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

Abstract

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.

6‐Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC‐1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1

“…Triglyceride content in red gastrocnemius was determined as described previously . Briefly, suitable aliquots of tissue homogenates were extracted and were analyzed for their triglyceride content with an enzymatic assay kit.…”

“…Western blotting was performed as described previously . Total protein was prepared from the red gastrocnemius, liver, and eWAT using the kit for tissue protein extraction (Thermo Fisher Scientific, Sunnyvale, CA) according to the manufacturer's instructions.…”

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

“…FFAs can be uptaken by several tissues via FFA transport proteins (FATPs) and CD36, both highly expressed in heart, adipose tissue, and skeletal muscle [69]. Fructose upregulates CD36 expression in adipose tissue [70] and skeletal muscle [71] to facilitate FFA uptake, resulting in local insulin resistance. Increased FFAs promote autophagy in skeletal muscle of mice with high fructose diet, likely as a compensate mechanism for clearance of lipotoxic intermediates [30].…”

The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission

“…Recently, it has been reported that MGF can attenuate high-fat diet (HFD)-induced metabolism syndrome through activating AMP-actived protein Kinase (AMPK) for abnormal lipid metabolism regulation, anti-inflammation, and insulin resistance improvement [19]. A recent study demonstrates that MGF can ameliorate endothelial dysfunction by regulating AMPK to inhibit the inflammation in ER stress [20].…”

“…Mangiferin (MGF) is one of the main constituents in common anemarrhena, a traditional medicine, for treating diabetes [19][20][21]. Recently, it has been reported that MGF can attenuate high-fat diet (HFD)-induced metabolism syndrome through activating AMP-actived protein Kinase (AMPK) for abnormal lipid metabolism regulation, anti-inflammation, and insulin resistance improvement [19].…”