Previously we reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and beta cell function. In this study, we examined whether chronic administration of FKN can exert durable effects to improve glucose tolerance in obese rodent models and performed a series of comprehensive mechanistic studies. Chronic administration of a long acting form of FKN (FKN-Fc fusion protein) into obese and insulin resistant mice improved glucose tolerance with improved beta cell function. Unexpectedly, FKN-Fc administration also led to decreased plasma glucagon levels. At the molecular level, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism in both alpha and beta cells. This led to enhanced glucose-stimulated action potential (AP) firing in beta cells, while it decreased alpha cell AP amplitude. Consistent with these results, FKN-Fc treatment increased GSIS and decreased glucagon secretion in beta and alpha cells, respectively. In addition to these effects in islet cells, chronic FKN-Fc treatment also decreased hepatic glucose production. In vitro and ex vivo experiments with normal and obese hepatocytes demonstrated that FKN treatment decreases glucagon-stimulated cAMP levels and CREB phosphorylation in a pertussis toxin-sensitive manner. Taken together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.


Y. Lee: None.

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