Serum proteins in type 1 diabetes (2007)

&lt;p&gt;We have previously shown that there are patients with type 1 diabetes T1D whose sera interfere with cytoplasmic free Ca2+-concentration ([Ca2+]i), resulting in â-cell apoptosis. In this study the frequency of sera, that induces this effect, was found to be around 35% in T1D patients, and 25% in first degree relatives (FDR) of T1D patients. The effect occurred in subjects of different gender, age and ethnicity, and was not related to the presence of autoantibodies. Hence, in a defined subgroup of patients with T1D and FDR a defect Ca2+-handling may aggravate the autoimmune response and thereby the development of â-cell destruction, and it might be possible to interfere early on with Ca2+-induced â-cell apoptosis.&lt;/p&gt;&lt;p&gt;Purification and fractionation of T1D sera, that affected [Ca2+]i, revealed that the protein that gave a higher increase in [Ca2+]i upon depolarization, was apolipoprotein CIII (apoCIII). ApoCIII increases the activity of voltage-gated Ca2+-channels. A proof for apoCIII being the responsible serum component was that the addition of an antibody against apoCIII abolished, not only the effects of apoCIII on [Ca2+]i and cell death, but most importantly the effects of T1D sera itself on â-cell function and survival.&lt;/p&gt;&lt;p&gt;During the procedure to purify the serum factor, we observed a band at 14 kDa on SDS/PAGE that was stronger in T1D than control sera. The protein in the band was identified by sequence analysis to be the monomeric form of transthyretin (TTR). TTR is a transport protein and exists mainly as a tetramer in sera from healthy individuals. In T1D sera the concentration of TTR was decreased, whereas the concentration of the monomer was increased. Physiological concentrations of the tetrameric form of TTR was shown to affect the â-cell stimulus-secretion coupling, promoting glucose-induced increases in [Ca2+]i and insulin release, which resulted from a direct effect on glucoseinduced electrical activity and voltage-gated Ca2+-channels. The tetrameric form of TTR also protected against apoCIII induced â-cell death. The monomer was without effect on glucose-stimulated insulin release and â-cell death. Therefore, conversion of TTR tetramer to monomer may be involved in the development of â-cell failure in T1D.&lt;/p&gt;&lt;p&gt;TTR was shown to bind to glucose regulated proteins (Grp), 78, 94 and 170 in both the membrane and cytosolic fractions of islet cell homogenates, and was internalized into the â-cell via a clathrin-dependent pathway, indicating the involvement of receptormediated endocytosis. The Grp complex of Grp78, 94 and 170 may serve as a plasma membrane protein responsible for the binding and uptake of TTR into the â-cell. These data may suggest that the effects of TTR on â-cell function and survival are due to intracellular effects of the protein.&lt;/p&gt;&lt;p&gt;In conclusion, there is a group of patients with T1D and FDR that have sera that affects [Ca2+]i and â-cell survival. The serum factor responsible for these effects was identified to be apoCIII, which is increased in T1D sera. The concentration of TTR tetramer is decreased, whereas that of the TTR monomer is increased in T1D sera. The tetrameric form of TTR was shown to have a positive role in the â-cell stimulussecretion coupling. These data support the possibility to develop a diagnostic test to identify individuals at risk to be subjected to Ca2+-induced â-cell damage and thereby aggravation of the autoimmune response in T1D.&lt;/p&gt;&lt;h3&gt;List of scientific papers&lt;/h3&gt;&lt;p&gt;I. Dekki N, Nilsson R, Norgren S, Rössner SM, Appelskog I, Marcus C, Simell O, Pugliese A, Alejandro R, Ricordi C, Berggren PO, Juntti-Berggren L (2006). "Defect pancreatic â-cell Ca2+-handling after exposure to serum from type 1 diabetic patients and first-degree relatives." (Submitted)&lt;/p&gt;&lt;p&gt;II. Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, Uhles S, Yu L, Griffiths WJ, Zaitsev S, Leibiger I, Yang SN, Olivecrona G, Jornvall H, Berggren PO. (2004). "Apolipoprotein CIII promotes Ca2+-dependent beta cell death in type 1 diabetes." Proc Natl Acad Sci U S A 101(27): 10090-4 &lt;br&gt;&lt;a href="https://pubmed.ncbi.nlm.nih.gov/15210953"&gt;https://pubmed.ncbi.nlm.nih.gov/15210953&lt;/a&gt;&lt;br&gt;&lt;br&gt;&lt;/p&gt;&lt;p&gt;III. Refai E, Dekki N, Yang SN, Imreh G, Cabrera O, Yu L, Yang G, Norgren S, Rossner SM, Inverardi L, Ricordi C, Olivecrona G, Andersson M, Jornvall H, Berggren PO, Juntti-Berggren L. (1970). "Transthyretin constitutes a functional component in pancreatic beta-cell stimulus-secretion coupling." Proc Natl Acad Sci U S A 102(47): 17020-5 &lt;br&gt;&lt;a href="https://pubmed.ncbi.nlm.nih.gov/16286652"&gt;https://pubmed.ncbi.nlm.nih.gov/16286652&lt;/a&gt;&lt;br&gt;&lt;br&gt;&lt;/p&gt;&lt;p&gt;IV. Wenna N, Refai E, Shafqat J, Ishrat M, Jörnvall H, Berggren PO, Juntti-Berggren L. (2006). "Transthyretin binds to glucose regulated proteins and is endocytosed into the pancreatic â-cell." (Manuscript)&lt;/p&gt;