Glucose augmentation of mastoparan-stimulated insulin secretion in rat and human pancreatic islets.

Straub, Susanne G.; James, R. F. L.; Dunne, Mark J.; Sharp, Geoffrey W. G.

doi:10.2337/diabetes.47.7.1053

Cited by 42 publications

(50 citation statements)

References 26 publications

(45 reference statements)

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“…Superphysiologic [cAMP] i , ϳ100-fold higher than basal levels, obtained with IBMX plus forskolin, has no stimulatory effect on insulin release from wild-type islets in low glucose, but does strongly potentiate insulin release from Sur1KO islets, which have elevated [Ca 2ϩ ] i , even in low glucose. The impaired response to incretins does not appear to result from a generalized defect in exocytosis, since insulin release is comparably stimulated from wildtype and Sur1KO islets by activators of PKC pathways and by mastoparan, which is reported to activate exocytosis at a late, GTP-dependent step (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…The insulinotropic peptide mastoparan stimulates insulin release from Sur1KO islets. Mastoparan is a cationic, amphiphilic, 14 amino acid peptide that stimulates insulin release (46) reportedly at a late stage of exocytosis (47,48), an effect that is attenuated by pertussis toxin (46), independent of increased [Ca 2ϩ ] i (47,49), augmented by nutrients, and dependent on GTP (48). Mastoparan prompts insulin release from Sur1KO islets in the absence of external Ca 2ϩ , and this effect is augmented by glucose, 3.5 Ϯ 0.8-fold for wild-type vs. 1.6 Ϯ 0.9-fold for Sur1KO islets (Fig.…”

Section: (25 Mg/l)-permeabilized Islets Incubated With ␥[mentioning

confidence: 99%

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

Nakazaki

Crane

et al. 2002

Diabetes

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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...

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Section: Discussionmentioning

confidence: 99%

Section: (25 Mg/l)-permeabilized Islets Incubated With ␥[mentioning

confidence: 99%

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

Nakazaki

Crane

et al. 2002

Diabetes

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“…In the present study, clozapine did not affect mastoparan-induced insulin secretion at 3.3 mmol/l glucose, but did suppress its augmentation of glucose in a Ca 2+ -independent manner. Glucose augments posttranslational modifications of specific small G proteins in a GTP-sensitive manner [38,39], and glucose augmentation is extremely dependent on GTP, which increases in parallel with ATP on glucose stimulation [40]. Therefore, clozapine may affect the activation of a specific G protein by inhibiting ATP production, and this could contribute, at least in part, to the alteration in distal steps of insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

et al. 2006

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Aims/hypothesis Diabetogenic effects of some atypical antipsychotic drugs have been reported, although the mechanisms are not fully understood. We investigated the long-term effects of culturing isolated rat pancreatic islets with atypical antipsychotic clozapine. Methods Glucose-and non-glucose-stimulated insulin secretion, glucose metabolism and intracellular Ca 2+ concentration ([Ca 2+ ] i ) were measured in islets cultured with or without clozapine. Results Although acute incubation or 3-day culture with clozapine did not affect glucose-stimulated insulin secretion, clozapine suppressed glucose-stimulated insulin secretion by 53.2% at 1.0 μmol/l (therapeutic concentration) after 7 days of culture. Islet glucose oxidation and [Ca 2+ ] i elevation by high glucose were not affected after 3 days of culture, but clozapine significantly inhibited islet glucose oxidation, ATP production, and [Ca 2+ ] i elevation by high glucose after 7 days of culture. Moreover, 7 days of culture with clozapine inhibited insulin secretion stimulated by: (1) membrane depolarisation induced by high K + ; (2) protein kinase C activation; and (3) mastoparan at 16.7 mmol/l glucose under stringent Ca 2+ -free conditions. Elevation of [Ca 2+ ] i by high K + -induced membrane depolarisation was similar in control and clozapine-treated islets. Clozapine, a muscarinic blocker, acutely inhibited carbachol-induced insulin secretion, as did atropine, whereas after 7 days of culture atropine did not have the inhibitory effect shown by clozapine after 7 days. The impairment of glucose-stimulated insulin secretion recovered 3 days after the removal of clozapine treatment. Conclusions/interpretationThe present study demonstrated that the atypical antipsychotic drug clozapine directly impaired insulin secretion via multiple sites including glucose metabolism and the distal step in insulin exocytosis in a long-term culture condition. These mechanisms may be involved in the form of diabetes mellitus associated with atypical antipsychotic drugs.

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“…This finding can be explained through the "K ATP channel-independent" pathway of glucose-induced secretion. Glucose "augmentation" routes have been described in rodent (36 -38) and human insulin-secreting cells (39,40). These pathways are uncovered in normal beta cells by using pharmacological agents that eliminate the contribution of K ATP channels to the operation of beta cells and are now recognized as accounting for the second phase of insulin release.…”

Section: Discussionmentioning

confidence: 99%

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Macfarlane¹,

Chapman²,

Shepherd³

et al. 1999

Journal of Biological Chemistry

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Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta celllike phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K ATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K ATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K ATP channel activity, and as a result of changes in intracellular Ca 2؉ homeostasis ([Ca 2؉ ] i ) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)1 is a potentially lethal disease of the newborn. It is characterized by inappropriate insulin release in relation to the corresponding levels of glycemia (1, 2). Affected children run the risk of severe neurological damage unless immediate and adequate steps are taken to avoid profound hypoglycemia. Treatment involves administration of glucose along with drugs such as diazoxide and somatostatin that inhibit insulin secretion. However, in many cases this is not effective, and within the first few weeks of birth a near total (ϳ95%) pancreatectomy is required to control blood glucose levels.Recently, it has been shown that PHHI arises from defects in the regulation of insulin secretion. This is due principally to the loss of function of ATP-regulated potassium (K ATP ) channels. Genetic linkage has identified a susceptibility locus for PHHI within a region of chromosome 11 that encodes subunits of these channels (3, 4), while direct recordings of beta cells isolated from PHHI patients (following pancreatectomy) have documented the absence of K ATP channels (5). In beta cells these channels are composed of at least two subunits as follows: a K ϩ channel pore, Kir6.2, and an ATP-binding cassette protein, SUR1 (6, 7). Open K ATP channels set the resting membrane potential for the beta cell and a change in the intracellular ATP/ADP ratio following glucose metabolism results in their closure and the initiation of a depolarization of the cell membrane. This in turn activates voltage-dependent calcium channels and the ensuing influx of calcium stimulates membrane docking and fusion of preformed insulin granules resulting ...

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Glucose augmentation of mastoparan-stimulated insulin secretion in rat and human pancreatic islets.

Cited by 42 publications

References 26 publications

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

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

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

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