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Biochim Biophys Acta. 2015 Sep;1852(9):1729-42. doi: 10.1016/j.bbadis.2015.05.013. Epub 2015 May 31.

Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling.

Author information

1
Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
2
Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
3
Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain.
4
Institute of Health Research-INCLIVA, 46010 Valencia, Spain; Departamento de Farmacología, Universidad de Valencia, 46010 Valencia, Spain.
5
Institute of Health Research-INCLIVA, 46010 Valencia, Spain; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain. Electronic address: gonzaleh@uv.es.

Abstract

Single nucleotide polymorphisms near the Ink4/Arf locus have been associated with type-2 diabetes mellitus. Previous studies indicate a protective role of the locus in the carbohydrate metabolism derangement associated with ageing in wild-type mice. The present study demonstrates that the increased Ink4/Arf locus expression in 1-year-old mice, partially-deficient for the insulin receptor substrate (IRS)2 (Irs2+/-SuperInk4/Arf mice) ameliorates hepatic steatosis, inflammation and insulin resistance. Irs2+/-SuperInk4/Arf mice displayed improved glucose tolerance and insulin sensitivity compared with Irs2+/- mice which were glucose intolerant and insulin resistant compared with age-matched wild-type mice. These changes in Irs2+/- mice were accompanied by enhanced hepatic steatosis, proinflammatory macrophage phenotype, increased Ly6C(hi)-monocyte percentage, T-lymphocyte activation and MCP1 and TNF-α cytokine levels. In Irs2+/-SuperInk4/Arf mice, steatosis and inflammatory parameters were markedly reduced and similar to those of wild-type counterparts. In vivo insulin signalling also revealed reduced activation of the IRS/AKT-dependent signalling in Irs2+/- mice. This was restored upon increased locus expression in Irs2+/-SuperInk4/Arf mice which display similar activation levels as those for wild-type mice. In vivo treatment of Irs2+/-SuperInk4/Arf mice with TNF-α diminished insulin canonical IRS/AKT-signalling and enhanced the stress SAPK/JNK-phosphoSer307IRS1-pathway suggesting that cytokine levels might potentially affect glucose homeostasis through changes in these insulin-signalling pathways. Altogether, these results indicate that enhanced Ink4/Arf locus expression restores glucose homeostasis and that this is associated with diminished hepatic steatosis and inflammation in mice with insulin resistance. Therefore, pharmacological interventions targeted to modulate the Ink4/Arf locus expression could be a tentative therapeutic approach to alleviate the inflammation associated with insulin resistance.

KEYWORDS:

CDKN2A/2B; Diabetes; Inflammation; Insulin resistance; Macrophage; Steatosis

PMID:
26022372
DOI:
10.1016/j.bbadis.2015.05.013
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