The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes1, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor–1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase2,3,4. 3-Phosphoinositide–dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic β cells (βPdk1−/− mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in βPdk1−/− mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.
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We thank T. Nakamura for discussion as well as M. Kawasaki and M. Nagano for technical assistance. This work was supported by grants for the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) to M.K. and Y.K.; a grant from the 21st Century COE Program 'Center of excellence for signal transduction disease: diabetes mellitus as model' from MEXT to M.K.; a grant for the Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER) from MEXT to M.K.; a grant from Yamaguchi Endocrine Research Association to Y.K. and grants from the Juvenile Diabetes Research Foundation, the US National Institutes of Health and the Swiss National Science Foundation to P.L.H.
The authors declare no competing financial interests.
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Hashimoto, N., Kido, Y., Uchida, T. et al. Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nat Genet 38, 589–593 (2006). https://doi.org/10.1038/ng1774
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