Possible role of carbonic anhydrase in rat pancreatic islets: enzymatic, secretory, metabolic, ionic, and electrical aspects

Sener, Abdullah; Jijakli, Hassan; Asl, Saleh Zahedi; Courtois, Philippe; Yates, Allen P.; Meuris, Sylvain; Best, Leonard; Malaisse, Willy

doi:10.1152/ajpendo.00631.2006

Cited by 24 publications

(23 citation statements)

References 20 publications

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“…Since rapamycin treatment did not affect glucokinase activity in islets, the primary cause of reduced glucose oxidation by the treatment is not likely to be reduced the velocity of glycolysis. Indeed, in islets, glucose utilization is also reduced when glucose oxidation is decreased by respiratory chain inhibitors including site III inhibitor in our results and site VI inhibitor (Sener et al 2007), suggesting that reduced glucose oxidation may decrease glucose utilization. Since glucokinase is a unique hexokinase, which lacks product inhibition (Matschinsky 2002), accumulation of glucose-6-phosphate by mitochondrial metabolic inhibition may not participate in glycolysis inhibition.…”

Section: Discussionsupporting

confidence: 56%

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism

Shimodahira

Fujimoto

Mukai³

et al. 2009

Journal of Endocrinology

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Rapamycin, an immunosuppressant used in human transplantation, impairs b-cell function, but the mechanism is unclear. Chronic (24 h) exposure to rapamycin concentration dependently suppressed 16 . 7 mM glucose-induced insulin release from islets (1 . 65G0 . 06 2G3 . 3 pmol/islet per 90 min, control, nZ9, P!0 . 01). Immunoblotting revealed that the expression of complex I, III, IV, and V was not affected by rapamycin. Mitochondrial ATP production indicated that the respiratory chain downstream of complex II was not affected, but that carbohydrate metabolism in the Krebs cycle was reduced by rapamycin. Analysis of enzymes in the Krebs cycle revealed that activity of a-ketoglutarate dehydrogenase (KGDH), which catalyzes one of the slowest reactions in the Krebs cycle, was reduced by rapamycin (10 . 08G0 . 82, rapamycin versus 13 . 82 G0 . 84 nmol/mg mitochondrial protein per min, control, nZ5, P!0 . 01). Considered together, these findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced KGDH activity.

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Section: Discussionsupporting

confidence: 56%

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism

Shimodahira

Fujimoto

Mukai³

et al. 2009

Journal of Endocrinology

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“…To our knowledge, there have been no previous reports of the effect of ZNS on blood glucose alone or in attenuating an acute drug-associated effect; however, studies with acetazolamide (a carbonic anhydrase inhibitor antiepileptic) in rats have shown that the integrity of carbonic anhydrase activity is required in order to allow a normal stimulation of insulin release by glucose (Sener et al, 2007). In addition, topiramate, a novel antiepileptic drug, with some similarities to ZNS, has been shown to attenuate OLZassociated weight gain (Liang et al, 2005;Wilkes et al, 2005a, b), decrease plasma glucose, and increase in vivo insulin sensitivity in adipocytes and skeletal muscle resulting from increases in adiponectin levels (Gustafson et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

Wallingford

Sinnayah

Bymaster

et al. 2008

Neuropsychopharmacol

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Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

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“…Likewise, intracellular pH measurements and electrophysiological experiments, both carried out with dispersed rat islet cells, were performed as previously described [1,21]. The membrane potential of insulinproducing cells was monitored with the perforated configuration of the patch clamp technique.…”

Section: Functional Studiesmentioning

confidence: 99%

“…It was recently proposed that, in rat pancreatic islets, carbon dioxide is converted to a large extent to bicarbonate (HCO 3 -) [1]. However, the mechanism by which HCO 3 -leaves the islet cells remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Expression of the electrogenic Na+–HCO3 −-cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells

Soyfoo

Bulur

Virreira

et al. 2009

Endocr

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It was recently proposed that, in rat pancreatic islets, the production of bicarbonate accounts for the major fraction of the carbon dioxide generated by the oxidative catabolism of nutrient insulin secretagogues. In search of the mechanism(s) supporting the membrane transport of bicarbonate, the possible role of the electrogenic Na ? -HCO 3 --cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells was investigated. Expression of NBCe1-A and NBCe1-B in rat pancreatic islet cells was documented by RT-PCR, western blotting, and immunocytochemistry. The latter procedure suggested a preferential localization of NBCe1-B in insulin-producing cells. Tenidap (3-100 lM), previously proposed as an inhibitor of NBCe1-A-mediated cotransport in proximal tubule kidney cells, caused a concentration-related inhibition of glucose-stimulated insulin secretion. It also inhibited 2-ketoisocaproate-induced insulin release and to a relatively lesser extent, the secretory response to L-leucine. Tenidap (50-100 lM) also inhibited the metabolism of D-glucose in isolated islets, increased 22 Na net uptake by dispersed islet cells, lowered intracellular pH and provoked hyperpolarization of plasma membrane in insulin-producing cells. This study thus reveals the expression of the electrogenic Na ? -HCO 3 --cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells, and is consistent with the participation of such transporters in the process of nutrient-stimulated insulin secretion.

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Possible role of carbonic anhydrase in rat pancreatic islets: enzymatic, secretory, metabolic, ionic, and electrical aspects

Abstract: Sener A, Jijakli H, Zahedi S, Courtois P, Yates AP, Meuris S, Best LC, Malaisse WJ. Possible role of carbonic anhydrase in rat pancreatic islets: enzymatic, secretory, metabolic, ionic, and electrical aspects.

Cited by 24 publications

References 20 publications

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

Expression of the electrogenic Na+–HCO3 −-cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells

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