The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse.

Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic beta-cell function and/or progressive loss of pancreatic beta-cell mass under the context of insulin resistance. alpha 7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of alpha 7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an alpha 7 nAChR knock-out (alpha 7(-/-)) mouse model fed a standard chow diet. The effects of the lack of alpha 7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young alpha 7(-/-)mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in beta-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, alpha 7(-/-) mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of alpha 7 nAChR in glucose homeostasis. The constitutive lack of alpha 7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.