S-Equol Activates cAMP Signaling at the Plasma Membrane of INS-1 Pancreatic β-Cells and Protects against Streptozotocin-Induced Hyperglycemia by Increasing β-Cell Function in Male Mice

• Published in: The Journal of nutrition Vol. 147; no. 9; pp. 1631 - 1639
• Main Authors: Horiuchi, Hiroko, Usami, Atsuko, Shirai, Rie, Harada, Naoki, Ikushiro, Shinichi, Sakaki, Toshiyuki, Nakano, Yoshihisa, Inui, Hiroshi, Yamaji, Ryoichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2017
• Subjects: Animals; Area Under Curve; Blood Glucose - metabolism; cAMP; Cell Enlargement - drug effects; Cell Membrane - drug effects; Cell Membrane - metabolism; CREB; Cyclic AMP - metabolism; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - prevention & control; enantiomer; equol; Equol - pharmacology; GRK; Hyperglycemia - blood; Hyperglycemia - chemically induced; Hyperglycemia - etiology; Hyperglycemia - prevention & control; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Isoflavones - metabolism; Isoflavones - pharmacology; Male; Mice, Inbred ICR; pancreatic β-cells; PKA; Rats; Signal Transduction; type 2 diabetes mellitus; GRK; T2DM; equol; GLP-1; PKA; Gαs; DAPI; siRNA; cAMP; ER; E2; pancreatic β-cells; CREB; TUNEL; CRE; enantiomer; type 2 diabetes mellitus; subunit group S GPCR; BrdU
• ISSN: 0022-3166; 1541-6100
• DOI: 10.3945/jn.117.250860

S-equol, which is enantioselectively produced from daidzein by gut microbiota, has been suggested as a chemopreventive agent against type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear. We investigated the effects of S-equol on pancreatic β-cell function. β-Cell growth and insulin secretion were evaluated with male Institute of Cancer Research mice and isolated pancreatic islets from the mice, respectively. The mechanisms by which S-equol stimulated β-cell response were examined in INS-1 β-cells. The effect of S-equol treatment on β-cell function was assessed in low-dose streptozotocin-treated mice. S-equol was used at 10 μmol/L for in vitro and ex vivo studies and was administered by oral gavage (20 mg/kg, 2 times/d throughout the experimental period) for in vivo studies. S-equol administration for 7 d increased Ki67-positive β-cells by 27% (P < 0.01) in mice. S-equol enantioselectively enhanced glucose-stimulated insulin secretion in mouse pancreatic islets by 41% (P < 0.001). In INS-1 cells, S-equol exerted stronger effects than daidzein on cell growth, insulin secretion, and cAMP-response element (CRE)-mediated transcription. These S-equol effects were diminished by inhibiting protein kinase A. The effective concentration of S-equol for stimulating cAMP production at the plasma membrane was lower than that for phosphodiesterase inhibition. S-equol-stimulated CRE activation was negatively controlled by the knockdown of G-protein α subunit group S (stimulatory) and positively controlled by that of G-protein-coupled receptor kinase-3 and -6. Compared with vehicle-treated controls, S-equol gavage treatment resulted in an increase in β-cell mass of 104% (P < 0.05), a trend toward high plasma insulin concentrations (by 118%; P = 0.06), and resistance to hyperglycemia after streptozotocin treatment (78% of AUC after glucose challenge; P < 0.01). S-equol administration significantly increased the number of Ki67-positive proliferating β-cells by 62% (P < 0.01) and decreased that of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic β-cells by 75% (P < 0.05). Our results show that S-equol boosts β-cell function and prevents hypoglycemia in mice, suggesting its potential for T2DM prevention.