Decreased enzyme activity and contents of hepatic branched-chain α-keto acid dehydrogenase complex subunits in a rat model for type 2 diabetes mellitus

Bajotto, Gustavo; Murakami, Taro; Nagasaki, Masaru; Sato, Yuzo; Shimomura, Yoshiharu

doi:10.1016/j.metabol.2009.04.029

Cited by 22 publications

(28 citation statements)

References 51 publications

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“…Studies have reported that decreased BCKD activity causes downregulation of BCAA catabolism in diabetes (6,7,36). It also has demonstrated that BDK is responsible for phosphorylation and inactivation of BCKD complex and considered a primary regulator of BCKD activation (6).…”

Section: Discussionmentioning

confidence: 99%

“…As with most nutrients, maintaining of the physiological level of BCAA is critical for cell metabolism and survival. However, many researchers have described increased BCAA and BCKA levels in diabetes and obesity (3,(5)(6)(7)(8). Furthermore, BCAA and their catabolites are strongly associated with insulin resistance (9-11), and elevated BCAA contributes to the development of insulin resistance (10,12).…”

mentioning

confidence: 99%

“…Phosphorylation catalyzed by BDK inhibits the enzymatic activity of the BCKD complex, whereas it becomes activated when the Ser 293 residue is dephosphorylated by BDP. A series of reports demonstrated that activation of BCKD was reduced in liver and adipose tissue, resulting in increased plasma BCAA and BCKA concentrations in diabetic and obese animals (6)(7)(8). Moreover, alterations of metabolism can influence BCKD activity partly through changes in BDK (3), suggesting that BDP might be suppressed.…”

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confidence: 99%

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Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

et al. 2014

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The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain a-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN 2/2 ) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain a-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN 2/2 and diabetic animals.Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state.The branched-chain amino acids (BCAA) are essential amino acids such as leucine, isoleucine, and valine; their homeostasis is determined largely by catabolic activities in a number of organs including liver, muscle and adipose tissue (1-3). The first step of BCAA catabolism generates a set of corresponding branched-chain a-keto acids (BCKA), which are irreversibly decarboxylated by the branched-chain a-keto acid dehydrogenase (BCKD) complex (4). As with most nutrients, maintaining of the physiological level of BCAA is critical for cell metabolism and survival. However, many researchers have described increased BCAA and BCKA levels in diabetes and obesity (3,(5)(6)(7)(8). Furthermore, BCAA and their catabolites are strongly associated with insulin resistance (9-11), and elevated BCAA contributes to the development of insulin resistance (10,12). Mechanistically, elevated BCAA levels activate mTOR/p70S6 kinase, resulting in an increased I insulin receptor substrate-1 phosphorylation, thereby inhibiting phosphatidylinositol 3-kinase. This inhibition of phosphatidylinositol 3-kinase in turn leads to impaired insulin signaling (13,14). It is also reported that BCAA are independent predictors of insulin resistance, diabetes, and cardiovascular events (15-17). Therefore, it is necessary to determine the mechanisms of abnormal BCAA catabolism in order to better understand their association with metabolic-related pathogenesis. The BCKD complex is the rate-limiting enzyme in BCAA catabolism (4,12); regulation o...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

et al. 2014

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“…The bio-breeding (BB) rat (33,34) and non-obese diabetic (NOD) mouse (35,36) both exhibit a susceptibility to the spontaneous development of autoimmune disease. Rodent models of diabetes mellitus include the genetically altered Zucker diabetic fatty (ZDF) rats (37,38), Otsuka Long Evans Tokushima fatty (OLETF) rats (39,40) and Goto Kakizaki (GK) rats (41,42), which feature insulin resistance and reduced β cell number and function. Over the past decade, molecular-based techniques have produced new animal models for diabetes mellitus research including knock-in, generalized knock-out, and tissue-specific knock-out rats and mice (15,16,43,44).…”

Section: Discussionmentioning

confidence: 99%

Establishment of inducible cAMP early repressor transgenic fibroblasts in a porcine model of human type 1 diabetes mellitus

Jung

Kim²,

Lee

et al. 2012

Mol Med Report

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Abstract. Diabetes mellitus is a metabolic disease caused by impaired insulin secretion from the pancreatic β cells and increased insulin resistance in peripheral tissues. Recently, the overexpression of inducible cyclic AMP (cAMP) early repressor (ICER) Iγ in rodent pancreatic β cells was found to induce insulin deficiency and glucagon overproduction similar to that found in human diabetes mellitus. ICER Iγ with only a DNA binding domain interrupts the transcriptional regulation of the cAMP responsive element-binding protein (CREB) target genes. Based on this information, we hypothesized that the overexpression of ICER Iγ, the most powerful competitor to CREB, could be useful for generating a pig model of diabetes. First, we evaluated the promoter activities of the human insulin gene for the β cell-specific overexpression of ICER Iγ in the pig pancreas. The maximum promoter activity region [-1,431 nucleotides (nt) to +1 nt, +1 = the transcriptional start site] of the insulin gene presented an activity level 3-fold higher than a promoterless construct. Second, ICER Iγ overexpression controlled by this promoter region significantly blocked the glucose-mediated insulin transcription, such as that regulated by the viral promoter in the pancreatic β cell line, MIN6. This suggests that the human insulin promoter may facilitate the overexpression of ICER Iγ in porcine pancreatic β cells.In addition, the overexpression of ICER Iγ in porcine β cells may induce human-like type 1 diabetes mellitus in pigs. In the present study, we generated transgenic fibroblasts containing ICER Iγ cDNA controlled by the human insulin promoter, as well as two screening markers, the green fluorescence protein and the neomycin resistance gene. These fibroblasts may provide a source for somatic cell nuclear transfer to generate a pig model that mimics human diabetes mellitus.

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“…A number of reports have demonstrated that BCKD expression and activity are significantly reduced in obesity or insulin resistance compared to lean controls [47,[161][162][163]. In particular, She et al found tissue specific alterations in BCAA catabolic enzymes involving a reduction in the BCKDH E1α subunit in liver and adipose tissue, but not in skeletal muscle.…”

Section: Amino Acids and The Preservation Or Augmentation Of Lean Bodmentioning

confidence: 99%

Essential Amino Acid Supplementation for the Prevention and Treatment of Obesity

D’Antona

2014

Nutrition in the Prevention and Treatment of Abdominal Obesity

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Decreased enzyme activity and contents of hepatic branched-chain α-keto acid dehydrogenase complex subunits in a rat model for type 2 diabetes mellitus

Cited by 22 publications

References 51 publications

Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

Establishment of inducible cAMP early repressor transgenic fibroblasts in a porcine model of human type 1 diabetes mellitus

Essential Amino Acid Supplementation for the Prevention and Treatment of Obesity

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