cAMP-Activated Protein Kinase-Independent Potentiation of Insulin Secretion by cAMP Is Impaired in SUR1 Null Islets

  1. Mitsuhiro Nakazaki1,
  2. Ana Crane2,
  3. Min Hu1,
  4. Victor Seghers1,
  5. Susanne Ullrich1,
  6. Lydia Aguilar-Bryan2 and
  7. Joseph Bryan1
  1. 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
  2. 2Department of Medicine, Baylor College of Medicine, Houston, Texas

    Abstract

    Whereas the loss of ATP-sensitive K+ channel (KATP channel) activity in human pancreatic β-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 β-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.

    Footnotes

    • Address correspondence and reprint requests to Joseph Bryan, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. E-mail: jbryan{at}bcm.tmc.edu.

      Received for publication 14 May 2002 and accepted in revised form 23 August 2002.

      M.N. and A.C. contributed equally to this study.

      M.N. is currently located at the First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Sakuragaoka, Kagoshima, Japan; and S.U. is currently located at the Institut fuer Physiologie, Universitaet Tuebingen, Gmelinstrasse, Tuebingen, Germany.

      [Ca2+]i, cytosolic Ca2+ concentration; [cAMP]i, intracellular content of cAMP; CREB, cAMP-response element-binding protein; Epac, exchange protein directly activated by cAMP; GEF, guanine-nucleotide exchange factor; GIIS, glucose-induced insulin secretion; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; H-89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide; HI, hyperinsulinemic hypoglycemia; IBMX, 3-isobutyl-1-methylxanthine; KATP channel, ATP-sensitive K+ channel; KD, estimated dissociation constant; Ki, constant for inhibition; KRB, Krebs-Ringer bicarbonate buffer; PKA, cAMP-activated protein kinase; PKC, protein kinase C; PKI, protein kinase inhibitor; Rp-cAMPS, (Rp)-Adenosine 3′,5′-monophosphorothioate; SUR1, sulfonylurea receptor-1; TPA, 12-O-tetradecanoylphorbol 13-acetate.

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