Abstract
Objective: To analyze the correlation between insulin requirements of type 1 diabetic (T1D) patients and genotype at type 2 diabetes (T2D) risk loci, obtained in our genome-wide association study. Methods: From a database of detailed insulin dosing of 567 patients, we selected 177 for whom we also had genome-wide genotyping data. Using PLINK software, we examined the association between insulin requirement as a quantitative trait and nineteen T2D risk loci. Results: Out of 19 single-nucleotide polymorphisms (SNPs), rs13266634 on chromosome 8 and rs7901695 on chromosome 10 showed nominal significance of association (p < 0.05). The first SNP is nonsynonymous (325 Arg>Trp) and maps to the SLC30A8 gene encoding the β-cell-specific ZnT8 zinc transporter, while the second is an intronic SNP in TCF7L2, the strongest known T2D association. Both loci exert their effect on β-cells and, in both, the T2D risk allele is associated with lower insulin requirements. Conclusion: We identified two T2D susceptibility loci that modulate insulin requirements in T1D patients. Our results are consistent with the association of lower insulin secretion with higher insulin sensitivity. To explain the continuation of this correlation after β-cell destruction, we hypothesize an epigenetic mechanism that alters insulin responsiveness in T1D patients based on β-cell function in early life. Such knowledge may allow a more precise approach to treatment.
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