Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Frankó, András; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K. H.; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sánchez-Lasheras, Carmen; Adamski, Jerzy; Prokisch, Holger; Beckers, Johannes; Walch, Axel; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J.; Angelis, Martin Hrabé de

doi:10.2337/db15-1670

Cited by 38 publications

(50 citation statements)

References 53 publications

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“…Pancreata were fixed in 4% paraformaldehyde and processed as published previously50. Briefly, cryo-sections were stained with anti-insulin (Invitrogen, Life Technologies, Germany), or with anti-amyloid fibril antibody 91D7E8 employing corresponding fluorescent-labeled secondary antibodies (Invitrogen, Life Technologies, Germany).…”

Section: Methodsmentioning

confidence: 99%

The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

Camargo

Tripsianes

Buday

et al. 2017

Sci Rep

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Type II diabetes (T2D) is characterized by diminished insulin production and resistance of cells to insulin. Among others, endoplasmic reticulum (ER) stress is a principal factor contributing to T2D and induces a shift towards a more reducing cellular environment. At the same time, peripheral insulin resistance triggers the over-production of regulatory hormones such as insulin and human islet amyloid polypeptide (hIAPP). We show that the differential aggregation of reduced and oxidized hIAPP assists to maintain the redox equilibrium by restoring redox equivalents. Aggregation thus induces redox balancing which can assist initially to counteract ER stress. Failure of the protein degradation machinery might finally result in β-cell disruption and cell death. We further present a structural characterization of hIAPP in solution, demonstrating that the N-terminus of the oxidized peptide has a high propensity to form an α-helical structure which is lacking in the reduced state of hIAPP. In healthy cells, this residual structure prevents the conversion into amyloidogenic aggregates.

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Section: Methodsmentioning

confidence: 99%

The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

Camargo

Tripsianes

Buday

et al. 2017

Sci Rep

Self Cite

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“…Experimental type 1 diabetes was induced by intraperitoneal (i.p.) injections of C57BL/6 mice with streptozotocin (STZ) as has been described previously (24,25).…”

Section: Streptozotocin Treatmentmentioning

confidence: 99%

Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes

et al. 2019

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Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivationresponsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator-activated receptor g coactivator 1-a (PGC-1a), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor a (ERRa)-dependent manner. However, PGC-1a knockout did not prevent fasting-induced suppression of CYP2R1 in the liver, indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting, suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1a-ERRa pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway.

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“…Indeed, PPAR-α, as a ligand-activated transcription factor, exerts positive and/or negative control over the expression of a range of metabolic and inflammatory genes 10 and regulates cognitive flexibility in mice. [12][13][14] Palmitoylethanolamide (PEA, C16:0), an endogenous PPAR-α agonist, has shown to have a bi-faced pharmacological profile. [12][13][14] Palmitoylethanolamide (PEA, C16:0), an endogenous PPAR-α agonist, has shown to have a bi-faced pharmacological profile.…”

Section: Introductionmentioning

confidence: 99%

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

et al. 2019

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Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice.Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload. K E Y W O R D Sadenosine monophosphate-activated protein kinase (AMPK), high-fat diet, metabolic flexibility, mitochondrial dysfunction, oxidative stress, peroxisome proliferator-activated receptor (PPAR)-α

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Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Cited by 38 publications

References 53 publications

The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

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