Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function
Matthew Riopel, … , Jerrold M. Olefsky, Yun Sok Lee
Matthew Riopel, … , Jerrold M. Olefsky, Yun Sok Lee
Published March 5, 2018
Citation Information: J Clin Invest. 2018;128(4):1458-1470. https://doi.org/10.1172/JCI94330.
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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 5

Electrophysiology studies in α cells.

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Electrophysiology studies in α cells. (A) Glucagon secretion in primary ...
(A) Glucagon secretion in primary mouse islets. Islets were incubated in 1 mM glucose medium for 16 hours and washed. Islet glucagon (Gcg) release was measured after incubation with insulin (100 nM) or FKN (100 or 500 ng/ml) for 1 hour. Mean ± SEM; n = 5 for control and 6 for other groups. *P < 0.05 vs. lane 1; **P < 0.01 vs. lane 1; #P < 0.05 vs. lane 2; 1-way ANOVA. (B) Glucagon secretion in αTC1 cells. αTC1 cells were incubated in 1 mM glucose medium for 16 hours and washed. Glucagon release was measured after incubation of the cells with FKN for 1 hour. Mean ± SEM; n = 3 (lane 4) or 7 (lane 1–3). *P < 0.05 vs. lane 1; #P = 0.051 vs. lane 1; 1-way ANOVA. (C) IHC analysis of CX3CR1 expression in primary WT mouse islets. Images were obtained at ×20 magnification. (D) Flow cytometry analysis of CX3CR1 expression in primary α and β cells in dispersed islet cells. Right lower box in the graph is for glucagon+/insulin– subset. Left upper box is for the glucagon–/insulin+ subset. (E) KATP currents in the presence or absence of FKN (100 ng/ml) in αTC1 cells. (F) KATP currents in the presence or absence of FKN (100 ng/ml) in primary α cells. (G) Membrane potential (Vm) and AP firing before and after FKN (100 ng/ml) treatment in αTC1 cells. Cells were incubated in 0.5 mM glucose medium, and depolarization of membrane potential (ΔVm), average AP peak, and AP frequency upon FKN treatment were analyzed. Ctl, control (before FKN treatment). Mean ± SEM; n = 7. **P < 0.01; 2-tailed unpaired t test. (H) Intracellular Ca2+ levels in the presence (n = 47) or absence (n = 31) of FKN. Lowering extracellular glucose concentration from 10 to 0.5 mM triggered Ca2+ rise in αTC1 cells. ***P < 0.01; 1-way ANOVA. See also Supplemental Figure 5.