Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle.
Mangiferin is one of the prominent active components responsible for the antidiabetic property of many traditional herbs, but its underlying mechanisms of action remain unclear. CD36 in skeletal muscle is known to contribute to the etiology of insulin resistance by facilitating fatty acid uptake. This study investigated the effect of mangiferin on insulin resistance. The results showed that treatment of Wistar-Kyoto rats with mangiferin (15 mg/kg, once daily, by oral gavage) for 7 weeks inhibited chronic liquid fructose consumption-induced increases in plasma insulin concentrations at the baseline and during oral glucose tolerance test (OGTT), and the homeostasis model assessment of insulin resistance index. It also suppressed the increases in fasted plasma nonesterified fatty acid (NEFA) concentration and the adipose tissue insulin resistance index. Mechanistically, mangiferin neither affected intakes of fructose and chow, and the increase in epididymal and perirenal fat, nor attenuated fructose-induced hypertension. In contrast, mangiferin attenuated fructose-induced acceleration of plasma NEFA clearance during OGTT, and tended to decrease excessive triglyceride accumulation in gastrocnemius. Immunofluorescence staining and subsequent rating of CD36-expressing fibers in gastrocnemius revealed that mangiferin restored fructose-stimulated sarcolemmal CD36 overexpression and decreased intracellular CD36 distribution. In addition, the effects of mangiferin on the parameters associated with insulin resistance and abnormal fatty acid metabolism were absent in the spontaneously hypertensive rats carrying numerous nonfunctional mutations in the CD36 gene. Thus, these results suggest that mangiferin treatment mitigates insulin resistance in a rat model of fructose-induced metabolic syndrome by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle.
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Liang
L
Zhou
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Yongquan
Y
Pan
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Ritsu
R
Chonan
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Robert
R
Batey
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Xianglu
X
Rong
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.).
Johji
J
Yamahara
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.) wjwcq68@163.com yuhao@sitcm.edu.au.
Jianwei
J
Wang
Faculty of Basic Medical Sciences (L.Z.), Laboratory Animal Center (Y.P.), and Laboratory of Traditional Chinese Medicine (J.W.), Chongqing Medical University, Chongqing, China; Koei Kogyo Co., Ltd., Tokyo, Japan (R.C.); Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia (R.B.); Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, and the Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China (X.R.); Pharmafood Institute, Kyoto, Japan (J.Y.); and Endocrinology and Metabolism Group, Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, Australia (Y.L.) wjwcq68@163.com yuhao@sitcm.edu.au.
Yuhao
Y
Li
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005632:Fructose; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014280:Triglycerides / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D014280:Triglycerides; D044004:Xanthones; C013592:mangiferin; D005632:Fructose