Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice
Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes. Here, we focused on a family of serine-threonine kinases known as homeodomain-interacting protein kinases (HIPKs). HIPKs are implicated in the modulation of Wnt signalling, which plays a crucial role in transcriptional activity, and in pancreas development and maintenance. The aim of the present study was to characterise the role of HIPKs in glucose metabolism.
We used RNA interference to characterise the role of HIPKs in regulating insulin secretion and transcription activity. We conducted RT-PCR and western blot analyses to analyse the expression and abundance of HIPK genes and proteins in the islets of high-fat diet-fed mice. Glucose-induced insulin secretion and beta cell proliferation were measured in islets from Hipk3 −/− mice, which have impaired glucose tolerance owing to an insulin secretion deficiency. The abundance of pancreatic duodenal homeobox (PDX)-1 and glycogen synthase kinase (GSK)-3β phosphorylation in Hipk3 −/− islets was determined by immunohistology and western blot analyses.
We found that HIPKs regulate insulin secretion and transcription activity. Hipk3 expression was most significantly increased in the islets of high-fat diet-fed mice. Furthermore, glucose-induced insulin secretion and beta cell proliferation were decreased in the islets of Hipk3 −/− mice. Levels of PDX1 and GSK-3β phosphorylation were significantly decreased in Hipk3 −/− islets.
Depletion of HIPK3 impairs insulin secretion and glucose tolerance. Decreased levels of HIPK3 may play a substantial role in the pathogenesis of type 2 diabetes.
- Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice
Volume 55, Issue 12 , pp 3318-3330
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- Glucose homeostasis
- Homeodomain-interacting protein kinase
- Insulin secretion
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- Author Affiliations
- 1. Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo, 113-8655 Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan
- 2. Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
- 3. Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan
- 4. National Center for Global Health and Medicine, Tokyo, Japan