β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet–Fed Mice
| Autor: | Patrick E. MacDonald, Austin Bautista, Ying Wayne Wang, Jean Buteau, Mourad Ferdaoussi, Aliya F. Spigelman, Sophie L. Lewandowski, Matthew J. Merrins, Tamadher A. Alghamdi, Yaxing Jin, Nancy Smith, Haopeng Lin, Jocelyn E. Manning Fox, Kunimasa Suzuki |
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| Rok vydání: | 2021 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism Incretin Diet High-Fat medicine.disease_cause Incretins Mice Downregulation and upregulation Insulin Regular Human Insulin-Secreting Cells Internal medicine Glucose Intolerance Internal Medicine medicine Animals Receptor Homeodomain Proteins Mice Knockout geography geography.geographical_feature_category Chemistry digestive oral and skin physiology Glucagon secretion Glucose Tolerance Test Islet Cysteine Endopeptidases Glucose Endocrinology Gene Expression Regulation Islet Studies Knockout mouse Trans-Activators hormones hormone substitutes and hormone antagonists Oxidative stress |
| Zdroj: | Diabetes |
| ISSN: | 0012-1797 |
| DOI: | 10.2337/db20-1235 |
| Popis: | 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 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 KO mice. 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. |
| Databáze: | OpenAIRE |
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