Functional Rest Through Intensive Treatment with Insulin and Potassium Channel Openers Preserves Residual β-Cell Function and Mass in Acutely Diabetic BB Rats

Diazoxide and the diazoxide-analogue. NNC 55-0118, are potassium channel openers that interfere with insulin secretion from β-cells. In vitro, we show that these two drugs inhibit insulin release from diabetes-resistant BB rat islets cultured at either low or high glucose concentration and cause an intracellular accumulation of insulin with high glucose. Preservation of β-cells was investigated in newly diabetic BB 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-peptide responses when challenged with glucose/arginine on day 9, whereas none of eight (0%) solvent-treated rats showed a C-peptide response. Immunohistochemical staining for insulin and glucagon showed that all the C-peptide responding rats had insulin-positive cells in their islets. In contrast, islets from non-responding rats displayed marked inflammation or end-stage lesions. Furthermore, rats with C-peptide response and treated with NNC 55-0118 exhibited only minimal signs of islet inflammation, whereas C-peptide responding diazoxide-treated rats had low level islet inflammation. These results imply that it is conceivable to preserve residual β-cells at diabetes onset by induction of target cell rest with potassium channel openers and continuous insulin treatment.

Key words

Type I Diabetes - IDDM - Animal Models - Auto-immunity - Ion Channels - β-Cell Rest