The Effects of Rosiglitazone on Insulin Sensitivity, Lipolysis, and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes

Mayerson, Adam B.; Hundal, Ripudaman S.; Dufour, Sylvie; Lebon, Vincent; Befroy, Douglas E.; Cline, Gary W.; Enocksson, Staffan; Inzucchi, Silvio E.; Shulman, Gerald I.; Petersen, Kitt Falk

doi:10.2337/diabetes.51.3.797

Cited by 588 publications

(479 citation statements)

References 50 publications

Supporting

Mentioning

429

Contrasting

Unclassified

Order By: Relevance

“…In humans, the impact of PPARγ agonism on lipidaemia is more modest than in rodent models. Although some human in vivo turnover studies did not report any effect of PPARγ agonism on the kinetics of lipolytic products [24,25], a net transcapillary release of NEFA from subcutaneous WAT was recently demonstrated in fasted type 2 diabetic subjects treated with rosiglitazone [26]. Taken together, these findings suggest that PPARγ agonism does stimulate the lipolytic process in the presence of low insulin concentrations.…”

Section: Discussionmentioning

confidence: 92%

“…In vitro basal, NA-stimulated, and insulin-inhibited lipolysis Adipose explants (20)(21)(22)(23)(24)(25) In vitro exposure of explants to rosiglitazone Minced pieces (40 mg/well) of each of the four depots described above, obtained from four control, untreated, fasted rats, were incubated in 1 ml of DMEM (Invitrogen, Burlington, ON, Canada) supplemented with pure rosiglitazone (Cayman Chemical Company, Ann Arbor, MI, USA) to a final concentration of 10 μmol/l, or carrier DMSO for 12 h. Treatments were performed in duplicate for each rat. Fat explants were then removed and frozen in liquid nitrogen until RNA isolation and analysis.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis The aim of this study was to investigate the effect and mechanisms of action of in vivo peroxisome proliferator-activated receptor γ (PPARγ) activation on white adipose tissue (WAT) lipolysis and NEFA metabolism. Materials and methods Study rats were treated for 7 days with 15 mg/kg of rosiglitazone per day; control rats were not treated. After a 6-h fast, lipolysis and levels of mRNA for lipases were assessed in explants from various adipose depots. Results Rosiglitazone markedly increased basal and noradrenaline (norepinephrine)-stimulated glycerol and NEFA release from WAT explants, and amplified their inhibition by insulin. Primary adipocytes isolated from PPARγ agonist-treated rats were also more responsive to noradrenaline stimulation expressed per cell, ruling out a contribution of an altered number of mature adipocytes in explants. Rosiglitazone concomitantly increased levels of mRNA transcripts for adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) in subcutaneous and visceral WAT, and mRNA for hormone-sensitive lipase (HSL) in subcutaneous WAT. Lipase expression increased within 12 h of in vitro exposure of naïve explants to rosiglitazone, suggesting direct transcriptional activation. In parallel, chronic in vivo treatment with rosiglitazone lowered plasma NEFAs and exerted in WAT its expected stimulatory action on glycerol and NEFA recycling, and on the expression of genes involved in NEFA uptake and retention by WAT, such processes counteracting net NEFA export. Conclusions/interpretation These findings demonstrate that, in the face of its plasma NEFA-lowering action, PPARγ agonism stimulates WAT lipolysis, an effect that is compensated by lipid-retaining pathways. The results further suggest that PPARγ agonism stimulates lipolysis by increasing the lipolytic potential, including the expression levels of the genes encoding adipose triglyceride lipase and monoglyceride lipase.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Of interest, PPAR-α deficiency is associated with lipid accumulation in the liver [176]. The complement to these studies is the observation that PPAR-γ agonist in humans reduced fat in the liver [177]. These observations indicate that the activation of PPAR α and PPAR-γ can influence the VLDL assembly at several sites and provide an option to tailor more efficient drugs that target the initial sites behind diabetic dyslipidaemia in the liver.…”

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

“…thiazolidinediones) exert their metabolic effects by binding to the PPAR-γ receptor, which is located primarily on the adipocytes [15]. Previous studies from our laboratory [16,17] and others [18,19] have demonstrated that thiazolidinedione (PPAR-γ agonists) treatment in patients with type 2 diabetes mellitus is associated with a reduction in plasma NEFA levels and NEFA turnover, a shift in fat distribution from visceral and hepatic to subcutaneous depots, improved hepatic and peripheral (muscle) insulin sensitivity and enhanced insulin signalling. Of note, positive relationships between increased hepatic fat content and various measures of insulin resistance have been observed in humans, independently of BMI [16,20].…”

Section: Introductionmentioning

confidence: 99%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

show abstract

The Effects of Rosiglitazone on Insulin Sensitivity, Lipolysis, and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes

Cited by 588 publications

References 50 publications

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

Diabetic dyslipidaemia: from basic research to clinical practice*

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Contact Info

Product

Resources

About