New knowledge about how type 2 diabetes develops
An international research team, led from Sweden’s Karolinska Institutet, have presented new knowledge about what happens when type 2 diabetes develops. By studying the insulin-producing beta cells in mice in real time, they have managed to identify a key part of the process that leads to the death of beta cells. The study is being published in the journal PNAS.
Type 2 diabetes is characterised by two main events in the body. At the initial stage the cells become insulin-resistant, i.e. insensitive to insulin. At the next stage, the insulin-producing beta cells, which are located in the islets of Langerhans in the pancreas, die. Exactly how the disease develops is still unknown, but investigators at Karolinska Institutet and colleagues from Singapore and the USA have added another piece of the jigsaw.
Ten years ago researchers at Karolinska Institutet discovered that blood levels of apolipoprotein CIII (apoCIII) become elevated in diabetes. This causes certain specific calcium channels in the beta cell wall to be overactivated which produces excessive calcium levels inside the beta cells. This has a toxic effect and results in beta cell death. However, the effect of apoCIII can be prevented by blocking the calcium channels.
In the study in question, researchers have used insulin-resistant mice with type 2 diabetes. Because of the disease, the mice had elevated levels of apoCIII in their blood. This apoCIII was mainly produced in the liver although the islets themselves could also produce apoCIII as a consequence of local islet insulin resistance.
Beta cell function and survival in real time
The researchers then used a self-developed technique to transplant islets of Langerhans to the anterior eye chamber – a technique that makes it possible to study beta cell function and survival in real time. Normal islets of Langerhans which produce apoCIII were transplanted to one eye while genetically modified, non-apoCIII-producing islets were transplanted to the other eye.
The researchers' main finding was that the beta cells reacted differently in each case. Despite the islets in both eyes being exposed to elevated levels of apoCIII circulating in the blood stream, only the apoCIII-producing islets showed an inflammatory reaction and, thereby, cell death. In the case of the genetically modified, non-apoCIII-producing islets, the beta cells survived.
“This shows that local production of apoCIII has damaging effects on beta cells. Circulating apoCIII had no direct damaging effect on the beta cell under type 2 diabetic conditions,” says Lisa Juntti-Berggren, chief physician and professor at the Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery at Karolinska Institutet.
Blocking the production of apoCIII locally
The researchers are currently proceeding with animal studies to investigate the possibilities of blocking the production of apoCIII locally in islets of Langerhans.
“Our goal is to develop a treatment strategy where you can prevent type 2 diabetes from developing in individuals with a high risk of the disease; people with insulin resistance, for example,” says Per-Olof Berggren, professor at the Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery at Karolinska Institutet.
The study in question is funded by the Swedish Diabetes Association, Karolinska Institutet, Swedish Research Council, Novo Nordisk Foundation, Knut and Alice Wallenberg Foundation, Skandia insurance company, Diabetes Wellness Foundation, Bert von Kantzow Foundation, The Family Erling-Persson Foundation, The Swedish Diabetes Foundation, Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grant, The Stichting af Jochnick Foundation and Diabetes Research Institute Foundation.
Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes
Karin Åvall, Yusuf Ali, Ingo B. Leibiger, Barbara Leibiger, Tilo Moede, Meike Paschen, Andrea Dicker, Elisabetta Daré, Martin Köhler, Erwin Ilegems, Midhat H. Abdulreda, Mark Graham, Rosanne M. Crooke, Vanessa S. Y. Tay, Essam Refai, Stefan K. Nilsson, Stefan Jacob, Lars Selander, Per-Olof Berggren and Lisa Juntti-Berggren
PNAS, 4 May 2015, doi: 10.1073/pnas.1423849112