Low AS160 and high SGK basal phosphorylation associates with impaired incretin profile and type 2 diabetes in adipose tissue of obese patients

Stafeev, Iurii; Sklyanik, Igor A.; Yahyaev, Kamil; Shestakova, Ekaterina A.; Yurasov, Anatoliy; Karmadonov, Andrey; Chibalin, Alexander V.; Menshikov, Mikhail; Vorotnikov, Alexander V.; Parfyonova, Yelena; Shestakova, Marina Vladimirovna

doi:10.1016/j.diabres.2019.107928

Cited by 7 publications

(12 citation statements)

References 38 publications

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“…[4][5][6] Compelling evidence indicates that SGK1 plays a role in the development of metabolic syndrome. [7][8][9] A variant of the SGK1 gene (harbouring polymorphisms in intron 6 [I6CC] and exon 8 [E8CC/CT]) leading to increased SGK1 activity has been shown to be associated with increased blood pressure, obesity and type 2 diabetes mellitus (T2DM). 10,11 High-fat diet-fed Tg.SGK1 mice manifested all clinical features of metabolic syndrome observed in human beings.…”

Section: Introductionmentioning

confidence: 99%

Serum‐ and glucocorticoid‐inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1

Zhang

Chen

Liu

et al. 2021

Diabetes Metabolism Res

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Aims Accumulating evidence indicates that serum‐ and glucocorticoid‐inducible kinase 1 (SGK1) plays a role in the development of metabolic syndrome via a poorly understood mechanism. This study aimed to investigate the direct effect of SGK1 on insulin sensitivity in adipose tissue. Materials and methods We ectopically expressed or silenced SGK1 in adipocytes via lentiviral transfection, measured glucose uptake and evaluated insulin signalling using western blotting. In vivo insulin resistance was measured at the whole‐body and adipose tissue levels in db/db mice treated with an inhibitor of SGK1. Results After 8 weeks of SGK1 inhibitor treatment, the serum insulin level and homeostasis model assessment of insulin resistance index were significantly decreased, and AKT phosphorylation in adipose tissue was enhanced in db/db mice. Overexpression of constitutively active SGK1 in adipocytes in vitro decreased AKT phosphorylation and insulin‐stimulated glucose uptake. Dexamethasone and oleic acid increased SGK1 expression and decreased AKT phosphorylation and insulin receptor substrate expression in adipocytes. Administration of an inhibitor of SGK1 or Lv‐shSGK1 reversed the suppression of insulin signalling induced by dexamethasone and oleic acid. SGK1 overexpression increased FoxO1 phosphorylation, and administration of Lv‐shSGK1 reversed an increase in FoxO1 phosphorylation induced by dexamethasone and oleic acid. Conclusions Thus, SGK1 mediates the effect of glucocorticoids and high‐fat feeding and induces insulin resistance in adipocytes. Our data suggest that SGK1 is a possible therapeutic target for metabolic syndrome and related complications.

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Section: Introductionmentioning

confidence: 99%

Serum‐ and glucocorticoid‐inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1

Zhang

Chen

Liu

et al. 2021

Diabetes Metabolism Res

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“…In our previous study, we found that phosphorylation of SGK1 in subcutaneous fat correlates with insulin resistance, T2DM, and impaired incretin profile ( 29 ). Therefore, we studied in more detail SGK1-dependent signaling in omental fat.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical studies also implicated SGK1 activity in adipose tissue inflammation and insulin resistance ( 28 ). We have reported that subcutaneous fat SGK1 is associated with the impaired incretin profile of T2DM individuals ( 29 ). SGK1 stimulates transcription factors FOXO1 (forkhead box protein O1) and NDRG1 (N-myc downstream-regulated gene type 1) which are involved in white adipogenesis ( 26 , 30 ).…”

Section: Introductionmentioning

confidence: 99%

“…Changes in the adipose tissue signaling state and alterations in paracrine factor secretion may affect distantly on other processes including incretin secretion. In our previous study, we found associations between the basal state of insulin/mTORC2 signaling via AS160 and SGK in subcutaneous fat with carbohydrate metabolism and incretin profile ( 29 ). However, as we discuss above, omental fat can have more critical roles in developing insulin resistance and this study aims to analyze the insulin- and mTORC2-dependent signaling downstream SGK1 in the omental fat depot, which can be critical to metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

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NDRG1 Activity in Fat Depots Is Associated With Type 2 Diabetes and Impaired Incretin Profile in Patients With Morbid Obesity

et al. 2021

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ObjectiveWe aimed to investigate insulin-, mTOR- and SGK1-dependent signaling basal states in morbidly obese patients’ fat. We analyzed the correlation between the signaling activity, carbohydrate metabolism, and incretin profiles of patients.MethodsThe omental and subcutaneous fat was obtained in patients with obesity. The omental study included 16 patients with normal glucose tolerance (NGT) and 17 patients with type 2 diabetes mellitus (T2DM); the subcutaneous study included 9 NGT patients and 12 T2DM patients. Insulin resistance was evaluated using the hyperinsulinemic euglycemic clamp test and HOMA-IR index. The oral glucose tolerance test (OGTT) for NGT patients and mixed meal tolerance test (MMTT) for T2DM patients were performed. The levels of incretins (GLP-1, GIP, oxyntomodulin) and glucagon were measured during the tests. Signaling was analyzed by Western blotting in adipose tissue biopsies.ResultsWe have shown equal levels of basal phosphorylation of insulin- and mTOR-dependent signaling in omental fat depot in NGT and T2DM obese patients. Nevertheless, pNDRG1-T346 was decreased in omental fat of T2DM patients. Correlation analysis has shown an inverse correlation of pNDRG1-T346 in omental fat and diabetic phenotype (HbA1c, impaired incretin profile (AUC GLP-1, glucagon)). Moreover, pNDRG1-T346 in subcutaneous fat correlated with impaired incretin levels among obese patients (inverse correlation with AUC glucagon and AUC GIP).ConclusionsAccording to results of the present study, we hypothesize that phosphorylation of pNDRG1-T346 can be related to impairment in incretin hormone processing. pNDRG1-T346 in adipose tissue may serve as a marker of diabetes-associated impairments of the systemic incretin profile and insulin sensitivity.

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“…Sgk1 mRNA is elevated in adipose tissue in obese mice and humans and is associated with inflammation ( Li et al, 2013 ; Schernthaner-Reiter et al, 2015 ). Phosphorylation of SGK1 Ser422 by mTORC2 is also increased in visceral fat of patients with T2D ( Stafeev et al, 2019 ). A common (5%) polymorphism in human SGK1 is associated with obesity and T2D ( Dieter et al, 2004 ; Li et al, 2014 ; Schwab et al, 2008 ; von Wowern et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase

Zhou

Zhang

et al. 2021

Cell Reports

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Serum-and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMPactivated protein kinase Graphical abstract Highlights d SGK1 drives insulin resistance in liver in response to high-fat diet consumption d SGK1 promotes insulin resistance by phosphorylating and inhibiting AMPK d Expression of AMPK that cannot be acted upon by SGK1 promotes insulin sensitivity d SGK1 is dominant among SGK family kinases regulating insulin sensitivity in liver

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Low AS160 and high SGK basal phosphorylation associates with impaired incretin profile and type 2 diabetes in adipose tissue of obese patients

Cited by 7 publications

References 38 publications

Serum‐ and glucocorticoid‐inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1

Serum‐ and glucocorticoid‐inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1

NDRG1 Activity in Fat Depots Is Associated With Type 2 Diabetes and Impaired Incretin Profile in Patients With Morbid Obesity

Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase

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