Insulin Sensitivity-Enhancing Activity of Phlorizin Is Associated with Lipopolysaccharide Decrease and Gut Microbiota Changes in Obese and Type 2 Diabetes (db/db) Mice

Abstract

Phlorizin exists in a number of fruits and foods and exhibits many bioactivities. The mechanism of its antidiabetic effect has been known as it can competitively inhibit sodium-glucose symporters (SGLTs). However, phlorizin has a wide range of two-phase metabolism in systemic circulation and shows poor oral bioavailability. An alternative mechanism may involve gut microbiota in intestine. Sixteen obese mice with type 2 diabetes (db/db) and eight age-matched control mice (db/+) were divided into three groups: diabetic group treated with phlorizin (DMT group), vehicle-treated diabetic group (DM group), and normal control group (CC group). Phlorizin was given in normal saline solution by intragastric administration for 10 weeks. After the last treatment course, body weight, energy intake, serum lipopolysaccharides (LPS), insulin resistance, and fecal short-chain fatty acids (SCFAs) were compared. 16S rRNA gene denaturing gradient gel electrophoresis (DGGE) and quantitative PCR were used to determine the changes in microbiome composition. Coadministration of phlorizin significantly prevented metabolic syndrome by decreasing weight gain, energy intake, serum lipopolysaccharides, and insulin resistance, and the fecal level of total SCFAs was dramatically increased, especially butyric acid. DGGE and quantitative PCR demonstrated that phlorizin coadministration increased the gut microbial diversity and the growth of Akkermansia muciniphila and Prevotella. Meanwhile, the gut microbiota structure of db/db mice after phlorizin treatment was improved and approached the normal group. The mechanism of the hypoglycemic action of phlorizin is associated with LPS decrease and gut microbiota changes; briefly, it acts in the intestine to modify gut microbial community structure, resulting in lower LPS load in the host and higher SCFAs producing beneficial bacteria.

Traditional, Indigenous Apple Varieties, a Fruit with Potential for Beneficial Effects: Their Quality Traits and Bioactive Polyphenol Contents

“…Dihydrochalcones are a specific group of polyphenolic compounds from apples with potential to reduce blood glucose levels [45,46] which is helpful in diabetes prevention. Oral antidiabetic drugs based on phloridzin conjugate were suggested as well [47].…”

Short-term phlorizin treatment attenuates adipose tissue inflammation without alerting obesity in high-fat diet fed mice

“…Since its isolation from the bark of the apple tree 180 years ago, it has been used in human medicine for long because of its extensive bioactivities (Barreca, Bellocco, Lagan, Ginestra, & Bisignano, ; Gosch, Halbwirth, & Stich, ; Rezk, Haenen, Van Der Vijgh, & Bast, ; Qin, Xing, Zhou, & Yao, ). Most studies revealed the anti‐diabetic effect of phlorizin (Mei et al, ; Rossetti, Smith, Shulman, Papachristou, & Defronzo, ) and some studies reported its antioxidant (Rezk et al, ) and anti‐inflammatory activities (Huang et al, ). Recently, a study has indicated that phlorizin supplementation attenuates obesity and decreased plasma pro‐inflammatory cytokines levels in high fat diet fed obese mice (Shin, Cho, Jung, Ryu, & Choi, ).…”

Purified Phlorizin from DocynIa Indica (Wall.) Decne by HSCCC, Compared with Whole Extract, Phlorizin and Non-Phlorizin Fragment Ameliorate Obesity, Insulin Resistance, and Improves Intestinal Barrier Function in High-Fat-Diet-Fed Mice

“…All of the following animal experimental procedures were approved by the animal ethics committee of Chengdu University. According to the literature and the results of previous research [ 46 , 47 ] the intragastric dose of PHZ was 20 mg/kg [body weight (BW)/day], and the dosage of the DIDE was fixed to be 45 mg/kg (BW/day) based on the content of PHZ contained (45% of PHZ in DIDE: 45 mg DIDE containing 20 mg PHZ and 25 mg NP), the intragastric dose of the NP is 25 mg/kg (BW/day). The mice were then randomly divided into 5 groups: (1) normal chow diet group (NCD, 10% energy from fat, n = 10); (2) high-fat diet group (HFD, 45% energy from fat, n = 10); (3) high-fat diet with DIDE groups (HFD + DIDE, 45 mg/kg (BW/day), n = 10); (4) high-fat diet with PHZ groups (HFD + PHZ, 20 mg/kg (BW/day), n = 10); (5) high-fat diet with NP groups (HFD + NP, 25 mg/kg (BW/day), n = 10).…”