OBJECTIVE: Beta-site amyloid precursor protein cleaving enzyme (BACE1) is highly expressed in pancreatic β-cells. The BACE1 gene is located in a region associated with a high diabetes risk in PIMA Indians. DESIGN AND METHODS: INS-1E cells were used to study the impact of siRNA-mediated BACE1 knockdown and glucose metabolism was characterized in Bace1(-/-) mice. BACE1 gene was sequenced in DNA samples from 48 subjects and 13 representative single nucleotide polymorphisms (SNPs) were then genotyped for association studies in 1,527 Caucasians. RESULTS: Reduction of Bace1 expression results in a significant decrease in insulin mRNA expression in INS-1E cells. Bace1(-/-) mice display significantly lower body weight, lower plasma insulin concentrations, but normal glucose tolerance and insulin sensitivity. In a case-control study including 538 healthy controls and 989 patients with type 2 diabetes (T2D), one SNP (rs535860) was significantly associated with T2D (P < 3.5 × 10(-5) , adjusted for age, sex, and BMI). CONCLUSIONS: Reduced Bace1 expression causes impaired insulin expression in pancreatic β-cells of Bace1(-/-) mice, suggesting that BACE1 plays a role in the regulation of insulin biogenesis. The functionally relevant rs535860 SNP may decrease BACE1 expression by creating a new miR-661 binding site and could therefore contribute to T2D development.
OBJECTIVE: Beta-site amyloid precursor protein cleaving enzyme (BACE1) is highly expressed in pancreatic β-cells. The BACE1 gene is located in a region associated with a high diabetes risk in PIMA Indians. DESIGN AND METHODS: INS-1E cells were used to study the impact of siRNA-mediated BACE1 knockdown and glucose metabolism was characterized in Bace1(-/-) mice. BACE1 gene was sequenced in DNA samples from 48 subjects and 13 representative single nucleotide polymorphisms (SNPs) were then genotyped for association studies in 1,527 Caucasians. RESULTS: Reduction of Bace1 expression results in a significant decrease in insulin mRNA expression in INS-1E cells. Bace1(-/-) mice display significantly lower body weight, lower plasma insulin concentrations, but normal glucose tolerance and insulin sensitivity. In a case-control study including 538 healthy controls and 989 patients with type 2 diabetes (T2D), one SNP (rs535860) was significantly associated with T2D (P < 3.5 × 10(-5) , adjusted for age, sex, and BMI). CONCLUSIONS: Reduced Bace1 expression causes impaired insulin expression in pancreatic β-cells of Bace1(-/-) mice, suggesting that BACE1 plays a role in the regulation of insulin biogenesis. The functionally relevant rs535860 SNP may decrease BACE1 expression by creating a new miR-661 binding site and could therefore contribute to T2D development.