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.
View: Text | PDF
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

×

Figure 3

Chronic FKN-Fc administration exerts tissue-specific effects to improve hepatic insulin sensitivity in HFD/obese insulin resistant mice.

Options: View larger image (or click on image) Download as PowerPoint
Chronic FKN-Fc administration exerts tissue-specific effects to improve ...
(A–D) FKN-Fc treatment improves hepatic insulin sensitivity in obese mice. 10 week HFD mice were treated with vehicle or 30 mg/kg FKN-Fc for 8 weeks and subjected to ITTs (A) or hyperinsulinemic euglycemic clamp studies (B–D). Final FKN-Fc dosing was given 6 hours before the tests, at the start of fasting. Glucose infusion rate (GIR; B), hepatic glucose production (HGP; C) and basal (GDR; D) and insulin-stimulated glucose disposal rates (IS-GDR; D) were calculated as described previously (53). n = 8 for ITTs and n = 4 for clamp studies. In panel A, ITT was performed 2 times in separate cohorts of mice and a representative figure is shown. (E) Gluconeogenic activity in NCD mouse hepatocytes. n = 4. (F) Intracellular cAMP levels 15 min after hormonal treatment(s) in NCD mouse hepatocytes. n = 4. (G) CREB and Akt phosphorylation 30 min after hormonal stimulation. (H) Gluconeogenic activity in pertussis toxin (PTX)-treated (30 min pretreatment) NCD mouse hepatocytes. n = 4. (I) Gluconeogenic activity in HFD mouse hepatocytes. n = 4. (J) Intracellular cAMP levels in HFD mouse hepatocytes 15 min after hormonal treatment(s). n = 4. For statistical analysis, ANOVA with post-hoc t tests between the individual groups (A), 2-tailed unpaired t test (B) or 1-way ANOVA (C, E, F, H–J) 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 < 0.001 versus lane 1; #P < 0.05 versus lane 2; ##P < 0.01 versus lane 2. See also Supplemental Figure 3. See complete unedited blots in the supplemental material.