Chronic fractalkine administration improves... : Journal of Clinical Investigation (original) (raw)

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

Matthew Riopel
Jong Bae Seo
Gautam K. Bandyopadhyay
Pingping Li
Joshua Wollam
Heekyung Chung
Seung-Ryoung Jung
Anne Murphy
Maria Wilson
Ron de Jong
Sanjay Patel
Deepika Balakrishna
James Bilakovics
Andrea Fanjul
Artur Plonowski
Duk-Su Koh
Christopher J. Larson
Jerrold M. Olefsky
Yun Sok Lee

Journal of Clinical Investigation

128

(

)

1458

1470

April 2, 2018

| DOI: 10.1172/JCI94330

We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin–sensitive manner. 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.