Editors' ChoiceDiabetes

It's a Matter of Life and Death

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Science Translational Medicine  23 Jun 2010:
Vol. 2, Issue 37, pp. 37ec99
DOI: 10.1126/scitranslmed.3001359

In Type 2 diabetes mellitus, an insufficient amount of insulin is produced in response to circulating glucose, and there is a decrease in pancreatic β-cell mass and function. Apoptosis (cell death), which causes much of the reduction in β-cell number, can be induced by several mechanisms, including high concentrations of fat and glucose or genetic influences. One genetic factor is an adaptive-response gene, activating transcription factor–3 (ATF-3), which is stimulated by stress signals similar to those that cause apoptosis. Zmuda et al. examined the role of ATF-3 in mediating high-fat diet–induced diabetes in a mouse model, hypothesizing that ATF-3 would contribute to β-cell apoptosis and therefore to the development of T2DM.

The authors studied wild-type mice with a normal complement of ATF-3 genes and compared them with mice in which the gene had been completely deleted (knockout mice). Six-week-old mice were fed either high-fat (60% fat) or normal fat (5% fat) chow for 16 weeks and were then evaluated for weight gain and glucose intolerance. All of the mice on the high-fat diet developed hyperglycemia and glucose intolerance. However, contrary to the authors’ expectations, apoptosis of pancreatic β cells was not evident in either group, and the wild-type mice were less glucose-intolerant and had higher serum insulin than did the knockout mice. This difference was observed even though both groups of mice had similar degrees of insulin resistance and proinflammatory cytokines.

This study is an elegant illustration of how a mouse model can be used to study human obesity-induced diabetes and to examine potential mechanisms of disease. Despite disproving their own original hypothesis, the authors uncovered an exciting role for ATF-3 in enhancing β-cell function, which can now direct future investigative efforts.

E. J. Zmuda et al., The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic β-cell dysfunction. Mol. Endocrinol.. 2 June 2010 (doi: 10.1210/me.2009-0463). [Abstract]

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