Effects of type‐selective phosphodiesterase inhibitors on glucose‐induced insulin secretion and islet phosphodiesterase activity

Open Access
Publisher Website
Google Scholar
Abstract
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 nonselective PDE inhibitor, 3-isobutyl-l-methylxanthine (IBMX, 10−5-10−3 M), as well as the type III selective PDE inhibitors SK&F 94836 (10−5-10−3 M), Org 9935 (10−7-10−4 M), SK&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&F 94836 (10−5 M) and forskolin (5 × 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&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&F 94836 or Org 9935. 6 Homogenates of rat islets showed a low Km (1.7 μm) and high Km (13 μm) cyclic AMP PDE in the supernatant fractions (from 48, 000 g centrifugation), whereas the particulate fraction showed only a low Km (1.4 μm) cyclic AMP PDE activity. 7 The PDE activity of both supernatant and pellet fractions were consistently inhibited by SK&F 94836 or Org 9935, the concentrations required to reduce particulate PDE activity by 50% being 5.5 and 0.05 μm 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.