Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Abstract

Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies

“…Previous studies have consistently shown that high-fat diet significantly reduced A. muciniphila abundance in different animal models (Anhê et al, 2015; Axling et al, 2012; Everard et al, 2013; Li et al, 2016; Roopchand et al, 2015; Zhou et al, 2016). A treatment of high-fat diet (60% fat) for as short as 8 weeks on DIO mice led to a 100-fold decrease of A. muciniphila (Everard et al, 2013).…”

“…A muciniphila ) play an important role mediating metformin activity. Further, exogenous LPS administration (subcutaneous injection, 50 μg/kg/day for 5 days) nearly completely blocked all these beneficial effects of metformin on glucose metabolism, insulin signaling and redox status in the mice (Zhou et al, 2016), indicating that LPS also plays an essential role in mediating metformin activity. Previous studies also consistently showed that A. muciniphila administration significantly reduced serum LPS levels (Everard et al, 2013; Li et al, 2016).…”

“…Despite its nature as the most popular anti-diabetic drug, the therapeutic mechanisms are not fully understood (Zhou et al, 2001). Interestingly, recent human and animal studies revealed that metformin was able to modulate the gut microbiota and this effect was associated with its anti-inflammatory and anti-obesity as well as its therapeutic efficacy on glucose metabolism (Lee & Ko, 2014; Napolitano et al, 2014; Shin et al, 2014; Zhou et al, 2016). Although no human trails available on A. muciniphila , all animal studies consistently showed that metformin significant promoted A. muciniphila abundance (as shown in Table 2).…”

Charting the Maternal and Infant Microbiome: What Is the Role of Diabetes and Obesity in Pregnancy?

“…Interestingly, the widely used diabetes drug metformin may help mitigate gut dysbiosis associated with obesity and diabetes. In human [55, 56] and mice [42•, 57–59] studies, metformin has been positively associated with the relative abundance of A. muciniphila and short chain fatty acid-producing bacteria in the gut microbiota. Based on this small but growing literature base, it is tempting to postulate that metformin—a drug with no known risks for the mother or fetus—could not only help ameliorate diabetes-associated dysbiosis in pregnancy, but also reduce transmission of diabesogenic bacteria to the newborn.…”

The stress polarity pathway: AMPK 'GIV'-es protection against metabolic insults

“…Numerous studies using the AMPK-activator, Metformin, squarely implicate the AMPK-dependent stress polarity pathway as a major therapeutic target in these metabolic disorders [79-81]. Metformin administration enhances gut barrier integrity, attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which accounts for the beneficial effects of metformin on glucose metabolism, enhanced metabolic insulin response, and reduced oxidative stress in liver and muscle of the mice [79].…”