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Pioglitazone-induced AMPK-Glutaminase-1 prevents high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system.

ABSTRACT: Prolonged hyperglycemia plays a major role in the progression of β-cell loss in diabetes mellitus. Here we report an insulin sensitizer thiazolidinedione Pioglitazone selectively preserves the beta cells against high glucose-induced dysfunction by activation of AMPK and Glutaminase 1 (GLS1) axis. AMPK activation increases the stability of Glutaminase 1 by HSP90 family mitochondrial heat shock protein 75 (HSP75/TRAP1). This is associated with an elevation of GSH/GSSG ratio which leads to inhibition of mitochondrial dysfunction by induction of BCL2/BCL-XL in high glucose conditions. Pioglitazone was able to also protect against high glucose-induced elevations in maladaptive ER stress markers and increase the adaptive unfolded protein response (UPR) by inhibiting mTORC1-eEF2 protein translation machinery. Moreover, the pioglitazone effect on AMPK activation was not dependent on the PPARγ pathway. Strikingly, chemical inhibition of AMPK signaling or glutaminase-1 inhibition abrogates the pioglitazone effect on the TRAP1-GLS1 axis and GSH/GSSG ratio linked to mitochondrial dysfunction. Finally, inhibition of AMPK signaling enhanced maladaptive ER stress markers by mTORC1-eEF2 activation. Altogether, these results support the proposal that pioglitazone induced AMPK activation stabilizes a novel interaction of TRAP1/HSP75-GLS1 and its downstream signaling leads to improved β-cell function and survival under high glucose conditions.

SUBMITTER: Karunakaran U

PROVIDER: S-EPMC8187239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system.

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MiR-574-3p inhibits glucose toxicity-induced pancreatic β-cell dysfunction by suppressing PRMT1.

Project description:BackgroundPancreatic β-cell dysfunction is commonly observed in patients with type 2 diabetes mellitus. Protein arginine methyltransferase 1 (PRMT1) plays an important role in pancreatic β-cell dysfunction. However, the detailed mechanisms remain largely unknown.MethodsRT-qPCR, western blotting, and immunofluorescence assays were used to evaluate PRMT1 and miR-574-3p levels. Cell Counting Kit-8, Advanced Dlycation End products (AGEs), Reactive Oxygen Species (ROS), and glucose-stimulated insulin secretion were assayed, and flow cytometry and RT-qPCR were performed to detect the role of PRMT1 and miR-574-3p in MIN6 cells. Luciferase reporter assays were performed to determine the interactions between PRMT1 and miR-574-3p.ResultsHigh-glucose treatment resulted in the high expression of PRMT1. PRMT1 silencing could alleviate the reduced proliferation, insulin secretion, and GLUT1 level, in addition to suppressing the induced apoptosis, and AGEs and ROS levels, under high glucose conditions. MiR-574-3p was established as an upstream regulator of PRMT1 using luciferase reporter assays. More importantly, miR-574-3p reversed the effect of PRMT1 silencing in MIN6 cells.ConclusionsmiR-574-3p suppresses glucose toxicity-induced pancreatic β-cell dysfunction by targeting PRMT1.

| S-EPMC9284709 | biostudies-literature

The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo.

Project description:Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 ?M silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy.

| S-EPMC3761209 | biostudies-literature

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