Two sites of glucose control of insulin release with distinct dependence on the energy state in pancreatic B-cells

Detimary, Philippe; Gilon, Patrick; Nenquin, Myriam; Henquin, Jean‐Claude

doi:10.1042/bj2970455

Cited by 75 publications

(64 citation statements)

References 38 publications

(51 reference statements)

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“…The contrasting effects of glipizide on the secretory responses to glucose on the one hand and to α-ketoisocaproate on the other hand (Fig. 2) [12] probably indicate that reactions involved in the generation of the amplification signal by glucose need a higher ATP/ADP ratio than reactions following formation of the signal [47]. Another likely consequence of a low ATP/ADP ratio is an inhibition of ATP-dependent regeneration of NADP (see above).…”

Section: Discussionmentioning

confidence: 99%

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Panten

Rustenbeck

2007

Diabetologia

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Aims/hypothesis The aim of this study was to examine whether the cytosolic NADPH/NADP + ratio of beta cells serves as an amplifying signal in fuel-induced insulin secretion and whether such a function is mediated by cytosolic α-ketoglutarate. Methods Pancreatic islets and islet cells were isolated from albino mice by collagenase digestion. Insulin secretion of incubated or perifused islets was measured by ELISA. The NADPH and NADP + content of incubated islets was determined by enzymatic cycling. The cytosolic Ca 2+ concentration ([Ca 2+ ] c ) in islets was measured by microfluorimetry and the activity of ATP-sensitive K + channels in islet cells by patch-clamping. Results Both 30 mmol/l glucose and 10 mmol/l α-ketoisocaproate stimulated insulin secretion and elevated the NADPH/NADP + ratio of islets preincubated in the absence of fuel. The increase in the NADPH/NADP + ratio was abolished in the presence of 2.7 μmol/l glipizide (closing all ATP-sensitive K + channels). However, α-ketoisocaproate, but not glucose, still stimulated insulin secretion. That glipizide did not inhibit α-ketoisocaproate-induced insulin secretion was not the result of elevated [Ca 2+ ] c , as glucose caused a more marked [Ca 2+ ] c increase. Insulin release triggered by glipizide alone was moderately amplified by dimethyl α-ketoglutarate (which is cleaved to produce cytosolic α-ketoglutarate), but there was no indication of a signal function of cytosolic α-ketoglutarate. Conclusions/interpretationThe results strongly suggest that the NADPH/NADP + ratio in the beta cell cytosol does not serve as an amplifying signal in fuel-induced insulin release. The study supports the view that amplification results from the intramitochondrial production of citrate by citrate synthase and from the associated export of citrate into the cytosol.

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Section: Discussionmentioning

confidence: 99%

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Panten

Rustenbeck

2007

Diabetologia

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“…Given that this is an energy-dependent process (21), it is not surprising that metabolic inhibitors dramatically reduce insulin release (22)(23)(24)(25)(26)(27). However, such inhibitors have more profound effects on the ␤-cell, because the cell's recognition of glucose as a secretory stimulus also depends on metabolism of the glucose (28).…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolism and Pulsatile Insulin Release From Isolated Islets

Westerlund

Bergsten²

2001

Diabetes

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T he circulating insulin concentration displays regular oscillations in normal human subjects (1). Disturbances of these oscillations are an early sign in the development of type 2 diabetes (2,3). Such alterations may lead to insulin resistance and glucose intolerance by downregulation of insulin receptors (4). The plasma insulin oscillations have been attributed to the pulsatile release of the hormone from the pancreas (5), a process that requires coordinated secretion from the pancreatic islets (6).When the ambient glucose concentration is raised, ␤-cell metabolism is stimulated (7). The resulting increase in the ATP/ADP ratio decreases the permeability of the ATP-sensitive K ϩ (K ATP ) channels and depolarizes the cell (8). Subsequent influx of Ca 2ϩ through voltage-dependent channels triggers the exocytosis of insulin granules (9). ATP produced by metabolism also plays an important role in providing energy for secretion by recruitment and priming of insulin granules for exocytosis (10). Impaired glucose metabolism in pancreatic ␤-cells has been implicated in the development of the disturbed plasma insulin pattern seen in type 2 diabetes (11). Support for this idea has been obtained from altered plasma insulin patterns in patients with mutations in genes coding for glycolytic enzymes, such as phosphofructokinase and glucokinase and mitochondrial tRNA (12)(13)(14)(15)(16)(17).In the present study, we attempted to determine the importance of glycolytic and mitochondrial metabolism for pulsatile insulin release by measuring insulin secretion and [Ca 2ϩ ] i from individual pancreatic islets exposed to metabolic inhibitors at basal and stimulatory glucose concentrations. RESEARCH DESIGN AND METHODS Materials.Reagents of analytical grade and deionized water were used. Collagenase, HEPES, and bovine serum albumin (fraction V) were obtained from Boehringer Mannheim (Mannheim, Germany). Antimycin A, iodoacetamide (IAA), 2,4-dinitrophenol (DNP), tetramethylbenzidine, and insulinperoxidase were obtained from Sigma (St. Louis, MO). The rat insulin standard was obtained from Novo Nordisk (Bagsvaerd, Denmark). IgGcertified microtiter plates were purchased from Nunc (Roskilde, Denmark). The insulin antibodies were raised in guinea pigs. Preparation and culture of islets. Pancreatic islets were collagenaseisolated from ob/ob mice taken from a local colony (18). For the insulin experiments, freshly isolated islets were perifused in a medium supplemented with 1 mg/ml albumin and containing (in mmol/l) 125 NaCl, 5.9 KCl, 1.2 MgCl 2 , 1.3 CaCl 2 , and 25 HEPES, titrated to pH 7.4 with NaOH. For the [Ca 2ϩ ] i experiments, the islets were cultured overnight in the presence of 5.5 mmol/l glucose in RPMI 1640 supplemented with 10% fetal calf serum, and the Ca 2ϩ concentration of the perifusion medium was 2.6 mmol/l. Measurements of insulin release. The kinetics of insulin release were studied essentially as described previously (6). A single islet was placed in a temperature-controlled (37°C) 10-l chamber and perifused with med...

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“…Even though glucose stimulation does not normally result in an increase in the cytosolic concentration of cAMP (24), an increase in cytosolic ATP concentration is suffucient to account for the potentiation of insulin exocytosis by glucose (aspect B). A role for ATP in the K ATP channel-independent action of glucose has previously been suggested by the observation that sodium azide, which reduces the cytosolic ATP concentration, is a potent inhibitor of insulin exocytosis (36,37).…”

Section: Fast Camp-sensitive Mode Of Exocytosismentioning

confidence: 99%

Fast and cAMP-Sensitive Mode of Ca2+-Dependent Exocytosis in Pancreatic β-Cells

Kasai

Suzuki²,

Liu³

et al. 2002

Diabetes

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The fast component (mode 1) of Ca 2؉ -dependent exocytosis in pancreatic ␤-cells, unlike that in adrenal chromaffin cells, is regulated by cytosolic ATP in a concentration-dependent manner. This action of ATP is apparent within 3 min and does not require ATP hydrolysis; rather, it requires the production of cAMP by adenylate cyclase. Moreover, the effect of cAMP is ATP dependent, as revealed by the observation that the fast component of exocytosis is facilitated by ATP, even in the presence of a saturating concentration of cAMP (200 mol/l). Thus, the amplitude of mode-1 exocytosis depends quadratically on the cytosolic ATP concentration and is facilitated by ATP, even in the absence of an increase in the concentration of cAMP. Given that high glucose concentrations increase the cytosolic ATP concentration, glucose-induced insulin secretion likely involves this action of ATP on mode-1 exocytosis, together with its effect on ATP-dependent K ؉ channels. In contrast to the fast component of exocytosis, the slow component (mode 2) of this process is independent of cAMP and ATP and can account for the slow component of insulin secretion, which does not require these nucleotides. Diabetes 51 (Suppl. 1):S19 -S24, 2002

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Two sites of glucose control of insulin release with distinct dependence on the energy state in pancreatic B-cells

Cited by 75 publications

References 38 publications

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Glucose Metabolism and Pulsatile Insulin Release From Isolated Islets

Fast and cAMP-Sensitive Mode of Ca2+-Dependent Exocytosis in Pancreatic β-Cells

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