J Clin Biochem Nutr. 2014 Sep;55(2):97-102.

Antidiabetic effect of the α-lipoic acid γ-cyclodextrin complex.

Naito Y1, Ikuta N2, Nakata D3, Terao K2,3, Matsumoto K4, Kajiwara N4, Okano A1, Yasui H1, Yoshikawa Y1,4


1Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University

2Department of Social/Community Medicine and Health Science, Food and Drug Evaluation Science, Kobe University Graduate School of Medicine

3CycloChem Bio Co., Ltd., Kobe, Japan

4Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women’s University



Recently, the number of diabetes mellitus patients is increasing. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and α-lipoic acid (αLA) has been recognized for many years. Pharmacologically, αLA improves glycemic control and polyneuropathies associated with diabetes mellitus. In this study, we found that the α-lipoic acid γ-cyclodextrin complex (αLA/γCD) exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKAy mice by using αLA and αLA/γCD. Our results show that αLA/γCD strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we conclude that intake of αLA/γCD exerts an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia.



Diabetes mellitus (DM) is a disease associated with absolute or relative insulin deficiency, and as of 2013, 382 million people have diabetes worldwide. Therefore novel approaches based on new concepts are needed.

Alpha-lipoic acid (αLA) functions as a cofactor for mitochondrial enzymes such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and the branched-chain alpha-keto acid dehydrogenase complex. Therefore, αLA plays an essential role in glucose and energy metabolism. αLA also is a powerful antioxidant with potent free radical scavenging activity. Many researchers have shown that αLA has beneficial effects on vascular [1] and endothelial function [2] in diabetic animal models or cell lines.

αLA has a chiral center at its C6 carbon, leading to two enantiomers, R- and S-αLA, of which R-αLA is the naturally occurring form. Commercially available αLA is a racemate of R- and S-αLA. αLA is unstable when exposed to low pH, light, or heat. Thus it is difficult to use αLA as a pharma- and nutra-ceutical. We have recently shown that it is possible to stabilize αLA through complex formation with γ-cyclodextrin (CD) yielding αLA/γCD [3].

γCD is a cyclic oligosaccharide that consists of eight α-1,4-linked glycopyranose units, and is capable of forming complexes with a variety of ionic and lipophilic substances by taking the entire molecule or part of it into its cavity. γCD is enzymatically broken down into monosaccharides and therefore functions as an energy source.

In this study, we compared the effect of αLA/γCD with free αLA in terms of DM-related biochemical parameters. Regarding the increased energy expenditure, the intracellular target is considered to be AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Moreover, we confirmed two factors related to glucose metabolism: gene expression of the PPARγ2 mRNA in adipose tissue and protein level of GLUT4 in skeletal muscle. We focused on commercially available racemic αLA complexed with γCD.

We prepared the αLA/γCD complex as previously described [3]. Male type 2 diabetic KKAy mice (4 weeks old and weighing 22–25 g) were used for in vivo studies when they were 8 weeks old. All animals had free access to water and semi-synthetic HFDs that were high in sugar and, therefore, hypercaloric (composition of the basal diet [%]: sucrose, 33.0; lard fat, 20.0; casein, 20.0). Diets were prepared for all groups using AIN-93N provided with mixture of the general diet (Oriental East Co., LTD., Japan). All diets were adjusted for an effective αLA content of 0.5% for day 1 to day 5 and 0.25% for day 6 to day 31. After 31days feeding, the mice were subjected to a 12-h fast, and blood samples, livers, adipose tissues, and skeletal muscle were collected. The blood samples were used for the analysis of biochemical parameters; urea nitrogen (BUN), triglyceride (TG), total cholesterol (TCHO) levels, and the plasma levels of adiponectin. mRNA expression analysis was conducted for mouse adipose tissue samples.

Food intake was equal across all groups and the body weights and blood glucose levels did not change in any group. The level of HbA1c, which indicates the average blood glucose levels over a long period, was significantly lowered in KKAy mice treated with αLA/γCD (8.3% ± 1.3%) compared to the untreated mice (10.7% ± 0.8%). Plasma adiponectin of the mice treated with αLA, especially αLA/γCD, showed a tendency to improve hypoadiponectinemia. We also found that the αLA/γCD group showed a tendency of increased expression levels of PPARγ2, which is one of the key transcription factors regulating adipogenesis and glucose and lipid metabolism. The expression levels of GLUT4 protein in the skeletal muscle were not different among the tested groups. Finally we found that the phosphorylation levels of AMPK in the liver increased in the αLAs groups, especially with significance in the αLA/γCD group. The oral feeding of αLA/γCD enhanced the phosphorylation level of AMPK.

From these results summarized in figure 1, it was shown that the antidiabetic effects of αLA/γCD were stronger than αLA itself. This suggests that αLA complexed with γCD could exist more stably in the living body and probably the bioavailability of αLA/γCD is higher than free αLA. We concluded that intake of αLA/γCD exerts an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise.

NI fig1


  1. Stevens MJ, Obrosova X, Cao X, van Huysen C, Greene DA. 2000. Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes 49:1006–1015.
  2. Keegan A, Cotter MA, Cameron NE. 1999. Effects of diabetes and treatment with the antioxidant alpha-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats. Diabetologia 42:343–350.
  3. Ikuta N, Sugiyama H, Shimosegawa H, Nakane R, Ishida Y, Uekaji Y, et al . 2013. Analysis of the enhanced stability of R(+)-alpha lipoic acid by the complex formation with cyclodextrins. Int J Mol Sci 14:3639–55.



The authors are deeply grateful to members of the Department of Analytical and Bioinorganic Chemistry of Kyoto Pharmaceutical University and Department of Health and Sports Nutrition of Kobe Women’s University.



Keiji Terao, Ph.D.

President of Cyclochem Co., Ltd

KIBC 654, 5-5-2, Minatojima-minamimachi,

Chuo-ku, Kobe, Hyogo, 650-0047, Japan



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