Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression. (5th July 2013)

• Record Type: Journal Article
• Authors: Hoffmeister, Albrecht; Tuennemann, Jan; Sommerer, Ines; Mössner, Joachim; Rittger, Andrea; Schleinitz, Dorit; Kratzsch, Jürgen; Rosendahl, Jonas; Klöting, Nora; Stahl, Tobias; Roßner, Steffen; Paroni, Federico; Maedler, Kathrin; Kovacs, Peter; Blüher, Matthias
• Is Part Of: Obesity. Volume 21:Number 12(2013:Dec.)
• Page Start: E626
• Page End: E633
• Publication Date: 2013-07-05
• Subjects: Obesity -- Periodicals; 616.398005
• DOI: 10.1002/oby.20482
• Languages: English
• ISSNs: 1930-7381

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="oby20482-sec-0001" sec-type="section"> <title>Objective</title> <p>Beta‐site amyloid precursor protein cleaving enzyme (BACE1) is highly expressed in pancreatic β‐cells. The <italic>BACE1</italic> gene is located in a region associated with a high diabetes risk in PIMA Indians.</p> </sec> <sec id="oby20482-sec-0002" sec-type="section"> <title>Design and Methods</title> <p>INS‐1E cells were used to study the impact of siRNA‐mediated <italic>BACE1</italic> knockdown and glucose metabolism was characterized in <italic>Bace1</italic><sup>–/–</sup> mice. <italic>BACE1</italic> 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.</p> </sec> <sec id="oby20482-sec-0003" sec-type="section"> <title>Results</title> <p>Reduction of <italic>Bace1</italic> expression results in a significant decrease in insulin mRNA expression in INS‐1E cells. <italic>Bace1</italic><sup>–/–</sup> 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 (<italic>P</italic> < 3.5 × 10<sup>−5</sup>, adjusted for age, sex, and BMI).</p> </sec> <sec id="oby20482-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Reduced <italic>Bace1</italic> expression causes impaired insulin expression in pancreatic β‐cells of <italic>Bace1</italic><sup>–/–</sup> 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.</p> </sec> </abstract>