PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Mathur, Alpana; Pandey, Vivek Kumar; Kakkar, Poonam

doi:10.1530/joe-17-0081

Cited by 28 publications

(14 citation statements)

References 91 publications

(85 reference statements)

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“…Other phosphatases directly involved in AKT inactivation are the Pleckstrin Homology domain leucine-rich repeat protein phosphatases-1 and -2 (PHLPP1, PHLPP2). In consequence of elevated expression levels of PHLPPs reported in insulin target tissues (subcutaneous adipose tissue, skeletal muscle, myotubes) of T2D and obese patients [128,129], and experimentally associated to an insulin resistance status, PHLPPs have been considered as potential therapeutic targets of for insulin resistance treatment [130]. This requires a detailed understanding of PHLPPs regulation including that exerted by miRNAs; indeed, miR-190, miR-214, miR-181a and miR-181b have been demonstrated to target PHLPP1 and PHLPP2 [131,132,133].…”

Section: Mirnas As Rheostats Of Insulin and Igf-1signalingmentioning

confidence: 99%

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

Nigi

Grieco

Ventriglia

et al. 2018

IJMS

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The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.

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Section: Mirnas As Rheostats Of Insulin and Igf-1signalingmentioning

confidence: 99%

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

Nigi

Grieco

Ventriglia

et al. 2018

IJMS

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“…Non‐small cell lung cancer (NSCLC) accounts for a striking 87% of all lung cancer cases with a five‐year survival rate of 21% after diagnosis . While various treatments such as surgery, chemotherapy, radiotherapy and immunotherapy have improved the prognosis of NSCLC to some extent, the risk of relapse remains high, highlighting the need to identify oncogenic and tumor suppressive genes related to patient prognosis as molecular biomarkers and to develop therapeutic targets …”

Section: Introductionmentioning

confidence: 99%

“…2 While various treatments such as surgery, chemotherapy, radiotherapy and immunotherapy have improved the prognosis of NSCLC to some extent, the risk of relapse remains high, highlighting the need to identify oncogenic and tumor suppressive genes related to patient prognosis as molecular biomarkers and to develop therapeutic targets. 3 PHLPP2, a pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPP) isozyme, catalyzes the dephosphorylation of AGC kinases including Akt. 4 Maintaining balanced levels of PHLPP2 expression is essential in preventing pathologies, as changes in steadystate levels of PHLPP2 are correlated with many diseases including diabetes, hepatic steatosis and cancer.…”

Section: Introductionmentioning

confidence: 99%

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

Wang

Tian

et al. 2019

Thoracic Cancer

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Background PH domain and leucine‐rich repeat protein phosphatase 2 (PHLPP2) has been reported to be a potent tumor suppressor in many human cancers. However, PHLPP2 has not been fully researched as a putative clinical prognostic biomarker of lung cancer. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases including data on 1383 non‐small cell lung cancer (NSCLC) patients were used to determine PHLPP2 expression. PHLPP2 expression was then examined by immunohistochemistry, and its clinical significance analyzed in 134 NSCLC patients, including 73 patients with adenocarcinoma and 81 with squamous cell carcinoma. Results We found PHLPP2 expression to be less pronounced in NSCLC tissue samples than that in nontumoral lung tissues according to data taken from TCGA and GEO datasets; this outcome was further validated by immunohistochemistry assay. The low PHLPP2 expression level was found to be associated with the presence of lymph node metastasis (P = 0.003). Importantly, PHLPP2 was found to be an independent indicator of prognosis for overall (hazard ratio [HR] = 0.520, 95% confidence interval [Cl] = 0.327–0.827; P = 0.006) and disease‐free survival (HR = 0.489, 95% Cl = 0.308–0.775; P = 0.002) in patients with surgically‐resected NSCLC by multivariate analysis. Conclusion Taken together, our findings show that PHLPP2 is a robust clinical marker for NSCLC survival and could serve as a potential therapeutic target.

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“…But the exact mechanism in these processes is not clear. Some experimental evidences explain that one mechanism is through tyrosine kinase [15][16][17]. That is vital in glucose transporter 4 (GLUT4) translocation and as a cofactor for ATPases that affect many steps of the glycolytic pathways [7,14,18].…”

Section: Introductionmentioning

confidence: 99%

Effect of magnesium sulfate administration to improve insulin resistance in type 2 diabetes animal model: using the hyperinsulinemic‐euglycemic clamp technique

Sohrabipour

Sharifi

Talebi

et al. 2018

Fundamemntal Clinical Pharma

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This study attempted to elucidate the possible mechanism of magnesium sulfate (MgSO ) administration on reducing insulin resistance in type 2 diabetic rats. Fifty Wistar rats were divided into five groups: NDC was fed the normal diet, CD received high-fat diet with 35 mg/kg of streptozotocin, CD-Mg animals received MgSO via drinking water, CD-Ins1, and CD-Ins2 animals treated with low or high dose of insulin. Body weight and blood glucose levels were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test, and metabolic cage assessment were performed monthly. After 12 weeks, the hyperinsulinemic-euglycemic clamp was performed for all animals and blood sample was taken to measure glycated hemoglobin (HbA1c), plasma insulin, glucagon, calcium, and magnesium levels. Liver and gastrocnemius muscle were isolated to measure glucagon receptor (GR), Glucose 6 phosphatase (G6Pase), Phosphoenolpyruvate carboxykinase (Pepck) and Glucose transporter 4 (Glut4) genes expression and GLUT4 protein translocation into the cell membrane. Consuming of high-fat diet generated insulin-resistant rats. Magnesium or insulin therapy altered insulin resistance, blood glucose, IPGTT, gluconeogenesis pathway, GR, body weight, the percentage of body fat, and HbA1C in diabetic rats. Administrations of MgSO or insulin in Type 2 diabetes mellitus animals increase GLUT4 gene and protein expression. Mg could improve glucose tolerance via stimulation of Glut4 gene expression and translocation and also suppression of the gluconeogenesis pathway and GR gene expression. Mg also increased glucose infusion rate and displayed beneficial effects in the treatment of glucose metabolism and improved insulin resistance.

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PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Cited by 28 publications

References 91 publications

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

Effect of magnesium sulfate administration to improve insulin resistance in type 2 diabetes animal model: using the hyperinsulinemic‐euglycemic clamp technique

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