Cytosolic ratios of free [NADPH]/[NADP+] and [NADH]/[NAD+] in mouse pancreatic islets, and nutrient-induced insulin secretion

Hedeskov, C. J.; Capito, Kirsten; Thams, Peter

doi:10.1042/bj2410161

Cited by 67 publications

(40 citation statements)

References 36 publications

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“…Alternatively, NADH enters the mitochondria via two shuttles (glycerol–phosphate and malate–aspartate shuttles) to produce ATP (Eto et al ., 1999; Hedeskov et al ., 1987; Malaisse et al ., 1979; Pralong et al ., 1990). Compared to most other mammalian cells, in β cells display high activities of the glycerol–phosphate shuttle and mitochondrial glycerol–phosphate dehydrogenase (mGPDH) suggesting an important role for NADH in β cell function (MacDonald et al ., 1990).…”

Section: Section IImentioning

confidence: 99%

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Hou

Min

Pessin

2009

Vitamins &Amp; Hormones

201

161

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It is becoming increasingly apparent that beta cell dysfunction resulting in abnormal insulin secretion is the essential element in the progression of patients from a state of impaired glucose tolerance to frank type 2 diabetes (Del Prato, 2003; Del Prato and Tiengo, 2001). Although extensive studies have examined the molecular, cellular and physiologic mechanisms of insulin granule biogenesis, sorting, and exocytosis the precise mechanisms controlling these processes and their dysregulation in the developed of diabetes remains an area of important investigation. We now know that insulin biogenesis initiates with the synthesis of preproinsulin in rough endoplastic reticulum and conversion of preproinsulin to proinsulin. Proinsulin begins to be packaged in the Trans-Golgi Network and is sorting into immature secretory granules. These immature granules become acidic via ATP-dependent proton pump and proinsulin undergoes proteolytic cleavage resulting the formation of insulin and C-peptide. During the granule maturation process, insulin is crystallized with zinc and calcium in the form of dense-core granules and unwanted cargo and membrane proteins undergo selective retrograde trafficking to either the constitutive trafficking pathway for secretion or to degradative pathways. The newly formed mature dense-core insulin granules populate two different intracellular pools, the readily releasable pools (RRP) and the reserved pool. These two distinct populations are thought to be responsible for the biphasic nature of insulin release in which the RRP granules are associated with the plasma membrane and undergo an acute calcium-dependent release accounting for first phase insulin secretion. In contrast, second phase insulin secretion requires the trafficking of the reserved granule pool to the plasma membrane. The initial trigger for insulin granule fusion with the plasma membrane is a rise in intracellular calcium and in the case of glucose stimulation results from increased production of ATP, closure of the ATP-sensitive potassium channel and cellular depolarization. In turn, this opens voltage-dependent calcium channels allowing increased influx of extracellular calcium. Calcium is thought to bind to members of the fusion regulatory proteins synaptogamin that functionally repressors the fusion inhibitory protein complexin. Both complexin and synaptogamin interact as well as several other regulatory proteins interact with the core fusion machinery composed of the Q- or t-SNARE proteins syntaxin 1 and SNAP25 in the plasmamembrane that assembles with the R- or v-SNARE protein VAMP2 in insulin granules. In this chapter we will review the current progress of insulin granule biogenesis, sorting, trafficking, exocytosis and signaling pathways that comprise the molecular basis of glucose-dependent insulin secretion.

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Section: Section IImentioning

confidence: 99%

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Hou

Min

Pessin

2009

Vitamins &Amp; Hormones

201

161

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“…where c is the ratio between the volumes of the cytosolic and mitochondrial compartments, here assumed to amount to 20 (30,39). Finally, for the reproduction of the results of Eto et al (26), we need the glucose oxidation rate j GO, which we measure as j GO ϭ j GPDH Ϫ j LDH (6) and the flux via the dehydrogenases IDH (3 isoforms) and OGDH, j DH, which we measure as…”

Section: Study Outline and Measurementsmentioning

confidence: 99%

“…. ]tot indicates total cellular content normalized by the cytosolic volume, and where c is the ratio between the volumes of the cytosolic and mitochondrial compartments, here assumed to amount to ϳ20 (30,39). In the case of ME, the equilibrium constant had to be divided by the tissue partial pressure of carbon dioxide (2), which amounts to ϳ0.06 bar (6), and then multiplied by the NADPc/ NADPHc ratio.…”

Section: Equilibrium Constantsmentioning

confidence: 99%

A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell

Westermark¹,

Kotaleski²,

Björklund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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The signal propagation goes via mitochondrial metabolism, which relays the signal to different routes. One route is an increased ATP production that, via ATP-sensitive K ϩ (KATP) channels, modulates the cell membrane potential to allow calcium influx, which triggers insulin secretion. There is also at least one other "amplifying" route whose nature is debated; possible candidates are cytosolic NADPH production or malonyl-CoA production. We have used mathematical modeling to analyze this relay system. The model comprises the mitochondrial NADH shuttles and the mitochondrial metabolism. We found robust signaling toward ATP, malonyl-CoA, and NADPH production. The signal toward NADPH production was particularly strong. Furthermore, the model reproduced the experimental findings that blocking the NADH shuttles attenuates the signaling to ATP production while retaining the rate of glucose oxidation (Eto K,

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“…Recent studies have strongly suggested that NADPH production via the malate-aspartate shuttle [162,163,164], also called pyruvate cycling [165], might be an important metabolic signal. Indeed, metabolisable insulin secretagogues increase the NADPH/NADP + ratio in rodent islets [166,167] and inhibition of NADPH formation reduces glucose-stimulated insulin secretion from rat islets [168,169]. Recent evidence suggests the existence of membrane associated aldehyde oxidoreductase-like enzyme activity in rat islets [170] and, as mentioned above, a number of oxidoreductase-like Kvβ subunits (Kvβ1, 2 and 3) are expressed in human and rat islets and INS-1 insulinoma cells [93].…”

Section: Regulation Of Kv Channel Activity In Beta Cellsmentioning

confidence: 99%

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

2003

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Insulin secretion from pancreatic islet beta cells is acutely regulated by a complex interplay of metabolic and electrogenic events. The electrogenic mechanism regulating insulin secretion from beta cells is commonly referred to as the ATP-sensitive K + (K ATP ) channel dependent pathway. Briefly, an increase in ATP and, perhaps more importantly, a decrease in ADP stimulated by glucose metabolism depolarises the beta cell by closing K ATP channels. Membrane depolarisation results in the opening of voltage-dependent Ca 2+ channels, and influx of Ca 2+ is the main trigger for insulin secretion. Repolarisation of pancreatic beta cell action potential is mediated by the activation of voltage-dependent K + (Kv) channels. Various Kv channel homologues have been detected in insulin secreting cells, and recent studies have shown a role for specific Kv channels as modulators of insulin secretion. Here we review the evidence supporting a role for Kv channels in the regulation of insulin secretion and discuss the potential and the limitations for beta-cell Kv channels as therapeutic targets. Furthermore, we review recent investigations of mechanisms regulating Kv channels in beta cells, which suggest that Kv channels are active participants in the regulation of beta-cell electrical activity and insulin secretion. [Diabetologia (2003[Diabetologia ( ) 46:1046[Diabetologia ( -1062

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Cytosolic ratios of free [NADPH]/[NADP+] and [NADH]/[NAD+] in mouse pancreatic islets, and nutrient-induced insulin secretion

Cited by 67 publications

References 36 publications

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

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