PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

Wang, Linyuan; Luk, Cynthia T.; Cai, Erica P.; Schroer, Stephanie A.; Allister, Emma M.; Shi, Sally Yu; Wheeler, Michael B.; Gaisano, Herbert Y.; Woo, Minna

doi:10.2337/db13-1715

Cited by 19 publications

(21 citation statements)

References 39 publications

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“…There is evidence showing that PTEN modulates hyperglycemia and insulin resistance [54]. In addition, PTEN deletion in pancreatic α-cells protects against HFD-induced insulin resistance [55]. PTEN, through its lipid phosphatase activity, catalyzes the conversion of PIP3 (Akt substrate) to PIP2 by dephosphorylating the 3-position of the inositol ring of PIP3, attenuating Akt/eNOS/NO signaling [56].…”

Section: Discussionmentioning

confidence: 99%

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Costa

Neves

Mestriner

et al. 2016

Cardiovasc Diabetol

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BackgroundHigh fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined.MethodsMesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction.ResultsVasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice.ConclusionTNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.

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Section: Discussionmentioning

confidence: 99%

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Costa

Neves

Mestriner

et al. 2016

Cardiovasc Diabetol

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“…Among them, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) antagonizes PI3K actions to negatively regulate the phosphorylation of AKT. Numerous studies revealed that overexpression of PTEN could suppress insulin-induced PtdIns (3,4) P2/PtdIns (3,4,5) P3 PIP3 production, thereby inhibiting AKT activation, GLUT4 translocation and glucose uptake121314.…”

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confidence: 99%

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

Guo

Dou

Meng

et al. 2017

Sci Rep

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Several studies have suggested an important role of miR-291b-3p in the development of embryonic stem cells. In previous study, we found that the expression of miR-291b-3p was significantly upregulated in the liver of db/db mice. However, the role of miR-291b-3p in glucose metabolism and its underlying mechanisms remain unknown. In the present study, we demonstrated that miR-291b-3p was abundantly expressed in the liver. Of note, hepatic miR-291b-3p expression was upregulated in HFD-fed mice and induced by fasting in C57BL/6 J normal mice. Importantly, hepatic inhibition miR-291b-3p expression ameliorated hyperglycemia and insulin resistance in HFD-fed mice, whereas hepatic overexpression of miR-291b-3p led to hyperglycemia and insulin resistance in C57BL/6 J normal mice. Further study revealed that miR-291b-3p suppressed insulin-stimulated AKT/GSK signaling and increased the expression of gluconeogenic genes in hepatocytes. Moreover, we identified that p65, a subunit of nuclear factor-κB (NF-κB), is a target of miR-291b-3p by bioinformatics analysis and luciferase reporter assay. Silencing of p65 significantly augmented the expression of PTEN and impaired AKT activation. In conclusion, we found novel evidence suggesting that hepatic miR-291b-3p mediated glycogen synthesis and gluconeogenesis through targeting p65 to regulate PTEN expression. Our findings indicate the therapeutic potential of miR-291b-3p inhibitor in hyperglycemia and insulin resistance.

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“…In addition, PTEN deletion in Rip-Cre neurons protected against type 2 diabetes and insulin resistance [32]. Moreover, PTEN deletion in pancreatic a-cells reversed HFD-induced hyperglucagonemia and insulin resistance [33]. Taken together, PTEN might play an important role in the development of insulin resistance and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 93%

MicroRNA 152 regulates hepatic glycogenesis by targeting PTEN

Wang

Dou

et al. 2016

The FEBS Journal

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Hepatic insulin resistance, defined as a diminished ability of hepatocytes to respond to the action of insulin, plays an important role in the development of type 2 diabetes and metabolic syndrome. Aberrant expression of mmu-miR-152-3p (miR-152) is related to the pathogenesis of tumors such as hepatitis B virus related hepatocellular carcinoma. However, the role of miR-152 in hepatic insulin resistance remains unknown. In the present study, we identified the potential role of miR-152 in regulating hepatic glycogenesis. The expression of miR-152 and the level of glycogen were significantly downregulated in the liver of db/db mice and mice fed a high fat diet. In vivo and in vitro results suggest that inhibition of miR-152 expression induced impaired glycogenesis in hepatocytes. Interestingly, miR-152 expression, glycogen synthesis and protein kinase B/glycogen synthase kinase (AKT/GSK) pathway activation were significantly decreased in the liver of mice injected with 16 lgÁmL À1 interleukin 6 (IL-6) by pumps for 7 days and in NCTC 1469 cells treated with 10 ngÁmL À1 IL-6 for 24 h.Moreover, hepatic overexpression of miR-152 rescued IL-6-induced impaired glycogenesis. Finally, phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-152 to mediate hepatic glycogen synthesis. Our findings provide mechanistic insight into the effects of miR-152 on the regulation of the AKT/GSK pathway and the synthesis of glycogen in hepatocytes. Downregulated miR-152 induced impaired hepatic glycogenesis by targeting PTEN. PTEN participated in miR-152-mediated glycogenesis in hepatocytes via regulation of the AKT/GSK pathway.

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PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

Cited by 19 publications

References 39 publications

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

MicroRNA 152 regulates hepatic glycogenesis by targeting PTEN

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