title: The fractalkine/CX3CR1 system regulates β cell function and insulin secretion.
abstract: Here, we demonstrate that the fractalkine (FKN)/CX3CR1 system represents a regulatory mechanism for pancreatic islet β cell function and insulin secretion. CX3CR1 knockout (KO) mice exhibited a marked defect in glucose and GLP1-stimulated insulin secretion, and this defect was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca(2+) and potentiated insulin secretion in both mouse and human islets. The KO islets exhibited reduced expression of a set of genes necessary for the fully functional, differentiated β cell state, whereas treatment of wild-type (WT) islets with FKN led to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and high-fat diet/obesity, suggesting that decreased FKN/CX3CR1 signaling could be a mechanism underlying β cell dysfunction in type 2 diabetes.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Kim
authors.forename: William
authors.initials: W
authors.lastname: Lagakos
authors.forename: Susan
authors.initials: S
authors.lastname: Taylor
authors.forename: Malik
authors.initials: M
authors.lastname: Keshwani
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Ayse G
authors.initials: AG
authors.lastname: Kayali
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
authors.forename: Jerrold
authors.initials: J
authors.lastname: Olefsky
mesh_terms: D000328:Adult; D000375:Aging; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002102:Cadaver; D054428:Chemokine CX3CL1 / Q000008:administration & dosage / Q000378:metabolism; D059305:Diet, High-Fat; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D007328:Insulin; D019707:Receptors, Chemokine; D005947:Glucose