Improved β-Cell Survival and Reduced Insulitis in a Type 1 Diabetic Rat Model After Treatment With a β-Cell–Selective KATP Channel Opener

Improved β-Cell Survival and Reduced Insulitis in a Type 1 Diabetic Rat Model After Treatment With a β-Cell–Selective K ATP Channel Opener Kresten Skak 1 , Carsten F. Gotfredsen 1 , Dorthe Lundsgaard 2 , John Bondo Hansen 3 , Jeppe Sturis 1 and Helle Markholst 2 1 Department of Pharmacology, Novo Nordisk A/S, Måløv, Denmark 2 Hagedorn Research Institute, Gentofte, Denmark 3 Department of Medicinal Chemistry, Novo Nordisk A/S, Måløv, Denmark Address correspondence and reprint requests to Helle Markholst, MD, Hagedorn Research Institute, Niels Steensens Vej 6, 2820 Gentofte, Denmark. E-mail: hmar{at}novonordisk.com Abstract Treatment with ATP-sensitive K + channel openers (KCOs) leads to inhibition of insulin secretion and metabolic “rest” in β-cells. It is hypothesized that in type 1 diabetes this may reduce β-cell death resulting from metabolic stress as well as reduce the immunogenicity of the β-cells during autoimmune β-cell destruction. We have investigated whether the β-cell−selective KCO compound, NN414, can be used to improve β-cell survival in DR-BB rats rendered diabetic by modulation of their immune system. The rats were treated three times daily on days 1–19 with NN414, diazoxide, or vehicle. On day 21, an intravenous glucose tolerance test was conducted to assess β-cell function. Postmortem histological analysis of rats’ pancreata assessed the degree of insulitis and β-cell volume. Among NN414-treated rats, 46% (16 of 35) were found to have a β-cell mass similar to that of nondiabetic controls and significant glucose-stimulated C-peptide values, whereas only 11% (4 of 36) of vehicle-treated rats possessed a normal β-cell mass and function ( P < 0.002, by χ 2 test). Furthermore, responsive NN414-treated rats were almost free of insulitis. Thus, this study demonstrated that treatment with KCO compounds can indeed lead to preservation of β-cell function and reduction of insulitis in a rat diabetes model. APC, antigen-presenting cell IVGTT, intravenous glucose tolerance test KATP, ATP-sensitive K+ channel KCO, KATP channel opener IL, interleukin poly(I:C), polyinosinic:polycytidylic acid Footnotes Accepted January 13, 2004. Received September 11, 2003. DIABETES