Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes.
Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca(2+)]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
['Åvall|Karin|K|', 'Ali|Yusuf|Y|', 'Leibiger|Ingo B|IB|', 'Leibiger|Barbara|B|', 'Moede|Tilo|T|', 'Paschen|Meike|M|', 'Dicker|Andrea|A|', 'Daré|Elisabetta|E|', 'Köhler|Martin|M|', 'Ilegems|Erwin|E|', 'Abdulreda|Midhat H|MH|', 'Graham|Mark|M|', 'Crooke|Rosanne M|RM|', 'Tay|Vanessa S Y|VS|', 'Refai|Essam|E|', 'Nilsson|Stefan K|SK|', 'Jacob|Stefan|S|', 'Selander|Lars|L|', 'Berggren|Per-Olof|PO|', 'Juntti-Berggren|Lisa|L|']
D000704:Analysis of Variance D000818:Animals D053305:Apolipoprotein C-III D015153:Blotting, Western D002118:Calcium D045744:Cell Line, Tumor D003924:Diabetes Mellitus, Type 2 D007150:Immunohistochemistry D007333:Insulin Resistance D050417:Insulin-Secreting Cells D051379:Mice D018345:Mice, Knockout D018613:Microscopy, Confocal D008928:Mitochondria D060888:Real-Time Polymerase Chain Reaction
insulin resistance diabetes apoCIII pancreatic islets