EFFECTS OF TYPE-SELECTIVE PHOSPHODIESTERASE INHIBITORS ON GLUCOSE-INDUCED INSULIN-SECRETION AND ISLET PHOSPHODIESTERASE ACTIVITY

1 We examined various type-selective phosphodiesterase (PDE) inhibitors on glucose-induced insulin secretion from rat isolated islets, on islet PDE activity and on islet cyclic AMP accumulation in order to assess the relationship between type-selective PDE inhibition and modification of insulin release. 2 The non-selective PDE inhibitor, 3-isobutyl-1 -methylxanthine (IBMX, 10(-5)-10(-3) M), as well as the type III selective PDE inhibitors SK and F 94836 (10(-5)-10(-3) M), Org 9935 (10(-7)-10(-4) M), SK and F 94120 (10(-5)-10(-4) M) and ICI 118233 (10(-6)-10(-4) M) each caused concentration-dependent augmentation (up to 40% increase) of insulin release in the presence of a stimulatory glucose concentration (10 mM), but not in the presence of 3 mM glucose. 3 Neither the type IV PDE inhibitor rolipram (10(-4) M) nor the type I and type V PDE inhibitor, zaprinast (10(-4)-10(-3) M) modified glucose-induced insulin release when incubated with islets, although a higher concentration of rolipram (10(-3) M) inhibited secretion by 55%, However, when islets were preincubated with these drugs followed by incubation in their continued presence, zaprinast (10(-6)-10(-4) M) produced a concentration-dependent inhibition (up to 45% at 10(-4) M). Under these conditions, rolipram inhibited insulin secretion at a lower concentration (10(-4) M) than when simply incubated with islets. 4 A combination of SK and F 94836 (10(-5) M) and forskolin (5 x 10(-8) M) significantly augmented glucose-induced insulin secretion (30% increase), although neither drug alone, in these concentrations, produced any significant effect. 5 Islet cyclic AMP levels, which were not modified by forskolin (10(-6) M), SK and F 94836 (10(-4) M) or Org 9935 (10(-5) M) were significantly elevated (approximately 3.7 fold increase) by forskolin in combination with either SK and F 94836 or Org 9935, 6 Homogenates of rat islets showed a low K-m (1.7 mu M) and high k(m) (13 mu M) cyclic AMP PDE in the supernatant fractions (from 48,000 g centrifugation), whereas the particulate fraction showed only a low K-m (1.4 mu M) cyclic AMP PDE activity. 7 The PDE activity of both supernatant and pellet fractions were consistently inhibited by SK and F 94835 or Org 9935, the concentrations required to reduce particulate PDE activity by 50% being 5,5 and 0.05 mu M respectively. 8 Rolipram (10(-5)-10(-4) M) did not consistently inhibit PDE activity in homogenates of rat islets and zaprinast (10(-4) M) consistently inhibited activity by 30% in the supernatant fraction, but not consistently in the pellet. 9 These data are consistent with the presence of a type III PDE in rat islets of Langerhans.