Abstract
It has been recognized that the exposure of β-cells to sustained hyperglycemia results in the impaired secretion of insulin to acute glucose challenge in both non-insulin dependent diabetic patients and experimental animals. To clarify the mechanisms of glucose induced “desensitization” of β-cells, we tried to establish an in vitro system using cultured islets. A time course study revealed that desensitization occurred when the islets were cultured for 48 hr in 3mg/ml glucose. In perfusion experiments, islets previously cultured in 3mg/ml glucose for 5 days were stimulated for 1 hr by 3 mg/ml glucose, 10mM theophylline, 10mM arginine, 150 /dem/ tolbutamide, 1 μM A 23187 or 200ng/ml phorbol 12-myristate 13-acetate. The amount of insulin released in response to 3mg/ml glucose showed a marked decrease in both the first (1-20 min) and the second (21-60 min) phases, however, these desensitized islets preserved their secretory response to secretagogues other than high glucose. The reversibility of impaired insulin secretion by high glucose was confirmed functionally and morphologically, when the desensitized islets were subsequently cultured for 2 days in 1mg/ml glucose. Our system is of use in pursuing the mechanisms of glucose induced desensitization of insulin secretion from β-cells.
