The voltage-dependent L-type calcium channel (L-VDCC) plays an essential role in regulating insulin secretion in pancreatic β-cell. Excessive calcium signaling due to metabolic stress has been reported to cause β-cell dysfunction and cell death. Therefore, the fine-tuning of calcium signaling is critical for the homeostatic regulation of insulin secretion. Dyslipidemia in type 2 diabetes is known to impair insulin secretion. However, the underlying mechanism has not been fully elucidated so far. In the present study, we focused on the relationship between calcium signaling and lipotoxicity to elucidate the molecular mechanism of insulin secretory failure. Protein expression of L-VDCC α₁ subunit Ca_V1.2 in pancreatic β-cell line MIN6 was detected by flowcytometry and western blotting. When MIN6 cells were cultured in the presence of certain fatty acids, the protein expression level of Ca_V1.2 was significantly reduced. We confirmed that there was no change in the gene expression level of Ca_V1.2. The fatty acid-induced reduction of Ca_V1.2 protein was blunted by MG132, a proteasome inhibitor, suggesting that fatty acid promoted the degradation of Ca_V1.2. These results indicate that a novel lipotoxic mechanism in degrading L-VDCC Ca_V1.2 may be involved in dyslipidemia-induced insulin secretory failure.