The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Lebrun, Patricia; Cognard, Emmanuelle; Gontard, P; Bellon-Paul, R; Filloux, Chantal; Berthault, M F; Magnan, Christophe; Ruberte, Jesús; Luppo, Mariana; Pujol, Anna; Pachera, Nathalie; Herchuelz, André; Bosch, Fátima; Obberghen, Emmanuel Van

doi:10.1007/s00125-010-1786-9

Cited by 24 publications

(24 citation statements)

References 55 publications

(54 reference statements)

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“…In these animals, treatment with human growth hormone improved hepatic lipid status, while significantly upregulating SOCS2 expression. SOCS2 has also been shown to regulate proinsulin processing and insulin secretion in pancreatic beta cells, potentially linking fatty liver susceptibility and insulin resistance [46]. In a morbidly obese cohort of women, similar to the one studied here, SOCS2 gene expression was decreased in liver RNA relative to patients who had lost a substantial amount of weight [47].…”

Section: Discussionmentioning

confidence: 84%

Genome-wide analysis of hepatic lipid content in extreme obesity

DiStefano

Kingsley

Wood³

et al. 2014

Acta Diabetol

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Individuals with type 2 diabetes have an increased risk of developing nonalcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals. Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2300 individuals on whom liver biopsy data were available. We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P<5.0 × 10−93), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver. These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.

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Section: Discussionmentioning

confidence: 84%

Genome-wide analysis of hepatic lipid content in extreme obesity

DiStefano

Kingsley

Wood³

et al. 2014

Acta Diabetol

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“…Interestingly, the increased ␤ cell mass in treated animals was correlated to a reduction in the fasting serum proinsulin:insulin ratio compared with untreated controls (Fig. 3C); this ratio has been suggested to re- flect ER capacity to properly fold and process proinsulin via the enzyme PC1/3, with higher ratios suggestive of a defect (27)(28)(29)(30)(31). These results suggest that inhibition of DHS preserves islet function and mass in the setting of obesity-related diabetes, possibly through effects on ER folding and processing capacity.…”

Section: C G H K and L)mentioning

confidence: 94%

Inhibition of Deoxyhypusine Synthase Enhances Islet β Cell Function and Survival in the Setting of Endoplasmic Reticulum Stress and Type 2 Diabetes

Robbins

Tersey

Ogihara

et al. 2010

Journal of Biological Chemistry

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Islet ␤ cell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the ␤ cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to ␤ cell dysfunction in models of type 2 diabetes in mice and ␤ cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced ␤ cell mass. Thapsigargin treatment of ␤ cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co-localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the ␤ cell.Obesity is increasing at a rapid rate worldwide, with estimates that place its prevalence at Ͼ300 million people. Obesity is perhaps the single greatest risk factor for the development of type 2 diabetes mellitus. The relationship between obesity and diabetes is complex, but it is apparent that a direct correlation exists between increasing visceral fat and insulin resistance (1-3). However, only ϳ30% of obese, insulinresistant individuals have diabetes, suggesting that other factors superimposing upon obesity must confer additional risks (4). It is now clear that defects in insulin secretion at the level of the islet ␤ cell are paramount in the transition from a normoglycemic, insulin-resistant state to frank diabetes (5), and it is postulated that underlying genetic defects at the level of the ␤ cell differentiates those who develop diabetes from those who do not (6). Prospective clinical (7) and autopsy (8) studies show significant reductions in ␤ cell function and mass, respectively, in the transition from obesity-induced insulin resistance to frank type 2 diabetes.The causes of islet dysfunction and death in the setting of insulin resistance include hyperglycemia, hyperlipidemia, cytokines, and deposition of islet amyloid polypeptide (9, 10). All of these causes stimulate intersecting pathways within the islet that lead to oxidative stress, inflammation, and endoplasmic reticulum (ER) 3 stress. These stress pathways are closely intertwined, such that activators of primarily one pathway acutely (e.g. cytokines ca...

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“…Interestingly, constant SOCS2 expression markedly impairs the response to insulin secretagogues. In transgenic animals, the first glucose‐stimulated insulin secretion peak was completely abolished, and the second phase was severely dampened . Despite the fact that constitutive SOCS2 expression does not impair glucose metabolism, it has been observed to attenuate the rise in cytosolic‐free calcium concentration induced by glucose.…”

Section: The Relationship Between Socs and Diabetesmentioning

confidence: 99%

“…Constitutive SOCS2 expression in mice disturbed proinsulin maturation, resulting in smaller insulin secretory granules of altered structure. Lowered production of the prohormone convertase 1/3, which is crucial in proinsulin cleavage, implicated the elevation of proinsulin levels, eventually impairing insulin secretion …”

Section: The Relationship Between Socs and Diabetesmentioning

confidence: 99%

“…31 Nevertheless, investigations by Lebrun et al shed new light on the role of SOCS2 in glucose tolerance regulation. 32 It has been noted that transgenic mice constitutively producing SOCS2 in b-cells develop hyperglycaemia and glucose intolerance with a predisposition to b-cell failure. However, this was not due to a loss of b-cell mass or insulin synthesis inhibition.…”

Section: Socs2mentioning

confidence: 99%

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SOCS and diabetes—ups and downs of a turbulent relationship

Suchy

Łabuzek

Machnik

et al. 2013

Cell Biochemistry & Function

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Diabetes mellitus is one of the most emerging diseases threatening the present world. Thus, intensive investigations are carried out to better understand the mechanisms occurring in type 1 (T1D) and 2 (T2D) diabetes, and to elaborate more potent methods to fight the disease. In this aspect, the suppressors of cytokine signalling (SOCS) are one of the most studied factors of recent years. SOCS proteins have been discovered as cytokine pathway inhibitors; however, presently, their influence seems wider. Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β-cell failure and eventually T1D and T2D. They are also involved in complications related with diabetes, such as retinopathy, nephropathy and cardiomyopathy. In T1D, SOCS proteins regulate β-cell mass, mediate resistance to damaging factors and improve pancreatic islet graft survival. Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. However, not all of the present data are consistent, and thus, further studies are required. Finally, for several pharmacologically active substances of importance regarding the treatment of diabetes, SOCS-modulating properties have already been described. Here, we review the findings of SOCS-diabetes relations of the last decade.

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The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Cited by 24 publications

References 55 publications

Genome-wide analysis of hepatic lipid content in extreme obesity

Genome-wide analysis of hepatic lipid content in extreme obesity

Inhibition of Deoxyhypusine Synthase Enhances Islet β Cell Function and Survival in the Setting of Endoplasmic Reticulum Stress and Type 2 Diabetes

SOCS and diabetes—ups and downs of a turbulent relationship

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