Insulin secretion is regulated by the glucose-dependent production of islet β cell macrophage migration inhibitory factor

Insulin secretion is regulated by the glucose-dependent production of islet β cell macrophage migration inhibitory factor

^*Department of Internal Medicine B and ^¶Division of Endocrinology and Metabolism, University Hospital, CHUV-1011 Lausanne, Switzerland; ^§Pharmacology and Toxicology Institute, University of Lausanne, 1005 Lausanne, Switzerland; ^‖Department of Anatomy and Cell Biology, Philipps University of Marburg, 35033 Marburg, Germany; and ^‡The Picower Institute for Medical Research, Manhasset, New York 11030

Abstract

Macrophage migration inhibitory factor (MIF), originally identified as a cytokine secreted by T lymphocytes, was found recently to be both a pituitary hormone and a mediator released by immune cells in response to glucocorticoid stimulation. We report here that the insulin-secreting β cell of the islets of Langerhans expresses MIF and that its production is regulated by glucose in a time- and concentration-dependent manner. MIF and insulin colocalize by immunocytochemistry within the secretory granules of the pancreatic islet β cells, and once released, MIF appears to regulate insulin release in an autocrine fashion. In perifusion studies performed with isolated rat islets, immunoneutralization of MIF reduced the first and second phase of the glucose-induced insulin secretion response by 39% and 31%, respectively. Conversely, exogenously added recombinant MIF was found to potentiate insulin release. Constitutive expression of MIF antisense RNA in the insulin-secreting INS-1 cell line inhibited MIF protein synthesis and decreased significantly glucose-induced insulin release. MIF is therefore a glucose-dependent, islet cell product that regulates insulin secretion in a positive manner and may play an important role in carbohydrate metabolism.

Footnotes

↵ † To whom reprint requests should be addressed at: Department of Internal Medicine B-/19–135, Centre Hospitalier Universitaire Vaudois, CHUV-1011 Lausanne, Switzerland. e-mail: Gerard.Waeber{at}chuv.unil.ch.
Helen M. Ranney, Alliance Pharmaceutical Corp., San Diego, CA
ABBREVIATIONS:

MIF,

macrophage migration inhibitory factor;

rMIF,

recombinant MIF