Metabolic, Ionic, and Secretory Response to D-Glucose in Islets from Rats with Acquired or Inherited Non-Insulin-Dependent Diabetes

The metabolic, ionic, and secretory response to D-glucose was investigated in islets of adult rats either injected with streptozotocin during the neonatal period (STZ rats) or presenting with inherited diabetes (GK rats). At a high concentration of D-glucose (16.7 mM), the ATP/ADP ratio was lower in islets from STZ and GK than control rats. This coincided with an impaired response of perifused islets to a rise in o-glucose concentration in terms of stimulation of insulin release, suppression of effluent radioactivity from islets prelabeled with [2-³H]adenosine, reduction in ⁸⁶Rb efflux, and induction of a phosphate flush in islets prelabeled with ³²P_i. The ratio in either D-[5-³H]glucose utilization or D-[2-¹⁴C]glucose oxidation at high/low hexose concentration, as well as the paired ratio between D-[2-¹⁴C]glucose oxidation and D-[5-³H]glucose utilization in islets incubated at a high concentration of the hexose, was also lower in STZ and GK rats than in control rats. Such was not the case, however, from the oxidation of [2-¹⁴C]pyruvate. Instead, the latter 2-keto acid, when tested at a 5.0 mM concentration, improved more efficiently the overall oxidative response of the islets to a rise in D-glucose concentration in STZ and GK rats than in control animals. It is proposed, therefore, that in both STZ and GK rats, the B-cell secretory defect is primarily attributable to an anomaly in oxidative glycolysis. In islets exposed to a high concentration of D-glucose, this metabolic deficiency results in impaired ATP generation, altered closing of ATP-responsive K⁺ channels, and, hence, diminished insulin output.