FOXC2 and CAPN10 as candidate genes for obesity, insulin resistance and type 2 diabetes

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The worldwide prevalence of obesity and type 2 diabetes is increasing rapidly. Both disorders depend on genetic and environmental factors. The studies included in this thesis investigated the possible association of the FOXC2 and CAPN10 genes with obesity, insulin resistance, type 2 diabetes, and related phenotypes. FOXC2 encodes a forkhead transcription factor, which was identified as a key regulator of adipocyte metabolism in mice overexpressing FOXC2 in adipose tissue. The exact function of FOXC2 in humans remains unknown. FOXC2 mRNA levels in both visceral fat and skeletal muscle correlated with measures of insulin sensitivity and FOXC2 mRNA expression was significantly higher in visceral compared to subcutaneous fat in humans. FOXC2 mRNA levels were upregulated in response to insulin in cultured human adipocytes. A common variant in the 5' untranslated region of the gene (C-512T) was identified. The C-allele was associated with higher triglyceride levels and higher HOMA-IR indeces in female sibling pairs as well as with obesity, and the Metabolic Syndrome in males. However, no association was found between this polymorphism and type 2 diabetes. CAPN10, encoding the cysteine protease calpain-10, was the first type 2 diabetes susceptibility gene discovered by a genome-wide scan and positional cloning. We found that CAPN10 mRNA expression is a heritable trait. Furthermore, a polymorphism in the gene (SNP-43) was associated with reduced CAPN10 mRNA levels in both subcutaneous fat and skeletal muscle. Subjects with normal glucose tolerance, but not subjects with impaired glucose tolerance, upregulated CAPN10 mRNA levels in response to fat during a hyperinsulinemic euglycemic clamp. These results suggest that the C-allele at FOXC2 C-512T and low FOXC2 mRNA expression predispose individuals to obesity and insulin resistance but not to type 2 diabetes. CAPN10 mRNA expression is a heritable trait and influenced by variation at SNP-43. Although CAPN10 SNP-43 is not associated with obesity, low CAPN10 mRNA expression, or inability to upregulate CAPN10 mRNA levels in response to elevated FFA and insulin, may predispose towards insulin resistance and type 2 diabetes.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Clinical Sciences, Malmö
Supervisors/Advisors
  • Ridderstråle, Martin, Supervisor
  • Groop, Leif, Supervisor
Award date2005 Apr 29
Publisher
Print ISBNs91-85439-30-4
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-04-29
Time: 09:15
Place: The Department of Pathology, Entrance 78, Malmö University Hospital

External reviewer(s)

Name: Zierath, Juleen
Title: Professor
Affiliation: Karolinska Institute, Stockholm

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<div class="article_info">Martin Ridderstråle, Emma Carlsson, Mia Klannemark, Anna Cederberg, Christina Kösters, Hans Tornqvist, Heidi Storgaard, Allan Vaag, Sven Enerbäck and Leif Groop. <span class="article_issue_date">2002</span>. <span class="article_title">FOXC2 mRNA expression and a 5’ untranslated region polymorphism of the gene are associated with insulin resistance.</span> <span class="journal_series_title">Diabetes</span>, <span class="journal_volume">vol 51</span> <span class="journal_pages">pp 3554-3560</span>.</div>
<div class="article_info">Emma Carlsson, Peter Almgren, Johan Hoffstedt, Leif Groop and Martin Ridderstråle. <span class="article_issue_date">2004</span>. <span class="article_title">The FOXC2 C-512T polymorphism is associated with obesity and dyslipidemia.</span> <span class="journal_series_title">Obesity Research</span>, <span class="journal_volume">vol 12</span> <span class="journal_pages">pp 1738-1743</span>.</div>
<div class="article_info">Emma Carlsson, Leif Groop and Martin Ridderstråle. <span class="article_issue_date">2005</span>. <span class="article_title">Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome.</span> <span class="journal_series_title">International Journal of Obesity</span>, <span class="journal_volume">vol 29</span> <span class="journal_pages">pp 268-274</span>.</div>
<div class="article_info">Emma Carlsson, Jenny Fredriksson, Leif Groop and Martin Ridderstråle. <span class="article_issue_date">2004</span>. <span class="article_title">Variation in the calpain-10 gene is associated with elevated triglyceride levels and reduced adipose tissue messenger ribonucleic acid expression in obese Swedish subjects.</span> <span class="journal_series_title">The Journal of Clinical Endocrinology & Metabolism</span>, <span class="journal_volume">vol 89</span> <span class="journal_pages">pp 3601-3605</span>.</div>
<div class="article_info">Emma Carlsson, Pernille Poulsen, Heidi Storgaard, Peter Almgren, Charlotte Ling, Christine Bjørn Jensen, Sten Madsbad, Leif Groop, Allan Vaag and Martin Ridderstråle. <span class="article_issue_date"></span>. <span class="article_title">Genetic and non-genetic regulation of CAPN10 mRNA expression in skeletal muscle.</span> (submitted)</div>

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Keywords

  • Biomedicinska vetenskaper
  • Biomedical sciences
  • Type 2 diabetes
  • Genetics
  • Obesity

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