Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice

Abstract

Enterolactone (ENL) is formed by the conversion of dietary precursors like strawberry lignans via the gut microbiota. Urinary concentrations of lignan metabolites are reported to be significantly associated with a lower risk of Type 2 diabetes (T2D). In the present study, antidiabetic effect of ENL and its modes of action were studied in vitro and in vivo employing a rat skeletal muscle-derived cell line, L6 myocytes in culture, and T2D model db/db mice. ENL dose-dependently increased glucose uptake in L6 myotubes under insulin absent condition. This increase by ENL was canceled by compound C, an inhibitor of 5'-adenosine monophosphate-activated protein kinase (APMK). Activation (=phosphorylation) of AMPK and translocation of glucose transporter 4 (GLUT4) to plasma membrane in L6 myotubes were demonstrated by Western blotting analyses. Promotion by ENL of GLUT4 translocation to plasma membrane was also visually demonstrated by immunocytochemistry in L6 myoblasts that were transfected with glut4 cDNA-coding vector. T2D model db/db mice were fed the basal 20 % casein diet (20C) or 20C supplemented with ENL (0.001 or 0.01 %) for 6 weeks. Fasting blood glucose (FBG) levels were measured every week and intraperitoneal glucose tolerance test (IPGTT) was conducted. ENL at a higher dose (0.01 % in 20C) suppressed the increases in FBG levels. ENL was also demonstrated to improve the index of insulin resistance (HOMA-IR) and glucose intolerance by IPGTT in db/db mice. From these results, ENL is suggested to be an antidiabetic chemical entity converted from dietary lignans by gut microbiota.

Ethanolic Extract of Folium Sennae Mediates the Glucose Uptake of L6 Cells by GLUT4 and Ca2+

“…The glucose uptake stimulatory effect of FSE was determined in L6 cells by a previously reported method [ 60 ] with slight modifications [ 61 , 62 ]. Briefly, L6 cells were grown in 96-well culture plates at 37 °C under 5% CO 2 and cultured for 3–4 days until the cells were confluent.…”

Hyperuricemia in type 2 diabetic model KK-Ay/Ta mice: a potent animal model with positive correlation between insulin resistance and plasma high uric acid levels

“…In the meantime, we have been engaged in studies on antidiabetic effects of food components in type 2 diabetes (T2D) model animals such as KK-A y /Ta [ 9 , 10 ], db/db [ 10 – 15 ] and ob/ob mice [ 16 , 17 ]. Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance (IR) [ 18 ], and diabetic nephropathy [ 19 ].…”

Fructose: A Dietary Sugar in Crosstalk with Microbiota Contributing to the Development and Progression of Non-Alcoholic Liver Disease

“…Specifically, certain food compounds and dietary strategies are suitable to activate AMPK and to mediate antidiabetic effects. Some intestinal bacteria are able to digest polyphenols and isoflavones from plants and convert it to enterolactone (ENL) or to equol, which both activates AMPK ( 63 , 90 ). Furthermore, ENL ameliorates abnormal lipid metabolism, inhibits anabolic glycogen storage, and improves insulin sensitivity ( 63 , 90 ).…”

“…Some intestinal bacteria are able to digest polyphenols and isoflavones from plants and convert it to enterolactone (ENL) or to equol, which both activates AMPK ( 63 , 90 ). Furthermore, ENL ameliorates abnormal lipid metabolism, inhibits anabolic glycogen storage, and improves insulin sensitivity ( 63 , 90 ). In the respective study it was shown that ENL dose dependently promoted glucose uptake under insulin absent condition, which was completely eliminated by an AMPK inhibitor suggesting that ENL is an antidiabetic substance.…”