scholarly journals Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Yves Lecarpentier ◽  
Victor Claes ◽  
Alexandre Vallée ◽  
Jean-Louis Hébert
Keyword(s):  
Type 2 Diabetes ◽  
Colon Cancer ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Ppar Gamma ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Beta Catenin ◽  
Canonical Wnt

In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet

2009 ◽  
Vol 423 (2) ◽  
pp. 243-252 ◽  
Author(s):  
Byounghoon Hwang ◽  
Nam Ho Jeoung ◽  
Robert A. Harris
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Blood Glucose ◽  
Knockout Mice ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Saturated Fat ◽  
Pyruvate Dehydrogenase Kinase ◽  
Wild Type

The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1α [PPARγ (peroxisome proliferator-activated receptor γ) coactivator 1α] and PPARα and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.

scholarly journals Pioglitazone in the Treatment of Type 2 Diabetes: Safety and Efficacy Review

2010 ◽  
Vol 3 ◽  
pp. CMED.S5372 ◽  
Author(s):  
Cyrus V. Desouza ◽  
Vijay Shivaswamy
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Ppar Gamma ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Cardiovascular Safety ◽  
Peroxisome Proliferator Activated Receptor ◽  
Safety And Efficacy ◽  
Beneficial Effects

The increase in obesity and the aging of the population has lead to an increase in the incidence of type 2 diabetes. This has led to the development of new drugs such as thiazolidinediones (TZDs) which are Peroxisome Proliferator-Activated Receptor (PPAR-gamma) agonists, to treat type 2 diabetes. TZDs have recently been at the center of a controversy with regards to their cardiovascular safety. Pioglitazone is a TZD which has been shown to be effective in glycemic control by lowering insulin resistance. Pioglitazone also has beneficial effects on lipid metabolism and cardiovascular risk. The safety and efficacy of pioglitazone including its pleotropic effects are discussed at length in this article.

scholarly journals The Effect of Periodic Exercise and Resveratrol Supplementation on the Expression of Pparg Coactivator-1 Alpha and Pyruvate Dehydrogenase Kinase Genes in Gastrocnemius Muscle of Old Rats With Type 2 Diabetes

2020 ◽  
Vol 26 (1) ◽  
pp. 68-81
Author(s):  
Ali Salehi ◽  
◽  
Hajar Abbaszadeh ◽  
Parvin Farzanegi ◽  
◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Pyruvate Dehydrogenase ◽  
Gastrocnemius Muscle ◽  
Diabetic Control ◽  
Pyruvate Dehydrogenase Kinase ◽  
Male Rats ◽  
Expression Levels ◽  
Old Rats

Aims: Type 2 diabetes is the result of complex interactions between genetic and environmental factors that affect fat and glucose metabolism. The purpose of this study was to determine the effect of periodic exercise and resveratrol supplement on the expression levels of Pparg Coactivator 1-Alpha (PGC-1α) and Pyruvate Dehydrogenase Kinase (PDK4) genes in gastrocnemius muscle of old rates with type 2 diabetes. Methods & Materials: 42 male rats (mean age= 40-50 weeks; mean body weight= 250-300 g) were randomly divided into 6 groups: healthy-control, diabetic-control, Diabetic+Periodic Exercise, Diabetic+Supplement, Diabetic+Periodic Exercise+Supplement and Saline. The type 2 diabetes was induced by intraperitoneal injection of Streptozotocin (50 mg/kg body weight). The exercise protocol consisted of 10 sets of 1-min activities at 50% intensity and a 2-min rest period between sets, and each week the speed was increased by 2 meters per minute. The exercises were performed for eight weeks. Resveratrol supplement was injected intraperitoneally daily at a dose of 20 mg/kg body weight. The expressions of PDK4 and PGC-1α in the gastrocnemius muscle were measured by real time Polymerase Chain Reaction (PCR) method. Findings: highest expression level of PDK4 and PGC-1α genes in gastrocnemius muscle was observed in the diabetic group received both periodic exercise and Resveratrol supplement and the lowest level was reported in the diabetic-control and saline groups. Conclusion The combination of resveratrol supplementation and periodic exercise can have beneficial effects on PDK4 and PGC-1α expression levels in the gastrocnemius muscle of old rats with type 2 diabetes and reduce the risks of diabetes-related complications.

Inhibition of pyruvate dehydrogenase complex activity by 3-bromopyruvate affects blood platelets responses in type 2 diabetes

2020 ◽  
Vol 72 (1) ◽  
pp. 225-237 ◽  
Author(s):  
Anna Michno ◽  
Katarzyna Grużewska ◽  
Hanna Bielarczyk ◽  
Marlena Zyśk ◽  
Andrzej Szutowicz
Keyword(s):  
Type 2 Diabetes ◽  
Pyruvate Dehydrogenase ◽  
Blood Platelets ◽  
Pyruvate Dehydrogenase Complex ◽  
Complex Activity ◽  
Dehydrogenase Complex

AZD7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2

2003 ◽  
Vol 31 (6) ◽  
pp. 1168-1170 ◽  
Author(s):  
J.A. Morrell ◽  
J. Orme ◽  
R.J. Butlin ◽  
T.E. Roche ◽  
R.M. Mayers ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pyruvate Dehydrogenase ◽  
Kinase Inhibitors ◽  
Selective Inhibitor ◽  
Pyruvate Dehydrogenase Kinase ◽  
Enzyme Complex ◽  
Specific Expression ◽  
Related Compounds

The PDH (pyruvate dehydrogenase) multi-enzyme complex catalyses a key regulatory step in oxidative glycolysis. Phosphorylation of the E1 subunit of the complex on serine residues results in the inactivation of enzyme activity. A family of four dedicated PDH kinase isoenzymes exists, each of which displays a distinct tissue-specific expression profile. AZD7545 is one of a series of PDH kinase inhibitors developed for the treatment of type 2 diabetes. The isoenzyme-selectivity profile of AZD7545 and related compounds is described and the consequences for their in vivo mode of action are discussed.

Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats

2003 ◽  
Vol 285 (1) ◽  
pp. E130-E137 ◽  
Author(s):  
Mary A. Selak ◽  
Bayard T. Storey ◽  
Iyalla Peterside ◽  
Rebecca A. Simmons
Keyword(s):  
Type 2 Diabetes ◽  
Oxidative Phosphorylation ◽  
Growth Retardation ◽  
Pyruvate Dehydrogenase ◽  
Intrauterine Growth Retardation ◽  
Glycogen Synthesis ◽  
Later Life ◽  
Pyruvate Dehydrogenase Kinase ◽  
Intrauterine Growth

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, α-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.

scholarly journals Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone

2003 ◽  
Vol 369 (3) ◽  
pp. 687-695 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Nicholas D. SMITH ◽  
Mary C. SUGDEN
Keyword(s):  
Thyroid Hormone ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Hormone Receptors ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Cpt I ◽  
Fat Feeding

Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-α (PPARα). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-α. Heterodimerization partners for retinoid X receptors (RXRs) include PPARα and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-α activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARα activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARα, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARα or TR with the RXR receptor and that effects of PPARα activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.

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