Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In using Western blot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoforms PDK2 and PDK4, this study demonstrates selective PDK isoform switching in specific skeletal muscle types in response to high-fat feeding that is associated with altered regulation of PDK activity by pyruvate. The administration of a diet high in saturated fats led to stable (approximately 2-fold) increases in PDK activities in both a typical slow-twitch (soleus [SOL]) muscle and a typical fast-twitch (anterior tibialis [AT]) muscle. Western blot analysis revealed that high-fat feeding significantly increased (approximately 2-fold; P < 0.001) PDK4 protein expression in SOL, with a modest (1.3-fold) increase in PDK2 protein expression. The relative increase in PDK4 protein expression in SOL was associated with a 7.6-fold increase in the pyruvate concentration that was required to elicit a 50% active pyruvate dehydrogenase complex, which indicates a marked decrease in the sensitivity of PDK to inhibition by pyruvate. In AT muscle, high-fat feeding elicited comparable (1.5- to 1.7-fold) increases (P < 0.05) in PDK4 and PDK2 protein expression. Loss of sensitivity of PDK to inhibition by pyruvate was less marked. The data suggest that a positive correlation exists between increases in PDK4 expression and the propensity with which muscles use lipid-derived fuels as respiratory substrates rather than with the degree of insulin resistance induced in skeletal muscles by high-fat feeding. In conclusion, high-fat feeding leads to selective upregulation of PDK4 expression in slow-twitch muscle in response to high-fat feeding in vivo, which is associated with a pronounced loss of sensitivity of PDK activity to acute inhibition by pyruvate. Thus, increased PDK4 expression may underlie the stable modification of the regulatory characteristics of PDK observed in slow-twitch muscle in response to high-fat feeding.
Diabetes 2000 May
PMID:Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding. 1090 86

Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).
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PMID:Current therapies and emerging targets for the treatment of diabetes. 1128 51

The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.
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PMID:Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. 1164 66

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyses the oxidative decarboxylation of pyruvate, and links glycolysis to the tricarboxylic acid cycle and ATP production. Adequate flux through PDC is important in tissues with a high ATP requirement, in lipogenic tissues (since it provides cytosolic acetyl-CoA for fatty acid (FA) synthesis), and in generating cytosolic malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase (CPT I). Conversely, suppression of PDC activity is crucial for glucose conservation when glucose is scarce. This review describes recent advances relating to the control of mammalian PDC activity by phosphorylation (inactivation) and dephosphorylation (activation, reactivation), in particular regulation of PDC by pyruvate dehydrogenase kinase (PDK) which phosphorylates and inactivates PDC. PDK activity is that of a family of four proteins (PDK1-4). PDK2 and PDK4 appear to be expressed in most major tissues and organs of the body, PDK1 appears to be limited to the heart and pancreatic islets, and PDK3 is limited to the kidney, brain and testis. PDK4 is selectively upregulated in the longer term in most tissues and organs in response to starvation and hormonal imbalances such as insulin resistance, diabetes mellitus and hyperthyroidism. Parallel increases in PDK2 and PDK4 expression appear to be restricted to gluconceogenesic tissues, liver and kidney, which take up as well as generate pyruvate. Factors that regulate PDK4 expression include FA oxidation and adequate insulin action. PDK4 is also either a direct or indirect target of peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha deficiency in liver and kidney restricts starvation-induced upregulation of PDK4; however, the role of PPAR alpha in heart and skeletal muscle appears to be more complex. These observations may have important implications for the pharmacological modulation of PDK activity (e.g. use of PPAR alpha activators) for the control of whole-body glucose, lipid and lactate homeostasis in disease states and suggest that therapeutic interventions must be tissue targeted so that whole-body fuel homeostasis is not adversely perturbed.
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PMID:Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia. 1247 89

(1) In this study we compared the molecular signalling elicited by rexinoids, selective retinoid X receptor (RXR)-activators, in several organs (i.e. liver, kidney, heart) and in hepatocytes of various species. (2) RXR plays the pivotal role of a hetero-dimerization partner for the members of the class II subset of nuclear receptors which regulate the transcription of numerous target genes, following chemical activation. Several of these selective activators are currently used to treat hyperlipidaemia (fibrates), type II diabetes (glitazones), or skin disorders (retinoic acid). Although these therapeutic pathways are not fully elucidated, receptor activation is considered a pre-requisite for efficacy. Therefore RXR, which accepts numerous dimeric partners, is considered a worthwhile pharmacological target. (3) We analysed a number of biochemical and molecular responses to rexinoids which were given orally to mice. Our results showed a prominent involvement of the peroxisome proliferator-activated receptor (PPARalpha) as a majority of the observed hepatic and renal regulations were abolished in PPARalpha-knockout animals. Therefore we documented the species-specificity of these rexinoid actions which were reproduced in rat primary hepatocyte cultures but not in cultures of rabbit or human origin. Conversely, we established that the regulation of the pyruvate dehydrogenase kinase (PDK4) gene in the heart, by rexinoids, is independent of PPARalpha expression. (4) Our results support the obligatory expression of the active, although quiescent, PPARalpha to sustain a subset of relevant regulations attributable to rexinoids in the liver and kidney. Their cardiac molecular signalling unveiled an alternate transduction pathway and therefore opens new prospects in the therapeutic potential of rexinoids.
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PMID:RXR activators molecular signalling: involvement of a PPAR alpha-dependent pathway in the liver and kidney, evidence for an alternative pathway in the heart. 1264 86

The pyruvate dehydrogenase complex (PDC) is inactivated in many tissues during starvation and diabetes to conserve three-carbon compounds for gluconeogenesis. This is achieved by an increase in the extent of PDC phosphorylation caused in part by increased pyruvate dehydrogenase kinase (PDK) activity due to increased PDK expression. This study examined whether altered pyruvate dehydrogenase phosphatase (PDP) expression also contributes to changes in the phosphorylation state of PDC during starvation and diabetes. Of the two PDP isoforms expressed in mammalian tissues, the Ca(2+)-sensitive isoform (PDP1) is highly expressed in rat heart, brain, and testis and is detectable but less abundant in rat muscle, lung, kidney, liver, and spleen. The Ca(2+)-insensitive isoform (PDP2) is abundant in rat kidney, liver, heart, and brain and is detectable in spleen and lung. Starvation and streptozotocin-induced diabetes cause decreases in PDP2 mRNA abundance, PDP2 protein amount, and PDP activity in rat heart and kidney. Refeeding and insulin treatment effectively reversed these effects of starvation and diabetes, respectively. These findings indicate that opposite changes in expression of specific PDK and PDP isoenzymes contribute to hyperphosphorylation and therefore inactivation of the PDC in heart and kidney during starvation and diabetes.
Diabetes 2003 Jun
PMID:Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. 1276 46

In Type 2 diabetes, glucose homeostasis is impaired due to either a decrease in insulin secretion or insulin action. In this symposium, molecular targets that could have an impact on either or both of these defects were discussed and data related to specific compounds were presented. Protein tyrosine phosphatase 1B inhibitors that relieve the negative control on insulin action and are active in cell assays, dipeptidyl peptidase IV inhibitors that raise postprandial glucagon-like peptide 1 levels in animals and humans, and pyruvate dehydrogenase kinase inhibitors that increase the levels of pyruvate dehydrogenase, which in turn improve insulin sensitivity, were all discussed. Roche presented for the first time their novel glucokinase activators and discussed both the in vitro and in vivo activity profiles of representative glucokinase activators as potential therapy for Type 2 diabetes. Second generation retinoid X receptor modulators that retain the desirable effects of full agonists, while devoid of their negative attributes, such as triglyceride accumulation, were discussed. Also, clinical efficacy results of synthetic exendin-4, Exenatide trade mark, a glucagon-like peptide 1 analogue, were presented. In the area of obesity, agonists of several central (melanocortin type 4, serotonin subtype 2C and cannabinoid receptor 1) receptors and one peripheral G-protein-coupled receptor, cholecystokinin receptor-A, all of which lead to reduced food intake in animals, were discussed.
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PMID:Metabolic diseases drug discovery world summit. July 28-29, 2003, San Diego, CA, USA. 1451 91

Starvation and experimental diabetes induce a stable increase in pyruvate dehydrogenase kinase (PDK) activity in skeletal muscle, which is largely due to a selective upregulation of PDK-4 expression. Increased free fatty acid (FFA) level has been suggested to be responsible for the upregulation. Because these metabolic states are also characterized by insulin deficiency, the present study was designed to examine whether insulin has a significant effect to regulate PDK mRNA expression in rat skeletal muscle. In study 1, overnight-fasted rats received an infusion of saline or insulin for 5 h (n = 6 each). During the insulin infusion, plasma glucose was clamped at basal levels (euglycemic hyperinsulinemic clamp). A third group (n = 6) received Intralipid infusion during the clamp to prevent a fall in plasma FFA. PDK-2 mRNA level in gastrocnemius muscle was not altered by insulin or FFA (i.e., Intralipid infusion). In contrast, PDK-4 mRNA level was decreased 72% by insulin (P < 0.05), and Intralipid infusion prevented only 20% of the decrease. PDK-4 protein level was decreased approximately 20% by insulin (P < 0.05), but this effect was not altered by Intralipid infusion. In study 2, overnight-fasted rats were refed or received an infusion of saline or nicotinic acid (NA, 30 micromol/h) for 5 h (n = 5 each). During the refeeding and NA infusion, plasma FFA levels were similarly (i.e., 60-70% vs. saline control) lowered. Muscle PDK-4 mRNA level decreased 77% after the refeeding (P < 0.05) but not after the NA infusion. In conclusion, the present data indicate that insulin had a profound effect to suppress PDK-4 expression in skeletal muscle and that, contrary to previous suggestions, circulating FFA had little impact on PDK-4 mRNA expression, at least within 5 h.
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PMID:Insulin suppresses PDK-4 expression in skeletal muscle independently of plasma FFA. 1502 5

Starvation and diabetes increase pyruvate dehydrogenase kinase-4 (PDK4) expression, which conserves gluconeogenic substrates by inactivating the pyruvate dehydrogenase complex. Mechanisms that regulate PDK4 gene expression, previously established to be increased by glucocorticoids and decreased by insulin, were studied. Treatment of HepG2 cells with dexamethasone increases the relative abundance of PDK4 mRNA, and insulin blocks this effect. Dexamethasone also increases human PDK4 (hPDK4) promoter activity in HepG2 cells, and insulin partially inhibits this effect. Expression of constitutively active PKB alpha abrogates dexamethasone stimulation of hPDK4 promoter activity, while coexpression of constitutively active FOXO1a or FOXO3a, which are mutated to alanine at the three phosphorylation sites for protein kinase B (PKB), disrupts the ability of PKB alpha to inhibit promoter activity. A glucocorticoid response element for glucocorticoid receptor (GR) binding and three insulin response sequences (IRSs) that bind FOXO1a and FOXO3a are identified in the hPDK4 promoter. Mutation of the IRSs reduces the ability of glucocorticoids to stimulate PDK4 transcription. Transfection studies with E1A, which binds to and inactivates p300/CBP, suggest that interactions between p300/CBP and GR as well as FOXO factors are important for glucocorticoid-stimulated hPDK4 expression. Insulin suppresses the hPDK4 induction by glucocorticoids through inactivation of the FOXO factors.
Diabetes 2004 Apr
PMID:Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. 1504 4

The pyruvate dehydrogenase multienzyme complex catalyses the oxidative decarboxylation of pyruvate, which is an important regulatory step in oxidative metabolism. Phosphorylation of the E1 (pyruvate decarboxylase) subunit on one of three specific serine residues results in loss of enzyme activity. Four dedicated PDHK (pyruvate dehydrogenase kinase) isoenzymes have been identified, each of which display a distinct tissue-specific expression profile, and have differential regulatory properties. Thus PDHK play a key role in controlling the balance between glucose and lipid oxidation according to substrate supply. Increasing glucose oxidation by inhibiting PDHK may be an effective mechanism to increase glucose utilization; additionally, increasing pyruvate oxidation may further contribute to lowering of glucose level by decreasing the supply of gluconeogenic substrates. A number of PDHK inhibitors are now available to enable this mechanism to be evaluated as a therapy for diabetes. The isoenzyme selectivity profile of AZD7545 and related compounds will be described and evidence for their non-ATP-competitive mode of action presented. These compounds increase PDH activity in vivo, and when dosed chronically, improve glycaemic control in Zucker rats. Furthermore, glucose lowering has been demonstrated in the hyperglycaemic Zucker diabetic fatty rat. This result supports the hypothesis that inhibition of PDHK may be an effective therapy for Type II diabetes.
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PMID:PDH kinase inhibitors: a novel therapy for Type II diabetes? 1578 8


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