Böhm, A. ; Ordelheide, A.-M. ; Machann, J. ; Heni, M.* ; Ketterer, C.* ; Machicao, F. ; Schick, F. ; Stefan, N. ; Fritsche, A. ; Häring, H.-U. ; Staiger, H.
     
 
    
        
Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.
    
    
        
    
    
        
        PLoS ONE 7:e34035 (2012)
    
    
    
		
		
			
				Objective: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. Subjects/Methods: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency >= 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). Results: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). Conclusion: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.
			
			
				
			
		 
		
			
				
					
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        Publikationstyp
        Artikel: Journalartikel
    
 
    
        Dokumenttyp
        Wissenschaftlicher Artikel
    
 
    
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        Herausgeber
        
    
    
        Schlagwörter
        EPITHELIUM-DERIVED FACTOR; NEUROTROPHIC ACTIVITY; FAT; IDENTIFICATION; RECEPTOR; GLUCOSE; LIPASE; PEDF; MASS
    
 
    
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        Sprache
        englisch
    
 
    
        Veröffentlichungsjahr
        2012
    
 
    
        Prepublished im Jahr 
        
    
 
    
        HGF-Berichtsjahr
        2012
    
 
    
    
        ISSN (print) / ISBN
        1932-6203
    
 
    
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	    Band: 7,  
	    Heft: 3,  
	    Seiten: ,  
	    Artikelnummer: e34035 
	    Supplement: ,  
	
    
 
  
        
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            Verlag
            Public Library of Science (PLoS)
        
 
        
            Verlagsort
            Lawrence, Kan.
        
 
	
        
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        Begutachtungsstatus
        Peer reviewed
    
 
     
    
        POF Topic(s)
        90000 - German Center for Diabetes Research
    
 
    
        Forschungsfeld(er)
        Helmholtz Diabetes Center
Genetics and Epidemiology
    
 
    
        PSP-Element(e)
        G-502400-001
G-502400-002
G-501900-065
    
 
    
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        Erfassungsdatum
        2012-07-23