions is answered with “no,” this indicates high risk of bias for that specific entry [20]. A third party was sought for decision harmonisation in case of inconsistent results between researchers.

Statistical analysis

In this systematic evaluation, meta-analysis was performed using RevMan 5.4 and Stata 17.0. All data were continuous variables and standard deviation ± mean (X ± SD) was used as an indicator of effect size, and the confidence interval (CI) of all the test results was 95%, when P < 0.05 was considered statistically significant. There were differences in parameters such as body weight and water intake between mice and rats, and in blood glucose, lipids, and insulin between genetic and non-genetic animal models; therefore, all subgroup analyses were performed to avoid excessive heterogeneity. Fixed-effects models were used when the included studies had P > 0.1 and I2 ≤ 50%; when P < 0.1 or I2 > 50%, large heterogeneity was considered, and the cause of heterogeneity was explored by subgroup analysis and sensitivity analysis. After analysis, random-effects model (REM) was used. For sensitivity analysis, RevMan was first used to exclude data one by one to find studies with excessive risk of bias; if the difference in I2 was large after excluding a study, the cause of excessive heterogeneity for that study was discussed individually. If there was no change in I2, then Stata was used to conduct a sensitivity analysis. Sensitivity analysis was conducted to assess the stability of the results. In addition, we explored whether other factors could influence the mechanism of effect of acupuncture, and we also performed subgroup analyses for some of the pathway factors (IRS-1 mRNA, PI3K p85) depending on the site of detection—a variable that can easily be overlooked. The results of subgroup analysis were considered statistically different when P < 0.05. Finally, we performed Begg and Egger tests using Stata to detect the presence of publication bias in this study (sample size n > 10).

Results

Literature screening results

A total of 546 articles in English and 661 articles in Chinese were found—a total of 1207 articles. After Noteexpress 3.2.0 checking, 472 duplicates were excluded, resulting in 735 remaining studies. In the first stage of systematic screening by reading the titles and abstracts, 596 papers were excluded, and the reasons for exclusion were as follows: systematic evaluations or reviews, clinical studies, not related to T2DM disease, acupuncture combined with or without acupuncture therapy, conference articles, case studies, scientific and technological results, unclear diagnosis of T2DM, and no blood glucose data. After conducting a comprehensive systematic review in the second phase, 79 studies were excluded based on reasons including unclear or unusable data, duplication of publication, and the research factors not being related to insulin pathway factors and AMPK pathway factors. We further excluded 29 articles with data unrelated to the outcome indicators, and finally included 27 Chinese studies and 4 English studies. The detailed screening procedure is shown in Fig. 1.

Fig. 1
figure 1

Flow diagram of study selection process

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Quality of the literature

Details of the literature quality are documented in Table 1. The quality assessment scores of the 31 studies included in the analysis ranged from 2 to 6. Of these, 8 studies [11, 13, 14, 23, 24, 40, 52, 57, 60] received the maximum score of 6, while 14 studies [7, 14,15,16, 30, 31, 34, 36, 48, 49, 55, 67, 69, 70, ] scored 5, 7 studies [1, 4, 15, 41, 50, 61, 63] scored 4, and 2 studies [21, 27] received a score of 2. The quality of the studies was assessed based on the rigor of their methodology. Among the studies, 12 studies [4, 7, 11, 14, 15, 23, 24, 40, 52, 57, 60, 69] used a random number table method for grouping T2DM animal models, 15 studies [1, 13, 16, 21, 27, 30, 34, 36, 41, 48,49,50, 55, 62, 63, ] employed random methods, and 4 [22, 31, 67, 70] studies did not specify any grouping method. 25 studies clearly described the baseline characteristics (including animal species, gender, age, weight, and blood glucose levels) of both the experimental and control groups, while 6 studies [1, 4, 15, 21, 27, 69] failed to report these details, resulting in potential risks of bias. Notably, none studies reported the methods of allocation concealment, resulting in an “unclear risk” of bias. Additionally, clear information on whether the experimenters and researchers were blinded, or whether the animals were randomly assigned to different groups for outcome assessment, was not provided. None of the studies employed blinding for the researchers regarding the intervention. Six studies did not report complete experimental results, and the completeness of the results in one study was unclear (which could imply selective reporting of results), while the remaining studies reported all the experimental results.

Table 1 Risk of Bias assessment based on the SYRCLE Tool
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Basic characteristics of the literature

The animals used in the T2DM experiment were SD rats, Wistar rats, C57 BL/6 mice, db/db mice, db/m mice, ZDF rats, ZL rats, and OLEFT rats; all rats were male. The modalities of modeling were broadly as follows: non-genetic model animals fed with a high-sugar and high-fat diet combined with intraperitoneal injection of a small dose of streptozotocin (STZ), genetic model animal fed with a high-sugar and high-fat chow diet, and a small-dose intraperitoneal injection of STZ alone. Modalities of acupuncture interventions were as follows: electroacupuncture, acupuncture alone. The following acupuncture points were selected (≥10 times): ST36 (30 times), SP6 (20 times), EX-B3 (15 times), BL20 (14 times). Sites from which tissue extraction was performed were as follows: skeletal muscles (gastrocnemius, quadriceps femoris, biceps femoris), liver, brain tissue (hypothalamus, hippocampal tissue), pancreas, muscle tissue, and adipose tissue. Details are shown in Table 2.

Table 2 Study characteristics
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Meta-analysis results

Symptom and blood lipid

As shown by Fig. 2. A total of 10 articles [16, 27, 30, 31, 34, 36, 49, 50, 55, 60] were included in the literature for the study. However, because of the different body weight changes in mice and rats, subgroup analyses were performed according to the categories of mice and rats. Data on body weight changes in rats and mice indicated that acupuncture effectively reduced weight or decreased body weight gain in the T2DM animal model compared with the model group. A total of three studies [31, 55, 60] were included for changes in water intake and food intake, two mice data and one rat data, and it was found that acupuncture significantly reduced food intake (P < 0.01) and water intake of the T2DM animal model compared with the model group, but the results of acupuncture on changes in water intake of mice were not statistically significant (P = 0.06 ), and the possible reason was considered to be inaccurate measurements by the researchers.

Fig. 2
figure 2

Forest plot of changes in body weight, water intake and food intake before and after the intervention in acupuncture and model groups

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We included nine studies [4, 13, 14, 16, 23, 30, 31, 36, 49] that investigated blood lipid content. The data analyzed by the analysis of data (TC, TG, LDL-C, vLDL, FFA), we found that acupuncture reduced blood lipids in the T2DM animal model compared with the model group (Fig. 3). The data of TC of T2DM gene rats show significant heterogeneity (I2=81%), and stability of the results was observed after employing the single-row method. TG of T2DM gene rats data using the single-row method found that the I2=0% after exclusion [31], it might be an abnormal assay process.

Fig. 3
figure 3

Forest plot of blood lipid levels. TC, TG, LDL-C, vLDL, HDL-C, FFA in acupuncture and model groups

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Glucose and insulin

As shown in Fig. 4, One study [55] was excluded due to excessively low blood glucose levels (FBG <7.1 mmol/L). We included three studies [7, 55, 63] for which post-intervention glycemic data showed a significant decrease in glycaemia in the acupuncture group in the animal model of T2DM compared with that in the model group. Analysis of 24 studies [1, 4, 7, 11, 13,14,15,16, 21, 23, 24, 27, 30, 31, 34, 36, 49, 50, 52, 60, 63, 67, 69, 70] reporting the change in FBG before and after the acupuncture intervention revealed that acupuncture significantly reduced FBG in non-genetic model and genetic model rats with T2DM compared with that in the model group (P < 0.01). However, I2 > 97% and I2 = 68%,therefore, the heterogeneity of the data in both groups did not change significantly after using the single-row method and the results were stable. Five [4, 13, 23, 30, 36] OGTT-AUG data were included, and one datum that did not differ between the model group and the acupuncture group was excluded. The results showed a significant area of decrease in OGTT in the acupuncture group compared with that in the model group (P < 0.01).

Fig. 4
figure 4

Forest plot of changes before and after blood glucose intervention. FBG, PBG and OGTT-AUC in acupuncture and model groups

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In the related indexes such as insulin content, the data that the INS units could not be unified in 2 [1, 60] groups were deleted. INS was investigated in 13 studies [4, 11, 13,14,15,16, 30, 36, 40, 49, 70], 22, 34, and the results showed that acupuncture was effective in decreasing the INS in the animal model of T2DM compared with that in the model group (P < 0.01, Fig. 5). Heterogeneity was found to be significantly reduced by the single-row method with the exclusion of one studies [30], we speculated that this might be an error in data interpretation. HOMA-IR was investigated in 10 [24], 4, 11, 13, 14, 23, 34, 36, 49, 61] studies, and the results showed that acupuncture was effective in alleviating IR compared with that in the model group (P < 0.01, Fig. 5). Furthermore, the results were stable with the use of the single-row method. Five studies [7, 16, 23, 40, 63] on ISI were included, and the results indirectly indicated that acupuncture could effectively reduce blood glucose (P < 0.01, Fig. 5),the heterogeneity was reduced to 0 after using the single-row method, because the ISI and HOMA-ISI calculation formulas were different.

Fig. 5
figure 5

Forest plot of serum insulin levels. INS, HOMA-IR and ISI in acupuncture and model groups

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Insulin signaling pathway

IRS-1 undergoes phosphorylation primarily on tyrosine and serine/threonine residues. In the context of insulin resistance (IR), serine/threonine phosphorylation competitively inhibits tyrosine phosphorylation [9]. We found by meta-analysis of IRS-1 307 data in four articles [24], 23, 31, 49] that acupuncture significantly reduced the phosphorylation level of IRS-1 at serine 307 compared with that in the model group. Five studies [1, 22, 49, 50, 70] found that acupuncture significantly increased the phosphorylation level of IRS-1 at tyrosine 895 compared with that in the model group. Four studies [7, 36, 40, 57] examining IRS-1 mRNA incorporation found that acupuncture significantly increased IRS-1 gene expression compared with that in the model group. The above studies were found to be stable after application of the single-row method. p-IRS-1 was examined in three studies [1, 31, 36], and it was found that acupuncture significantly decreased the expression of p-IRS-1 compared with that in the model group. However, the results were not statistically significant after application of the single-row method, which may be due to the selection of the REM. Results for PI3K p85 protein expression were found to be stable after application of the single-row method. PI3K p85 protein expression was found to be significant in the model group. In eight studies [23, 49, 50, 52, 57, 60, 67, 69], acupuncture significantly increased the expression of PI3K p85 protein compared with that in the model group (P < 0.01). In regard to PI3K mRNA expression, two studies [67, 69] found that acupuncture significantly increased the expression of PI3K mRNA compared with that in the model group (P < 0.01). In regard to AKT protein expression, five studies [1, 11, 22, 52, 57] showed that acupuncture significantly increased the expression of AKT protein compared with that in the model group (P < 0.01). In regard to p-AKT incorporation, three studies [1, 31, 52] showed that acupuncture significantly increased the expression of p-AKT protein compared with that in the model group (P < 0.01). One article [4] was excluded from the GLUT 4 dataset due to variations in the detection of internal reference substrates, while another article [7] was excluded due to the detection of deficient concentrations. GLUT 4 protein content was investigated in eight studies [13, 14, 16, 22,23,24, 30, 49] studies, and GLUT 4 mRNA expression was investigated in two studies [15, 41]. The research findings indicate that acupuncture significantly increases the expression levels of GLUT 4 protein and GLUT 4 mRNA compared to the control group (P < 0.01), and the single-row method deleted one study [24] was significantly less heterogeneous, which may be for the difference in the number of readings of the investigators. As in Fig. 6.

Fig. 6
figure 6

Forest plot of insulin signaling pathway. IRS-1 307, IRS-1 895, IRS-1 mRNA, p-IRS-1,PI3K p85, PI3K mRNA, AKT, p-AKT, GLUT 4 and GLUT 4 mRNA in acupuncture and model groups

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Mitochondrial AMPK pathway

In regard to the AMPK pathway, four articles [13, 30, 34, 48] studied the AMPK protein. Results showed a significant increase in AMPK compared with the model group (P < 0.01, Fig. 7). Using the single-row method, after exclusion of one study [30] it was found that I2 = 0%,this was considered to be due to incorrect reading for the researcher. It was found that there was no statistically significant difference in the results for AMPK mRNA between the acupuncture group and the model group (P = 0.11, Fig. 7) [34, 57]. One study [27] found that PGC-1α mRNA and NRF1 mRNA were significantly higher in the acupuncture group than in the model group (P<0.01, Fig. 7). Similarly, SIRT1 protein [55] and PGC-1α protein [30] were significantly increased in the acupuncture group compared with that in the model group (P < 0.01, Fig. 7). However, there was no significant change in SIRT1 mRNA in the acupuncture group relative to the model group (P = 0.61, Fig. 7),given only one piece of data was available, an accurate conclusion could not be drawn. Further studies could be conducted to explore this more deeply in the future.

Fig. 7
figure 7

Forest plot of the mitochondrial AMPK signaling pathway. AMPK, AMPK mRNA, p-AMPK, SIRT1, SIRT1 mRNA, PGC-1α, PGC-1α mRNA and NRF1 mRNA in acupuncture and model groups

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Subgroup analysis

TC (I2 = 68%), FBG change (I2 = 96%), OGTT-AUC (I2 = 82%), INS (I2 = 53%), ISI (I2 = 96%), IRS-1 307 (I2 = 96%), IRS-1 mRNA (I2 = 68%), p-IRS-1 (I2 = 98%), and PI3K p85 (I2 = 88%) exhibited high heterogeneity (I2 > 50%). Therefore, subgroup analyses were performed based on animal species, intervention methods, acupoint selection, and intervention duration. Additionally, since the expression of IRS-1 307, IRS-1 mRNA, p-IRS-1, and PI3K p85 is closely related to sampling sites, we conducted a subgroup analysis based on sampling sites.

Animal species

Subgroup analyses were performed based on animal species for TC, FBG change, OGTT-AUC change, ISI, INS, IRS-1 307, IRS-1 895, IRS-1 mRNA, p-IRS-1, and PI3K p85. Subgroup analysis results are presented in Table 3. The included animals were: SD rats, ZDL rats, db/db mice, Wistar rats, OLEFT rats, and C57BL/6 mice. Acupuncture in ZDL rats showed more significant effects on TC, FBG change, IRS-1 307, IRS-1 mRNA, IRS-1 895, and PI3K p85, but no significant difference in ISI compared to the model group (P = 0.2). In SD rats, acupuncture had more pronounced effects on OGTT-AUC and ISI, but no significant difference in IRS-1 mRNA or ISI compared to the model group (P = 0.05). In Wistar rats, acupuncture significantly influenced IRS-1 mRNA expression, but showed no significant difference in FBG change (P = 0.4) or INS (P = 0.5) compared to the model group. Acupuncture in C57BL/6 mice significantly affected INS expression. Finally, we observed that heterogeneity remained high across these data, indicating that the high heterogeneity is unrelated to animal species. No statistically significant differences were found between subgroups for OGTT-AUC change (P = 0.39), IRS-1 307 (P = 0.09), and IRS-1 895 (P = 0.64).

Table 3 Subgroup analysis of animal species
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Intervention method

Subgroup analyses were performed based on intervention type (acupuncture vs. electroacupuncture) for FBG change, OGTT-AUC change, ISI, IRS-1 mRNA, and PI3K p85 data. Subgroup analysis results are presented in Table 4.We found that acupuncture had a more significant effect on FBG change and ISI, while electroacupuncture had a more pronounced effect on IRS-1 mRNA expression. No significant differences were observed between acupuncture and electroacupuncture for OGTT-AUC change or PI3K p85. Heterogeneity decreased across all data, indicating that different acupuncture interventions were not the source of increased heterogeneity. Furthermore, no statistically significant differences were found between subgroups for OGTT-AUC change (P = 0.99), ISI (P = 0.27), IRS-1 mRNA (P = 0.29), or PI3K p85 (P = 0.98).

Table 4 Subgroup analysis of intervention method
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Acupoint select

Subgroup analyses were performed based on acupoint selection for TC, FBG change, OGTT-AUC change, ISI, INS, IRS-1 895, IRS-1 mRNA, p-IRS-1, and PI3K p85. The acupoints were divided into four groups: ST-36, EX-B3, Group 1 (including EX-B3, ST36, SP6, BL20), and Group 2 (including LI11, LI14, SP6, SP8, SP9, SP10, ST36, ST40, LR3, CV12). The results of the subgroup analysis are shown in Table 5. Acupuncture with the G1 acupoint combination had a more significant effect on TC, INS, IRS-1 895, and PI3K p85, but no significant difference was found in OGTT-AUC change (P = 0.05) or ISI (P = 0.31) compared to the model group. Acupuncture with the G2 acupoint combination had a more significant effect on FBG change and ISI. Acupuncture at EX-B3 had a more pronounced effect on OGTT-AUC change, IRS-1 mRNA, and p-IRS-1 expression. No significant difference was observed for OGTT-AUC (P = 0.18), IRS-1 895 (P = 0.26), or p-IRS-1 (P = 0.30) with acupuncture at ST36 compared to the model group. The subgroup analysis revealed that the heterogeneity for IRS-1 mRNA was 0, indicating that the high heterogeneity in IRS-1 mRNA data may be due to acupoint selection. No statistically significant differences were found between subgroups for OGTT-AUC change (P = 0.39), IRS-1 307 (P = 0.09), or IRS-1 895 (P = 0.64).

Table 5 Subgroup analysis of acupoint select
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Duration

Subgroup analyses were performed based on intervention duration for FBG change, INS, IRS-1 307, IRS-895, IRS-1 mRNA, p-IRS-1, and PI3K p85. Subgroup analysis results are presented in Table 6.Two intervention durations were selected: short-term (≤ 4 weeks) and long-term (≥ 4 weeks). We found that long-term acupuncture was more effective in improving FBG change, INS, and IRS-1 307 expression, while short-term acupuncture had a more significant effect on IRS-1 895, IRS-1 mRNA, and p-IRS-1 expression. No significant difference was observed in PI3K p85 expression between short-term and long-term acupuncture. Additionally, no statistically significant differences were found between subgroups for FBG change (P = 0.2), INS (P = 0.44), IRS-1 307 (P = 0.09), IRS-1 895 (P = 0.45), or PI3K p85 (P = 0.88). As shown in Fig. 6.

Table 6 Subgroup analysis of intervention duration
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Sample site

Finally, subgroup analyses were performed based on sampling sites for IRS-1 mRNA, p-IRS-1, and PI3K p85. Four sampling sites were used: skeletal muscle, liver, brain tissue, and pancreas. Subgroup analysis results are presented in Table 7.We found that acupuncture more effectively modulated IRS-1 mRNA, p-IRS-1, and PI3K p85 expression in skeletal muscle, suggesting that insulin signaling factors in skeletal muscle are more sensitive to acupuncture effects. However, the different sampling tissues did not account for the high heterogeneity in IRS-1 mRNA, p-IRS-1, and PI3K p85 expression.

Table 7 Subgroup analysis of sample site
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Sensitivity analysis

Sensitivity analyses were performed, using Stata 17.0, on studies with statistically significant but heterogeneous I2 >75% (for FBG change of T2DM rats, IRS-1 307, p-IRS-1, PI3K p85) to examine the effect of individual studies on the total effect size and to assess the stability of the results for the effect of acupuncture on animal models of T2DM. After the analysis, we found that I2, CI, and SD for the four parameters did not change significantly. This was consistent with the results prior to applying the single-row method, indicating that the results were very stable, as shown in Fig. 8.

Fig. 8
figure 8

Sensitivity analysis of acupuncture on FBG change, IRS-1 307, p-IRS-1and PI3K p 85 in animal models of T2DM

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Publication bias

We used the Begg test and Egger test to measure the publication bias of the studies. P < 0.05 indicated that the studies might have publication bias. We included data on the difference in FBG before and after acupuncture in the studies, and the results, as shown in Figs. 9 and 10 (P = 0.667 in the Egger test and P = 0.217 in the Begg test) indicated that there was no publication bias in the included studies. This is shown in Figs. 9 and 10.

Fig. 9
figure 9

Begg test of pre-post changes in FBG difference in an animal model of T2DM with acupuncture intervention

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Fig. 10
figure 10

Egger test of pre and post changes in FBG differentials in an animal model of T2DM with acupuncture intervention

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Positive control group

Finally, we compared the results of the acupuncture group with those of the positive control group. 4 studies included positive controls: three used glimepiride and one used metformin. We focused on those with glimepiride as the positive control (Fig. 11). Our analysis found no significant difference between acupuncture and glimepiride in improving blood glucose, blood lipids, and IR. However, acupuncture demonstrated superior effects compared to glimepiride in improving OGTT-AUC (P < 0.01), HOMA-IR (P < 0.01), IRS-1 mRNA(P < 0.01), and P-IRS-1 (P < 0.01). These findings suggest that the effects of acupuncture on T2DM are either comparable to or potentially greater than those of glimepiride.

Fig. 11
figure 11

Forest plots of weight change, TC, TG, LDL-C, HDL-C, FBG, INS, ISI, HOMA-IR, OGTT-AUC, and the expression levels of IRS-1 mRNA and p-IRS-1 in acupuncture and glimepiride groups

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Discussion

Summary of main findings

A systematic evaluation and analysis of 31 T2DM animal studies found that acupuncture plays a beneficial role in T2DM animals. Obesity is an important factor contributing to T2DM, and weight loss can effectively improve or even reverse T2DM metabolic abnormalities [33]. We found that animal models that underwent high-sugar and high-fat feeding had significantly higher body weights and lipid levels, while acupuncture significantly reduced weight gain in T2DM animals. Our systematic review results are consistent with clinical findings. Clinical studies have shown that compared to healthy individuals, T2DM patients exhibit higher FBG, TG, TC, and LDL-C levels, along with lower HDL-C levels [61]. Clinical studies show that after three courses of acupuncture treatment in 83 patients with T2DM, the overall effective rate reached 80.7%. The results found significant reductions in FBG, TC, TG, and LDL-C (all P < 0.01), and significant increases in ISI, HOMA-β, and HDL-C (all P < 0.01) [51]. Abnormal blood lipid metabolism exacerbates IR, impeding pancreatic β-cell function. By analysing the lipid data, we found that acupuncture significantly reduced the levels of two blood lipid factors, TC and TG. TC is a measure of lipid metabolism, and TG is closely related to pancreatic β-cell function [39]. Acupuncture can improve lipid metabolism, reduce body weight, alleviate IR, and improve T2DM by lowering blood lipid factors such as TC and TG. However, unexpectedly, there was no statistically significant difference between the LDL-C and HDL-C of the genetic model rats and the model group with acupuncture, which we considered to be due to the small amount of data in the study and the selection of animals. This needs to be verified in subsequent studies. Typical symptoms of T2DM are excessive drinking, eating, and urinating, so we also investigated changes in water intake and food intake. We found that acupuncture reduced water intake and food intake in the T2DM animal model.

We analyzed the changes in blood glucose and insulin levels to verify the effectiveness of acupuncture in the treatment of T2DM. Blood glucose data revealed that acupuncture significantly reduced FBG, PBG, and OGTT-AUC in the T2DM animal model, while the effect on PBG was more significant, which was consistent with the results of clinical studies [38]. In addition to that, the significant reduction of INS and IR index after acupuncture also more strongly confirmed the effectiveness of acupuncture in treating T2DM.

The insulin pathway is closely linked to the pathological mechanisms of T2DM. We found that in the insulin pathway, acupuncture inhibited the phosphorylation of IRS-1 at the 307 site, significantly promoted the phosphorylation of tyrosine 895, and also increased the expression levels of IRS-1 mRNA and p-IRS-1. IRS-1 is a key mediator in the insulin signaling pathway, and phosphorylation of IRS-1 stimulates the downstream signaling cascade of glucose metabolism, which then regulates glucose metabolism [56]. Serine/threonine and tyrosine phosphorylation are the primary types of phosphorylation for IRS-1. Tyrosine phosphorylation provides a high-affinity binding site for downstream signaling proteins, while serine/threonine phosphorylation at the 307 site plays a crucial negative regulatory role in the insulin pathway [28]. However, in the context of IR, serine/threonine phosphorylation competitively inhibits tyrosine phosphorylation [54]. Acupuncture can modulate the balance of IRS-1 phosphorylation, activating the insulin signaling pathway, enhancing the GLUT 4 translocation rate, promoting glucose uptake.

In the mitochondrial pathway, we found that acupuncture significantly increased the expression of mitochondrial AMPK pathway factors; this effect was same as that of acupuncture on the insulin pathway. However, the effect of acupuncture on the mitochondrial AMPK pathway in T2DM animals has been less studied. Most studies have focused on the expression of AMPK protein, which is an energy-sensing enzyme that can regulate glucose and lipid metabolism by increasing the translocation of GLUT 4, and also regulate mitochondrial function and cell growth by phosphorylating a series of enzyme substrates downstream, especially PGC-1α [46]. PGC-1α is a marker of the mitochondrial biosynthesis pathway and AMPK—by activating PGC-1—which initiates the mitochondrial biosynthesis pathway. Mitochondrial biosynthesis is essential for mitochondrial function, cell renewal, and glycolipid metabolism [25]. We found that acupuncture promoted the expression of AMPK and PGC-1α, which increased mitochondrial biosynthesis and ameliorated the abnormalities of T2DM glycolipid metabolism.

Acupuncture treatment is largely dependent on the selection of acupoints, so we performed a subgroup analysis based on acupoints. The results of the meta-analysis indicate that different acupoints produce varying effects in the treatment of T2DM. The combination of multiple acupoints is more effective than single acupoints in reducing blood glucose and lipids, correcting IR, and enhancing insulin signaling pathways. Clinically, a multi- acupoints approach should be adopted to improve efficacy. Furthermore, we identified ST36 (30 sessions), SP6 (20 sessions), EX-B3 (15 sessions), and BL20 (14 sessions) as key acupoints for diabetes treatment, consistent with the findings of [59]. Additionally, acupuncture interventions in T2DM animal models generally last from 12 days to 8 weeks. Systematic reviews suggest that interventions lasting longer than 4 weeks are more effective in improving FBG, insulin levels, and IRS-1 expression compared to those lasting less than 4 weeks. However, no studies have investigated interventions lasting longer than 8 weeks, so the long-term effects of acupuncture on T2DM remain unclear.

Furthermore, this systematic review found that manual acupuncture was more effective than electroacupuncture in lowering fasting blood glucose. However, no significant differences were observed between the two methods in OGTT-AUC change (P = 0.99), ISI (P = 0.27), IRS-1 mRNA (P = 0.29), or PI3K p85 expression (P = 0.98). These findings contrast with clinical studies [19], which reported that both manual acupuncture and electroacupuncture improved blood glucose in T2DM patients, with electroacupuncture yielding faster and more pronounced effects. Electroacupuncture, combining manual acupuncture and electrical stimulation, offers advantages such as greater quantifiability and reproducibility [53].The discrepancy between systematic review results and clinical outcomes may stem from experimental animals’ heightened sensitivity to electrical stimulation. Compared with manual acupuncture, electroacupuncture might induce greater psychological distress in experimental animals, leading to an increase in inflammatory factors, as well as adverse reactions such as struggling and mortality [66].

In addition, we found that the selection of animal models of T2DM may have an impact on the study of the acupuncture mechanism. In the subgroup analysis of the effect of acupuncture in T2DM animal models, it was found that acupuncture had a significant effect on both T2DM ordinary rats and T2DM genetic model rats, a result that could potentially provide a basis for the treatment of hereditary diseases with acupuncture. However, the included studies only selected rodents, and did not study other species of animals to explore the differences in the effects of acupuncture on different diabetic model animals. Compared to other animals, rodents have advantages such as low cost, easy availability, simple handling, and ease of breeding [6]. In terms of gender, although males are more likely to develop T2DM, and earlier, than females because of a number of factors [26], the selection of males for the animals included in the studies had a certain selective bias on the experimental results. We hypothesize that this is due to the researchers’ assumption that the hormones of female animals have an effect on the efficacy of acupuncture in the treatment of T2DM [45]. Nonetheless, acupuncture has been demonstrated to have significant glucose- and lipid-lowering effects in female patients with T2DM in some clinical studies, and also correct IR and increase pancreatic β-cell function [19, 64].

Finally, it was found that acupuncture had consistent effects on the insulin signaling pathway and mitochondrial AMPK pathway factors at different tissues in T2DM animals. However, in our subgroup analysis, we found that insulin signaling pathway factors in skeletal muscle tissue were more sensitive to acupuncture.

Acupuncture demonstrates significant therapeutic effects in treating T2DM, with advantages such as simplicity, safety, and the absence of toxic side effects [44]. Compared to conventional Western drug therapies, it offers notable benefits. In comparison with glimepiride, acupuncture’s therapeutic effect is at least equivalent to or greater than that of glimepiride. Therefore, acupuncture can serve as an effective complementary therapy for T2DM.

Strengths and limitations

To our knowledge, this is the first systematic review exploring the effects of acupuncture on the insulin signaling pathway and mitochondrial AMPK pathway of T2DM animal model, and the first study evaluating the effects of acupuncture interventions in an animal model of T2DM. The findings should provide a basis for future studies on the mechanisms of T2DM and animal experiments. We comprehensively searched three Chinese databases and seven English databases with 10 entries in the SYRCLE’s risk of bias tool for quality assessment, and validated our findings by extracting general and pathway factor data from the included literature. Our study provides scientific evidence for the selection of acupuncture points and treatment duration in the clinical acupuncture management of T2DM. During acupuncture treatment for T2DM, an individualized approach should be adopted, combining multiple acupuncture points and intervention techniques based on the patient’s symptoms. Furthermore, this study provides a theoretical basis for future exploration of the mechanism of action of acupuncture in the treatment of disease.

However, this study has the following limitations:(1) The included studies did not perform silencing experiments on insulin signaling pathways or mitochondrial AMPK pathways. (2) Due to language restrictions, we only searched nine Chinese and English databases, potentially introducing selection bias that may compromise the representativeness and accuracy of results. (3)All the T2DM animal models incorporated were male rodents, and further validation is needed for other species and clinical outcomes. (4) Some results exhibited high heterogeneity, which may be attributed to factors such as animal species, intervention methods, acupoint selection, and intervention duration. Further research is needed to confirm. Despite these limitations, we hope that this systematic evaluation provides a good theoretical basis for exploring the mechanisms of acupuncture in the treatment of T2DM.

Conclusion

In conclusion, acupuncture may promote glucose metabolism and alleviate IR by promoting cytokine production in the insulin signaling and mitochondrial AMPK pathways. Furthermore, our study also shows that acupuncture improves lipid metabolism and reduces body weight.

Data availability

No datasets were generated or analysed during the current study.

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Funding

This study was supported by the Project of Sichuan Provincial Science and Technology Department (2023YFS0323) and the Natural Science Foundation of Sichuan Province (2022NSFSC0853).

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Authors and Affiliations

  1. School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China

    Fang Luo, Zhijun Ma, Chengguo Su & Jun Zhu

  2. College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China

    Hanhan Chen & Junjie Feng

  3. School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China

    Zhuoxuan Li

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Contributions

F L took responsibility for the content of the study and data accuracy. Z-JM and H-HC designed the research protocol and drafted the manuscript. J-JF and Z-XL collected data, performed analysis and interpretation. C-GS and J Z gave some guidance and suggestions for improvement in solving challenging or complex problems in the article. JZ directed the entire article.

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Luo, F., Ma, Z., Chen, H. et al. Effects of acupuncture on the insulin signaling pathway and mitochondrial AMPK pathway in an animal model of type 2 diabetes mellitus: systematic evaluation and meta-analysis. Diabetol Metab Syndr 17, 146 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01634-7

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01634-7

Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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