Role of NADH Shuttle System in Glucose-Induced Activation of Mitochondrial Metabolism and Insulin Secretion

Eto, Kazuhiro; Tsubamoto, Yoshiharu; Terauchi, Yasuo; Sugiyama, Takuya; Kishimoto, T.; Takahashi, Noriko; Yamauchi, Naoko; Kubota, Naoto; Murayama, Shigeo; Aizawa, Toru; Akanuma, Yasuo; Aizawa, Shinichi; Kasai, Hideaki; Yazaki, Yoshio; Kadowaki, Takashi

doi:10.1126/science.283.5404.981

Cited by 440 publications

(392 citation statements)

References 25 publications

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“…Although several previous reports have described mGPDH -/-mice as normal [14,15,16,17], our results showed that the blood concentrations of triglycerides and cholesterol in mGPDH -/-mice are increased. These results could be due to the absence of mGPDH activity in the liver, but not in the pancreas.…”

Section: Discussioncontrasting

confidence: 99%

“…The lower body weight showed by the mGPDH -/-mice was already reported in the papers describing the mGPDH knockouts [14,15], and our data agree with the percentage reported in those papers. Moreover, the high carbohydrate diet induces an increase in the thermogenesis, and the mice show a lower weight gain compared to standard diet [31], similar to what we observed in our experiments.…”

Section: Discussionsupporting

confidence: 93%

“…Therefore, several authors have suggested that mGPDH could play an important role in the pathogenesis of Type 2 diabetes [11,12,13]. To determine the role of the glycerol-3-phosphate shuttle in glucose-induced insulin secretion, mice with a targeted disruption of the mGPDH gene were generated [14,15]. mGPDH -/-knockout mice are not diabetic, only when the activities of both shuttles are halted by the use of aminooxyacetate, to block the malate-aspartate shuttle, are insulin secretion, glucose metabolism, and calcium oscillations severely impaired [16,17].…”

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A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse

et al. 2003

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Aims/hypothesis. The electrons of the glycolysis-derived reduced form of NADH are transferred to mitochondria through the NADH shuttle system. There are two NADH shuttles: the glycerol phosphate and malate-aspartate shuttle. Mice with a targeted disruption of mitochondrial glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme of the glycerol phosphate shuttle, are not diabetic and have normal islet glucoseinduced secretion. In this study, we analyzed if environmental factors, such as a high carbohydrate diet could contribute to the development of Type 2 diabetes mellitus in mice with a specific defective genetic background. Methods. The mice were fed with a high carbohydrate diet for 1 and 6 months, and several biochemical parameters were analysed. The mitochondrial respiratory activity was assayed by polarography; and the islet function was studied by islet perifusion and pancreas perfusion.Results. The high carbohydrate diet induced hyperglycaemia, hyperinsulinaemia, and islet hyperplasia in the wild-type and heterozygote mice. Activity of the respiratory chain complex I also increased in these mice. In contrast, these effects were not observed in the null mice fed with the diet; in addition, these null mice had an increased insulin sensitivity compared to wild-type mice. Conclusion/interpretation. The phenotype of the mice with an impairment of NADH shuttles does not worsen when fed a high carbohydrate diet; moreover, the diet does not compromise islet function. [Diabetologia (2003[Diabetologia ( ) 46:1394[Diabetologia ( -1401 Keywords High carbohydrate diet, mitochondrial metabolism, mGPDH, beta cell, glycerol phosphate shuttle, insulin secretion. A. Barberà and M. Gudayol have contributed equally to this paper Diabetologia

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 93%

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confidence: 99%

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A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse

et al. 2003

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“…Insulin release by the pancreatic islets was measured by static incubation with KRB containing 0.2% (wt/vol.) bovine serum albumin [15]. In the static incubation, batches of ten freshly isolated islets were preincubated at 37°C for 30 min in KRB containing 2.8 mmol/l glucose.…”

Section: Methodsmentioning

confidence: 99%

Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration

et al. 2008

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Aims/hypothesis A decrease in plasma adiponectin levels has been shown to contribute to the development of diabetes. However, it remains uncertain whether adiponectin plays a role in the regulation of insulin secretion. In this study, we investigated whether adiponectin may be involved in the regulation of insulin secretion in vivo and in vitro. Methods The effect of adiponectin on insulin secretion was measured in vitro and in vivo, along with the effects of adiponectin on ATP generation, membrane potentials, Ca 2+ currents, cytosolic calcium concentration and state of 5′-AMP-activated protein kinase (AMPK). In addition, insulin granule transport was measured by membrane capacitance and total internal reflection fluorescence (TIRF) analysis.Results Adiponectin significantly stimulated insulin secretion from pancreatic islets to approximately 2.3-fold the baseline value in the presence of a glucose concentration of 5.6 mmol/l. Although adiponectin had no effect on ATP generation, membrane potentials, Ca 2+ currents, cytosolic calcium concentrations or activation status of AMPK, it caused a significant increase of membrane capacitance to approximately 2.3-fold the baseline value. TIRF analysis revealed that adiponectin induced a significant increase in the number of fusion events in mouse pancreatic beta cells under 5.6 mmol/l glucose loading, without affecting the status of previously docked granules. Moreover, intravenous injection of adiponectin significantly increased insulin secretion to approximately 1.6-fold of baseline in C57BL/6 mice. Diabetologia (2008) Conclusions/interpretation The above results indicate that adiponectin induces insulin secretion in vitro and in vivo.

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“…[36] dinucleotide (reduced form; NADH) equivalents derived from glycolysis are transferred into mitochondria via the glycerol-phosphate, dihydroxyacetone-phosphate, and malate-aspartate shuttles. Blockage of either shuttle alone has little effect on glucose-stimulated insulin secretion, whereas blockage of both pathways in mitochondrial glycerolphosphate dehydrogenase null mice [50,51] strongly inhibits first-phase insulin release and abolishes secondphase secretion in response to elevated glucose. How the NADH equivalents from glycolysis, via generation of ATP, inhibit K ATP channels has not been established, but the results suggest that β-cell K ATP channels are not sensing "bulk" cytosolic [ATP] i .…”

Section: Dual Regulation Of K Atp Channel Activity By Adenine Nucleotmentioning

confidence: 99%

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

Bryan

Muñoz

Zhang

et al. 2006

Pflugers Arch - Eur J Physiol

147

117

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The sulfonylurea receptors (SURs) ABCC8/ SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K + selective pores, either K IR 6.1/KCNJ8 or K IR 6.2/ KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K + channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K + (K ATP ) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotidebinding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic β cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K ATP channel activity by a K IR 6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K ATP channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.

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Role of NADH Shuttle System in Glucose-Induced Activation of Mitochondrial Metabolism and Insulin Secretion

Cited by 440 publications

References 25 publications

A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse

A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse

Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

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