GSK-3 Inhibitors: Anti-Diabetic Treatment Associated with Cardiac Risk?

Nabben, Miranda; Neumann, Dietbert

doi:10.1007/s10557-016-6669-y

Cited by 9 publications

(4 citation statements)

References 16 publications

(20 reference statements)

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“…Pyruvate kinase, one of the major enzymes involved in glucose homeostasis, shows remarkable crosstalk with insulin levels in individuals with diabetes [31]. GSK-3, another key signaling molecule in the insulin pathway, modulates the process of glucose metabolism and is thus a particularly intriguing candidate target for diabetes treatment [32]. Consistent with previous studies that successfully confirmed the beneficial effects of natural products in diabetic conditions, the IOs ameliorated the metabolic disturbance of glycogen synthesis in diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic activities of polysaccharides separated from Inonotus obliquus via the modulation of oxidative stress in mice with streptozotocin-induced diabetes

Wang

et al. 2017

PLoS ONE

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This study evaluated the effects of Inonotus obliquus polysaccharides (IOs) on diabetes and other underlying mechanisms related to inflammatory factors and oxidative stress in a mouse model of streptozotocin (STZ)-induced diabetes. Four weeks administration of metformin (120 mg/kg) and IO1-4 (50%-80% alcohol precipitation), or IO5 (total 80% alcohol precipitation) at doses of 50 mg/kg reverses the abnormal changes of bodyweights and fasting blood glucose levels of diabetic mice. IOs significantly increased the insulin and pyruvate kinase levels in serum, and improved the synthesis of glycogen, especially for IO5. IOs restored the disturbed serum levels of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde. The down-regulation of interleukin-2 receptor, matrix metalloproteinase-9, and the enhancement of interleukin-2 in serum of diabetic mice were significantly attenuated by IOs. Histologic and morphology examinations showed that IOs repaired the damage on kidney tissues, inhibited inflammatory infiltrate and extracellular matrix deposit injuries in diabetic mice. Compared with untreated diabetic mice, IOs decreased the expression of phosphor-NF-κB in the kidneys. These results show that IOs treatment attenuated diabetic and renal injure in STZ-induced diabetic mice, possibly through the modulation of oxidative stress and inflammatory factors. These results provide valuable evidences to support the use of I. obliquus as a hypoglycemic functional food and/or medicine.

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Section: Discussionmentioning

confidence: 99%

Antidiabetic activities of polysaccharides separated from Inonotus obliquus via the modulation of oxidative stress in mice with streptozotocin-induced diabetes

Wang

et al. 2017

PLoS ONE

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“…As previously described, through a signaling cascade, insulin plays an important role by activating pathways that lead to phosphorylation of GSK3β and inactivating this protein by an Akt‐dependent mechanism, thereby increasing GS activity and initiating glycogen synthesis (Perry et al, 2014). Thus, GSK3β activity has been described as a determinant in the genesis of complications associated with insulin resistance (Nabben & Neumann, 2016; Rao et al, 2007). In an elegant study, Rao et al (2007) observed that the use of L803‐mts (highly specific peptide inhibitor of GSK3) improved glycemic homeostasis and reduced hyperinsulinemia and hyperleptinemia in OB mice.…”

Section: Discussionmentioning

confidence: 99%

FOXO1 is downregulated in obese mice subjected to short‐term strength training

Pereira

Rodrigues

Sant’Ana

et al. 2022

Journal Cellular Physiology

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Obesity is a worldwide health problem and is directly associated with insulin resistance and type 2 diabetes. The liver is an important organ for the control of healthy glycemic levels, since insulin resistance in this organ reduces phosphorylation of forkhead box protein 1 (FOXO1) protein, leading to higher hepatic glucose production (HGP) and fasting hyperglycemia. Aerobic physical training is known as an important strategy in increasing the insulin action in the liver by increasing FOXO1 phosphorylation and reducing gluconeogenesis. However, little is known about the effects of strength training in this context. This study aimed to investigate the effects of short-term strength training on hepatic insulin sensitivity and glycogen synthase kinase-3β (GSK3β) and FOXO1 phosphorylation in obese (OB) mice. To achieve this goal, OB Swiss mice performed the strength training protocol (one daily session for 15 days). Short-term strength training increased the phosphorylation of protein kinase B and GSK3β in the liver after insulin stimulus and improved the control of HGP during the pyruvate tolerance test. On the other hand, sedentary OB animals reduced FOXO1 phosphorylation and increased the levels of nuclear FOXO1 in the liver, increasing the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) content. The bioinformatics analysis also showed

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“…However, a large majority of these approaches rely on chronic interventions. Since the GSK-3β and mTORC signaling also regulate T cell proliferation and survival, the chronic interventions are limited and can produce side effects [25,26].…”

Section: Introductionmentioning

confidence: 99%

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Taborska

Stakheev

Svobodová

et al. 2020

Cancers

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CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18–24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.

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GSK-3 Inhibitors: Anti-Diabetic Treatment Associated with Cardiac Risk?

Cited by 9 publications

References 16 publications

Antidiabetic activities of polysaccharides separated from Inonotus obliquus via the modulation of oxidative stress in mice with streptozotocin-induced diabetes

Antidiabetic activities of polysaccharides separated from Inonotus obliquus via the modulation of oxidative stress in mice with streptozotocin-induced diabetes

FOXO1 is downregulated in obese mice subjected to short‐term strength training

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

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