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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.

Author information

1
Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA.
2
Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
3
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.
4
Department of Pharmacology, UCSD, La Jolla, California, USA.
5
Cardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, California, USA.
6
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
7
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.

Abstract

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.

KEYWORDS:

Diabetes; Endocrinology; Gluconeogenesis; Insulin; Metabolism

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