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![Mitochondrial schematic showing respiration, the citric acid cycle, and transporters of metabolites across the mitochondrial inner membrane. Respiration via the oxidation of NADH and flavoproteins pumps protons (H ϩ ) out of mitochondria. The diffusion of protons back across the inner mitochondrial membrane powers ATP synthesis. Metabolism of substrates in the TCA cycle reduces NAD to NADH and reduces flavoproteins, e.g., succinate dehydrogenase. The mitochondrial inner membrane is impermeable to many metabolites, and, therefore, transporters have evolved to carry metabolites across the inner membrane, frequently in exchange for another metabolite. Some carriers are capable of transporting more than one metabolite, and some metabolites are transported on more than one carrier. The red X s at top right indicate that oxaloacetate (OAA), NAD(P)(H), and acetyl-CoA (Ac-CoA) are not transported as such across the inner membrane and must be transported either as parts of other molecules (oxaloacetate and acetyl-CoA) or as equivalents in the form of reduced or oxidized metabolites [NAD(P)(H)].](profile/Mindy-Kendrick/publication/8141631/figure/fig2/AS:277660996521992@1443210948475/Mitochondrial-schematic-showing-respiration-the-citric-acid-cycle-and-transporters-of.png)
Mitochondrial schematic showing respiration, the citric acid cycle, and transporters of metabolites across the mitochondrial inner membrane. Respiration via the oxidation of NADH and flavoproteins pumps protons (H ϩ ) out of mitochondria. The diffusion of protons back across the inner mitochondrial membrane powers ATP synthesis. Metabolism of substrates in the TCA cycle reduces NAD to NADH and reduces flavoproteins, e.g., succinate dehydrogenase. The mitochondrial inner membrane is impermeable to many metabolites, and, therefore, transporters have evolved to carry metabolites across the inner membrane, frequently in exchange for another metabolite. Some carriers are capable of transporting more than one metabolite, and some metabolites are transported on more than one carrier. The red X s at top right indicate that oxaloacetate (OAA), NAD(P)(H), and acetyl-CoA (Ac-CoA) are not transported as such across the inner membrane and must be transported either as parts of other molecules (oxaloacetate and acetyl-CoA) or as equivalents in the form of reduced or oxidized metabolites [NAD(P)(H)].
Source publication
The importance of mitochondrial biosynthesis in stimulus secretion coupling in the insulin-producing beta-cell probably equals that of ATP production. In glucose-induced insulin secretion, the rate of pyruvate carboxylation is very high and correlates more strongly with the glucose concentration the beta-cell is exposed to (and thus with insulin re...
Context in source publication
Context 1
... glutamate to form leucine and -ketoglutarate (31, 51) ( Fig. 4, reaction 20 ) and via ␣ -ketoglutarate’s metabolism, as well as by the conversion of KIC to acetyl-CoA, (Fig. 4, reaction 19 plus the 5 reactions indicated by no. 25 ). The leucine derived from transamination can enhance glutamate metabolism by activation of glutamate dehydrogenase, as mentioned above. The reason KIC is a much more potent secretagogue than leucine might be because metabolism of KIC supplies acetoacetate and acetyl-CoA at a faster rate than does metabolism of leucine. Methyl esters of succinate. Methyl esters of succinate are about one-third as potent as glucose as insulin secretagogues and are about equal to leucine in potency (28, 34, 58, 59, 70, 71, 74, 75, 85, 86, 121) in fresh rat pancreatic islets. Methyl esters of succinate probably stimulate insulin release by producing both oxaloacetate and acetyl-CoA. After hydrolysis of the ester to succinate and conversion of the succinate to fumarate and then malate in the mitochondrion, malate can be exported to the cytosol and converted to pyruvate in the malic enzyme reaction [Fig. 4, reactions 21 , 8 , 9 (or 22 ), and 12 ]. Pyruvate can then be taken up into the mitochondrion and carboxylated to oxaloacetate (Fig. 4, reaction 2 ) or decarboxylated to acetyl-CoA (Fig. 4, reaction 1 ). The carboxylation route of conversion of malate to oxaloacetate (Fig. 4, reactions 12 and 2 ) generates cytosolic NADPH and, unlike the direct E6 SIGNALING ROLES OF conversion of malate to oxaloacetate (Fig. 4, reaction 10 ), does not generate mitochondrial NADH. Succinate-derived oxaloacetate can then condense with acetyl-CoA derived from the pyruvate (Fig. 4, reaction 3 ) to form any citric acid cycle intermediate (58, 63, 64, 86). Interestingly, esters of other citric acid cycle intermediates do not stimulate insulin release (75). A possible explanation for this fact is that succinate is ideally situated among metabolic pathways to supply both NADPH and mevalonate as discussed below (see SUCCINATE MECHANISM ). Fatty acids. The consensus about the effect of fatty acids such as palmitate on insulin release is that they potentiate glucose-induced insulin secretion when added acutely to islets, but they cannot stimulate insulin release by themselves (18, 34, 96). The long-term effect of incubation of islets with palmitate is a reduction in glucose-induced insulin release (the lipotoxicity hypothesis) (9, 34, 92, 114). Fatty acids are metabolized to acetyl-CoA, (Fig. 2), which can be metabolized in the citric acid cycle, but acetyl-CoA cannot be anaplerotic unless there is a source of oxaloacetate to combine with it. Perhaps this is why fatty acids do not, by themselves, stimulate insulin release. When pyruvate is supplied to suspensions of -cell mitochondria, the export of malate is increased markedly (64, 65), and the export of other citric acid cycle intermediates increases to various extents. Although the export of citrate is not increased as much as malate, evidence from intact cell experiments suggests that anaplerosis of citrate is necessary for insulin secretion (19, 29, 30, 97, 102). We observed that most of the citrate and malate are extramitochondrial in suspensions of  -cell mitochondria (61), and others have previously made the same observation with mitochondria from other tissues (44, 113). The extramitochondrial location of citrate may enable it to act as a communicator among individual mitochondria to synchronize their metabolism with one another and to synchronize mitochondrial processes with other cellular processes (73), as discussed in the last section of this perspective. The high rate of carboxylation of pyruvate in the  -cell indicates that it is possible that each citric acid cycle intermediate is synthesized in amounts that exceed its consumption in the citric acid cycle, and the excess is exported from the mitochondria to the cytosol, where it has a role in stimulating or supporting insulin secretion. [Obviously, some intermediates cannot cross the mitochondrial inner membrane and are exported in the form of another intermediate and are converted back to the same intermediate outside the mitochondria. For example, oxaloacetate cannot cross the mitochondrial inner membrane but can be exported as malate, fumarate, citrate, or isocitrate (Figs. 2 and 4, reactions 10 , 9 , 22 , 12 , 13 , and 26 ), and acetyl-CoA is also not transported as such but can be transported as citrate (Figs. 2 and 4, reaction 13 ).] The follow- ing sections discuss the possible extramitochondrial roles for each cycle intermediate. Less will be said about well-studied extramitochondrial mechanisms and more will be said about possible actions for which evidence is emerging. Malate. The conversion of oxaloacetate to malate and the export of malate to the cytosol form a pyruvate-malate shuttle (61), permitting the export of NADPH equivalents to the cytosol. Malate and NADP are converted to NADPH and pyruvate by malic enzyme. Pyruvate can then reenter mitochondrial pools (Fig. 4, reactions 10 , 12 , 1 , and 2 ). The potential roles of NADPH are depicted (see Fig. 6) and discussed below. Citrate and isocitrate. The citrate-pyruvate shuttle (21, 29, 30, 102, 103) utilizes portions of the malate-pyruvate shuttle and additional pathways to export both NAD equivalents and NADPH equivalents from mitochondria. Exported citrate is cleaved to acetyl-CoA and oxaloacetate by ATP citrate lyase in the cytosol. Cytosolic malate dehydrogenase catalyzes the conversion of exported oxaloacetate and cytosolic NADH to malate and NAD, thus exporting NAD equivalents from the mitochondria. The malate can be converted to pyruvate by malic enzyme, thus exporting NADPH equivalents to the cytosol (Fig. 4, reactions 13 , 11 , and 12 ). The acetyl-CoA can be carboxylated to malonyl-CoA, which can be used in the synthesis of lipids. Malonyl-CoA itself is believed also to have a signaling role (12, 18, 23, 29, 30, 102, 103) because it inhibits carnitine palmitoyl-CoA transferase-1, an enzyme that is required for the transport of long-chain acyl-CoAs into mitochondria, where they are metabolized. Inhibition of this enzyme should increase the level of long-chain acyl-CoAs in the cytosol, where these molecules are believed to have numerous signaling activities (Fig. 5). The proposed signaling roles of long-chain acyl-CoAs include influences on the K ATP channel, glucokinase, ATPases, and vesicular trafficking (18). The malonyl-CoA hypothesis, originally championed by the late Den- nis McGarry (Chen et al., Ref. 15) and by Corkey and coworkers (18, 19) and Prentki et al. (97), is one of the more popular and well-studied hypotheses about the role of anaplerotic products in insulin secretion. Evidence in support of this hypothesis abounds, and, as with all popular hypotheses, there is some evidence against it (18, 39, 90). Many excellent reviews of this hypothesis have been published (18, 23, 96). ␣ -Ketoglutarate. ␣ -Ketoglutarate, when it is exported from mitochondria, can act as a transporter of oxidizing equivalents of NAD out of mitochondria in the malate-aspartate shuttle (Fig. 4, reactions 10 , 11 , 23 , and 16 ) and of NADP into mitochondria in the isocitrate shuttle, which transports NADPH out of mitochondria (Fig. 4, reactions 5 , 15 , 23 , 11 , 10 , and 16 ). There are no fuel secretagogues that cannot produce ␣ -ketoglutarate, as described below. ␣ -Ketoglutarate almost certainly has a ...
Citations
... However, a second or "metabolic amplifying" pathway is necessary for proper insulin secretion response, involving the external replenishment of the Krebs, or tricarboxylic acid (TCA), cycle via anaplerosis (6), and is distinct to the neurohormonal amplification pathways (e.g., incretin system) that are related to the activation of G protein-coupled receptors (GPCRs) (7). In addition to this dual and hierarchical control of insulin secretion, emerging evidence points to important roles for anaplerotic TCA cycle substrates that act as second messengers in the cytosol to drive insulin granule exocytosis (8). Within this framework, energy metabolites are increasingly recognized as signaling molecules (9). ...
Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Mice with β-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
... Within β-cells, additional sources of NADPH, such as cytosolic isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), increase the overall NADPH pool. Downregulation of IDH1 and ME1 resulted in reduced NADPH levels, subsequently impacting GSIS [60,61]. Consequently, under high glucose conditions, PPP-derived NADPH is amplified by cytosolic enzymes IDH1 and ME1, potentially enhancing NOX4-derived H 2 O 2 production and maintaining the ATP/ADP ratio, which is crucial for insulin exocytosis. ...
Purpose of Review
This review outlines NADPH oxidase structure and function in pancreatic β-cells. Furthermore, methods for detecting reactive oxygen species and NADPH oxidase inhibitors are discussed.
Recent Findings
NADPH oxidase–derived ROS regulates β-cell metabolism and insulin release. This review highlights new findings of the NADPH oxidase family, such as NOX4, in regulating β-cell function. For instance, NOX4-derived H2O2 and increased ATP levels promote the closure of ATP-sensitive K⁺ channels to induce insulin release. In addition, NOX2 inhibitors, such as the tetrahydroquinolines CPP11G and CPP11H, have been shown to interact with p47phox, preventing NOX2 assembly and activity.
Summary
NADPH oxidase family is involved in the physiology and pathophysiology of pancreatic β-cells. However, more studies are necessary to fully understand when, where, and how NADPH oxidase–derived ROS regulate β-cell function. Better improved NADPH oxidase inhibitors are essential to tackle this problem and develop new strategies with in-depth research.
... In this study, they found that the use and regulation of Gln metabolism in hypoxic cells, which identified a critical role for oxygen in regulating carbon use to produce Acetyl coenzyme A and support lipid synthesis in mammalian cells [32]. Furthermore, in 2007, the first burst of co-cited references commenced [52], peaking in 2020. A total of five references had a burst that lasted until 2022 [53][54][55]. ...
Objective
“Metabolism affects function” is the consensus of researchers at present. It has potential clinical application value to study the effects of regulating glutamine (Gln) metabolism on diabetes physiology or pathology. Our research aimed to summarize the latest research progress, frontier hot topics and future development trends in this field from the perspective of scientometrics.
Methods
Relevant literatures and reviews were obtained from the Web of Science (WoS) between January 1, 2001 and May 31, 2022. An online analysis platform of bibliometrics, CiteSpace, and VOS viewer software were used to generate visual knowledge network graphs, including publication countries, institutions and authors partnership analysis, co-occurrence analysis, co-citation analysis, as well as citations and keywords burst detection to acquire research trends and hotspots.
Results
Our results showed that a total of 945 publications in the WoS database met the analysis requirements, with articles being the main type. The overall characteristics showed an increasing trend in the number of publications and citations. The United States was leading the way in this research and was a hub for aggregating collaborations across countries. Vanderbilt University delivered high-quality impact with the most published articles. DeBerardinis, RJ in this field was the most representative author and his main research contents were Gln metabolism and mitochondrial glutaminolysis. Significantly, there was a relative lack of collaboration between institutions and authors. In addition, “type 2 diabetes”, “glutamine”, “metabolism”, “gene expression” and “metabolomics” were the keywords categories with high frequency in co-citation references and co-occurrence cluster keywords. Analysis of popular keywords burst detection showed that “branched chain”, “oxidative phosphorylation”, “kinase”, “insulin sensitivity”, “tca cycle”, “magnetic resonance spectroscopy” and “flux analysis” were new research directions and emerging methods to explore the link between Gln metabolism and diabetes. Overall, exploring Gln metabolism showed a gradual upward trend in the field of diabetes.
Conclusion
This comprehensive scientometric study identified the general outlook for the field and provided valuable guidance for ongoing research. Strategies to regulate Gln metabolism hold promise as a novel target to treat diabetes, as well as integration and intersection of multidisciplinary provides cooperation strategies and technical guarantees for the development of this field.
... their first-order and total-effects sensitivity coefficients are markedly different). These three enzymes are known to be important participants in pyruvate cycling pathways [43]. ...
Insulin, a key hormone in the regulation of glucose homoeostasis, is secreted by pancreatic β‐cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β‐cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP and other key metabolic signals, including a rise in the NADPH:NADP⁺ ratio. Experimental evidence indicates that pyruvate‐cycling pathways play an important role in the elevation of the NADPH:NADP⁺ ratio in response to glucose. The authors developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. The authors successfully validated the model against experimental observations and performed a sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier and the pyruvate transporter are the most important regulators of pyruvate cycling and NADPH production. In contrast, the analysis showed that variation in the pyruvate carboxylase flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for the treatment of type 2 diabetes.
... Parentheses indicate that KIV and Val are alternative substrates and products. Numbers indicate enzymes: 1, pyruvate kinase; 2, cytosolic malic enzyme 1; 3, mitochondrial malic enzyme 2 and 3; 4, pyruvate carboxylase; 5, pyruvate dehydrogenase; 6, citrate synthase; 7, mitochondrial aconitase; 8, NAD + -dependent isocitrate dehydrogenase 3; 9, NADP + -dependent isocitrate dehydrogenase 2; 10, alpha-ketoglutarate dehydrogenase; 11, GTP-specific succinyl- Beta-cell mitochondria have a high activity of pyruvate carboxylase, which is unusual for non-gluconeogenic cells (MacDonald et al. 2005). The generation of oxaloacetate by pyruvate carboxylase ensures adequate supply of citrate cycle intermediates for rapid increase in citrate cycle activity and export of intermediates into the cytosol (cataplerosis) (Jitrapakdee et al. 2010;Prentki et al. 2013). ...
... In addition to glucose, only few metabolic fuels (calorigenic nutrients) by themselves trigger insulin release (MacDonald et al. 2005). Alpha-ketoisocaproate (KIC), the transamination product of leucine, has gained interest because its metabolism does not involve glycolysis and its insulin-releasing potency is about as high as the potency of glucose (Lenzen and Panten 1980;Hutton et al. 1980;Panten et al. 1981). ...
... In islets exposed to glipizide, 5 min exposure to 10 mmol/L KIC significantly decreased the acetyl-CoA plus CoA-SH content (Fig. 4A), suggesting that CoA-SH was consumed by increase in thioester production. CoA-SH can be trapped by a rapid rise in the cytosolic production of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), malonyl-CoA, and fatty acyl-CoA, synthesized by fuel-induced supply of cytosolic acetyl-CoA (MacDonald et al. 2005, Prentki et al. 2013, see also Fig. 1). After 20 min exposure to KIC, the acetyl-CoA plus CoA-SH content was no longer decreased (Fig. 4B), presumably due to more rapid consumption of non-acetyl-CoA thioesters than at minute 5. ...
Glucose and alpha-ketoisocaproate, the keto acid analogue of leucine, stimulate insulin secretion in the absence of other exogenous fuels. Their mitochondrial metabolism in the beta-cell raises the cytosolic ATP/ADP ratio, thereby providing the triggering signal for the exocytosis of the insulin granules. However, additional amplifying signals are required for the full extent of insulin secretion stimulated by these fuels. While it is generally recognized that the amplifying signals are also derived from the mitochondrial metabolism, their exact nature is still unclear. The current study tests the hypothesis that the supply of cytosolic acetyl-CoA is a signal in the amplifying pathway. The contents of acetyl-CoA and acetyl-CoA plus CoA-SH were measured in isolated mouse islets. Insulin secretion was recorded in isolated perifused islets. In islets, the ATP-sensitive K⁺ channels of which were pharmacologically closed and which were preincubated without exogenous fuel, 10 mmol/L alpha-ketoisocaproate enhanced the acetyl-CoA content after 5 and 20 min incubations and decreased the acetyl-CoA plus CoA-SH within 5 min, but not after 20 min. In islets not exposed to drugs, the preincubation with 3 mmol/L glucose, a non-triggering concentration, elevated the acetyl-CoA content. This content was further increased after 5 min and 20 min incubations with 30 mmol/L glucose, concurrent with a strong increase in insulin secretion. Alpha-ketoisocaproate and glucose increase the supply of acetyl-CoA in the beta-cell cytosol during both phases of insulin secretion. Most likely, this increase provides a signal for the metabolic amplification.
... To fulfill the role of a nutrient secretagogue in the betacells, the nutrient has to have 2 sites of entry into the citric acid cycle (35). Glucose enters via pyruvate decarboxylation yielding acetyl-CoA and via pyruvate carboxylation yielding oxaloacetate (Fig. 10). ...
It is unclear whether the secretion of glucagon is regulated by an alpha-cell-intrinsic mechanism and whether signal recognition by the mitochondrial metabolism plays a role in it. To measure changes of the cytosolic ATP/ADP ratio, single alpha-cells and beta-cells from NMRI mice were adenovirally transduced with the fluorescent indicator PercevalHR. The cytosolic Ca 2+ concentration ([Ca 2+]i) was measured by use of Fura2 and the mitochondrial membrane potential by use of TMRE. Perifused islets were used to measure the secretion of glucagon and insulin. At 5 mM glucose, the PercevalHR ratio in beta-cells was significantly lower than in alpha-cells. Lowering glucose to 1 mM decreased the ratio to 69% within 10 minutes in beta-cells, but only to 94% in alpha-cells. In this situation 30 mM glucose, 10 mM alpha-ketoisocaproic acid and 10 mM glutamine plus 10 mM BCH (a non-metabolizable leucine analogue) markedly increased the PercevalHR ratio in beta-cells. In alpha-cells only glucose was slightly effective. However, none of the nutrients increased the mitochondrial membrane potential in alpha-cells, whereas all did so in beta-cells. The kinetics of the PercevalHR increase were reflected by the kinetics of [Ca 2+]i. increase in the beta-cells and insulin secretion. Glucagon secretion was markedly increased by washing out the nutrients with 1 mM glucose, but not by reducing glucose from 5 mM to 1 mM. This pattern was still recognizable when the insulin secretion was strongly inhibited by clonidine. It is concluded that mitochondrial energy metabolism is a signal generator in pancreatic beta-cells, but not in alpha-cells.
... 11,12 In β-cells, glycolysis is coupled to oxidative phosphorylation such that most of the carbons in glucose are oxidized to CO 2 on supply of the sugar substrate. [13][14][15] This metabolic flux allows for β-cells to respond to blood glucose changes with changes in insulin secretion that are controlled by glucose sensing and the rates of oxidation. 16 In diabetes, when blood glucose is chronically elevated, electron leak during increased oxidative phosphorylation may increase ROS, contributing to β-cell damage. ...
Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletions, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1fl/fl; Ins1Cre/+, βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
... We focus on the three mitochondrial shuttles and one shunt where balanced transport across the mitochondria inner membrane occurs (Figure 4, green boxes) and provide a rationale to assign them to Mito Ox or Mito Cat . While we strongly agree that anaplerotic/cataplerotic metabolism is important for b cell function, we are unable to firmly identify any direct pathway linking PC anaplerosis and cytosolic NADPH synthesis via IDH1 despite suggestions otherwise (Ferdaoussi et al., 2015;MacDonald et al., 2005;Prentki et al., 2013). The reason for this is explained below. ...
In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the “canonical” model, in which an oxidative phosphorylation-driven rise in ATP production closes KATP channels. We discuss the importance of intrinsic β cell metabolic oscillations; the phasic alignment of relevant metabolic cycles, shuttles, and shunts; and how their temporal and compartmental relationships align with the triggering phase or the secretory phase of pulsatile insulin secretion. Metabolic signaling components are assigned regulatory, effectory, and/or homeostatic roles vis-à-vis their contribution to glucose sensing, signal transmission, and resetting the system. Taken together, these functions provide a framework for understanding how allostery, anaplerosis, and oxidative metabolism are integrated into the oscillatory behavior of the secretory pathway. By incorporating these temporal as well as newly discovered spatial aspects of β cell metabolism, we propose a much-refined MitoCat-MitoOx model of the signaling process for the field to evaluate.
... It has been suggested that histone acetylation and memethylation can positively regulate gluconeogenesis by promoting the expression of glucose-6-phosphatase and PCK (46,47), while the acetylation and phosphorylation of forkhead box class O1 (FoxO1) negatively regulate the transcriptional expression of gluconeogenic genes (48,49). Similar to acetate, succinate entering cells can be converted to succinyl-CoA and enhance lysine succinylation (50)(51)(52). In addition, histone succinylation tends to stimulate gene transcription (53). ...
Succinate is widely used in the food and feed industry as an acidulant, flavoring additive, and antimicrobial agent. This study investigated the effects of dietary succinate on growth, energy budget, nutritional metabolism, protein succinylation, and gut microbiota composition of zebrafish. Zebrafish were fed a control-check (0% succinate) or four succinate-supplemented diets (0.05, 0.10, 0.15, and 0.2%) for 4 weeks. The results showed that dietary succinate at the 0.15% additive amount (S0.15) can optimally promote weight gain and feed intake. Whole body protein, fat, and energy deposition increased in the S0.15 group. Fasting plasma glucose level decreased in fish fed the S0.15 diet, along with improved glucose tolerance. Lipid synthesis in the intestine, liver, and muscle increased with S0.15 feeding. Diet with 0.15% succinate inhibited intestinal gluconeogenesis but promoted hepatic gluconeogenesis. Glycogen synthesis increased in the liver and muscle of S0.15-fed fish. Glycolysis was increased in the muscle of S0.15-fed fish. In addition, 0.15% succinate-supplemented diet inhibited protein degradation in the intestine, liver, and muscle. Interestingly, different protein succinylation patterns in the intestine and liver were observed in fish fed the S0.15 diet. Intestinal proteins with increased succinylation levels were enriched in the tricarboxylic acid cycle while proteins with decreased succinylation levels were enriched in pathways related to fatty acid and amino acid degradation. Hepatic proteins with increased succinylation levels were enriched in oxidative phosphorylation while proteins with decreased succinylation levels were enriched in the processes of protein processing and transport in the endoplasmic reticulum. Finally, fish fed the S0.15 diet had a higher abundance of Proteobacteria but a lower abundance of Fusobacteria and Cetobacterium. In conclusion, dietary succinate could promote growth and feed intake, promote lipid anabolism, improve glucose homeostasis, and spare protein. The effects of succinate on nutritional metabolism are associated with alterations in the levels of metabolic intermediates, transcriptional regulation, and protein succinylation levels. However, hepatic fat accumulation and gut microbiota dysbiosis induced by dietary succinate suggest potential risks of succinate application as a feed additive for fish. This study would be beneficial in understanding the application of succinate as an aquatic feed additive.
... Beta-cell mitochondria have a high activity of pyruvate carboxylase, which is unusual for nongluconeogenic cells (MacDonald et al., 2005). The generation of oxaloacetate by pyruvate carboxylase ensures adequate supply of citrate cycle intermediates for the rapid increase in citrate cycle activity and export of intermediates into the cytosol (cataplerosis) (Jitrapakdee et al., 2010, Prentki et al., 2013. ...
... In addition to glucose only a few metabolic fuels (calorigenic nutrients) by themselves trigger insulin release (MacDonald et al., 2005). Alpha-ketoisocaproate (KIC), the transamination product of leucine, has gained interest because its metabolism does not involve glycolysis and its insulin-releasing potency is about as high as the potency of glucose (Lenzen and Panten, 1980, Hutton et al., 1980, Panten et al., 1981. ...
... This event is suggested by the signi cantly decreased acetyl-CoA plus CoA-SH content under this condition (Fig. 4A). CoA-SH can be trapped by a rapid rise in the cytosolic production of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), malonyl-CoA and fatty acyl-CoA (Prentki et al., 2013, MacDonald et al., 2005, synthesized by fuel-induced supply of cytosolic acetyl-CoA (see Fig. 1). These thioesters do not include the cytosolic acetyl-CoA, the increase of which had trapped corresponding amounts of CoA-SH via citrate lyase and acetoacetyl-CoA synthetase (see Fig. 1). ...
Purpose: Glucose and alpha-ketoisocaproate, the keto acid analogue of leucine, stimulate insulin secretion in the absence of other metabolic fuels. Their mitochondrial metabolism in the beta-cell raises the cytosolic ATP/ADP ratio, thereby providing the triggering signal for the exocytosis of the insulin granules. However, additional amplifying signals are required for the full extent of insulin secretion stimulated by these fuels. While it is generally recognized that they are also derived from the mitochondrial metabolism, their exact nature is still unclear. The current study tests the hypothesis that cytosolic acetyl-CoA is a signal in the amplifying pathway.
Methods: The contents of acetyl-CoA and acetyl-CoA plus CoA-SH were measured in isolated mouse islets. Insulin secretion was recorded in isolated perifused islets.
Results: In islets which were preincubated without metabolic fuel while the ATP-sensitive K⁺ channels were pharmacologically closed, 10 mmol/L alpha-ketoisocaproate strongly enhanced the acetyl-CoA content after 5 and 20 min incubations and decreased the acetyl-CoA plus CoA-SH content within 5 min, but not after 20 min. Compared with the preincubation of islets without metabolic fuel, the preincubation with 3 mmol/L glucose, a non-triggering concentration, elevated the acetyl-CoA content. This content was further increased after 5 min and 20 min incubations with 30 mmol/L glucose, concurrent with a strong increase in insulin secretion.
Conclusion: Alpha-ketoisocaproate and glucose increase the supply of acetyl-CoA in the beta-cell cytosol during both phases of insulin secretion. Most likely this increase provides a signal for the metabolic amplification.
