| First Author | Lin H | Year | 2021 |
| Journal | Diabetes | Volume | 70 |
| Issue | 11 | Pages | 2626-2638 |
| PubMed ID | 34462260 | Mgi Jnum | J:314545 |
| Mgi Id | MGI:6790346 | Doi | 10.2337/db20-1235 |
| Citation | Lin H, et al. (2021) beta-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet-Fed Mice. Diabetes 70(11):2626-2638 |
| abstractText | 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 (pSENP1-KO) mice 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 wild-type littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and beta-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 beta-cell-specific SENP1 KO mice. These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired beta-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca(2+) levels. Thus, beta-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling. |
