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Electroacupuncture treatment of insulin resistance in diabetes mellitus
  1. Philip V Peplow
  1. Correspondence to Dr Philip Peplow, Department of Anatomy, Medical School, University of Otago, PO Box 56, Dunedin 9054, New Zealand; phil.peplow{at}otago.ac.nz

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Insulin resistance is closely associated with obesity, type 2 diabetes mellitus (DM), hypertension and the metabolic syndrome, and is also a risk factor for cardiovascular disease. There is increasing clinical evidence for the effectiveness of acupuncture as a treatment for insulin resistance.1

From a mechanistic point of view, the post-receptor responses and signal transduction pathways that are initiated when insulin binds to its receptor in the cell plasma membrane are well described (http://themedicalbiochemistrypage.org/insulin.php). These include the association of insulin receptor substrates (IRSs) with the insulin receptor (IR), which results in the activation of phosphatidylinositol-3-kinase (PI3K) and growth factor receptor binding protein 2 (GRB2). Activated PI3K phosphorylates membrane phospholipids and the main product is phosphatidylinositol-3,4,5-triphosphate (PIP3), which in turn activates PIP3-dependent kinase 1 (PDK1). PDK1 activates another kinase called protein kinase B (PKB, also known as Akt). Insulin-mediated activation of Akt causes inhibition of lipolysis and gluconeogenesis and activation of protein and glycogen synthesis. Insulin signalling also activates the mitogen activated protein kinase (MAPK) pathway either by IR phosphorylation of Src homology 2 domain-containing protein (SHC), which then interacts with GRB2, or via IRS1 activation. Insulin decreases hepatic glucose production (HGP) and increases the rate of glucose uptake, primarily in striated muscle and adipose tissue. In muscle and fat cells, the clearance of circulating glucose depends on the insulin-stimulated translocation of the glucose transporter 4 (GLUT4) isoform to the cell surface.

Altered insulin signalling in diabetes

Obesity and type 2 DM are associated with raised concentrations of insulin, saturated fatty acids (eg, palmitate) and cytokines (eg, tumour necrosis factor-α (TNF-α)) both in the circulation and locally in the hypothalamus, which eventually lead to central insulin resistance. Chronic hyperinsulinemia desensitises IRs, thereby reducing insulin-mediated signalling pathways via IRS proteins. Raised concentrations of palmitate induce intracellular signalling cascades that further interfere with IR-mediated phosphorylation of IRS proteins. Palmitate also activates the transcription factor NF-κB, which induces the expression of one of the main negative regulators of insulin signalling, suppressor of cytokine signalling 3 (SOCS3). SOCS3 interferes with insulin-induced phosphorylation of the IR and its downstream molecules and further targets IRS proteins for proteasomal degradation.2 NF-κB induces endoplasmic reticulum stress that results in increased activity of c-jun N-terminal kinase (JNK), which in turn leads to inhibitory phosphorylation events on IRS proteins.3 Similarly, increased concentrations of TNF-α activate JNK and NF-κB, as well as their downstream signalling pathways.4

Mechanisms of action of electroacupuncture

While electroacupuncture (EA) has been shown to be effective in improving insulin sensitivity and lowering blood glucose in diabetic humans1 and rodents,5 ,6 there are very few studies that have examined the biochemical mechanisms and signalling pathways underlying these effects. This issue of Acupuncture in Medicine includes two papers that have investigated intracellular signalling pathways associated with the hypoglycaemic effect of EA in rat models of diabetes. In the first article by Liao et al7 the efficacy of a combination of EA and metformin in the treatment of DM was tested in a rat model of steroid-induced insulin resistance (SIIR) created by injection of dexamethasone. Dexamethasone induces short-term insulin resistance that mimics type 2 diabetes. It was found that EA at ST36 bilaterally (15 Hz frequency and 10 mA intensity for 60 min) together with metformin resulted in a greater glucose-lowering effect, higher levels of insulin secretion, lower plasma free fatty acid concentrations and higher concentrations of MAPK than metformin alone. The hypoglycaemic effect and increased insulin sensitivity obtained following combined treatment with EA and metformin is determined in part by its ability to activate GLUT4 through upregulation of MAPK expression. Insulin sensitivity is governed at least in part by activation and translocation of GLUT4 via the MAPK and IRS-1/peroxisome proliferator-activated receptor-γ (PPAR-γ) pathways, respectively. Recently a gut–brain–liver axis has been identified that mediates intestinal nutrient- and hormone-induced lowering of HGP. Intraduodenal infusion of metformin for 50 min activated duodenal mucosal AMP-activated protein kinase (AMPK) and lowered HGP in a model of insulin resistance induced by feeding rats a high-fat diet for 3 days.8 Interestingly, EA at ST25 and ST36 bilaterally (3 Hz frequency and 2 mA intensity for 20 min/day, 6 days/week for 4 weeks) inhibited weight gain, activated hypothalamic liver kinase B1 and AMPK, and inhibited acetyl-CoA carboxylase expression in the hypothalamus.5

In the second article by Tzeng et al9 a microarray analysis was used to examine various signalling pathways that may contribute to the glucose-lowering effect of EA at ST36 bilaterally (15 Hz frequency and 10 mA intensity for 60 min) in streptozotocin-induced diabetic rats and to screen for relationships between gene sets and DM. It was found that cell adhesion molecules and type 1 DM pathways were significantly associated with the hypoglycaemic effect. Although not significantly affected in this study, many of the pathways they examined have been implicated physiologically in DM and glucose metabolism.

The role of systemic inflammation

Plasma concentrations of cell adhesion molecules such as ICAM-1 and E-selectin are correlated with obesity, which is associated with chronic low-grade inflammation through the release of pro-inflammatory cytokines such as TNF-α and interleukin-6. This chronic low-grade inflammation may induce insulin resistance and endothelial dysfunction in obesity and diabetes. TNF-α induces expression of ICAM-1 and E-selectin. Adiponectin, which is decreased in obesity, modulates endothelial adhesion molecules.10

In a recent study, EA at ST36 and CV4 (3 Hz frequency and 0.5–0.8 mA intensity for 10 min/day, 5 days/week for 8 weeks) improved insulin sensitivity in obese diabetic mice through increased expression of sirtuin 1 and induced expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and acyl-CoA oxidase in skeletal muscle. This in turn could enhance mitochondrial biosynthesis and fatty acid oxidation and upregulate insulin-associated signal transduction with a subsequent improvement in insulin resistance.6 Insulin signalling can be enhanced or inhibited by cytokines secreted by adipose tissue, and changes in their concentrations may contribute to the development of insulin resistance and type 2 diabetes. The role of TNF-α in the inhibition of phosphorylation events on IRS proteins has already been mentioned. Obesity is a major risk factor for type 2 diabetes and is associated with an increased production of leptin11 and decreased production of adiponectin by adipose tissue.12 While leptin is a pro-inflammatory cytokine, adiponectin is anti-inflammatory and increases insulin sensitivity. EA at CV4 and CV12 (10 Hz frequency and 15 mA intensity for 30 min/day, 3 days/week for 2 weeks) has been shown to decrease leptin concentrations in the serum and adipose tissue of obese Zucker diabetic fatty (ZDF) rats at 12–14 weeks of age.13 EA also lowered serum TNF-α in the obese ZDF rat, which exhibits insulin resistance and is a model of the metabolic syndrome.14

FUTURE DIRECTIONS

Interestingly, laser acupuncture treatment of streptozotocin-induced diabetic rats also decreases blood glucose levels relative to untreated diabetic controls and may have a role in the treatment of diabetes.15

Further knowledge about how the altered signalling pathways in insulin resistance are affected by acupuncture and related techniques may enable more effective therapies to be developed for obesity and diabetes, possibly in synergistic combinations with other treatment modalities.

References

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Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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