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Impaired Gene and Protein Expression of Exocytotic Soluble N-Ethylmaleimide Attachment Protein Receptor Complex Proteins in Pancreatic Islets of Type 2 Diabetic Patients

¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
² Departments of Medicine and Physiology, University of Toronto, Toronto, Canada
³ Department of Transplantation Surgery, Karolinska Institutet, Stockholm, Sweden
⁴ Department of Neuropharmacology, Scripps Research Institute, La Jolla, California

Address correspondence and reprint requests to Claes-Goran Ostenson, MD, PhD, Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: claes-goran.ostenson{at}karolinska.se

Key Words: GABA, -aminobutyric acid • GLP-1, glucagon-like peptide 1 • IRS-2, insulin receptor substrate-2 • Kir6.2, inwardly rectifying K⁺-channel protein • PDX-1, pancreatic duodenal homeobox-1 • SNARE, soluble N-ethylmaleimide attachment protein receptor • SUR1, sulfonylurea receptor 1

Exocytosis of insulin is dependent on the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins in the B-cells. We assessed insulin release as well as gene and protein expression of SNARE complex protein in isolated pancreatic islets of type 2 diabetic patients (n = 4) and nondiabetic control subjects (n = 4). In islets from the diabetic patients, insulin responses to 8.3 and 16.7 mmol/l glucose were markedly reduced compared with control islets (4.7 ± 0.3 and 8.4 ± 1.8 vs. 17.5 ± 0.1 and 24.3 ± 1.2 µU · islet^–1 · h^–1, respectively; P < 0.001). Western blot analysis revealed decreased amounts of islet SNARE complex and SNARE-modulating proteins in diabetes: syntaxin-1A (21 ± 5% of control levels), SNAP-25 (12 ± 4%), VAMP-2 (7 ± 4%), nSec1 (Munc 18; 34 ± 13%), Munc 13-1 (27 ± 4%), and synaptophysin (64 ± 7%). Microarray gene chip analysis, confirmed by quantitative PCR, showed that gene expression was decreased in diabetes islets: syntaxin-1A (27 ± 2% of control levels), SNAP-25 (31 ± 7%), VAMP-2 (18 ± 3%), nSec1 (27 ± 5%), synaptotagmin V (24 ± 2%), and synaptophysin (12 ± 2%). In conclusion, these data support the view that decreased islet RNA and protein expression of SNARE and SNARE-modulating proteins plays a role in impaired insulin secretion in type 2 diabetic patients. It remains unclear, however, to which extent this defect is primary or secondary to, e.g., glucotoxicity.

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