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CELLULAR AND MITOCHONDRIAL METABOLISM
Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
Submitted 16 August 2007 ; accepted in final form 20 December 2007
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ABSTRACT |
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 TOP ABSTRACT EXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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-ketoisocaproate (KIC), and monomethyl succinate (MMS) alone did not stimulate insulin release. Lactate released very little insulin. When acetoacetate, β-hydroxybutyrate, or KIC were combined with MMS, or either ketone body was combined with lactate, insulin release was stimulated 10-fold to 20-fold the controls (almost as much as with glucose). Pyruvate was a potent stimulus of insulin release. In rat pancreatic islets, β-hydroxybutyrate potentiated MMS- and glucose-induced insulin release. The pathways of their metabolism suggest that, in addition to producing ATP, the ketone bodies and KIC supply the acetate component and MMS supplies the oxaloacetate component of citrate. In line with this, citrate was increased by β-hydroxybutyrate plus MMS in INS-1 cells and by β-hydroxybutyrate plus succinate in mitochondria. The two ketone bodies and KIC can also be metabolized to acetoacetyl-CoA and acetyl-CoA, which are precursors of other short-chain acyl-CoAs (SC-CoAs). Measurements of SC-CoAs by LC-MS/MS in INS-1 cells confirmed that KIC, β-hydroxybutyrate, glucose, and pyruvate increased the levels of acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethylglutaryl-CoA, and malonyl-CoA. MMS increased incorporation of 14C from β-hydroxybutyrate into citrate, acid-precipitable material, and lipids, suggesting that the two molecules complement one another to increase anaplerosis. The results suggest that, besides citrate, some of the products of anaplerosis are SC-CoAs, which may be precursors of molecules involved in insulin secretion.
monomethyl succinate; -ketoisocaproate; short-chain acyl-coenzyme A; acetoacetyl-coenzyme A; mass spectrometry; pyruvate; INS-1 832/13 cells
We previously observed that secretagogues, such as glucose and -ketoisocaproate (KIC), significantly increased the concentration of acetoacetate in pancreatic islets and INS-1 832/13 cells (23), and, therefore, we studied the effects of acetoacetate and its reduced partner β-hydroxybutyrate on insulin secretion. In the present study, we extend an experimental paradigm that we think has given us new clues about some of these anaplerotic products. We discovered that INS-1 cells can take up and metabolize acetoacetate and β-hydroxybutyrate. We previously observed that methyl succinate and low concentrations of KIC interact synergistically to stimulate insulin release in INS-1 cells almost as well as glucose, even though in INS-1 cells neither KIC alone nor methyl succinate alone stimulates insulin release (23). Similarly, the ketone bodies by themselves cannot stimulate insulin release from the INS-1 cells. However, when either ketone body is combined with monomethyl succinate or lactate, a very strong stimulation of insulin release occurs. We hypothesized that if a combination of metabolites stimulates insulin release almost as well as glucose, their distal pathways of metabolism may generate whatever glucose generates to stimulate insulin release. Because studying the individual metabolic contributions of complementary nonsecretagogues may permit the dissection of the pathways important for insulin secretion not obtainable from studying individual secretagogues, we used this synergism and complementarity paradigm to begin to further delve into the downstream pathways that couple anaplerosis to insulin exocytosis in INS-1 cells.
It was previously proposed that citrate is a product of β-cell anaplerosis (5, 6, 25), and we recently proposed that some of the anaplerotic pathways involve citrate formation and short-chain acyl-CoA formation (23, 28). The current results support these ideas. From the pathways through which they are known to be metabolized and from our previous data that showed that methyl succinate increases malate (21–23), and thus its redox partner oxaloacetate, many fold in β-cells, it can be deduced that the synergism between the ketone bodies and methyl succinate results from the ketone bodies supplying acetyl-CoA and methyl succinate supplying oxaloacetate, which condense to form citrate in the citrate synthase reaction. Indeed, the current study shows that methyl succinate in combination with β-hydroxybutyrate increases citrate levels in INS-1 cells and that succinate plus β-hydroxybutyrate increases citrate in INS-1 mitochondria. Since all other citric acid cycle intermediates can be formed from citrate, the synergism between the two types of molecules further supports the idea that anaplerosis of citric acid cycle intermediates is important for insulin secretion. Further in line with the idea that the synergism involves anaplerosis, we found that methyl succinate increases the incorporation of β-[14C]hydroxybutyrate into citrate, acid-precipitable material, and lipids of INS-1 cells.
Since acetoacetate can be converted to acetoacetyl-CoA, a precursor of other short-chain acyl-CoAs, and methyl succinate can be a precursor of succinyl-CoA, we measured several short-chain acyl-CoA molecules in secretagogue-stimulated INS-1 cells. The synergistic combinations of nonsecretagogues, as well as single secretagogues, such as glucose or pyruvate, increased acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethyglutaryl-CoA, and malonyl-CoA to various extents as judged from LC-MS/MS measurements. Although increased malonyl-CoA has previously been implicated in insulin secretion, our results support the idea that multiple short-chain acyl-CoAs may be precursors of molecules that play important currently unknown roles in signaling insulin secretion.
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EXPERIMENTAL PROCEDURES |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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INS-1 cells and pancreatic islet studies. INS-1 832/13 cells (12) were maintained in INS-1 medium (2) [RPMI-1640 medium (contains 11.1 mM glucose) supplemented with 10% fetal calf serum, 1 mM sodium pyruvate, 50 µM β-mercaptoethanol, 10 mM sodium HEPES buffer, pH 7.3, 100 U/ml penicillin, and 100 µg/ml streptomycin]. Insulin release was performed in 24-well tissue culture plates. One day before an insulin release experiment was to be performed, the glucose concentration in the tissue culture medium was reduced to 5 mM. Two hours before the experiment, the medium was replaced with Krebs-Ringer bicarbonate buffer, pH 7.3 (modified to contain 15 mM HEPES and 15 mM NaHCO3 with the NaCl concentration adjusted to maintain osmolarity at 310) containing 3 mM glucose and 0.5% BSA. Cells were washed once with the Krebs-Ringer-HEPES-BSA solution, and insulin release was studied in 1 ml of this same solution containing secretagogues or nonsecretagogues as controls. After 1 h at 37°, samples of incubation solution were collected and centrifuged to sediment any cells floating in the incubation solution. An aliquot of the supernatant fraction was removed and saved for insulin measurements by radioimmunoassay. The plates were then washed once with Krebs-Ringer solution containing no added protein, water was added to the plates, and the mixture containing the cells was removed and saved for estimation of total protein by the Bradford method using a dye reagent from Bio-Rad. The incorporation by INS-1 832/13 cells of 14C from β-[3-14C]hydroxybutyrate into acid-precipitable material was measured after cells were incubated in suspension for 30 min in the Krebs-Ringer-BSA solution, cellular material was precipitated with 20 volumes of 10% trichloroacetic acid, and the pellet was washed six or more times with 10% trichloroacetic acid until the radioactivity in the supernatant fraction of the final wash equaled background levels. An aqueous suspension of this material was further extracted with 2.5 volumes of chloroform/methanol (3:1) to extract lipids. Radioactivity in the acid precipitate, organic fraction, and CO2 was measured by liquid scintillation spectrometry as previously described (17, 18, 21). The incorporation of 14C into citrate was estimated by precipitating cells with 6% perchloric acid, separating metabolites in the supernatant fraction with paper chromatography on Whatman no. 1 paper in a mixture of 10 parts isobutyric acid and 6 parts 1 M ammonium hydroxide and counting the radioactivity in spots cut from the paper (21). The Rf values for citrate, acetoacetate, and β-hydroxybutyrate were 0.35, 0.95, and 1.0, respectively. Insulin release from fresh rat pancreatic islets was studied in the presence of Krebs-Ringer bicarbonate, buffer pH 7.3, containing 0.5% BSA as previously described (24, 26). Alkali-enhanced fluorescence (22) was used to measure citrate and malate in INS-1 832/13 cells. Cells were maintained in the presence of 5 mM glucose for 24 h before an experiment was performed, as described above, and incubated in suspension with or without methyl succinate or β-hydroxybutyrate in the modified Krebs-Ringer bicarbonate buffer for 30 min (23). Citrate and malate were also measured in mitochondria isolated from INS-1 832/13 cells as previously described (23) and were incubated with or without succinate and β-hydroxybutyrate in 5 mM potassium phosphate, 2 mM potassium ADP, 210 mM mannitol, 65 mM sucrose, and 5 mM HEPES buffer, pH 7.5 (21, 22).
Short-chain acyl-CoAs measurements. INS-1 832/13 cells were maintained on 150-mm tissue culture plates as described above, including the incubation in the presence of 5 mM glucose for 1 day before an experiment was to be performed (but not including the incubation in the presence of 3 mM glucose in Krebs-Ringer solution for 2 h). The plates were then washed twice with phosphate-buffered saline and once with the Krebs-Ringer-HEPES-BSA solution and incubated with 10 ml of the Krebs-Ringer-HEPES-BSA solution containing insulin (non)secretagogues. After 30 min, this solution was quickly removed, 2 ml of 1% trifluoroacetic acid and 50% methanol was added to each plate, and the plates were placed at –80°. After 5–10 min at –80°, cells were scraped off the plates, and the CoA thioesters were measured by LC-ESI-MS/MS at the Mass Spectrometry Facility of the University of Wisconsin Biotechnology Center as previously described (23).
Data analysis. Statistical significance was confirmed with Student's t-test.
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RESULTS |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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-cyano-4-hydroxycinnamate, inhibited insulin release by pyruvate alone and also by acetoacetate and β-hydroxybutyrate when they were present along with methyl succinate or lactate (Table 4).
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Insulin release from pancreatic islets. We also tested some of the combinations of fuels that produced insulin release from INS-1 cells in fresh rat pancreatic islets. β-Hydroxybutyrate in combination with either 10 mM methyl succinate or 5.6 mM glucose more than doubled insulin release from rat pancreatic islets. However, β-hydroxybutyrate alone or in combination with lactate did not stimulate or potentiate insulin release from freshly isolated rat islets, and pyruvate alone, in agreement with previous studies, did not stimulate insulin release from the islets (Table 5).
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50–60% above the control value by β-hydroxybutyrate with or without methyl succinate. KIC alone or with methyl succinate caused the largest increases in acetoacetyl-CoA, succinyl-CoA, and hydroxymethylglutaryl-CoA (200–250% of the control value). Pyruvate and glucose increased acetoacetyl-CoA (200% of the control value), acetyl-CoA (170–200% of the control value), and malonyl-CoA (200% of the control value). Methyl succinate alone caused a moderate increase in succinyl-CoA levels (70% above the control value) (Fig. 5).
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DISCUSSION |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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Citrate formation. First, the data are consistent with the idea that insulin secretagogues need to produce more than ATP to stimulate insulin secretion. For any cell to produce 95% of the ATP it needs, all that is required is for it to metabolize acetyl-CoA in the citric acid cycle. If only ATP production was necessary for insulin exocytosis, acetoacetate, β-hydroxybutyrate, and KIC would stimulate insulin release by themselves because they are located proximal to acetyl-CoA in biochemical pathways and can thus produce a large amount of acetyl-CoA (Fig. 6). The fact that these metabolites require a complementing molecule to stimulate insulin release provides information on the additional metabolic requirements for stimulation of insulin secretion. Methyl succinate alone does not stimulate insulin release in INS-1 832/13 cells (Table 1), unlike the situation in fresh rat pancreatic islets where it is a fairly potent insulin secretagogue (18–21, 24–26, 30). Although the reason for this difference between fresh islets and INS-1 cells is unknown, mitochondrial acetyl-CoA should be formed from methyl succinate via malic enzyme converting succinate-derived malate to pyruvate in the cytosol and the pyruvate entering mitochondria where pyruvate dehydrogenase converts it to acetyl-CoA (Fig. 6). This pathway is circuitous and may be dampened in INS-1 cells [even though the levels of the enzymes of the pathway are not decreased (22 and M. J. MacDonald, unpublished observations)] because agents that supply acetyl-CoA synergize with methyl succinate to stimulate insulin release in INS-1 cells. It is well established that methyl succinate generates a high amount of malate in islets and INS-1 cells (22, 23). This will increase mitochondrial oxaloacetate via the mitochondrial malate dehydrogenase reaction, and, by itself, this oxaloacetate cannot be further metabolized within mitochondria. However, low concentrations of KIC, acetoacetate, and β-hydroxybutyrate, which can be directly metabolized to acetyl-CoA (Fig. 6), can synergize with methyl succinate to strongly stimulate insulin release (Tables 1 and 2 and Figs. 1 and 2). In addition, β-hydroxybutyrate potentiated methyl succinate-induced insulin release in fresh pancreatic islets (Table 5). It can be surmised that the increased acetyl-CoA from any of the synergizing agents can combine with the methyl succinate-derived oxaloacetate to form citrate in the citrate synthase reaction (Fig. 5). This idea is supported by the fact that either KIC, as shown before (23), or β-hydroxybutyrate in combination with methyl succinate increases citrate in INS-1 cells and succinate plus β-hydroxybutyrate increases citrate in INS-1 mitochondria (Table 6). When lactate synergizes with either acetoacetate or β-hydroxybutyrate to stimulate insulin release (Figs. 1 and 3), lactate is probably supplying oxaloacetate via its conversion to pyruvate by lactate dehydrogenase and pyruvate's conversion to oxaloacetate by pyruvate carboxylase (Fig. 6).
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The ability of the two ketone bodies to form acetyl-CoA, but their failure to stimulate insulin release when applied alone to INS-1 cells supports the idea that increased formation of acetyl-CoA alone is not sufficient for insulin release. The oxaloacetate derived from methyl succinate can combine with acetyl-CoA, enabling the net synthesis of citrate from which all citric acid cycle intermediates can be formed. The oxidation of acetyl-CoA in the citric acid cycle will generate ATP, but without a net increased formation of oxaloacetate, the increased synthesis of citric acid cycle intermediates, i.e., anaplerosis (3, 25), cannot occur. The anaplerotic products formed from citric acid cycle intermediates can be exported to the cytosol. For example, citrate is a carrier of an acetyl group, plus oxaloacetate, from mitochondria to the cytosol (25). The acetyl group can be converted into short-chain acyl-CoAs and lipids, which may be important for supporting insulin secretion (5, 6, 25), and oxaloacetate can participate in the malate aspartate shuttle, the malate pyruvate shuttle, and the citrate pyruvate shuttle. These shuttles may be important for insulin secretion (5, 6, 17, 21, 25).
Formation of short-chain acyl-CoAs. The idea that short-chain acyl-CoAs may be important for insulin release is suggested by the fact that acetoacetate and β-hydroxybutyrate, which can be metabolized into various short-chain acyl-CoA molecules, are potent insulin secretagogues in INS-1 cells when used in conjunction with methyl succinate or lactate (Tables 2 and 4 and Figs. 1–3). LC-MS/MS measurements of five short-chain acyl-CoA molecules showed that β-hydroxybutyrate, as well as single insulin secretagogues such as glucose and pyruvate, variously increased the levels of the CoA thioesters in INS-1 cells. The potentiation by β-hydroxybutyrate of methyl succinate-induced and glucose-induced insulin release in fresh rat pancreatic islets (Table 5) suggests that formation of short-chain acyl-CoAs may also be involved in insulin secretion in normal β-cells. β-Hydroxybutyrate and acetoacetate can directly form acetoacetyl-CoA via the reaction catalyzed by succinyl-CoA: 3-ketoacid CoA transferase in mitochondria (Fig. 6). The succinate derived from methyl succinate can, via the succinyl-CoA synthetase reaction, supply the succinyl-CoA for this reaction. Methyl succinate alone or in the presence of β-hydroxybutyrate caused a moderate increase in succinyl-CoA (Fig. 5). Acetoacetyl-CoA can be converted to acetyl-CoA via the mitochondrial acetyl-CoA acetyltransferase (ACAT-1) reaction. Acetoacetyl-CoA can also be formed from acetoacetate via acetoacetyl-CoA synthetase in the cytosol, thus increasing cytosolic acetoacetyl-CoA levels. This acetoacetyl-CoA can be converted to acetyl-CoA via the cytosolic acetyl-CoA acetyltransferase (ACAT-2) reaction (Fig. 6). Acetyl-CoA plus acetoacetyl-CoA can be converted to hydroxymethylglutaryl-CoA via hydroxymethylglutaryl-CoA synthase in the cytosol (4, 23, 28). β-Hydroxybutyrate alone or in combination with methyl succinate caused the largest relative increases in acetoacetyl-CoA and malonyl-CoA. β-Hydroxybutyrate also increased hydroxymethylglutaryl-CoA, succinyl-CoA, and acetyl-CoA to lesser extents (Fig. 5). Pyruvate is as potent an insulin stimulant in INS-1 cells as glucose (Fig. 4), and pyruvate caused large increases in acetyl CoA, acetoacetyl-CoA, hydroxymethylglutaryl CoA, and malonyl-CoA (Fig. 5).
KIC alone at 10 mM is about as potent an insulin stimulant as glucose in rat pancreatic islets, fresh or cultured. Although, as mentioned above, KIC alone does not stimulate insulin release in INS-1 832/13 cells, it does synergize with methyl succinate to potently stimulate insulin release in these cells (Table 2). KIC increases acetoacetate in rat pancreatic islets and INS-1 832/13 cells (23). Since acetoacetate is interconvertible with acetoacetyl-CoA (Fig. 6), KIC should also form high levels of acetyl-CoA and acetoacetyl-CoA in these cells. In addition, KIC forms -ketoglutarate (7, 23), from which succinyl-CoA can be formed (Fig. 6). Indeed, KIC significantly increased the levels of various CoA thioesters in INS-1 cells (Fig. 5).
The data also show that short-chain acyl-CoAs are not the only metabolites necessary for insulin secretion. KIC alone and β-hydroxybutyrate alone, which do not by themselves stimulate insulin release in INS-1 832/13 cells, increased the levels of many short-chain acyl-CoAs. This indicates that other factors in addition to short-chain acyl-CoAs are necessary for stimulating or supporting insulin secretion. Previous studies suggest that one of these other factors may be an increased level of NADPH. NADPH can be increased via the increased malate supplied by methyl succinate via the pyruvate malate shuttle (21). There is evidence that NADPH may be involved in the stimulation of insulin secretion (16, 21, 25).
Monocarboxylates and insulin release in INS-1.
Insulin release by the monocarboxylates in INS-1 cells deserves a brief comment. The reason three-carbon or four-carbon monocarboxylates (pyruvate alone and acetoacetate, β-hydroxybutyrate, and lactate in combination with another molecule) can stimulate insulin release in INS-1 cells is probably because INS-1 cells, unlike normal pancreatic islets (34), possess a plasmalemmal monocarboxylate transporter (1, 13) enabling these molecules to penetrate their plasma membrane. -Cyano-4-hydroxycinnamate, an inhibitor of monocarboxylate transporters, inhibited insulin release by these agents when they were present as complementing compounds and also by pyruvate when it was applied alone to INS-1 832/13 cells (Table 4). (Since it also inhibited glucose-induced insulin release, it cannot be excluded that the inhibitor was acting on a monocarboxylate transporter in the mitochondrial inner membrane in addition to inhibiting transporters in the plasma membrane.) The monocarboxylate β-hydroxybutyrate probably has at least a limited ability to penetrate pancreatic islet β-cells because it potentiates insulin release by either methyl succinate (Table 5) or glucose in islets (Table 5; Refs. 8, 29, and 31). Lactate alone, which can be converted to pyruvate, only slightly stimulates insulin release in INS-1 832/13 cells and only stimulates a large amount of insulin release in combination with either acetoacetate or β-hydroxybutyrate. The limited ability of lactate alone to stimulate insulin release is probably related to a slow rate of conversion of lactate to pyruvate due to the low level of lactate dehydrogenase in β-cells in general and an even lower level in INS-1 cells (13), as well as possibly less efficient transport of lactate into the cell in comparison with pyruvate transport. Ishihara and coworkers (13) showed that overexpression of lactate dehydrogenase in INS-1 cells enabled a low concentration of lactate to stimulate insulin release that was almost as large as the insulin release induced by pyruvate. In addition, the monocarboxylate transporters of mammalian cells have a much lower Km for pyruvate (0.08 to 1 mM) than for lactate (0.5 to 3.5 mM) (9), suggesting that pyruvate should be transported into cells at a more rapid rate than lactate.
The reason why pyruvate at low concentrations is as potent an insulin secretagogue as glucose at high concentrations in INS-1 cells is probably because the rate of glucose metabolism to pyruvate is controlled by glucokinase, which catalyzes the first step in glycolysis (33). However, the rate of metabolism of exogenous pyruvate is not limited by glycolysis. After it is transported into the INS-1 cell, pyruvate can rapidly and directly enter mitochondrial metabolism, and this probably explains why pyruvate at 1 mM and lower concentrations is a potent insulin secretagogue in the INS-1 cell (Fig. 4).
Conclusions. The synergistic insulin release by compounds that can be metabolized to mitochondrial acetyl-CoA, such as KIC, β-hydroxybutyrate, or acetoacetate, in combination with methyl succinate that can be metabolized to mitochondrial oxaloacetate, suggests that acetyl-CoA and oxaloacetate condense in the citrate synthase reaction to form citrate. Numerous compounds can be formed from citrate, and citrate can carry acetyl-CoA and oxaloacetate out of the mitochondria to the cytosol. Many compounds, including most short-chain acyl-CoAs, can be formed from acetyl-CoA in the cytosol. KIC and β-hydroxybutyrate can also be directly converted to acetoacetate and acetyl-CoA in the mitochondria. Acetoacetate can be exported to the cytosol and converted to acetoacetyl-CoA to form several other short-chain acyl-CoAs. The results support the idea that anaplerosis is important for insulin secretion and suggest that multiple short-chain acyl-CoAs may be some of the products of anaplerosis in the β-cell.
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GRANTS |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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