Yuki Naito1, Naoko Ikuta2, Ayaka Okano1, Hinako Okamoto3, Daisuke Nakata3, Keiji Terao3, Kinuyo Matsumoto4, Naemi Kajiwara4, Hiroyuki Yasui1, Yutaka Yoshikawa5. 1. Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, Japan. 2. Department of Social/Community Medicine and Health Science, Food and Drug Evaluation Science, Kobe University Graduate School of Medicine, Japan. 3. CycloChem Bio Co., Ltd., Kobe, Japan. 4. Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women's University, Japan. 5. Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, Japan; Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women's University, Japan. Electronic address: y-yoshikawa@yg.kobe-wu.ac.jp.
Abstract
AIMS: Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability.We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKAy mice. MAIN METHODS: Male type 2 diabetic KKAy mice were divided into 5 groups, and fed either a high-fat-diet (HFD),HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. KEY FINDINGS: The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using amale type 2 diabetic KKAy mousemodel. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. SIGNIFICANCE: These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.
AIMS: Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability.We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKAy mice. MAIN METHODS: Male type 2 diabetic KKAy mice were divided into 5 groups, and fed either a high-fat-diet (HFD),HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. KEY FINDINGS: The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using amale type 2 diabetic KKAy mousemodel. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. SIGNIFICANCE: These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.
Entities:
Keywords:
AMP-activated protein kinase; Anti-diabetic effect; High fat diet (HFD); Peroxisome proliferator-activated receptor (PPAR); R-α-lipoic acid/γ-cyclodextrin (γCD) complex