Kinetics of insulin secretion to acute, repetitive stimulation of islets in vivo in Sprague Dawley rats.

The exhaustibility of in vivo insulin secretion under repeated stimulations was investigated in male Sprague Dawley rats. Eight pulses of either 300 mg/kg glucose (G), or 300 mg/kg glucose plus 0.25 mg/kg forskolin (G+F) were administered for each rat at every 30 min for 4 hours through the jugular vein. Forskolin is a chemical that potentiates glucose-stimulated insulin release by raising intracellular cAMP levels. After each infusion, blood samples from the hepatic portal vein were collected at 2, 5, 10, 15 and 29 min and glucose, insulin and C-peptide levels were measured. Analyses of our results indicate that: (1) the addition of forskolin led to increased insulin release as judged by peak insulin secretion values and by incremental insulin release for both first and second phases; (2) despite the enhanced insulin release, the G+F protocol did not increase glucose disposal more than the G protocol alone, as judged by the maximum and minimum glucose levels that the system could attain in each cycle; and most importantly, (3) insulin secretion from β-cells was not exhausted, even after 8 repeated half-hourly stimulations with either G or G+F. We believe that this is the first study to investigate in vivo β-cell exhaustion by repeated stimulation in an animal model and our data show that in an acute setting, islets are capable of robust insulin secretion. The extension of this study to investigate insulin secretion in pre-diabetic states may be informative of the early pathogenic mechanisms.