Impaired phasic insulin and amylin secretion in diabetic rats.

We have proposed that a hyperstimulated insulin secretion causing β-cell degranulation is the basis for the impaired glucose-potentiated insulin secretion in type 2 diabetes ("overworked β-cell"). To confirm this idea, we previously investigated tolbutamide-infused euglycemic rats. Two novel kinds of β-cell dysfunction were observed: altered phasic glucose-potentiated insulin secretion with preferential sparing of the first phase and a raised secreted ratio of amylin to insulin. The current study tested these parameters in 90% (intact β-cell insulin stores) and 95% (markedly lowered insulin stores) pancreatectomized (Px) diabetic rats. Rats underwent pancreas perfusion 5-6 wk postsurgery. Controls showed nonchanging insulin secretion during a 20-min perfusion of 16.7 mM glucose + 10 mM arginine. In contrast, both Px groups showed an altered phasic pattern, with the first phase being supernormal (for the β-cell mass) but the second phase reduced in tandem with the insulin content. Amylin secretion from control and 90% Px rats paralleled the insulin output, so that the amylin-to-insulin ratio averaged 0.12 ± 0.03% in the controls and 0.16 ± 0.01% in the 90% Px rats over the two secretory phases. In contrast, the amylin-to-insulin ratio in 95% Px rats equaled that of controls during the first phase (0.12 ± 0.1%) but was twice normal during the second phase (0.32 ± 0.4%). These results confirm the validity of the overworked β-cell schema by showing identical β-cell functional defects in Px rats and tolbutamide-infused normoglycemic rats.