Apolipoprotein CIII and Ljungan virus in diabetes

Abstract: It has been shown that there are patients with type 1 diabetes (T1D), whose sera induce an increased activity of voltage-gated Ca2+-channels in pancreatic beta-cells, resulting in increased cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Purification of the protein in the active fraction of T1D sera revealed that the observed effects were mediated by apolipoprotein CIII (apoCIII), and this protein was shown to be increased in serum from T1D patients. To be able to evaluate the importance of apoCIII in vivo for the development of T1D there is a need for a suitable animal model. We used the animal model diabetes-prone BB rat (DPBB) that spontaneously, at the age of around 60 days, develops a human-like T1D. Isolated islet cells cultured overnight in the presence of 10% sera from 60 days old prediabetic BB rats had a higher increase in [Ca2+]i upon depolarization with K+, an impaired glucose-induced insulin secretion and a decreased viability, compared to cells exposed to age-matched control sera. The prediabetic sera with this effect are referred to as positive (pos). The effect on [Ca2+]i was abolished when an antibody against apoCIII was present during culture. The relative amounts of apoCIII in pos, neg and control sera from 60 days old rats were evaluated and the content in pos sera was significantly higher. To investigate the effects of apoCIII in vivo, DPBB rats were treated with either active or inactive antisense against apoCIII between the age of 12 to 40 days. The apoCIII antisense treatment significantly delayed the onset of diabetes. Wild bank voles (Myodes glareolus) develop T1D and a picornavirus, named Ljungan virus (LV), has been isolated from these animals. If CD-1 mice, that normally do not carry LV, are infected with this virus in utero and exposed to stress after birth, the male offspring get type 2 diabetes. In BB rats LV was found in both prediabetic- and diabetic DPBB rats, as well as in diabetes-resistant rats. To evaluate if the presence of virus influences the onset of T1D, prediabetic rats were given antiviral treatments, which prolonged the prediabetic phase with approximately one week. The interplay between LV and diabetes is complicated and still not understood, and our data does not exclude a role of this virus in the development of diabetes.