Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

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We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and 13 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 beta cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased a cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered beta cell action potential (AP) firing and decreased alpha 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.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Issue Date
2018-04
Language
English
Article Type
Article
Keywords

GLUCAGON RECEPTOR ANTAGONIST; BETA-CELL DEDIFFERENTIATION; K-ATP CHANNELS; INSULIN-RESISTANCE; DIABETES-MELLITUS; BLOOD-GLUCOSE; INTRAVENOUS GLUCOSE; BODY-WEIGHT; TNF-ALPHA; SECRETION

Citation

JOURNAL OF CLINICAL INVESTIGATION, v.128, no.4, pp.1458 - 1470

ISSN
0021-9738
DOI
10.1172/JC194330
URI
http://hdl.handle.net/10203/242429
Appears in Collection
MSE-Journal Papers(저널논문)
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