| First Author | Briere DA | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 2 | Pages | 309-320 |
| PubMed ID | 29203510 | Mgi Jnum | J:258050 |
| Mgi Id | MGI:6112999 | Doi | 10.2337/db17-0607 |
| Citation | Briere DA, et al. (2018) Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and Metabolic Surgery. Diabetes 67(2):309-320 |
| abstractText | Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" ( approximately 50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 ( approximately 5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations ( approximately 300-400 pmol/L), drastically reducing glucose in Gipr null and Lepr(db/db) mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens. |
