| First Author | Ferdaoussi M | Year | 2020 |
| Journal | Physiol Rep | Volume | 8 |
| Issue | 8 | Pages | e14420 |
| PubMed ID | 32339440 | Mgi Jnum | J:346298 |
| Mgi Id | MGI:7614980 | Doi | 10.14814/phy2.14420 |
| Citation | Ferdaoussi M, et al. (2020) Improved glucose tolerance with DPPIV inhibition requires beta-cell SENP1 amplification of glucose-stimulated insulin secretion. Physiol Rep 8(8):e14420 |
| abstractText | Pancreatic islet insulin secretion is amplified by both metabolic and receptor-mediated signaling pathways. The incretin-mimetic and DPPIV inhibitor anti-diabetic drugs increase insulin secretion, but in humans this can be variable both in vitro and in vivo. We examined the correlation of GLP-1 induced insulin secretion from human islets with key donor characteristics, glucose-responsiveness, and the ability of glucose to augment exocytosis in beta-cells. No clear correlation was observed between several donor or organ processing parameters and the ability of Exendin 4 to enhance insulin secretion. The ability of glucose to facilitate beta-cell exocytosis was, however, significantly correlated with responses to Exendin 4. We therefore studied the effect of impaired glucose-dependent amplification of insulin exocytosis on responses to DPPIV inhibition (MK-0626) in vivo using pancreas and beta-cell specific sentrin-specific protease-1 (SENP1) mice which exhibit impaired metabolic amplification of insulin exocytosis. Glucose tolerance was improved, and plasma insulin was increased, following either acute or 4 week treatment of wild-type (betaSENP1(+/+) ) mice with MK-0626. This DPPIV inhibitor was ineffective in betaSENP1(+/-) or betaSENP1(-) (/) (-) mice. Finally, we confirm impaired exocytotic responses of beta-cells and reduced insulin secretion from islets of betaSENP1(-) (/) (-) mice and show that the ability of Exendin 4 to enhance exocytosis is lost in these cells. Thus, an impaired ability of glucose to amplify insulin exocytosis results in a deficient effect of DPPIV inhibition to improve in vivo insulin responses and glucose tolerance. |
