Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion.
OBJECTIVE
Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion.


METHODS
We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion.


RESULTS
In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p<0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p<0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p>0.6).


CONCLUSIONS
Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.
Kirchhoff
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Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Eberhard-Karls-Universität Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
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D000328:Adult; D019540:Area Under Curve; D002096:C-Peptide / Q000097:blood; D027682:Cation Transport Proteins / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D005858:Germany; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000378:metabolism / Q000502:physiology*; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases
D002096:C-Peptide; D027682:Cation Transport Proteins; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D011384:Proinsulin; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human