Improved β-cell survival and reduced insulitis in a type 1 diabetic rat model after treatment with a β-cell-selective [K.sub.ATP] channel opener

Treatment with ATP-sensitive [K.sup.+] 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 [chi square] 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.