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

Abstract

Whereas the loss of ATP-sensitive K؉ channel (K ATP channel) activity in human pancreatic ␤-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 glucosedependent 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 I nsulin secretion is a unique example of exocytosis controlled by metabolic, ionic, and hormonal pathways. An imbalance in insulin release due to disruption of these pathways can produce the profound changes in glucose homeostasis associated with either hyperglycemia (diabetes) or hypoglycemia (e.g., hyperinsulinemic hypoglycemia [HI]). In pancreatic ␤-cells, ATPsensitive K ϩ channels (K ATP channels), composed of Kir6.2 and the sulfonylurea receptor-1 (SUR1), and voltage-gated Ca 2ϩ channels are key players linking increased glucose metabolism to elevation of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ). Membrane depolarization induced by closure of K ATP channels, secondary to changes in ADP/ ATP resulting from glucose metabolism, leads to the generation of Ca 2ϩ -dependent action potentials and [Ca 2ϩ ] i oscillations, which are considered to be a major mediator of insulin secretion. Sulfonylureas that block ␤-cell K ATP channels are commonly used to restore insulin secretion in type 2 diabetes. The loss or constitutive closure of ␤-cell K ATP channels, as a result of mutations in either subunit, is a cause of both dominant and recessive forms of HI (HI-SUR1 or HI-Kir6.2), characterized by elevated plasma insulin values inconsistent with the observed hypoglycemia (reviewed in 1,2). Studies on islets isolated from patients diagnosed with HI are consistent with hypersecretion of insulin (3,4). By comparison, the clinical phenotype of mice lacking ␤-cell/neuronal K ATP channels is strikingly normal. Kir6.2 null (Kir6.2KO) (5) and Sur1KO (6) mice are normoglycemic when fed, displaying only mild glucose intolerance, consistent with their loss of first phase and attenuated second phase of insulin release. Sur1KO mice exhibit greater hypoglycemia upon fasting, consistent with their inability to rapidly repolarize their ␤-cells and reduce insulin release (6). No compensating ionic mechanisms have been identified, and the electrophysiological phenotype of isolated K ATP KO mouse ␤-cells, i.e., constant membrane depolarization, presence of Ca 2ϩ -dependent action potentials, and elevated oscillating [Ca 2ϩ ] i in low glucose, is quite similar to that of ␤-cells from HI neonates (compare 5-7); therefore, it is unclear why K ATP KO islets lack the elevated basal insulin release observed in HI islets (3,4).In a search for dif...

Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC)

“…Several studies have proposed roles for EPAC and͞or its effector Rap1 in cAMP-induced processes, such as regulation of the H ϩ ͞ K ϩ -ATPase in rat kidney cortical collecting duct cells (19) or insulin secretion by pancreatic islets (20,21). The aim of this work was to study the contribution of the EPAC-and PKA-dependent pathways to the cAMP-induced inhibition of NHE3 and NaPi-IIa.…”

“…A role of EPAC in several cAMP-regulated processes such as cell adhesion and migration (16), insulin secretion (20,21), and regulation of the H ϩ ͞K ϩ -ATPase in the kidney cortical collecting duct (19) has been already demonstrated. Several intracellular cascades may mediate these effects.…”

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

“…Third, sulphonylureas enhance exocytosis as measured by an increase in b-cell membrane capacitance (Hoy et al 2000). Fourth, the ability of cyclic AMP to potentiate insulin exocytosis in a PKA-independent manner is impaired in SUR1 knockout mice (Nakazaki et al 2002). This may be related to the fact that Epac (cAMP-GEFII ) specifically binds to NBD1 of SUR1 in a cAMP-dependent manner (Shibasaki et al 2004a).…”

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

“…Doliba et al [41] and Nakazaki et al [106] reported that acetylcholine and carbachol stimulate insulin release from Sur1KO islets even in low glucose. Doliba et al [41] argue secretion is impaired in the Sur1KO mice and suggest acetylcholine, released in response to feeding, enhances insulin secretion, thus contributing to their euglycemia.…”

“…Shiota et al [137] showed that Sur1KO mice failed to increase their plasma insulin in response to exogenous GLP-1, and Nakazaki et al [106] demonstrated that, whereas GLP-1, gastric inhibitory peptide (GIP), and exendin 4 increased the cAMP level in isolated islets, their potentiation of glucose-stimulated insulin release was reduced. The impaired incretin response was secondary to a blunted response to elevated cAMP acting via a protein kinase A (PKA)-independent pathway [48,106]. The impaired response was specific for cAMP, and Sur1KO islets were stimulated by carbachol, a nonhydrolyzable analog of acetylcholine, and by tissue plasminogen activator (TPA), a protein kinase C (PKC) activator.…”