Studies with leucine, β-hydroxybutyrate and ATP citrate lyase-deficient beta cells support the acetoacetate pathway of insulin secretion

MacDonald, Michael J.; Hasan, Noaman; Longacre, Melissa J.

doi:10.1016/j.bbagen.2008.03.017

Cited by 35 publications

(46 citation statements)

References 29 publications

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“…Most AAs, including leucine, acutely stimulate insulin secretion from pancreatic b cells in a dose-and glucosedependent manner (Liu et al 2008), and leucine stimulates insulin secretion by serving as both a metabolic fuel and an allosteric activator of glutamate dehydrogenase , MacDonald et al 2008). Leucine and its transaminated product a-ketoisocaproate may also affect insulin secretion via direct inhibition of b-cell ATP-regulated potassium channel currents .…”

Section: Introductionmentioning

confidence: 99%

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Liu

Jeppesen

Gregersen

et al. 2012

Journal of Endocrinology

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Chronic hyperglycemia and hyperlipidemia cause deleterious effects on b-cell function. Interestingly, increased circulating amino acid (AA) levels are also a characteristic of the prediabetic and diabetic state. The chronic effects of AAs on b-cell function remain to be determined. Isolated mouse islets and INS-1E cells were incubated with or without excess leucine. After 72 h, leucine increased basal insulin secretion and impaired glucose-stimulated insulin secretion in both mouse islets and INS-1E cells, corroborating the existence of aminoacidotoxicity-induced b-cell dysfunction. This took place concomitantly with alterations in proteins and genes involved in insulin granule transport, trafficking (e.g. collapsin response mediator protein 2 and GTP-binding nuclear protein Ran), insulin signal transduction (proteasome subunit a type 6), and the oxidative phosphorylation pathway (cytochrome c oxidase). Leucine downregulated insulin 1 gene expression but upregulated pancreas duodenum homeobox 1 and insulin 2 mRNA expressions. Importantly, cholesterol (CH) accumulated in INS-1E cells concomitantly with upregulation of enzymes involved in CH biosynthesis (e.g. 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonate (diphospho) decarboxylase, and squalene epoxidase) and LDL receptor, whereas triglyceride content was decreased. Our findings indicate that chronic exposure to elevated levels of leucine may have detrimental effects on both b-cell function and insulin sensitivity. Aminoacidotoxicity may play a pathogenic role in the development of type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Liu

Jeppesen

Gregersen

et al. 2012

Journal of Endocrinology

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“…They are produced by the liver and used peripherally as energy sources for various organs, particularly the skeletal muscle and brain, under conditions that include starvation, limited carbohydrate availability, and the neonatal period (41). AA participates in various biological processes that do not involve 3HB, including insulin release in vitro (42), generation of free oxygen radicals (43)(44)(45), and lipid peroxidation (46). AA also stimulates chaperone-mediated autophagy (47) and down-regulates the expression of ATP-binding cassette transporter A1 (ABCA1) in vitro (48).…”

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confidence: 99%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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“…This model has it pros and cons, which have been reviewed extensively elsewhere [12,48]. Our recent studies [25,38], as well as others [49][50][51] have now shown a consistent lack of evidence for a direct role of malonyl-CoA in regulation of GSIS, whereas its potential role in lipid-mediated potentiation of GSIS remains a possibility. Our results showing that inhibition of DIC NADPH has also been suggested to play an important role as a metabolic messenger regulating insulin release [15,17,19,[22][23][24]52].…”

Section: Discussionmentioning

confidence: 88%

The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells

et al. 2010

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Aims/hypothesis We have previously described a strong correlation between pyruvate cycling and insulin secretion. We have also demonstrated a particularly important role for a pyruvate-isocitrate cycling pathway involving the mitochondrial citrate/isocitrate carrier (CIC) and cytosolic NADP-dependent isocitrate dehydrogenase. CIC requires cytosolic malate as a counter-substrate during citrate and isocitrate export. Thus, considering that the mitochondrial dicarboxylate carrier (DIC) provides an important source of cytosolic malate, we investigated the potential role of DIC in control of glucose-stimulated insulin secretion (GSIS). Methods We used pharmacological and small interfering RNA (siRNA) tools to assess the role of DIC in insulin release in clonal insulin-secreting 832/13 cells and isolated rat islets. Results Butylmalonate, an inhibitor of malate transport, reduced cytosolic malate and citrate levels, and inhibited GSIS in a dose-dependent manner in 832/13 cells. Suppression of DIC expression resulted in inhibition of GSIS by 5% to 69%, the extent of inhibition of insulin secretion being proportional to the level of Dic (also known as Slc25a10) gene knockdown. The most effective siRNA duplex against Dic did not affect glucose utilisation, glucose oxidation or ATP/ADP ratio, but did suppress glucose-induced increments of the NADPH/NADP + ratio. Confirmation of our results in primary cultures of isolated rat islets showed that butylmalonate and an adenovirus expressing an siRNA against Dic-inhibited GSIS. Conclusions/interpretation Malate transport by DIC may play an important role in GSIS, possibly by providing cytosolic malate as a counter-substrate for citrate and/or isocitrate export by CIC. These studies also suggest that malate transport by DIC is (1) a critical component of NADPH production mediated by pyruvate-cycling and (2) regulates GSIS.

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Studies with leucine, β-hydroxybutyrate and ATP citrate lyase-deficient beta cells support the acetoacetate pathway of insulin secretion

Cited by 35 publications

References 29 publications

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells

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