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.
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Karin
K
Åvall
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637 553;
Yusuf
Y
Ali
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Ingo B
IB
Leibiger
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Barbara
B
Leibiger
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Tilo
T
Moede
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Meike
M
Paschen
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Andrea
A
Dicker
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Elisabetta
E
Daré
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Martin
M
Köhler
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Erwin
E
Ilegems
Diabetes Research Institute, Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136;
Midhat H
MH
Abdulreda
Isis Pharmaceuticals, Carlsbad, CA 92010; and.
Mark
M
Graham
Isis Pharmaceuticals, Carlsbad, CA 92010; and.
Rosanne M
RM
Crooke
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637 553;
Vanessa S Y
VS
Tay
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Essam
E
Refai
Department of Medical Biosciences, Unit of Physiological Chemistry 6M, Umeå University, SE-901 85 Umeå, Sweden.
Stefan K
SK
Nilsson
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Stefan
S
Jacob
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden;
Lars
L
Selander
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637 553; Diabetes Research Institute, Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136; lisa.juntti-berggren@ki.se Per-Olof.Berggren@ki.se.
Per-Olof
PO
Berggren
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden; lisa.juntti-berggren@ki.se Per-Olof.Berggren@ki.se.
Lisa
L
Juntti-Berggren
D000704:Analysis of Variance; D000818:Animals; D053305:Apolipoprotein C-III / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D053305:Apolipoprotein C-III; D002118:Calcium
apoCIII; diabetes; insulin resistance; pancreatic islets