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Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance

Genes & Immunity volume 7, pages 316–321 (2006)Cite this article

Abstract

Type II diabetes is caused by a failure of the pancreatic β-cells to compensate for insulin resistance leading to hyperglycaemia. There is evidence for an essential role of an increased β-cell apoptosis in type II diabetes. High glucose concentrations induce IL-1β production in human β-cells, Fas expression and concomitant apoptosis owing to a constitutive expression of FasL. FASL and FAS map to loci linked to type II diabetes and estimates of insulin resistance, respectively. We have tested two functional promoter polymorphisms, FAS-670 G>A and FASL-844C>T as well as a microsatellite in the 3′ UTR of FASL for association to type II diabetes in 549 type II diabetic patients and 525 normal-glucose-tolerant (NGT) control subjects. Furthermore, we have tested these polymorphisms for association to estimates of β-cell function and insulin resistance in NGT subjects. We found significant association to type II diabetes for the allele distribution of the FASL microsatellite (P-value 0.02, Bonferroni corrected). The FAS-670G>A was associated with homeostasis model assessment insulin resistance index and body mass index (P-values 0.02 and 0.02). We conclude that polymorphisms of FASL and FAS associate with type II diabetes and estimates of insulin resistance in Danish white subjects.

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Abbreviations

AP-1:

activation protein-1

ASK-1:

apoptosis signal-regulating kinase 1

BMI:

body mass index

DISC:

death-inducing signalling complex

EBPβ:

enhancer-binding protein beta element

FLIP:

FLICE (caspase-8) inhibitory protein

HOMA:

homeostasis model assessment

IR1:

fasting-insulin/fasting-glucose ratio

IRS-1:

insulin receptor substrate 1

JNK:

c-Jun N-terminal kinase

MAPK:

mitogen-activated protein kinase

NGT:

normal-glucose-tolerant

OGTT:

oral glucose tolerance test

STAT:

signal transducer and activator of transcription

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Acknowledgements

We thank Marja Deckert, Anette Hellgren, Annemette Forman, Lene Aabo, Marianne Stendal and Inge Lise Wantzin for dedicated and careful technical assistance and Karen Rahbek Kruse and Grete Lademann for secretarial support. The study was supported by grants from the Danish Medical Research Council, the Danish Diabetes Association and the European Union (EUGENE2, LSHM-CT-2004-512013).

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Authors and Affiliations

  1. Steno Diabetes Center, Niels Steensensvej 2, Gentofte, Denmark

    R L Nolsøe, Y H Hamid, F Pociot, S Paulsen, K M Andersen, K Borch-Johnsen, T Hansen, O Pedersen & T Mandrup-Poulsen

  2. Research Centre for Prevention and Health, Copenhagen County, Glostrup University Hospital, Glostrup, Denmark

    T Drivsholm

  3. Institute for Clinical Sciences, University of Lund, Sweden

    F Pociot

  4. Faculty of Health Science, University of Aarhus, Aarhus, Denmark

    O Pedersen

  5. Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden

    T Mandrup-Poulsen

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  1. R L Nolsøe
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Correspondence to T Mandrup-Poulsen.

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Nolsøe, R., Hamid, Y., Pociot, F. et al. Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance. Genes Immun 7, 316–321 (2006). https://doi.org/10.1038/sj.gene.6364300

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