Objective: Functional voltage-gated calcium channels of the L-type are essential triggers for insulin secretion in rodents but little is known about the role in the human beta-cell. We here set out to determine the role of the L-type channel subtype Ca_v1.3 (encoded by CACNA1D) for human insulin secretion. Methods: Gene expression in human islets: Total RNA was isolated from pancreatic islet donors from 45 non-diabetics (24 males, 21 females, age=5610, BMI=263) using the AllPrep DNA/RNA Mini Kit (Qiagen) and analyzed using Gene 1.0 ST whole transcript based assays. Genetic studies: DNA from the Diabetic Genetics Initiative was analysed with the Affymetrix Human Mapping 500K GeneChip® in order to identify single nucleotide polymorphisms. Six candidate SNPs were verified in 766 non-diabetics (358 males, 408 females, age=4913, BMI=254) from the Botnia study by genotyping using Taqman allelic discrimination assays and common variants were detected by ABI PRISM 7900. Phenotypes were assessed with oral (OGTT) or intravenous (IVGTT) glucose tolerance tests. Results: The SNP rs6763768 associated significantly with inappropriate glucose levels after 2 and 4 minutes (IVGTT, p=0.015 and 0.018 respectively) as well as with reduced insulin concentrations after 60 minutes (p=0.035). Microarray data revealed this SNP to correlate also with reduced mRNA expression in minor allele carriers. The marker rs10490772 associated with elevated glucose after 8 and 10 minutes (IVGTT, p=0.006 and 0.01) and rs312480 affected fasting, 10 and 30 minute (during challenge) insulin levels (IVGTT, p=0.04, 0.03 and 0.02). Marker rs17309406 correlated with reduced insulin levels after 120 minutes (OGTT, p=0.03). Furthermore, the expression of the Cav1.2 and 1.3 subtypes are strongly correlating with each other (R=0.795, p=1.6*10^-11). Conclusion: Common variants of CACNA1D affect gene expression of the channel in islets and associate with inappropriate insulin release.