Editors' ChoiceDiabetes

Mayday, Mayday, Mayday! Answering the Distress Call of the β Cell

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Science Translational Medicine  08 Feb 2012:
Vol. 4, Issue 120, pp. 120ec20
DOI: 10.1126/scitranslmed.3003792

Type 1 diabetes is characterized by nearly complete autoimmune destruction of insulin-secreting pancreatic β cells. When the disease first becomes apparent, the diabetic patient has already lost more than 90% of β cell function and mass. In fact, clinical and preclinical data suggest that β-cell destruction in diabetes is a smoldering process that begins years before symptoms appear. Even in individuals with known genetic risk, however, this early damage cannot be detected. Now, Akirav and colleagues have developed a noninvasive method for the detection of β-cell death in vivo, a tool that may allow earlier identification and, most important, preventative and immodulatory therapies.

Among cells, only pancreatic β cells can synthesize and secrete physiologically relevant amounts of insulin, a unique ability conferred by the epigenetic architecture of the insulin locus. In most cells, the insulin gene is silenced by histone modifications and methylation of CpG islands in the promoter. But in β cells, these marks are missing. Akirav et al. exploited this distinction by identifying differentially methylated regions of the insulin gene and, with a polymerase chain reaction–based assay, measuring the ratio of demethylated to methylated insulin DNA. A higher demethylation index identified DNA derived from the β cell. In a proof-of-principle experiment, the demethylation index of DNA in serum from diabetic mice that had been treated with the β-cell toxin streptozotocin was increased nearly fourfold. Serum DNA from prediabetic NOD (nonobese diabetic) mice showed an even higher demethylation index, suggesting that this assay may be able to detect β-cell death even before the onset of frank hyperglycemia. As a final confirmation, the demethylation index was quantitated in serum DNA from human subjects with new-onset Type 1 diabetes and found to be significantly increased as compared with age-matched controls.

A mayday call is a standard emergency procedure for a vessel in distress. The term is derived from the French phrase “venez m’aider,” which means simply “come help me.” Although larger studies in diabetic and prediabetic human subjects are needed, the assay developed by Akirav and colleagues offers new hope that the β-cell distress signal in Type 1 diabetes may finally be answered.

E. M. Akirav et al., Detection of β cell in diabetes using differentially methylated circulating DNA. Proc. Natl. Acad. Sci. U.S.A. 108, 19018–19023 (2011). [PubMed]

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