Journal
DIABETES
Volume 51, Issue 12, Pages 3440-3449Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.51.12.3440
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- NIDDK NIH HHS [DK 57671, DK 52771] Funding Source: Medline
- PHS HHS [DL50750] Funding Source: Medline
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Whereas the loss of ATP-sensitive K+ channel (K-ATP channel) activity in human pancreatic P-cells causes severe hypoglycemia in certain forms of hyperinsulinemic hypoglycemia, similar channel loss in sulfonylurea receptor-1 (SUR1) and Kir6.2 null mice yields a milder phenotype that is characterized by normoglycemia, unless the animals are stressed. 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 beta-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-isoquinollnesulfonamide) and KT5720, inhibitors of PKA, do not affect stimulation by GLP-1, GIP, or ex-endin-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 K-ATP channel activity.
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