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Research Article

Lowering apolipoprotein CIII delays onset of type 1 diabetes

Rebecka Holmberg, Essam Refai, Anders Höög, Rosanne M. Crooke, Mark Graham, Gunilla Olivecrona, Per-Olof Berggren, and Lisa Juntti-Berggren
  1. aThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
  2. bDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
  3. cDepartment of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden;
  4. dAntisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA 92008; and
  5. eDepartment of Medical Biosciences and Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden

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PNAS June 28, 2011 108 (26) 10685-10689; https://doi.org/10.1073/pnas.1019553108
Rebecka Holmberg
aThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
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Essam Refai
aThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
bDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
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Anders Höög
cDepartment of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden;
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Rosanne M. Crooke
dAntisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA 92008; and
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Mark Graham
dAntisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA 92008; and
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Gunilla Olivecrona
eDepartment of Medical Biosciences and Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden
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Per-Olof Berggren
aThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
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Lisa Juntti-Berggren
aThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
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  • For correspondence: lisa.juntti-berggren@ki.se
  1. Edited* by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 19, 2011 (received for review December 29, 2010)

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Abstract

Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.

  • BB rat model
  • cytoplasmic free Ca2+ concentration
  • insulin release
  • β-cell destruction
  • diabetes onset

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: lisa.juntti-berggren{at}ki.se.
  • Author contributions: R.H., P.-O.B., and L.J.-B. designed research; R.H., E.R., and L.J.-B. performed research; R.M.C., M.G., and G.O. contributed new reagents/analytic tools; R.H., E.R., A.H., and L.J.-B. analyzed data; and P.-O.B. L.J.-B. wrote the paper.

  • Conflict of interest statement: P.-O.B. is a co-founder of Biocrine, a company that is developing apoCIII as a target for the treatment of type 1 diabetes and its complications. R.M.C. and M.G. are affiliated with ISIS, a company whose main focus is to develop antisense treatment strategies for various diseases.

  • ↵*This Direct Submission article had a prearranged editor.

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Lowering apolipoprotein CIII delays onset of type 1 diabetes
Rebecka Holmberg, Essam Refai, Anders Höög, Rosanne M. Crooke, Mark Graham, Gunilla Olivecrona, Per-Olof Berggren, Lisa Juntti-Berggren
Proceedings of the National Academy of Sciences Jun 2011, 108 (26) 10685-10689; DOI: 10.1073/pnas.1019553108

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Lowering apolipoprotein CIII delays onset of type 1 diabetes
Rebecka Holmberg, Essam Refai, Anders Höög, Rosanne M. Crooke, Mark Graham, Gunilla Olivecrona, Per-Olof Berggren, Lisa Juntti-Berggren
Proceedings of the National Academy of Sciences Jun 2011, 108 (26) 10685-10689; DOI: 10.1073/pnas.1019553108
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Proceedings of the National Academy of Sciences: 108 (26)
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