A Tailored Therapy for the Metabolic Syndrome

Etgen, Garret J.; Oldham, Brian A.; Johnson, W. Thomas; Broderick, Carol L.; Montrose, Chahrzad; Brozinick, Joseph T.; Misener, Elizabeth A.; Bean, James S.; Bensch, William R.; Brooks, Dawn A.; Shuker, Anthony J.; Rito, Christopher J.; McCarthy, James R.; Ardecky, Robert; Tyhonas, John S.; Dana, Sharon L.; Bilakovics, James; Paterniti, James R.; Ogilvie, Kathleen M.; Liu, Sha; Kauffman, Raymond F.

doi:10.2337/diabetes.51.4.1083

Cited by 99 publications

(50 citation statements)

References 33 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conceptually, the development of PPAR α/γ agonists represents a promising line to produce tailored compounds that can correct both pertubations of lipid metabolism and insulin resistance. Recently a dual PPAR α/γ agonist (LY 465608) has been reported to improve glycaemia as well as lipid parameters in the db/db mouse [174].…”

Section: New Perspectives Of Lipid Management In Type 2 Diabetesmentioning

confidence: 99%

Diabetic dyslipidaemia: from basic research to clinical practice*

2003

View full text Add to dashboard Cite

The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent" VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes.Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia. [Diabetologia (2003) 46:733-749]

show abstract

Section: New Perspectives Of Lipid Management In Type 2 Diabetesmentioning

confidence: 99%

Diabetic dyslipidaemia: from basic research to clinical practice*

2003

View full text Add to dashboard Cite

show abstract

“…26 In the past few years, dual PPARa and PPARg agonists have been developed and their utility as antidiabetic drugs has been suggested. [27][28][29][30][31] Nevertheless, only few reports have explored the effects of cotreatment with PPARa and PPARg agonists, 7,30 particularly when focusing on body weight regulation.…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

et al. 2005

View full text Add to dashboard Cite

AIMS/HYPOTHESIS:Fibrates and thiazolidinediones are commonly used for the treatment of dyslipidemia and type 2 diabetes, respectively. The aim of this study was to investigate the effects on body weight as well as on glucose and lipid homeostasis of ligands for PPARa and PPARg, Fenofibrate and Rosiglitazone, alone or in association. METHODS: Ob/ob mice were divided into four groups: control, and mice daily injected (intraperitoneally), either with 10 mg/kg Rosiglitazone, 100 mg/kg Fenofibrate or both molecules. Body weight and food intake were monitored daily. After 13 days of treatment, mice were killed, and blood samples were collected for posterior metabolite quantification. The liver and adipose tissues were dissected and weighed. RESULTS: Body weight was significantly reduced or increased by Fenofibrate and Rosiglitazone, respectively. The effect of Rosiglitazone was prevented by coadministration of Fenofibrate. This was accompanied by a normalization of the daily food efficiency. Compared to those treated with Rosiglitazone, animals treated with Fenofibrate alone or in combination presented a decreased white adipose tissue mass. Fenofibrate or Rosiglitazone alone significantly reduced the levels of plasma lipid parameters. Surprisingly, Fenofibrate also decreased blood glucose levels in ob/ob mice, despite having no effect on insulin levels. By contrast, both glucose and insulin levels were decreased by Rosiglitazone treatment. Coadministration of both drugs improved all parameters as with Rosiglitazone. Fenofibrate restored almost normal hepatocyte morphology and significantly reduced the triglyceride content of the liver. This was accompanied by an increase in fatty acid oxidation in the liver in all groups receiving Fenofibrate. CONCLUSION/INTERPRETATION: These biological effects suggest that combined therapy with a PPARa and a PPARg ligand is more effective in ameliorating, specifically, lipid homeostasis than in activating any of this receptor separately. Furthermore, Fenofibrate prevents one of the most undesirable effects of Rosiglitazone, namely increased adiposity and body weight gain.

show abstract

“…In the past few years, there has been a considerable effort in identifying antidiabetes drugs capable of exerting their effects without affecting body weight, but most compounds developed thus far do not overcome this adverse effect (28,35,36).…”

mentioning

confidence: 99%

S 26948

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE-Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator-activated receptor (PPAR)␥ modulator, the aim of this study was to characterize the properties of a new PPAR␥ ligand, S 26948, with special attention in body-weight gain.RESEARCH DESIGN AND METHODS-We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate its pattern of coactivator recruitment compared with rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3-F442A cell line and its in vivo effects in ob/ob mice (for antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knockin mice (E2-KI) (for antiatherogenic capacity).RESULTS-S 26948 displayed pharmacological features of a high selective ligand for PPAR␥ with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPAR␥ coactivator-1␣. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPAR␥ ligand class able to decrease atherosclerotic lesions.CONCLUSIONS-These findings establish S 26948 as a selective PPAR␥ ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo.

show abstract

A Tailored Therapy for the Metabolic Syndrome

Cited by 99 publications

References 33 publications

Diabetic dyslipidaemia: from basic research to clinical practice*

Diabetic dyslipidaemia: from basic research to clinical practice*

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

S 26948

Contact Info

Product

Resources

About