A nucleotide variation in the proinsulin gene is located at the C-peptide-A-chain junction (C65, causes Arg to His), and the His65 substitution prevents processing of the dibasic cleavage site, resulting in hyperproinsulinemia that is caused by the accumulation of a circulating, biologically defective form of the proinsulin intermediate peptide, which fails to be metabolized via receptor-mediated endocytosis (35). This evidence concerns the gene INS and hyperproinsulinemia.