Improving glucose tolerance via the gut–brain axis

Type 2 diabetes mellitus (T2DM) is associated with insulin resistance, altered intestinal glucose sensing and hypercontractility. In this study, Fournel and colleagues now present a mechanism by which apelin, a bioactive peptide known to aid glucose absorption, ameliorates glucose tolerance by targeting the enteric nervous system (ENS) and decreasing duodenal contraction in mice.

“...glucose sensing in the intestine modulates the gut–brain axis...”

“Previous work from our team demonstrates that glucose sensing in the intestine modulates the gut–brain axis, and this is associated with modulation of glucose entry in skeletal muscle. However, the mechanisms are poorly understood,” explain corresponding authors Claude Knauf and Patrice Cani.

By measuring mechanical contractions ex vivo in duodenal preparations and electrical duodenal activity in vivo in mice, Fournel et al. confirmed that apelin is indeed able to control duodenal motility. In the intestine, apelin dose-dependently modified acetylcholine and nitric oxide (NO) release by ENS neurons. NO is a central factor involved in glucose metabolism. Whereas 100 nM of oral apelin increased duodenal contractility and decreased glucose entry into the muscle (but not into the liver or adipose tissue) via the hypothalamic NO relay, chronic oral treatment with 1 μM of apelin for a week exerted a contrasting effect. High dose apelin decreased basal duodenal contractility, led to a more pronounced insulin release in response to glucose, increased oral glucose tolerance and an upregulation of glucose transporter type 4 mRNA expression and glucose entry into the muscle.

Apelin restores normal duodenal motility and glucose tolerance in a mouse model of diabetes. Image produced in consultation with C. Knauf and P. Cani.

In mice fed a high-fat diet, the resulting hypercontractility of the duodenum could be counterbalanced by treatment with 1 μM of apelin, which induced increased NO release and improved glucose utilization. Chronic treatment for 1 week improved glycaemia, insulin resistance, glucose tolerance and glucose entry into the muscle.

“Our work proposes a novel approach: targeting the ENS neurons via bioactive peptides present in the gut lumen. In addition, we discovered a new mode of communication between the gut and the brain (mechanical contraction) to control glycaemia,” summarize Knauf and Cani.

“We aim to find potential novel molecular actors (peptides, nutrients or others) present in the lumen able to modulate ENS activity. We hope that our findings will contribute to propose new therapeutic strategies to treat hyperglycaemia associated with T2DM, preferentially via an oral route.”


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    Fournel, A. et al. Apelin targets gut contraction to control glucose metabolism via the brain. Gut

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Weber, C. Improving glucose tolerance via the gut–brain axis. Nat Rev Gastroenterol Hepatol 13, 4 (2016).

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