"Imaging Diabetes" - 3D molecular imaging of β-cell mass and function
366 million people suffered from diabetes in 2011, resulting in health care expenditures corresponding to 11% of the world’s health care costs. The number of people with diabetes is expected to reach 552 million people by 2030 and related healthcare costs may rise to 40% of the total healthcare budget in high incidence countries (Source: International Diabetes Federation). Despite these daunting numbers, our knowledge about the pathophysiology of diabetes type 1 and 2 remains limited and many questions about the relation of the β-cell mass, β-cell function and the metabolism of different tissues remain unanswered, largely due to insufficient technology.
In our research we combine new techniques for biomedical imaging with classic molecular genetics approaches to study the mechanisms underlying pancreas development and diabetes. In particular, we are working with a mesoscopic imaging platform, optical projection tomography (OPT) (Sharpe et al., Science 2002), to study how the insulin producing cells of the pancreas (the β-cells) are affected during the development of diabetes. These cells are together with other hormone producing cell types organized into the islets of Langerhans, thousands of which are scattered throughout the much greater exocrine tissue. Employing traditional techniques, attempts to calculate e.g. the pancreatic β-cell content has proven to be a great challenge. We have by a series of developments adapted the OPT technique to allow for 3D modeling and quantification of the intact adult pancreas in rodent models for the disease. Hereby the impact of diabetes disease progression on β-cell mass distribution (or other cell types) may be assessed throughout the volume of the entire gland and down to level of the individual islets (see e.g. Alanentalo et al., Nature Methods 2007 and Diabetes 2010, and Hörnblad et al., Islets 2011).
Another major research undertaking in our lab is to exploit the OPT technique as a tool in the development of contrast agents intended for non-invasive imaging of β-cell mass and/or function by nuclear molecular imaging (NMI) techniques (such as MRI and SPECT). Today we largely depend on indirect means for such assessments. Innovative enabling techniques to non-invasively characterize BCM and/or islet/β-cell function in the course of diabetes are hence in demand and would have a tremendous impact on avenues to study diabetes aetiology in experimental models and in clinical environments. By an adaptation of the OPT technique to enable imaging also in the near infrared spectrum (NIR-OPT) we have recently increased the multichannel capacity (and penetration depth) of OPT for assessments of the pancreas (Eriksson et al., J Vis Exp 2013). By this capacity, NIR-OPT has been recognized by the EU FP7 consortia “In Vivo Imaging of Beta-cell Receptors by Applied Nanotechnology” (VIBRANT) and the Marie Curie ITN European “Training Network for Excellence in Molecular Imaging in Diabetes” (BetaTrain) as the “gold standard” to evaluate new experimental imaging probes by virtue of its capacity to evaluate the up-take specificity of such probes and to cross- calibrate the non-invasive read out. We are currently running a number of projects on this line in which the developed imaging platform plays a central role.
OPT based iso-surface reconstructions of adult mouse pancreas (splenic lobe) from a type 1 diabetic animal (left, Non Obese Diabetic), a healthy control animal (centre) and from a model system for obesity and insulin resistance (ob/ob, right). The islet β-cell volumes (red) are reconstructed based on the signal from insulin specific antibodies. Note the variations in β-cell mass distribution. The specimens are ~1.4 x 0.7 cm.
Our research is/was funded by:
The Swedish Research Council, The Juvenile Diabetes Foundation, The Kempe Foundations, Umeå University, Diabetesfonden, NovoNordisk, The diabetes Wellness foundation, Barndiabetesfonden and the European Union (FP7).