Association of SGK1 Gene Polymorphisms with Type 2 Diabetes

Schwab, Matthias; Lupescu, Adrian; Moța, Maria; Moţa, E; Frey, Andreas; Simon, Perikles; Mertens, Peter R.; Floege, Jürgen; Luft, Friedrich C.; Asante-Poku, S.; Schaeffeler, Elke; Läng, Florian

doi:10.1159/000113757

Cited by 58 publications

(43 citation statements)

References 94 publications

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“…A common SGK1 gene variant is associated with increased blood pressure, obesity, and type 2 diabetes (Schwab et al 2008). Upregulation of intestinal SGK1 expression may partially stimulate the Na + -coupled glucose transporter SGLT1, consequently leading to fat deposition and obesity (Fujita et al 1998;Dieter et al 2004;Lang and Stournaras 2013).…”

Section: Discussionmentioning

confidence: 99%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases. KEYWORDS iron; serum and glucocorticoid inducible kinase SGK-1; lipid uptake; obesity; C. elegans D UE to its essential roles in numerous cellular functions across nearly all living organisms, including oxygen transport, electron transport, DNA synthesis, and enzyme catalysis, exploring how iron is stored and regulated has been a growing focus in numerous fields. Dietary iron is absorbed primarily by duodenal enterocytes via the divalent metal-ion transporter 1 (DMT1) after it is reduced at the apical membrane. Subsequently, it is either stored in ferritin, which dynamically regulates iron sequestration, storage, and release or it is transported from enterocytes into the blood stream via the basolateral transporter ferroportin (Fleming and Ponka 2012). Consequently, the total amount of iron in the body is determined by its intake and storage, which are all finely regulated by many factors and signaling pathways at various levels (Fleming and Ponka 2012;Hubler et al. 2015), many of which not entirely understood.Human epidemiology studies revealed that elevated levels of ferritin may be an indication of systemic iron overload (Cook et al. 1974;Zimmermann 2008) and are positively associated with obesity (Wenzel et al. 1962;Gillum 2001;Iwasaki et al. 2005) and obesity-related diseases such as diabetes, hypertension, dyslipidaemia, or nonalcoholic fatty liver disease (Jehn et al. 2004;Bozzini et al. 2005;Mascitelli et al. 2009;Dongiovanni et al. 2011;Kim et al. 2011; see Zafon et al. 2010 for review). Precisely why elevations in ferritin levels or systemic iron overload are associated w...

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Section: Discussionmentioning

confidence: 99%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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“…SGK1 upregulates blood pressure, fosters the development of obesity and type 2 diabetes, and augments platelet activation, all key features of metabolic syndrome (Lang & Voelkl 2013). A certain variant of the SGK1 gene (the combined presence of distinct polymorphisms in intron 6 (I6CC) and exon 8 (E8CC/CT)) has been shown to be associated with increased blood pressure (Busjahn et al 2002, von Wowern et al 2005, obesity, and type 2 diabetes mellitus (Dieter et al 2004, Schwab et al 2008.…”

Section: Introductionmentioning

confidence: 99%

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Hao

Pan

et al. 2016

Journal of Molecular Endocrinology

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This study investigates the effectiveness and mechanisms of a serum-and glucocorticoidinducible kinase 1 (SGK1) inhibitor in counteracting hyperglycemia. In an in vivo experiment, we demonstrated that after an 8-week treatment with an SGK1 inhibitor, the fasting blood glucose and HbA1c level significantly decreased in db/db mice. RT-PCR and western blot analyses revealed that intestinal SGK1 and sodium glucose co-transporter 1 (SGLT1) expression were enhanced in db/db mice. Treatment with an SGK1 inhibitor decreased excessive SGLT1 expression in the intestine of db/db mice. In vitro experiments with intestinal IEC-6 cells showed that the co-administration of an SGK1 inhibitor partly reversed the SGLT1 expression and glucose absorption that were induced by dexamethasone. In conclusion, this study revealed that the favorable effect of an SGK1 inhibitor on hyperglycemia is partly due to decreased glucose absorption through SGLT1 in the small intestine. These data collectively suggest that SGK1 may be a potent target for the treatment of diabetes and other metabolic disorders.

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“…Inappropriate glucocorticoid independent formation and activity of SGK1 could indeed elicit some sequelae of glucocorticoid excess at normal or even decreased plasma glucocorticoid levels. The hypothesis is supported by the recent observation of the enhanced prevalence of the SGK1 gene variant in patients with type II diabetes [73] .…”

Section: Discussionmentioning

confidence: 72%

Role of Serum- and Glucocorticoid-Inducible Kinase SGK1 in Glucocorticoid Regulation of Renal Electrolyte Excretion and Blood Pressure

Boini

Nammi²,

Grahammer³

et al. 2008

Kidney Blood Press Res

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Background/Aims: The serum- and glucocorticoid-inducible kinase SGK1 was originally cloned as a glucocorticoid-regulated gene and later as a transcriptional target for mineralocorticoids. SGK1 regulates channels and transporters including the renal Na⁺ channel ENaC. It contributes to mineralocorticoid regulation of renal Na⁺ excretion and salt appetite. The present study explored the contribution of SGK1 to effects of glucocorticoids on mineral and electrolyte metabolism. Methods: SGK1-knockout mice (sgk1^–/–) and their wild-type littermates (sgk1^+/+) were analyzed in metabolic cages with or without treatment for 14 days with dexamethasone (3 mg/kg b.w., i.p.). Blood pressure was determined by the tail-cuff method. Results: Prior to treatment fluid intake, urinary flow rate, urinary Na⁺, K⁺, phosphate and Cl^– excretion, plasma electrolyte and glucose concentrations as well as blood pressure were similar in sgk1^–/– and sgk1^+/+ mice. Dexamethasone did not significantly alter renal Na⁺, K⁺, Cl^– and Ca²⁺ excretion but decreased plasma Ca²⁺ and phosphate concentration in sgk1^+/+ mice. The effect on Ca²⁺ was significantly augmented and the effect on phosphate significantly blunted in sgk1^–/– mice. Dexamethasone significantly increased fasting blood glucose concentrations in both genotypes. Dexamethasone increased blood pressure in sgk1^+/+ mice, an effect significantly blunted in sgk1^–/– mice. Conclusions: The present observations disclose SGK1-sensitive glucocorticoid effects on calcium-phosphate metabolism and blood pressure.

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Association of SGK1 Gene Polymorphisms with Type 2 Diabetes

Cited by 58 publications

References 94 publications

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Role of Serum- and Glucocorticoid-Inducible Kinase SGK1 in Glucocorticoid Regulation of Renal Electrolyte Excretion and Blood Pressure

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