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
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
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Research Article Endocrinology Metabolism

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

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.

Authors

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

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Figure 4

Electrophysiology studies in β cells.

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Electrophysiology studies in β cells. (A) KATP channel current in Min6 c...
(A) KATP channel current in Min6 cells. U0216 (200 nM) was pretreated 1 hour before the measurements. (B) Dose-dependent inhibition of KATP channel activity by FKN in the presence or absence of 200 nM U0126 or 10 nM PD98059. n = 3, 12, 3, 4, 5, 8 and 4 for lane 1–7, respectively. **P < 0.01; ***P < 0.001; 2-tailed unpaired t test. (C) ATP/ADP ratio in Min6 cells with or without FKN (100 ng/ml) treatment for 60 min. (D) Oxygen consumption rate in Min6 cells. Oligo, oligomycin (ATP synthase inhibitor); FCCP, trifluoromethoxy carbonylcyanide phenylhydrazone (a protonophoric uncoupler). (E and F) KATP channel current in primary WT (n = 5; E) and CX3CR1 KO (n = 4; F) β cells in intact islets. FKN effects were seen relatively slower, probably due to surrounding cells in the intact islet. (G) Plasma membrane potential (Vm) and AP firing in low glucose conditions in Min6 cells. A representative figure is presented (left). Bar graphs (right) represent average electrical activities 30 seconds after FKN application. (H) Vm and AP firing in high glucose conditions in Min6 cells. Min6 cells were incubated in 2 mM glucose for 16 h and challenged by high glucose. 5 minutes after, FKN was applied. A representative figure from 7 independent experiments (left). n = 8 (17 mM glucose) and n = 7 (17 mM glucose + FKN condition). *P < 0.05. (I) VDCC currents activated by voltage steps (insets). A representative recording from four measurements. (J) Time course measurement of VDCC currents at +20 mV. n = 4. Throughout the figure, values in bar graphs represent mean ± SEM. See also Supplemental Figure 4.