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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uncoupling proteins (UCPs) are mitochondrial membrane transporters involved in the control of energy conversion in mitochondria. Experimental and genetic evidence relate dysfunctions of UCPs with metabolic syndrome and obesity. The PPAR subtypes mediate to a large extent the transcriptional regulation of the UCP genes, with a distinct relevance depending on the UCP gene and the tissue in which it is expressed. UCP1 gene is under the dual control of PPARgamma and PPARalpha in relation to brown adipocyte differentiation and lipid oxidation, respectively. UCP3 gene is regulated by PPARalpha and PPARdelta in the muscle, heart, and adipose tissues. UCP2 gene is also under the control of PPARs even in tissues in which it is the predominantly expressed UCP (eg, the pancreas and liver). This review summarizes the current understanding of the role of PPARs in UCPs gene expression in normal conditions and also in the context of type-2 diabetes or obesity.
PPAR Res 2007
PMID:PPARs in the Control of Uncoupling Proteins Gene Expression. 1738 66

The interest in genetic manipulations of PPARs is as old as their discovery as receptors of ligands with beneficial clinical activities. Considering the effects of PPAR ligands on critical aspects of systemic physiology, including obesity, lipid metabolism, insulin resistance, and diabetes, gene knockout (KO) in mice is the ideal platform for both hypothesis testing and discovery of new PPAR functions in vivo. With the fervent pursuit of the magic bullet to eradicate the obesity epidemic, special emphasis has been placed on the impacts of PPARs on obesity and its associated diseases. As detailed in this review, understanding how PPARs regulate gene expression and basic metabolic pathways is a necessary intermediate en route to deciphering their effects on obesity. Over a decade and dozens of genetic modifications of PPARs into this effort, valuable lessons have been learned, but we are left with more questions to be answered. These lessons and future prospects are the subject of this review.
PPAR Res 2007
PMID:Genetic manipulations of PPARs: effects on obesity and metabolic disease. 1738 68

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key regulator of lipid metabolism and energy balance implicated in the development of insulin resistance and obesity. The identification of putative natural and synthetic ligands and activators of PPAR-gamma has helped to unravel the molecular basis of its function, including molecular details regarding ligand binding, conformational changes of the receptor, and cofactor binding, leading to the emergence of the concept of selective PPAR-gamma modulators (SPPARgammaMs). SPPARgammaMs bind in distinct manners to the ligand-binding pocket of PPAR-gamma, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved antidiabetic agents for the treatment of diabetes are in development. This review summarizes the current knowledge on the mechanism of action and biological effects of recently characterized SPPARgammaMs, including metaglidasen/halofenate, PA-082, and the angiotensin receptor antagonists, recently characterized as a new class of SPPARgammaMs.
PPAR Res 2007
PMID:Selective Modulators of PPAR-gamma Activity: Molecular Aspects Related to Obesity and Side-Effects. 1738 69

At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARgamma ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the "search is on" to identify the next generation of PPARgamma modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARgamma activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARgamma that support such a therapeutic strategy.
PPAR Res 2007
PMID:'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies. 1738 71

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the women of reproductive age. Familial clustering of PCOS has been consistently reported suggesting that genetic factors play a role in the development of the syndrome although PCOS cases do not exhibit a clear pattern of Mendelian inheritance. It is now well established that PCOS represents a complex trait similar to type-2 diabetes and obesity, and that both inherited and environmental factors contribute to the PCOS pathogenesis. A large number of functional candidate genes have been tested for association or linkage with PCOS phenotypes with more negative than positive findings. Lack of universally accepted diagnostic criteria, difficulties in the assignment of male phenotype, obscurity in the mode of inheritance, and particularly small sample size of the study populations appear to be major limitations for the genetic studies of PCOS. In the near future, utilizing the genome-wide scan approach and the HapMap project will provide a stronger potential for the genetic analysis of the syndrome.
PPAR Res 2007
PMID:The Genetic Basis of the Polycystic Ovary Syndrome: A Literature Review Including Discussion of PPAR-gamma. 1738 70

Antiobesity drugs that target peripheral metabolism may avoid some of the problems that have been encountered with centrally acting anorectic drugs. Moreover, if they cause weight loss by increasing fat oxidation, they not only address a cause of obesity but also should promote loss of fat rather than lean tissue and improve insulin sensitivity. Weight loss may be slow but more sustained than with anorectic drugs, and thermogenesis may be insufficient to cause any discomfort. Some thermogenic approaches are the activation of adrenergic, thyroid hormone or growth hormone receptors and the inhibition of glucocorticoid receptors; the modulation of transcription factors [e.g. peroxisome proliferator-activated receptor delta (PPARdelta) activators] or enzymes [e.g. glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors] that promote mitochondrial biogenesis, and the modulation of transcription factors (PPAR alpha activators) or enzymes (AMP-activated protein kinase) that promote fatty acid oxidation. More surprisingly, studies on genetically modified animals and with enzyme inhibitors suggest that inhibitors of fatty acid synthesis [e.g. ATP citrate lyase, fatty acid synthase, acetyl-CoA carboxylase (ACC)], fatty acid interconversion [stearoyl-CoA desaturase (SCD)] and triglyceride synthesis (e.g. acyl-CoA : diacylglycerol acyltransferase) may all be thermogenic. Some targets have been validated only by deleting genes in the whole animal. In these cases, it is possible that deletion of the protein in the brain is responsible for the effect on adiposity, and therefore a centrally penetrant drug would be required. Moreover, whilst a genetically modified mouse may display resistance to obesity in response to a high fat diet, it requires a tool compound to demonstrate that a drug might actually cause weight loss. Even then, it is possible that differences between rodents and humans, such as the greater thermogenic capacity of rodents, may give a misleading impression of the potential of a drug.
Diabetes Obes Metab 2007 May
PMID:Thermogenic and metabolic antiobesity drugs: rationale and opportunities. 1739 Nov 51

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a transcriptional regulator of the expression of mitochondrial thioesterase I (MTE-I) and uncoupling protein 3 (UCP3), which are induced in the heart at the mRNA level in response to diabetes. Little is known about the regulation of protein expression of MTE-I and UCP3 or about MTE-I activity; thus, we investigated the effects of diabetes and treatment with a PPAR alpha agonist on these parameters. Rats were either made diabetic with streptozotocin (55 mg/kg ip) and maintained for 10-14 days or treated with the PPAR alpha agonist fenofibrate (300 mg/kg/day) for 4 weeks. MTE-I and UCP3 protein expression, MTE-1 activity, palmitate export, and oxidative phosphorylation were measured in isolated cardiac mitochondria. Diabetes and fenofibrate increased cardiac MTE-I mRNA, protein, and activity ( approximately 4-fold compared with controls). This increase in activity was matched by a 6-fold increase in palmitate export in fenofibrate-treated animals, despite there being no effect in either group on UCP3 protein expression. Both diabetes and fenofibrate caused significant decreases in state III respiration of isolated mitochondria with pyruvate + malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Both diabetes and specific PPAR alpha activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expression.
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PMID:Diabetes or peroxisome proliferator-activated receptor alpha agonist increases mitochondrial thioesterase I activity in heart. 1743 40

PPARdelta differs from the other two PPAR isotypes (alpha and gamma) by its more wide-spread tissue-specific expression pattern, its involvement in developmental processes and its profound impact on muscle and heart fat metabolism. Activation of PPARdelta modulates inflammatory responses of macrophages and is linked to altered lipoprotein metabolism, most importantly a significant raise of HDL cholesterol. PPARdelta activation in the liver decreases hepatic glucose output, thereby contributing to improved glucose tolerance and insulin sensitivity. Several studies have shown that PPARdelta polymorphisms are associated with plasma lipid levels, body mass index and the risk for diabetes and coronary heart disease. These findings support that high affinity PPARdelta agonists may be promising drugs of the future to treat the metabolic syndrome which is an expanding overweight-related health threat characterized by insulin resistance, hyperglycemia, dyslipidemia, hypertension, and accelerated atherosclerosis.
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PMID:Emerging roles of PPARdelta in metabolism. 1758 7

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5 alpha-androstan-3 alpha-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
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PMID:Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor. 1759 76

Among individuals with diabetes mellitus, cardiovascular disease remains the leading cause of death, despite the many treatment modalities that have been developed over time. The PPAR family, including PPAR-alpha, play important roles in glucose and lipid metabolism and atherosclerosis and thus are potential therapeutic targets. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. Several large prospective clinical trials have shown both primary prevention and secondary prevention benefit with fibrates, although they only had small subgroups of patients with diabetes. The first large outcome study to exclusively study those with diabetes was the FIELD study, which showed no reduction in the primary cardiovascular end-point and only some benefit in the secondary end-point. There are many potential explanations for these results; however, it would appear that at present, there is no role for fibrates as monotherapy for the reduction of cardiovascular risk among those with diabetes. However, their potential role in combination with statin therapy remains to be further elucidated with ongoing studies.
Diabetes Obes Metab 2008 Sep
PMID:PPAR-alpha: therapeutic role in diabetes-related cardiovascular disease. 1759 34


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