Abstract
Aims/HypothesisRecently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs) in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans.MethodsWe genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707). The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR) imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps.ResultsAfter appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels.ConclusionsIn conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin-desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity.
Highlights
Diabetes, which is characterized by chronic hyperglycaemia, occurs either by developing insulin resistance and/or by beta-cell failure
Cardiotrophin-1 (CT-1) is a member of the interleukin-6 (IL-6) family of cytokines with a molecular mass of 21.5 kDa, which interacts with the glycoprotein 130/leukaemia inhibitory factor receptor (LIFR) heterodimer [4]
Genotyping of CTF1 tagging single nucleotide polymorphisms (SNPs) The 1,771 study participants were genotyped for the SNPs rs1046276, rs1458201, and rs8046707 covering all common genetic variation in the CTF1 gene locus with minor allele frequencies (MAFs) $0.05 (Figure 1)
Summary
Diabetes, which is characterized by chronic hyperglycaemia, occurs either by developing insulin resistance and/or by beta-cell failure. Possible trigger for both are cytokines, which may be produced by the liver (hepatokines), skeletal muscle (myokines), or adipose tissue (adipokines). Recombinant CT-1 treatment corrected insulin resistance and reduced adiposity in ob/ob and high-fat diet (HFD) receiving mice, pointing to a key regulatory role of CT-1 in glucose and lipid metabolism [6]. Beside regenerative and anti-apoptotic functions in several tissues, e.g. motoneurons and hepatocytes [7,8], in a recent study, CT-1 was reported to protect beta cells from apoptosis and to enhance glucose-stimulated insulin secretion, and to prevent streptozotocin-induced diabetes in a mouse model [9]
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