Evidence of a role for GTP in the potentiation of Ca(2+)-induced insulin secretion by glucose in intact rat islets.

Meredith, Melissa; Rabaglia, Mary E.; Metz, Stewart A.

doi:10.1172/jci118127

Cited by 42 publications

(43 citation statements)

References 40 publications

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“…On average, GTP levels corresponded to about 20% of ATP levels. This compares well with a proportion of 23% in two recent studies (19,22) but is lower than the values of 33-38% of other reports (16,18). The present study confirms that glucose increases GTP levels and the GTP:GDP ratio in islets (16,18,19) and, contrary to a previous study (18), shows that this effect is concentration-dependent and of rapid onset and reversibility.…”

Section: Discussionsupporting

confidence: 81%

See 1 more Smart Citation

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Detimary¹,

Berghe

Henquin³

1996

Journal of Biological Chemistry

129

110

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Changes in the ATP:ADP ratio in pancreatic B cells may participate in the regulation of insulin secretion by glucose. Here, we have investigated the possible role of guanine nucleotides. Mouse islets were incubated in a control medium (when K ؉ -ATP channels are the major site of regulation) or in a high K ؉ medium (when glucose modulates the effectiveness of cytosolic Ca 2؉ on exocytosis). Glucose induced a concentration-dependent (0 -20 mM) increase in GTP and a decrease in GDP in both types of medium, thus causing a progressive rise of the GTP:GDP ratio. ATP and ADP levels were 4 -5-fold higher but varied in a similar way as those of guanine nucleotides. Insulin secretion was inversely correlated with ADP and GDP levels and positively correlated with the ATP:ADP and GTP:GDP ratios between 6 and 20 mM glucose in control medium and between 0 and 20 mM glucose in high K ؉ medium. The increases in the GTP: GDP and ATP:ADP ratios induced by a rise of glucose were faster than the decreases induced by a fall in glucose, but the changes of both ratios were again parallel. In conclusion, glucose causes large, concentration-dependent changes in guanine as well as in adenine nucleotides in islet cells. This raises the possibility that both participate in the regulation of nutrient-induced insulin secretion.The regulation of pancreatic B cell function differs from that of other secretory cells in that the control of insulin secretion does not depend on the binding of the major physiological stimulator, glucose, to a receptor, but on its metabolism within B cells (reviewed in Refs. 1-5). It is now widely accepted that this metabolism generates several signals that close ATP-sensitive K ϩ channels (K ϩ -ATP channels) 1 in the plasma membrane. This closure (hereafter referred to as the "primary mechanism" of control) leads to membrane depolarization with subsequent opening of voltage-dependent Ca 2ϩ channels, Ca 2ϩ influx, rise in cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i ), and eventual triggering of insulin secretion (4 -9). A "second mechanism" of control by glucose exists, which also depends on changes in metabolism (10 -12). It does not involve a further change in [Ca 2ϩ ] i but an increase in the effectiveness of Ca 2ϩ on its intracellular targets (12). Despite numerous studies, the nature of the signals that link the acceleration of metabolism to the closure of K ϩ -ATP channels and to the increase in Ca 2ϩ action has only partially been elucidated. Purine nucleotides clearly stand out as potential candidates.The popular hypothesis that variations in the cytosolic concentrations or ratio of adenine nucleotides are involved in the primary mechanism of control by glucose rests primarily on the fact that K ϩ channels, which control the B cell membrane potential, are regulated by intracellular ATP and ADP (6,8,9,13). Although this hypothesis has long been disputed (reviewed in Ref. 14), our demonstration of a correlation between insulin release and the ATP:ADP ratio in islets incubated in the presence of...

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Section: Discussionsupporting

confidence: 81%

“…However, the reported changes were smaller (17)(18)(19) and slower (18) than those of adenine nucleotides. Moreover, they were generally observed at one single glucose concentration and, when evaluated further, no concentration dependence could be found (17,18).…”

mentioning

confidence: 74%

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Detimary¹,

Berghe

Henquin³

1996

Journal of Biological Chemistry

129

110

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“…It had been suggested that fatty acid oxidation results in increased ATP production, which is thought to initiate the process of insulin secretion induced by glucose (Warnotte et al, 1994). However, the ATP-mediated hypothesis for nutrient stimulation of insulin secretion has sometimes been questioned (MacDonald, 1990), leading propositions for the existence of both ATPdependent and ATP-independent pathways for glucose induction of insulin secretion (Aizawa et al, 1994;Meredith et al, 1995). Signal-transduction process for the ATP-independent pathway may involve phospholipase C and PKC activation (Aizawa et al, 1994;Komatsu et al, 1997) (Fig.…”

Section: Fa Metabolism In B-cellsmentioning

confidence: 99%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

148

102

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Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic b-cells have long been recognized. Acute exposure of the pancreatic b-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for b-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acylCoA (LC-CoA) controls several aspects of the b-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide-and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.

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“…In contrast to ATP, GTP is capable of initiating insulin exocytosis in a Ca 2ϩ -independent manner both in native (45,46) and in clonal ␤-cells (24,40,45). Thus, GTP is generated by glucose and also modulates exocytosis di- rectly, which qualifies it as a messenger molecule (47). Whether heterotrimeric G-proteins or the monomeric Gprotein Rab3 is the target for GTP remains to be established (24,48).…”

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confidence: 99%

β-Cell Mitochondria and Insulin Secretion

Wollheim¹,

Maechler²

2002

Diabetes

107

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The ␤-cell mitochondria are known to generate metabolic coupling factors, or messengers, that mediate plasma membrane depolarization and the increase in cytosolic Ca 2؉ , the triggering event in glucose-stimulated insulin secretion. Accordingly, ATP closes nucleotide-sensitive K ؉ channels necessary for the opening of voltage-gated Ca 2؉ channels. ATP also exerts a permissive action on insulin exocytosis. In contrast, GTP directly stimulates the exocytotic process. cAMP is considered to have a dual function: on the one hand, it renders the ␤-cell more responsive to glucose; on the other, it mediates the effect of glucagon and other hormones that potentiate insulin secretion. Mitochondrial shuttles contribute to the formation of pyridine nucleotides, which may also participate in insulin exocytosis. Among the metabolic factors generated by glucose, citrate-derived malonyl-CoA has been endorsed, but recent results have questioned its role. We have proposed that glutamate, which is also formed by mitochondrial metabolism, stimulates insulin exocytosis in conditions of permissive, clamped cytosolic Ca 2؉ concentrations. The evidence for the implication of these and other putative messengers in metabolism-secretion coupling is discussed in this review. Diabetes 51 (Suppl.

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Evidence of a role for GTP in the potentiation of Ca(2+)-induced insulin secretion by glucose in intact rat islets.

Cited by 42 publications

References 40 publications

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Pleiotropic effects of fatty acids on pancreatic β‐cells

β-Cell Mitochondria and Insulin Secretion

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