Ablation of PDK1 in pancreatic cells induces diabetes as a result of loss of cell mass

Naoko Hashimoto¹, Yoshiaki Kido¹, Tohru Uchida¹, Shun-ichiro Asahara¹, Yutaka Shigeyama¹, Tomokazu Matsuda¹, Akihiko Takeda¹, Daisuke Tsuchihashi¹, Akihiko Nishizawa¹, Wataru Ogawa¹, Yoshito Fujimoto², Hitoshi Okamura², Karen C Arden³, Pedro L Herrera⁴, Tetsuo Noda⁵ & Masato Kasuga¹

¹  Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

²  Department of Brain Sciences, Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

³  Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093-0660, USA.

⁴  Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.

⁵  Department of Cell Biology, Cancer Institute, Tokyo 135-8550, Japan.

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-kinase^{2, 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 cells (Pdk1^-/- 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 Pdk1^-/- mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.

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