Ca2+-Dependent Glucose Transport in Skeletal Muscle by Diphlorethohydroxycarmalol, an Alga Phlorotannin: In Vitro and In Vivo Study

Abstract

Diphlorethohydroxycarmalol (DPHC), a type of phlorotannin isolated from the marine alga Ishige okamurae, reportedly alleviates impaired glucose tolerance. However, the molecular mechanisms of DPHC regulatory activity and by which it exerts potential beneficial effects on glucose transport into skeletal myotubes to control glucose homeostasis remain largely unexplored. The aim of this study was to evaluate the effect of DPHC on cytosolic Ca²⁺ levels and its correlation with blood glucose transport in skeletal myotubes in vitro and in vivo. Cytosolic Ca²⁺ levels upon DPHC treatment were evaluated in skeletal myotubes and zebrafish larvae by Ca²⁺ imaging using Fluo-4. We investigated the effect of DPHC on the blood glucose level and glucose transport pathway in a hyperglycemic zebrafish. DPHC was shown to control blood glucose levels by accelerating glucose transport; this effect was associated with elevated cytosolic Ca²⁺ levels in skeletal myotubes. Moreover, the increased cytosolic Ca²⁺ level caused by DPHC can facilitate the Glut4/AMPK pathways of the skeletal muscle in activating glucose metabolism, thereby regulating muscle contraction through the regulation of expression of troponin I/C, CaMKII, and ATP. Our findings provide insights into the mechanism of DPHC activity in skeletal myotubes, suggesting that increased cytosolic Ca²⁺ levels caused by DPHC can promote glucose transport into skeletal myotubes to modulate blood glucose levels, thus indicating the potential use of DPHC in the prevention of diabetes.