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While investigating potential compensatory mechanisms, we found that incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), can increase the cAMP content of Sur1KO islets but do not potentiate glucose-stimulated insulin release. This impairment is secondary to a restriction in the ability of Sur1KO \u03b2-cells to sense cAMP correctly. Potentiation does not appear to require cAMP-activated protein kinase (PKA) because H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) and KT5720, inhibitors of PKA, do not affect stimulation by GLP-1, GIP, or exendin-4 in wild-type islets, although they block phosphorylation of cAMP-response element-binding protein. The impaired incretin response in Sur1KO islets is specific; the stimulation of insulin release by other modulators, including mastoparan and activators of protein kinase C, is conserved. The results suggest that the defect responsible for the loss of cAMP-induced potentiation of insulin secretion is PKA independent. We hypothesize that a reduced release of insulin in response to incretins may contribute to the unexpected normoglycemic phenotype of Sur1KO mice versus the pronounced hypoglycemia seen in neonates with loss of KATP channel activity.<\/jats:p>","DOI":"10.2337\/diabetes.51.12.3440","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"3440-3449","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":86,"title":["cAMP-Activated Protein Kinase-Independent Potentiation of Insulin Secretion by cAMP Is Impaired in SUR1 Null Islets"],"prefix":"10.2337","volume":"51","author":[{"given":"Mitsuhiro","family":"Nakazaki","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Crane","sequence":"additional","affiliation":[{"name":"Department of Medicine, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor","family":"Seghers","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Ullrich","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Aguilar-Bryan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Bryan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031223235792200_R1","doi-asserted-by":"crossref","unstructured":"Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. 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