Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 S6.2

ECE2007 Symposia Diabetes and insulin (4 abstracts)

Cytokines as pathogenetic effectors in type 1 and type 2 diabetes

Thomas Mandrup-Poulsen


Steno Diabetes Center, Gentofte, Denmark; Karolinska Institute, Stockholm, Sweden.


The pro-inflammatory cytokine interleukin-1 is selectively cytotoxic to rodent and human beta-cells in vitro, and anti-IL-1 therapies reduce diabetes incidence in animal prevention models: (1) IL-1 alone or in combination with other inflammatory cytokines causes beta-cell destruction in rodent and human islets and in perfused pancreas via MAPK and NFkB signaling, (2) IL-1 given i.p. to non-diabetes prone animals causes transient insulinopenic diabetes (3) IL-1 is expressed early in islets of the non-obese diabetic (NOD) mouse, a model of spontaneous autoimmune diabetes (4) anti-IL-1 intervention prevents diabetes development in animal models of Type 1 diabetes and islet graft destruction and (5) transgenic mice with knock-out of the IL-1 receptor reduces diabetes incidence.

We recently completed a 13-week clinical study of IL-1 Receptor Antagonist (IL-1Ra, anakinra, KineretR, Amgen) therapy in Type 2 diabetics based on the rationale that in vitro glucotoxicity to human beta-cells can be prevented with IL-1Ra, and that glucose induces islet IL-1 production, which causes beta-cell apoptosis by pathways similar to those believed to operate in Type 1 diabetes. This study provided proof-of-principle that inhibition of IL-1 signalling can improve glycemia and beta-cell function in humans. Interestingly, maximal effect on glycosylated hemoglobin with anakinra was seen after 4 weeks, and fasting blood glucose was significantly reduced already after 1 week, suggesting rapid effects on beta-cell secretory capacity. These preclinical and clinical studies warrant studies to investigate the effect of IL-1 blockade in patients with recent-onset Type 1 diabetes mellitus.

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