long_term_HFD_SENP1_V11_Supplemental.pdf (25.64 MB)

β-cell knockout of SENP1 reduces responses to incretins and worsens oral glucose tolerance in high fat diet-fed mice

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posted on 30.08.2021, 03:33 by Haopeng Lin, Nancy Smith, Aliya F Spigelman, Kunimasa Suzuki, Mourad Ferdaoussi, Tamadher A. Alghamdi, Sophie L Lewandowski, Yaxing Jin, Austin Bautista, Ying Wayne Wang, Jocelyn E. Manning Fox, Matthew J Merrins, Jean Buteau, Patrick E MacDonald
SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout mice (pSENP1-KO) on a high fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls, but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 1 (GLP-1) responses were identical in pSENP1-KO and -WT littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist Exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell-specific SENP1 knockout mice (βSENP1-KO). These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca2+ levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling.


This work was funded by a Foundation Grant to PEM from the Canadian Institutes of Health Research (CIHR: 148451). SLL and MJM were supported by grants from the National Institutes of Health (F31DK126403 to SLL, and R01DK113103 and R01DK127637 to MJM). YJ was supported by a University of Alberta Office of the Provost and VP (Academic) Summer Studentship. HL was supported by a from the Sino-Canadian Studentship from Shantou University. PEM holds the Canada Research Chair in Islet Biology.