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 2

Chronic FKN-Fc administration enhances GSIS and decreases apoptosis in the islets of obese mice.

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Chronic FKN-Fc administration enhances GSIS and decreases apoptosis in t...
(A) Static GSIS in primary mouse islets. (B) Relative apoptotic activity in primary mouse islet cells. Pal, palmitate. (C–E) Chronic FKN-Fc administration improves GSIS and decreases apoptosis in islets of HFD WT mice. 10 week HFD mice were treated with vehicle or FKN-Fc for an additional 8 weeks. Islets were isolated and similar sized islets were picked under the microscope and subjected to in vitro GSIS (C), quantitative RT-PCR (Q-PCR) (D) and caspase-3/7 activity assays (E). (F–G) Chronic FKN-Fc administration decreases β cell apoptosis in ob/ob mice. 8 week-old ob/ob mice were ip injected with vehicle or 30 mg/kg FKN-Fc every other day for 7 weeks. β cell apoptosis and apoptoic gene expression was assessed by immunohistochemistry (IHC) analyses using anti-insulin and anti-active (cleaved) caspase-3 antibodies (F) and Q-PCR (G), respectively. n = 4. (H and I) Morphometric analyses of HFD mouse islets. 10 week HFD mice were treated with FKN-Fc every other day for 8 weeks. A whole pancreas was harvested from each mouse, weighed and then fixed for IHC analyses. β Cell mass (H) and islet number per unit pancreatic area (I) were measured after staining with anti-insulin antibody, as described in Methods. Images are obtained at ×20 magnification. AU, arbitrary unit. For statistical analysis, 2-tailed paired t test (C, E, F, and H) or 1-way ANOVA (A, B, D, and G) was performed. In all graph panels, values are mean ± SEM and the symbols indicate statistical analysis: *P < 0.05 versus lane 1; **P < 0.01 versus lane 1; #P < 0.05 versus lane 2; ##P < 0.01 versus lane 2. See also Supplemental Figure 2.