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University of Geneva Medical Center, Geneva, Switzerland
Address all correspondence and requests for reprints to: Dr. Claes B. Wollheim, Department of Cell Physiology and Metabolism, University Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail: claes.wollheim{at}medecine.uinge.ch.
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Abstract |
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 Top Abstract IntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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Introduction |
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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Glucose Metabolism in the ß-Cell |
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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). This glucose sensor mechanism adjusts glycolytic flux to the plasma glucose concentration in hepatocytes and islet cells (7).
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In the mitochondrial matrix, pyruvate has two main fates: oxidation by pyruvate dehydrogenase to form acetyl-coenzyme A (acetyl-CoA; oxidative pathway) or carboxylated by pyruvate carboxylase to form oxaloacetate (anaplerotic pathway) (9, 10). Acetyl-CoA enters the tricarboxylic acid (TCA) cycle to undergo additional oxidation steps generating CO2 and the reducing equivalents, flavin adenine dinucleotide and reduced nicotinamide adenine dinucleotide (NADH). These reducing equivalents enter the respiratory chain to form an electrochemical gradient across the inner mitochondrial membrane. The final electron acceptor of these reactions is molecular oxygen. The proton motive force then drives ATP synthesis at complex V (ATP synthase), thereby linking respiration to the synthesis of ATP from ADP and inorganic phosphate (2) (Fig. 1
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Synthesis of oxaloacetate from pyruvate serves a separate, possibly as important, function in mitochondrial metabolism, especially in the ß-cell that has high pyruvate carboxylase activity (9, 11). As suggested by the term anaplerotic pathway, oxaloacetate fills up or adds new intermediate metabolites to the TCA cycle. Unlike oxaloacetate itself, some of the intermediates derived from oxaloacetate, such as malate, citrate, isocitrate, and 2-oxoglutarate, can leave the TCA cycle and cross the inner mitochondrial membrane (12). This process depends on the mitochondrial membrane potential. Thus, these metabolites can serve as precursors for many essential molecules in the mitochondrial matrix as well as in the cytoplasm. Importantly, glutamate aspartate transport is rate limiting to mitochondrial metabolism, because overexpression of aralar1 enhances glucose-stimulated insulin secretion (GSIS) (13). Anaplerotic metabolism in the ß-cell may be used to generate coupling factors that contribute to GSIS (see below). Due to the very low lactate dehydrogenase expression in ß-cells, NADH formed during glycolysis would accumulate and reduce glycolytic flux unless NADH is reoxidized. Therefore, the hydrogen shuttles (malate/aspartate and glycerophosphate shuttles) that transport reducing equivalents from the cytoplasm to the mitochondria are particularly active in the ß-cell (8, 14).
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Mitochondrially Derived ATP in Metabolism Secretion Coupling |
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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Thus, compelling evidence demonstrates that ATP is a key factor coupling mitochondrial metabolism to insulin secretion. ATP production is accelerated after glucose stimulation to provide the energy for insulin exocytosis, replenishing of insulin granules, and establishment of a new steady state of ion gradients. Despite increased ATP consumption, cytosolic ATP levels in ß-cells are increased by about 40% after a shift from basal to high glucose (17). ATP synthesized in the mitochondrial matrix is transported to the cytosol in exchange for cytosolic ADP via adenine nucleotide translocators. The resulting increase in the cytosolic ATP:ADP ratio reduces the opening probability of the plasma membrane KATP channel. Among the molecular components regulating insulin secretion, the KATP channel has proven to be a very useful target, because its opening is blocked by sulfonylurea compounds (5). These are widely used in the treatment of type 2 diabetes. Functional KATP channels are essential for GSIS, and a common polymorphism in the KATP channel has been linked to type 2 diabetes (19). Closure of KATP channels depolarizes the plasma membrane, triggering the opening of voltage-dependent Ca2+ channels (Fig. 1). As in other exocytotic fusion events, Ca2+ is an essential trigger of insulin granule exocytosis (20). The Ca2+ signal resulting from mitochondrial activation completes the chain of events between glucose uptake into the ß-cells and insulin exocytosis.
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Role of Ca2+ in Mitochondrial Activation |
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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). This is amplified by hyperpolarization of the inner mitochondrial membrane, increasing the driving force for Ca2+ uptake (17). Inside the organelle, Ca2+ activates several matrix dehydrogenases (pyruvate dehydrogenase, isocitrate dehydrogenase, and 2-oxoglutarate dehydrogenase). This is reflected by Ca2+-driven oscillations of reduced nicotinamide adenine nucleotide phosphate, NAD(P)H, in glucose-stimulated ß-cells (21). Ca2+ has also been suggested to stimulate ATP synthase directly (22). These coordinated actions should reinforce GSIS, possibly during the second phase of insulin secretion. Both first and second phases of GSIS are attenuated in type 2 diabetic patients and first degree relatives (for review, see Ref.23). Ca2+ can also be sensed at the outer surface of the inner mitochondrial membrane, because the above-mentioned glutamate/aspartate transporter arlar1 is regulated by cytosolic Ca2+ (24). Together, these mechanisms converge to ensure sustained ATP generation during cell activation. Ca2+ accumulated by mitochondria must be removed. Increases in matrix Ca2+ are counteracted principally by the Na+/Ca2+ exchanger. Its activity is an important determinant of the extent and duration of mitochondrial Ca2+ transients. Inhibition of the Na+/Ca2+ exchanger has been exploited as a potential target in diabetes research. An inhibitor of the exchanger (CGP37157) was shown to prolong mitochondrial Ca2+ signals and increase insulin secretion (25). The same compound has been shown to prolong mitochondrial Ca2+ signals and ATP production in fibroblasts from patients with complex I deficiency (26).
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Coupling Factors in the Amplifying Pathway of Insulin Exocytosis |
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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-toxin-permeabilized cells, permitting clamping of cytoplasmic Ca2+ and ATP, succinate stimulates insulin secretion through mitochondrial activation (28, 29). Interestingly, glycerophosphate was unable to stimulate insulin secretion under the same conditions. Via the glycerol phosphate shuttle, glycerophosphate can provide reducing equivalents, but not carbons, to the mitochondria, demonstrating the need for anaplerotic input to the TCA cycle for the potentiation of insulin secretion. Thus, the synthesis of coupling factors supporting the action of ATP could be linked to the anaplerotic pathway of pyruvate metabolism. In support of this possibility, inhibition of pyruvate carboxylase impairs GSIS (11, 30). Several mitochondria-derived molecules have been proposed to serve such a role. Citrate exported from mitochondria can act as an allosteric activator of acetyl-CoA synthase, which leads to a rapid increase in the malonyl-CoA concentration after glucose stimulation of the ß-cell (31). This suggests that malonyl-CoA could have a direct impact on insulin secretion. Suppressing the increases in malonyl-CoA by the overexpression of malonyl-CoA carboxylase, however, did not impair the glucose responsiveness of ß-cells. Although these results argue against a direct involvement of malonyl-CoA in GSIS, it is likely to facilitate fatty acid-mediated potentiation by diminishing fatty acid oxidation, favoring their actions on exocytosis (31, 32). Although short-term exposure of islets to palmitate and other free fatty acids acutely enhances GSIS, longer exposure of islets is inhibitory. It is of interest in this context that infusion of free fatty acids for 4 d into healthy members of families with a history of type 2 diabetes causes marked inhibition of GSIS, contrasting with slight stimulation in control subjects (33).
Another possible metabolic event linked to insulin secretion is pyruvate cycling. This process is initiated in response to glucose as pyruvate is carboxylated to form oxaloacetate. In pyruvate cycling, malate and/or citrate derived from oxaloacetate are transported out of the mitochondria, where they can be converted to pyruvate. The last step of these reactions is mediated by malic enzyme, which oxidatively decarboxylates malate, also generating NADPH (Fig. 1). Pyruvate completes the cycle to be used again as substrate for mitochondrial matrix enzymes. As measured by 13C nuclear magnetic resonance, pyruvate cycling is stimulated 2- to 3-fold after a shift of INS-1 cells to elevated glucose. Using different INS-1 clones that vary in their secretory response, it was also shown that pyruvate cycling, but not pyruvate oxidation, was proportional to GSIS (11). However the correlation between pyruvate cycling and insulin secretion is lost in the presence of free fatty acids (34). Both malonyl-CoA and pyruvate cycling in insulin secretion merit additional investigation.
Pyruvate cycling, as described above, generates reducing equivalents in the cytosol in the form of NADPH. A recent study suggests that NADPH can stimulate Ca2+ induced insulin exocytosis, as monitored by capacitance changes (35). This is an attractive mechanism, because glucose increases the ratios of both NADH:NAD+ and NADPH:NADP+. Interestingly, the effect was specific for NADPH, because injection of NADH did not influence capacitance. However, glutathione as well as glutaredoxin could also stimulate exocytosis (35). In summary, the results suggest that the redox state of the cell could have a direct impact on the granule fusion machinery.
Glutamate is generated from the TCA cycle intermediate 2-oxoglutarate by glutamate dehydrogenase, from other transamination reactions, or from glutamine in the cytoplasm. In response to glucose, glutamate levels rise in islets (29, 36), as also shown by nuclear magnetic resonance in clonal ß-cells (11, 37). The same technique was used to demonstrate anaplerotic input to the TCA cycle from glucose and cataplerotic generation of glutamate via glutamate dehydrogenase under conditions favoring GSIS (10). As argued above, glutamate, therefore, has the potential to act as an intermediate that stimulates insulin secretion. Because glutamate levels rise only 5–10 min after glucose addition, it is likely to impact mainly on second phase insulin secretion (29). Consistent with a role in insulin secretion, the cell membrane-permeable glutamate analog dimethylglutamate increases glucose sensitivity, resulting in insulin secretion. Additional evidence for the implication of glutamate in GSIS is suggested by down-regulation of glutamate dehydrogenase, resulting in a 50% inhibition of insulin secretion in response to glucose (6). Glucose-derived glutamate is generated by mitochondria and acts downstream as a possible link between mitochondrial metabolism and the exocytotic machinery (Fig. 1). Glutamate directly enhances Ca2+-stimulated exocytosis, as demonstrated in both permeabilized cells and capacitance recordings, under conditions of clamped ATP (29, 38). The underlying mechanism remains to be established. It is of interest that familial hyperinsulinism has been linked to gain of function mutations in glutamate dehydrogenase, which render the ß-cell sensitive to glutamine (normally not insulinotropic) as a secretagogue (39).
In summary, a good case has been made for several mitochondrially derived factors that could potentiate GSIS. Changes in mitochondrial metabolism after glucose stimulation of the ß-cell is associated with changes in the concentration of many metabolites. Several of these metabolites could synergize to optimally stimulate insulin secretion; for example, NADPH and glutamate may affect different processes required for insulin exocytosis. Although malonyl-CoA would potentiate the effect of fatty acids, glutamate could enhance the second phase of GSIS.
Unfortunately, mechanistically we know rather little about the downstream mediators of the proposed coupling factors. The identification of components involved in insulin secretion that are directly regulated by coupling factors would certainly open up new possibilities for the treatment of type 2 diabetes.
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Fatigue of ß-Cell Mitochondria in Type 2 Diabetes |
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The impact of mitochondrial DNA mutations is most pronounced in tissues with a low mitotic rate, such as brain, muscle, and islet cells. Cells depending on high ATP production, such as ß-cells, are particularly susceptible to a diminished fraction of functional mitochondria, which tend to decompensate with time. This leads to apoptosis and decreased ß-cell mass, which, together with defective secretion coupling, cause impaired GSIS. These patients may even require insulin therapy (41, 42). Mitochondrial diabetes illustrates how the gradual loss of mitochondrial activity is deleterious for ß-cell secretory function and survival.
In analogy, decreased mitochondrial activity in ß-cells would predispose individuals to develop ß-cell dysfunction in type 2 diabetes. In individuals with a family history of type 2 diabetes, mitochondrial respiratory function may be sufficient during a normal workload, but may deteriorate under conditions that put stress on the ß-cells, such as insulin resistance or already slightly increased glycemia (43). These states require increased insulin output to maintain glucose homeostasis. This confirms that both genetic predisposition and environmental factors could precipitate ß-cell dysfunction.
The prevalence of type 2 diabetes increases with age. Unfortunately, measurements of mitochondrial activity during aging are only available for insulin target tissues. One of the take-home messages is that mitochondrial function decreases with increasing age (see below).
A key determinant of aging is the production of reactive oxygen species (ROS) (44). Irreversible damage caused by ROS interferes with mitochondrial function. Interestingly, it is the mitochondria themselves that in large part are responsible for ROS production resulting in damage to their lipids, proteins, and mtDNA. ROS are produced in the mitochondria as a side reaction of respiration. Rather than reducing molecular oxygen to water at complex IV, some electrons escape to reduce oxygen directly to form superoxide. The superoxide radical can then react further to give rise to H2O2 and hydroxyl radicals. The mtDNA is vulnerable to the formed ROS. First, ROS are generated nearby in the matrix space, and second, mtDNA is not protected by histones. A role for mtDNA damage in aging has been convincingly demonstrated in a mouse model expressing a mitochondrial DNA polymerase lacking proof-reading activity (45). These mice accumulate more mtDNA mutations and show all the phenotypes of premature aging. mtDNA mutations have also been shown to accumulate in humans as a function of age (46). ß-Cell-targeted disruption of the frataxin gene, encoding a mitochondrial iron-binding protein, causes diabetes in the mouse. This was linked to increased islet ROS production and decreased ß-cell mass. Patients with mutations in the frataxin gene develop a neurodegenerative disease, associated with type 2 diabetes in 20% of cases (47). Whether these patients or patients with common forms of type 2 diabetes have reduced ß-cell mass as a consequence of mitochondrial dysfunction remains to be firmly established.
In the ß-cell, glucose has been reported to promote ROS production through its hyperpolarizing effect on mitochondrial membrane potential (48, 49). When a similar methodology was combined with measurements of reduced pyrimidine and flavin nucleotide fluorescence in ß-cells, surprisingly, physiological as well as high glucose concentrations lowered superoxide production. This was related to the initial metabolic state of the cells, i.e. suppression was most pronounced in cells with the highest initial NADPH levels (50). In view of these conflicting results, ROS generation as well as their putative detrimental actions in the ß-cell need additional study.
Despite the reported low expression of superoxide dismutase and catalase in ß-cells under normal conditions, antioxidant systems are sufficient to prevent oxidative damage (51). Exogenous antioxidants have been investigated for the treatment of diabetes (52). For detailed discussion of ß-cell apoptosis in general and implication of mitochondria in particular, the reader is referred to the recent literature (53, 54).
How can we boost the fatigued ß-cell? Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein receiving considerable attention as target for improved ß-cell function (3). UCP2 is homologous to UCP1, which is expressed in brown adipose tissue. UCP1 has been shown to uncouple mitochondria to generate heat by transporting protons down their electrochemical gradient. By doing so, UCP1 dissipates the energy, disconnecting respiration from ATP synthesis. Whether UCP2 in ß-cells and UCP3 in skeletal muscle carry out an identical molecular function is not yet known. It has been clearly demonstrated that increased expression of UCP2 has a negative impact on GSIS both in vitro and in vivo (3). A common human polymorphism in the promoter of UCP2 that leads to its overexpression attenuates GSIS both in vivo and in incubated islets (55). Most interestingly, in UCP2–/– mice, GSIS is stimulated (56). Introduction of the UCP2–/– mutation in the ob/ob mouse background improved glycemic control as well as GSIS in vitro. It was therefore suggested that inhibition of UCP2 function increases the coupling efficiency of respiration and ATP production. The more pronounced increase in mitochondrial membrane potential also augmented ROS production (49). Superoxide can activate UCP2. This may be a trick of nature to prevent excessive mitochondrial damage in cells that tend to hyperpolarize their inner mitochondrial membrane. Indeed, overexpression of UCP2 reduces cytokine induced ROS production and apoptosis (57). Treatment of type 2 diabetes by inhibition of UCP2 may therefore be fraught with danger because of the long-term deleterious effects on ß-cells.
Among the possible treatments for type 2 diabetes is increased biogenesis of active mitochondria to replace those harboring mtDNA defects. The nuclear-encoded mitochondrial transcription factor A (TFAM) is essential for control of mtDNA copy number and transcription (58). ß-Cell-specific disruption of TFAM in the mouse results in a phenotype resembling human mitochondrial diabetes with early impairment of GSIS and late loss of ß-cell mass (59). Dominant negative suppression of the maturity-onset diabetes of the young 4 gene, Pdx1, in islets reduced the expression of TFAM and consequently mitochondrially encoded genes. Such islets are refractory to glucose-stimulated ATP generation and insulin secretion (60). Moreover, Pdx1+/– mice show age-dependent ß-cell apoptosis (61). Conversely, increasing TFAM expression should, in theory, increase mitochondrial function. Unfortunately, TFAM-transgenic mice with up-regulated mtDNA copy number do not display increased number and function of mitochondria (58). It should be tested whether other nuclear factors are more efficient in promoting mitochondrial biogenesis.
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Fatigue of Target Tissue Mitochondria in Type 2 Diabetes |
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Fatty acid oxidation takes place inside mitochondria. In a well-balanced system, the mitochondria, for example of skeletal muscle, will oxidize fatty acids efficiently to prevent the intramyocellular accumulation of triglycerides. Flooding the system with free fatty acids may overwhelm the mitochondria, leading to the accumulation of intracellular lipids and the development of insulin resistance (63). Elevation of free fatty acids during a hyperinsulinemic euglycemic clamp can induce insulin resistance over a time frame of only a few hours (64). More modest elevation of fatty acids over longer periods of time in combination with a diminished oxidative capacity of mitochondria may also lead to the accumulation of triglycerides inside liver muscle or ß-cells.
With increasing age, mitochondrial activity decreases, with a consequent reduction in fatty acid oxidation. This has been demonstrated, for instance, by comparing lean subjects in different age groups. The elderly (61–84 yr) in this study had developed insulin resistance, showed increased levels of intramyocellular and intrahepatic lipid accumulation, and, most importantly, had a 46% decrease in the mitochondrial ATP synthesis rate (65). Similarly, in young lean offspring of patients with type 2 diabetes, intramyocellular triglycerides were elevated, and muscle ATP synthesis was reduced (66). The reduced ATP synthesis in these experiments may either be the cause or the consequence of impaired insulin action. Reduced insulin signaling or the accumulated triglycerides may affect mitochondrial biogenesis or function (67). Alternatively, mitochondrial dysfunction could cause insulin resistance. Most likely, these two mechanisms act together in a vicious cycle of insulin resistance. Glucose tolerance remains normal, provided the ß-cells can compensate by maintaining elevated circulating insulin. The development of type 2 diabetes is mainly determined by genetic factors controlling ß-cell function and occurs in approximately 20% of overweight, insulin-resistant subjects. Compensation occurs by both hypersecretion of insulin and increased ß-cell mass (66) (53). In summary, partial loss of mitochondrial activity goes hand in hand with the development of insulin resistance.
AMP-dependent kinase (AMPK) has been proposed as a target for prevention of the metabolic syndrome, characterized by dislipidemia, obesity, hypertension, and insulin resistance, eventually leading to type 2 diabetes. Malonyl-CoA is the gatekeeper of fatty acid oxidation by inhibition of mitochondrial carnithine-palmitoyl transferase I. The activation of AMPK by exercise, leptin, or the antidiabetic drug metformin lowers the concentration of malonyl-CoA in the muscle through several mechanisms, including inhibition of acetyl-CoA carboxylase by phosphorylation (reviewed in Ref.68). In contrast, metformin-induced activation of AMPK is associated with inhibition of GSIS in human islets (69). This is one of several examples of differential responses in ß-cells and insulin target cells.
AMPK also signals to increase the expression of OXPHOS genes. This is mediated by the peroxisome proliferator-activated receptor-
coactivator 1 (PGC1). This transcription factor coordinately regulates the expression of a large set of OXPHOS genes, enhancing mitochondrial activity (70). Interestingly, an impressive 89% (94 of 106) genes classified as OXPHOS genes showed lower expression in muscle of type 2 diabetic patients. Two thirds of the identified OXPHOS genes are coregulated by PGC1. The results clearly demonstrate that transcriptional regulation contributes to mitochondrial defects in the target tissues of diabetic patients (67, 70). This role of PGC1 is particularly interesting, because it was also found to be a positive regulator of mitochondrial biogenesis. However, the effects of PGC1 are tissue specific. For instance, overexpression of PGC1 in ß-cells decreased the levels of several glycolytic enzymes, causing glucose intolerance after islet transplantation in vivo and impaired GSIS in vitro (71).
Nonetheless, improving mitochondrial respiration and fatty acid oxidation in insulin target tissues are attractive drug targets in type 2 diabetes. In contrast, increased levels of malonyl-CoA in the hypothalamus result in reduced food intake and weight loss in obese animals (72). This and the above-mentioned examples illustrate the difficulty of finding novel drugs for the prevention and improved treatment of type 2 diabetes. One of the difficulties lies in the multiorgan regulation of normal blood glucose homeostasis.
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Footnotes |
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First Published Online March 23, 2006
Abbreviations: acetyl-CoA, Acetyl-coenzyme A; AMPK, AMP-dependent kinase; GLUT, glucose transporter; GSIS, glucose-stimulated insulin secretion; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine nucleotide phosphate; OXPHOS, oxidative phosphorylation; PGC1, peroxisome proliferator-activated receptor- coactivator-1; ROS, reactive oxygen species; TCA, tricarboxylic acid; TFAM, mitochondrial transcription factor A; UCP2, uncoupling protein 2.
Received January 18, 2006.
Accepted for publication February 21, 2006.
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TopAbstractIntroductionGlucose Metabolism in the...Mitochondrially Derived ATP in...Role of Ca2+ in...Coupling Factors in the...Fatigue of ß-Cell...Fatigue of Target Tissue...References |
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-cells. Nat Cell Biol 5:330–335[CrossRef][Medline]-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273[CrossRef][Medline]. Dev Cell 5:73–83[CrossRef][Medline]This article has been cited by other articles:
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  A.M. Hall, R.J. Unwin, M.G. Hanna, and M.R. Duchen Renal function and mitochondrial cytopathy (MC): more questions than answers? QJM, May 16, 2008; (2008) hcn060v1. [Abstract] [Full Text] [PDF]
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 J.-a Kim, Y. Wei, and J. R. Sowers Role of Mitochondrial Dysfunction in Insulin Resistance Circ. Res., February 29, 2008; 102(4): 401 - 414. [Abstract] [Full Text] [PDF]
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 N. H. McClenaghan Physiological regulation of the pancreatic {beta}-cell: functional insights for understanding and therapy of diabetes Exp Physiol, May 1, 2007; 92(3): 481 - 496. [Abstract] [Full Text] [PDF]
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 S. E. Wiley, A. N. Murphy, S. A. Ross, P. van der Geer, and J. E. Dixon MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity PNAS, March 27, 2007; 104(13): 5318 - 5323. [Abstract] [Full Text] [PDF]
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