Functional rest through intensive treatment with insulin and potassium channel openers preserves residual beta-cell function and mass in acutely diabetic BB rats

Diazoxide and the diazoxide-analogue, NNC 55-0118, are potassium channel op eners that interfere with insulin secretion from beta-cells. In vitro, we s how that these two drugs inhibit insulin release from diabetes-resistant BE rat islets cultured at either low or high glucose concentration and cause an intracellular accumulation of insulin with high glucose. Preservation of beta-cells was investigated in newly diabetic BE rats treated with insulin implants from day 0-8 under oral diazoxide, NNC 55-0118 or solvent gavage once a day from day 0-7. Three of eight rats (37.5%) treated with diazoxide and three of ten (30%) treated with NNC 55-0118 retained near normal C-pep tide responses when challenged with glucose/arginine on day 9, whereas none of eight (0%) solvent-treated rats showed a C-peptide response. Immunohist ochemical staining for insulin and glucagon showed that all the C-peptide r esponding rats had insulin-positive cells in their islets. In contrast, isl ets from non-responding rats displayed marked inflammation or end-stage les ions. Furthermore, rats with C-peptide response and treated with NNC 55-011 8 exhibited only minimal signs of islet inflammation, whereas C-peptide res ponding diazoxide-treated rats had low level islet inflammation. These resu lts imply that it is conceivable to preserve residual beta-cells at diabete s onset by induction of target cell rest with potassium channel openers and continuous insulin treatment.