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

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 insulinsecreting ␤ 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 ␤ 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.

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

“…It co-localizes with insulin in secretory granules of b-cells and is secreted in the same manner as insulin upon glucose stimulus. 14 Further, MIF potentiates glucose-stimulated insulin secretion, whereas MIF expression is upregulated in the presence of high glucose. 14,21 However, MIF might be involved in b-cell apoptosis induction as its blockade by anti-MIF antibody stimulates INS-1 cell proliferation 22 and prevents b-cell death in the multiple low doses of streptozotocin-induced diabetes.…”

“…14 Further, MIF potentiates glucose-stimulated insulin secretion, whereas MIF expression is upregulated in the presence of high glucose. 14,21 However, MIF might be involved in b-cell apoptosis induction as its blockade by anti-MIF antibody stimulates INS-1 cell proliferation 22 and prevents b-cell death in the multiple low doses of streptozotocin-induced diabetes. 23 There is also evidence that MIF promotes apoptotic cell death in primary bladder muscle cells, B lymphocytes, tumor cell lines, cardiomyocytes and neurons.…”

“…12 This potentially includes macrophage migration inhibitory factor (MIF), a cytokine produced by various immune and non-immune cells including pancreatic b-cells. 13,14 It is a multifunctional molecule generally described as pro-inflammatory and glucocorticoid-induced regulator involved in both innate and adaptive immunity. 13,15 In addition, MIF functions as an enzyme with D-dopachrome tautomerase activity and blockade of its active site accounts for several biological implications such as inhibition of MIF-mediated stimulation of TNF-a and arachidonic acid production and glucocorticoid-regulating activity.…”

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

“…4 MIF is also produced by pancreatic beta cells and acts as a positive regulator of insulin secretion when the cells are stimulated with glucose. 5 Furthermore, MIF expressed in muscle has a catabolic effect via induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase. 6 MIF is also expressed in adipose tissue and is upregulated by glucose and insulin.…”

“…10 Although this finding was not replicated in other populations, it is possible that 22q11.23 is a susceptibility locus for abdominal adiposity in a particular population. Two polymorphisms are known to exist in the promoter region of the MIF gene, a tetranucleotide CATT repeat located at position À794 (À794[CATT] [5][6][7][8] ) and a single-nucleotide G/C substitution located at position À173 (À173G/C). 11,12 The polymorphisms at À794 and at À173 were shown to be associated with severity of rheumatoid arthritis and with risk of systemiconset juvenile idiopathic arthritis, respectively.…”