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- Title
Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function.
- Authors
Riopel, Matthew; Jong Bae Seo; Bandyopadhyay, Gautam K.; Pingping Li; Wollam, Joshua; Heekyung Chung; Seung-Ryoung Jung; Murphy, Anne; Wilson, Maria; de Jong, Ron; Patel, Sanjay; Balakrishna, Deepika; Bilakovics, James; Fanjul, Andrea; Plonowski, Artur; Duk-Su Koh; Larson, Christopher J.; Olefsky, Jerrold M.; Yun Sok Lee; Seo, Jong Bae
- 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.
- Subjects
FRACTALKINE; GLUCOSE tolerance tests; ISLANDS of Langerhans; CREB protein; PHOSPHORYLATION; GLUCAGON
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 4, p1458
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI94330