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J Clin Invest. 2018 Apr 2;128(4):1458-1470. doi: 10.1172/JCI94330. Epub 2018 Mar 5.

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function.

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Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA.
Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Department of Pharmacology, UCSD, La Jolla, California, USA.
Cardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, California, USA.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.


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.


Diabetes; Endocrinology; Gluconeogenesis; Insulin; Metabolism

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