Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β‑Cell Function and Suppressing Hepatic Lipid Accumulation in <i>db</i>/<i>db</i> Mice

This study investigated the molecular mechanisms underlying the antidiabetic effect of an ethanol extract of soy leaves (ESL) in <i>db</i>/<i>db</i> mice. Control groups (<i>db</i>/+ and <i>db</i>/<i>db</i>) were fed a normal diet (ND), whereas the <i>db</i>/<i>db</i>-ESL group was fed ND with 1% ESL for 8 weeks. Dietary ESL improved glucose tolerance and lowered plasma glucose, glycated hemoglobin, HOMA-IR, and triglyceride levels. The pancreatic insulin content of the <i>db</i>/<i>db</i>-ESL group was significantly greater than that of the <i>db</i>/<i>db</i> group. ESL supplementation altered pancreatic <i>IRS1</i>, <i>IRS2</i>, <i>Pdx1</i>, <i>Ngn3</i>, <i>Pax4</i>, <i>Ins1</i>, <i>Ins2</i>, and <i>FoxO1</i> expression. Furthermore, ESL suppressed lipid accumulation and increased glucokinase activity in the liver. ESL primarily contained kaempferol glycosides and pheophorbides. Kaempferol, an aglycone of kaempferol glycosides, improved β-cell proliferation through IRS2-related FoxO1 signaling, whereas pheophorbide <i>a</i>, a product of chlorophyll breakdown, improved insulin secretion and β-cell proliferation through IRS1-related signaling with protein kinase A in MIN6 cells. ESL effectively regulates glucose homeostasis by enhancing IRS-mediated β-cell insulin signaling and suppressing SREBP-1-mediated hepatic lipid accumulation in <i>db</i>/<i>db</i> mice