Effects of the dual <scp>PPAR</scp>‐α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat

Bénardeau, Agnès; Verry, P.; Atzpodien, Elke; Funk, Jürgen; Meyer, Markus; Mizrahi, Jacques; Winter, Michael; Wright, Matthew B.; Uhles, Sabine; Seböková, E

doi:10.1111/dom.12006

Cited by 15 publications

(11 citation statements)

References 35 publications

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“…Investigations on the potential beneficial effects of duel or triple PPAR ligands are emerging. This novel class of PPAR ligands may be able to avoid potential side effects of each single ligand [93] . Phase Ⅱ clinical trials for a dual PPARα/γ agonist, aleglitazar, validate their hypoglycemic and hypolipidemic effects [94] .…”

Section: Regulating Redoxmentioning

confidence: 99%

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

Kim

Yang²

2013

WJC

102

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Peroxisome-proliferator-activated receptors (PPARs) comprise three subtypes (PPARα, δ and γ) to form a nuclear receptor superfamily. PPARs act as key transcriptional regulators of lipid metabolism, mitochondrial biogenesis, and anti-oxidant defense. While their roles in regulating lipid metabolism have been well established, the role of PPARs in regulating redox activity remains incompletely understood. Since redox activity is an integral part of oxidative metabolism, it is not surprising that changes in PPAR signaling in a specific cell or tissue will lead to alteration of redox state. The effects of PPAR signaling are directly related to PPAR expression, protein activities and PPAR interactions with their coregulators. The three subtypes of PPARs regulate cellular lipid and energy metabolism in most tissues in the body with overlapping and preferential effects on different metabolic steps depending on a specific tissue. Adding to the complexity, specific ligands of each PPAR subtype may also display different potencies and specificities of their role on regulating the redox pathways. Moreover, the intensity and extension of redox regulation by each PPAR subtype are varied depending on different tissues and cell types. Both beneficial and adverse effects of PPAR ligands against cardiovascular disorders have been extensively studied by many groups. The purpose of the review is to summarize the effects of each PPAR on regulating redox and the underlying mechanisms, as well as to discuss the implications in the cardiovascular system.

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Section: Regulating Redoxmentioning

confidence: 99%

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

Kim

Yang²

2013

WJC

102

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“…Combined PPAR‐α/γ activation with aleglitazar has favourable effects on glucose and lipid profiles, biomarkers of cardiovascular risk and renal function . Aleglitazar's effects are believed to be partly achieved by improvement of β‐cell function . The present phase II trial investigated the potential metabolic effect of aleglitazar on whole‐body and liver insulin sensitivity, β‐cell function and other components of cardiometabolic syndrome, compared with placebo, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy.…”

Section: Introductionmentioning

confidence: 99%

Aleglitazar, a dual peroxisome proliferator‐activated receptor‐α/γ agonist, improves insulin sensitivity, glucose control and lipid levels in people with type 2 diabetes: findings from a randomized, double‐blind trial

Stirban

Andjelković

Heise

et al. 2016

Diabetes Obesity Metabolism

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The present single-centre, randomized, double-blind, placebo-controlled phase II study investigated the effect of the balanced dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on whole-body and liver insulin sensitivity, β-cell function and other components of cardiometabolic syndrome after 16 weeks of treatment in patients with type 2 diabetes inadequately controlled with metformin monotherapy who received once-daily 150 µg aleglitazar or matching placebo as add-on therapy to metformin. Baseline and 16-week assessments included a two-step hyperinsulinaemic-euglycaemic clamp, followed by a hyperglycaemic clamp, as well as evaluation of glycated haemoglobin (HbA1c), lipids and safety variables. The primary endpoint was change in whole-body insulin sensitivity (M-value) from baseline compared with placebo, derived from the second clamp step. M-value improved significantly from baseline with aleglitazar (n = 16) compared with placebo (n = 24; p = 0.05 for difference between arms). We found statistically significant treatment differences with aleglitazar versus placebo in fasting hepatic insulin resistance index (p = 0.01), and in total glucose disposal (p = 0.03) at the second insulin infusion step. Aleglitazar treatment resulted in significant improvements in HbA1c and lipids and was well tolerated.

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“…Total RNA was extracted from cultured cells using TRIzol ® reagent (Invitrogen; Thermo Fisher Scientific, Inc.). Single-stranded complementary (c)DNA was generated from DNaseI-treated RNA samples using Moloney murine leukemiavirus reverse transcriptase and oligo(dT) [12][13][14][15][16][17][18] (Toyobo Life Science, Osaka, Japan). A total of 1 µl cDNA samples were used for conventional PCR amplifications.…”

Section: H-fabp Small Interfering (Si)rna Transfectionmentioning

confidence: 99%

“…PPARα is of interest, as it has the ability to reflect the glucose-lowering and lipid-modifying properties of H-FABP knockdown (18). Substantial evidence has demonstrated that PPAR-α agonists have direct effects on several critical pathways contributing to the development and progression of diabetic kidney disease, and in diabetic PPAR-α-knockout mice, diabetic nephropathy is more severe than in wild-type mice, as reviewed by Thomas et al (19).…”

Section: Si-h-fabp Reduces Pa-induced Oxidative Stress In Podocytesmentioning

confidence: 99%

Overexpression of heart-type fatty acid binding protein enhances fatty acid-induced podocyteï¿½injury

et al. 2017

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Abstract. Deregulated lipid metabolism is a characteristic of metabolic diseases including type 2 diabetes and obesity, and likely contributes to podocyte injury and end-stage kidney disease. Heart-type fatty acid binding protein (H-FABP) was reported to be associated with lipid metabolism. The present study investigated whether H-FABP contributes to podocyte homeostasis. Podocytes were transfected by lentiviral vector to construct a cell line which stably overexpressed H-FABP. Small interfering RNA capable of effectively silencing H-FABP was introduced into podocytes to construct a cell line with H-FABP knockdown. Certain groups were treated with palmitic acid (PA) and the fat metabolism, as well as inflammatory and oxidative stress markers were measured. PA accelerated lipid metabolism derangement, inflammatory reaction and oxidative stress in podocytes. Overexpression of H-FABP enhanced the PA-induced disequilibrium in podocytes. The mRNA and protein expression levels of acyl-coenzyme A oxidase 3 and monocyte chemotactic protein 1, and the protein expression levels of 8-hydroxy-2'-deoxyguanosine and 4-hydroxynonenal were upregulated in the H-FABP overexpression group, while the mRNA and protein expression of peroxisome proliferator activated receptor α was downregulated. Knockdown of H-FABP inhibited the PA-induced injury and lipid metabolism derangement, as well as the inflammatory reaction and oxidative stress in podocytes. These results indicated that overexpression of H-FABP enhances fatty acid-induced podocyte injury, while H-FABP inhibition may represent a potential therapeutic strategy for the prevention of lipid metabolism-associated podocyte injury.

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Effects of the dual PPAR‐α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat

Abstract: Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat.

Cited by 15 publications

References 35 publications

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

Aleglitazar, a dual peroxisome proliferator‐activated receptor‐α/γ agonist, improves insulin sensitivity, glucose control and lipid levels in people with type 2 diabetes: findings from a randomized, double‐blind trial

Overexpression of heart-type fatty acid binding protein enhances fatty acid-induced podocyteï¿½injury

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