Dan Kawamori1,2,3, Jun Shirakawa1, Chong Wee Liew1,4, Jiang Hu1, Tomoaki Morioka1,5, Alokesh Duttaroy6, Bryan Burkey7, Rohit N Kulkarni8,9,10. 1. Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Room 410, One Joslin Place, Boston, MA, 02215, USA. 2. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan. 3. Medical Education Center, Faculty of Medicine, Osaka University, Osaka, Japan. 4. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA. 5. Department of Metabolism, Endocrinology and Molecular Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan. 6. Cardiovascular & Metabolic Diseases, Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA. 7. Zafgen Inc., Boston, MA, USA. 8. Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Room 410, One Joslin Place, Boston, MA, 02215, USA. Rohit.Kulkarni@joslin.harvard.edu. 9. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Rohit.Kulkarni@joslin.harvard.edu. 10. Harvard Stem Cell Institute, Boston, MA, USA. Rohit.Kulkarni@joslin.harvard.edu.
Abstract
AIMS/HYPOTHESIS: We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function. METHODS: Beta cell-specific insulin receptor knockout (βIRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated. RESULTS: The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating βIRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two- to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated βIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired. CONCLUSIONS/ INTERPRETATION: Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.
AIMS/HYPOTHESIS: We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function. METHODS: Beta cell-specific insulin receptor knockout (βIRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated. RESULTS: The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating βIRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two- to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated βIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired. CONCLUSIONS/ INTERPRETATION: Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.
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