Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons

Abstract

ObjectiveDecreasing duodenal contraction is now considered as a major focus for the treatment of type 2 diabetes. Therefore, identifying bioactive molecules able to target the enteric nervous system, which controls the motility of intestinal smooth muscle cells, represents a new therapeutic avenue. For this reason, we chose to study the impact of oral galanin on this system in diabetic mice.MethodsEnteric neurotransmission, duodenal contraction, glucose absorption, modification of gut–brain axis, and glucose metabolism (glucose tolerance, insulinemia, glucose entry in tissue, hepatic glucose metabolism) were assessed.ResultsWe show that galanin, a neuropeptide expressed in the small intestine, decreases duodenal contraction by stimulating nitric oxide release from enteric neurons. This is associated with modification of hypothalamic nitric oxide release that favors glucose uptake in metabolic tissues such as skeletal muscle, liver, and adipose tissue. Oral chronic gavage with galanin in diabetic mice increases insulin sensitivity, which is associated with an improvement of several metabolic parameters such as glucose tolerance, fasting blood glucose, and insulin.ConclusionHere, we demonstrate that oral galanin administration improves glucose homeostasis via the enteric nervous system and could be considered a therapeutic potential for the treatment of T2D.

Inflammation and Gut-Brain Axis During Type 2 Diabetes: Focus on the Crosstalk Between Intestinal Immune Cells and Enteric Nervous System

“…The gut-brain axis is shown as a major signaling pathway controlling glucose homeostasis, and its disturbance is associated with a T2D phenotype ( Abot et al, 2018a , b ). In normal conditions, glucose is detected by intestinal glucose sensors (such as SGLT1, GLUT2, TASR1/2) present on intestinal cells (enteroendocrine and brush cells, enteric glial cells and neurons) which inform the whole body from the presence of glucose via the release of various factors (i.e., gut hormones, neurotransmitters, metabolites) ( Fournel et al, 2016 ).…”

“…One of the main functions of ENS is to regulate contractions of intestinal smooth muscle cells. In physiological conditions, the reduction of intestinal contractions provokes a decreased fed hyperglycemia ( Fournel et al, 2017 ; Abot et al, 2018b ). The modifications of mechanical contractions are detected by the hypothalamus, which controls glucose utilization ( Fournel et al, 2017 ).…”

“…The modifications of mechanical contractions are detected by the hypothalamus, which controls glucose utilization ( Fournel et al, 2017 ). During T2D, intestinal inflammation is clearly associated with a dysfunction of ENS neurons ( Gonzalez-Correa et al, 2017 ), which could favor duodenal hyper-contractility ( Abot et al, 2018b ). Our group has demonstrated that duodenal hyper-contractility participates to the establishment of hyperglycemia of HFD mice by modulating the hypothalamic NO release ( Fournel et al, 2017 ).…”

The gut microbiota to the brain axis in the metabolic control

“…1). When they are activated, they could transmit a neuronal message to the VN participating to the glycemia regulation through the gut-brain axis [14,28,30]. Furthermore, when the enteric neurons are pharmacologically destroyed, the GLP-1-induced gut-brain axis stimulation is decreased, impairing neuronal glucose detection [14].…”

Impact of Intestinal Peptides on the Enteric Nervous System: Novel Approaches to Control Glucose Metabolism and Food Intake

“…Alteration of nutrients and/or hormones sensing in the intestine are associated with aberrant hypothalamic responses that could lead to pathological states including T2D ( 10 – 12 ). For example, obese/diabetic mice and humans exhibit a decrease of nNOS expression in the digestive tract in correlation with an alteration of the ENS activity associated with intestinal hyper-contractility ( 12 – 16 ). In fact, physiopathological mechanism of diabetes-induced GI enteric neuropathy is complex and multifactorial.…”