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 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.

scholarly journals Protective Effects of Konjac and Inulin Extracts on Type 1 and Type 2 Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Tianle Gao ◽  
Yue Jiao ◽  
Yang Liu ◽  
Tao Li ◽  
Zhiguo Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Dose Group ◽  
Vehicle Control ◽  
Continuous Treatment ◽  
High Risk Population ◽  
Wild Type ◽  
Group A

Objective. The present study was designed to determine whether konjac and inulin extracts or their combination, konjac-inulin (KI) composition, as diet supplementary, can exert beneficial effects against type 1 diabetes and type 2 diabetes using animal models. Methods. A total of 60 diabetic (type 1) rats induced by streptozotocin (STZ) were randomly assigned to five groups: vehicle control (STZ group), KI combination at low dose group (KI-L group), KI combination at medium dose group (KI-M group), KI combination at high dose group (KI-H group), konjac extract group (konjac group), and inulin extract group (inulin group). A sham group (without STZ) was also included. Levels of blood glucose were monitored at each week. After continuous treatment of each diet for 24 days, a glucose tolerance test was performed. After 28 days of treatment, plasma biochemical indicators including glycated serum proteins, total cholesterol, and triglycerides were measured and immunohistochemistry staining of the rat pancreas was performed, to study the insulin expressions. Type 2 diabetes was developed in db/db mice. A total of 28 db/db mice were divided into 4 groups: vehicle control (db/db group), KI composition group (KI group), konjac extract group (konjac group), and inulin extract group (inulin group). A wild-type control group (wild-type group) for db/db mice was also included. Levels of blood glucose, body weight, and blood triglycerides were monitored at each week. Results. Daily use of the KI composition significantly decreased levels of blood glucose and blood triglycerides, as well as improved the insulin production in islets or reduced development of obesity in STZ-induced diabetic rats or in db/db mice. Such effects from KI composition were better than single ingredient of konjac or inulin extract. Conclusion. The results of this study suggest that daily use of KI composition has a protective role on type 1 and 2 diabetes and provided experimental basis for further development of KI composition as a food supplement for diabetic or diabetic high-risk population.

The plasma 5′-AMP acts as a potential upstream regulator of hyperglycemia in type 2 diabetic mice

2012 ◽  
Vol 302 (3) ◽  
pp. E325-E333 ◽  
Author(s):  
Ying Zhang ◽  
Zhongqiu Wang ◽  
Yue Zhao ◽  
Ming Zhao ◽  
Shiming Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Adenosine Monophosphate ◽  
Plasma Free Fatty Acid ◽  
Hepatic Glycogen ◽  
Diabetic Mice ◽  
Wild Type ◽  
Upstream Regulator ◽  
Type 2 Diabetic

Increased plasma free fatty acid (FFA) level is a hallmark of type 2 diabetes. However, the underlying molecular basis for FFA-caused hyperglycemia remains unclear. Here we identified plasma 5′-adenosine monophosphate (pAMP) markedly elevated in the plasma of type 2 diabetic mice. High levels of FFAs induced damage in vein endothelial cells and contributed to an increase in pAMP. Administration of synthetic 5′-AMP caused hyperglycemia and impaired insulin action in lean wild-type mice. 5′-AMP elevated blood glucose in mice deficient in adenosine receptors with equal efficiency as wild-type mice. The function of pAMP was initiated by the elevation of cellular adenosine levels, directly stimulating G-6-Pase enzyme activity, attenuating insulin-dependent GLUT4 translocation in skeletal muscle, and displaying a rapid and steep increase in blood glucose and a decrease in hepatic glycogen level. It was followed by an increase in the gene expression of hepatic Foxo1 and its targeting gene Pepck and G6Pase, which was similar to diabetic phenotype in db/db mice. Our results suggest that pAMP is a potential upstream regulator of hyperglycemia in type 2 diabetes.

scholarly journals Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

2008 ◽  
Vol 295 (1) ◽  
pp. E46-E54 ◽  
Author(s):  
Nam Ho Jeoung ◽  
Robert A. Harris
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Pyruvate Dehydrogenase Kinase ◽  
Wild Type ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Liver And Kidney

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4−/− mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4−/− mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4−/− mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4−/− mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4−/− mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4−/− mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4−/− mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4−/− mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-α transgenic mice

2003 ◽  
Vol 285 (1) ◽  
pp. H270-H276 ◽  
Author(s):  
Teresa A. Hopkins ◽  
Mary C. Sugden ◽  
Mark J. Holness ◽  
Ray Kozak ◽  
Jason R. B. Dyck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

The pyruvate dehydrogenase enzyme complex (PDC) is rate limiting for glucose oxidation in the heart. Inhibition of PDC by end-product feedback and phosphorylation by pyruvate dehydrogenase kinase (PDK) operate in concert to inhibit PDC activity. Because the transcriptional regulator peroxisome proliferator-activated receptor (PPAR)-α increases PDK expression in some tissues, we examined what role PPAR-α has in regulating glucose oxidation in hearts from mice overexpressing PPAR-α (MHC-PPAR-α mice). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPAR-α mice compared with wild-type littermates (428 ± 113 vs. 771 ± 63 nmol · g dry weight-1 · min-1, respectively), which was accompanied by a parallel increase in fatty acid oxidation. However, there was no difference in PDC activity between MHC-PPAR-α and wild-type animals, even though the expression of the PDK isoform PDK1 was increased in MHC-PPAR-α mice. Glucose oxidation rates in both MHC-PPAR-α and wild-type mouse hearts were decreased after 48-h fasting (which increases PPAR-α expression) or by treatment of mice with the PPAR-α agonist WY-14,643 for 1 wk. Despite this, PDC activity in both animal groups was not altered. Taken together, these data suggest that glucose oxidation rates in the heart can be dramatically altered independent of PDK phosphorylation and inhibition of PDC by PDK. It also suggests that PPAR-α activation decreases glucose oxidation in hearts mainly by decreasing the flux of pyruvate through PDC due to negative feedback of PDC by fatty acid oxidation reaction products rather than by the phosphorylated state of the PDC complex.

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.

scholarly journals Codon-54 Polymorphism of the Fatty Acid-Binding Protein 2 Gene Is Associated with Elevation of Fasting and Postprandial Triglyceride in Type 2 Diabetes*

2000 ◽  
Vol 85 (9) ◽  
pp. 3155-3160 ◽  
Author(s):  
Angeliki Georgopoulos ◽  
Omer Aras ◽  
Michael Y. Tsai
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Plasma Triglyceride ◽  
Wild Type ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Fasting Plasma

Abstract Patients with type 2 diabetes are frequently dyslipidemic or hypertriglyceridemic. To assess whether increased intestinal triglyceride input leads to elevated fasting and postprandial triglycerides in type 2 diabetes, we used the codon 54 polymorphism of the fatty acid-binding protein 2 gene, which results in the substitution of threonine (Thr) for alanine and is associated with increased intestinal input of triglyceride. Of the 287 diabetic patients screened, 108 (37.6%) were heterozygous and 31 (10.8%) were homozygous for the Thr-54 allele. Mean (±sem) fasting plasma triglyceride levels in patients with the wild-type (n = 80), those heterozygous for the Thr-54 allele (n = 57), and those homozygous for it (n = 18) were 2.0 ± 0.09, 2.7 ± 0.20, and 3.8 ± 0.43 mmol/L, respectively. A linear relationship of mean fasting plasma triglyceride levels (r2 = 0.97) between the 3 groups was found. After fat ingestion, the postprandial area under the curve of plasma triglyceride (P = 0.025) and chylomicrons (Sf > 400, P = 0.013) was higher in the Thr-54/Thr-54 (n = 6) than in the wild-type (n= 9). Our results are consistent with the hypothesis that, in type 2 diabetes, increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.

Sign in / Sign up

Export Citation Format

Share Document