Regulation of energy metabolism in pancreatic islets by glucose and tolbutamide

Panten, U.; Zünkler, Bernd J.; Scheit, S.; Kirchhoff, Kerstin; Lenzen, Sigurd

doi:10.1007/bf00869265

Cited by 60 publications

(47 citation statements)

References 37 publications

(60 reference statements)

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“…Glibenclamide effects on oxygen consumption depend on media composition. As in other studies of oxygen consumption (15,22), glibenclamide increased oxygen consumption in KRB but not in RPMI. We suggest two explanations for this.…”

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confidence: 81%

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Regulation of ATP/ADP in Pancreatic Islets

et al. 2004

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ATP and ADP levels are critical regulators of glucosestimulated insulin secretion. In many aerobic cell types, the phosphorylation potential (ATP/ADP/P i ) is controlled by sensing mechanisms inherent in mitochondrial metabolism that feed back and induce compensatory changes in electron transport. To determine whether such regulation may contribute to stimulus-secretion coupling in islet cells, we used a recently developed flow culture system to continuously and noninvasively measure cytochrome c redox state and oxygen consumption as indexes of electron transport in perifused isolated rat islets. Increasing substrate availability by increasing glucose increased cytochrome c reduction and oxygen consumption, whereas increasing metabolic demand with glibenclamide increased oxygen consumption but not cytochrome c reduction. The data were analyzed using a kinetic model of the dual control of electron transport and oxygen consumption by substrate availability and energy demand, and ATP/ADP/P i was estimated as a function of time. ATP/ADP/P i increased in response to glucose and decreased in response to glibenclamide, consistent with what is known about the effects of these agents on energy state. Therefore, a simple model representing the hypothesized role of mitochondrial coupling in governing phosphorylation potential correctly predicted the directional changes in ATP/ADP/P i . Thus, the data support the notion that mitochondrial-coupling mechanisms, by virtue of their role in establishing ATP and ADP levels, may play a role in mediating nutrient-stimulated insulin secretion. Our results also offer a new method for continuous noninvasive measures of islet cell phosphorylation potential, a critical metabolic variable that controls insulin secretion by ATP-sensitive K ؉ -dependent and -independent mechanisms. Diabetes 53: [401][402][403][404][405][406][407][408][409] 2004 F ree ATP and ADP levels are understood to couple glucose metabolism with the closing of ATPsensitive K ϩ (K ATP ) channels and the ionic events leading to the exocytosis of insulin (1,2). Furthermore, the phosphorylation potential (ATP/ADP/P i ) may augment insulin secretion beyond that mediated by K ATP channels (3). Although it is well established that the critical ATP and ADP levels depend on islet substrate metabolism and mitochondrial electron transport (4 -6), it is less broadly appreciated that ADP stimulates electron transport and ATP production (7,8) as a feedback regulator of ATP/ADP/P i (9,10). Thus, mitochondrial ATP production, the ATP/ADP/P i , and ultimately the insulin secretory rate depend dually on both substrate supply as well as energy demand.Although the mechanisms by which mitochondria sense ADP levels and control ATP/ADP/P i are not fully established, a likely candidate is cytochrome c oxidase, the rate-limiting step in the electron transport chain (11). Wilson et al. (11,12) validated a mathematical model correlating substrate supply and energy demand (i.e., as phosphorylation potential) to the redox state and oxygen cons...

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confidence: 81%

“…Rates of oxygen consumption obtained depend on the method used. Whereas Cartesian divers record a nearly instantaneous response to glucose (26), continuous flow systems (22,27; the present study [ Fig. 5]) record a slow (45-to 60-min) rise in oxygen consumption.…”

Section: Fig 3 Effect Of Glucose and Oxygen On Cytochrome C In Rat mentioning

confidence: 73%

Regulation of ATP/ADP in Pancreatic Islets

et al. 2004

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“…The depolarisation was believed to result either from direct inhibition of the mitochondrial K ATP channels or from uncoupling of oxidative phosphorylation. In mouse islets incubated in the absence of exogenous fuels, tolbutamide (about 400 μmol/l free concentration) slightly stimulated oxygen consumption [26,42]. Decrease in ATP content induced by high sulfonylurea concentrations was observed in mouse and rat islets incubated in the absence of exogenous fuels or in the presence of low glucose concentrations [43][44][45][46].…”

Section: Discussionmentioning

confidence: 95%

“…After thawing the tube in an ice bath, 40 μl of ice-chilled NaOH (60 mmol/l+7.5 mmol/l cysteine) was added. The stoppered tube was immediately sonicated as described previously [26] and centrifuged for 1 min at 20,000 g (4°C). Aliquots (15 μl) of the supernatant were added to 7.5 μl of NaOH (40 mmol/l+5 mmol/l cysteine; for NADPH determination) and to 7.5 μl of HCl (200 mmol/l; for NADP + determination).…”

Section: Nadph and Nadpmentioning

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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“…The glucose dependence of the insulinotropic effect may therefore be a concentration-dependent phenomenon. In principle, such a dependence on the presence of nutrient secretagogues also applies for the insulinotropic effect of the sulfonylureas, the prototypical class of K ATP channel blockers [21], but it is generally agreed that sulfonylureas stimulate insulin secretion in the presence of a basal glucose concentration and, at high concentrations, even in the absence of glucose [22].…”

Section: Characteristics Of Fluoroquinolone-induced Insulin Secretionmentioning

confidence: 99%