Glucose-induced insulin secretion was inhibited in a concentration-dependent manner by ritonavir and nelfinavir but not by indinavir. Ritonavir and nelfinavir lowered [Ca²⁺]_c in the presence of a stimulatory glucose concentration whereas indinavir again had no effect. Ritonavir and nelfinavir completely inhibited the effect of tolbutamide, which normally increases [Ca²⁺]_c by blocking K_ATP channels. This observation points to an action of both drugs on K_ATP channels or a step distal to these channels in stimulus-secretion coupling. Ritonavir was used to further evaluate the direct effects of HIV protease inhibitors on -cell ion channel currents. Unexpectedly, ritonavir inhibited neither the whole-cell K_ATP current nor the whole-cell L-type Ca²⁺ current. Tolbutamide almost completely suppressed the K_ATP current in the presence of ritonavir excluding that ritonavir alters the tolbutamide sensitivity of the K_ATP channel. Ritonavir increased the length and decreased the frequency of glucose-induced action potentials. This effect can be attributed to inhibition of voltage-dependent K⁺ currents. Intracellular stores seem not to be involved in the ritonavir-induced lowering of [Ca²⁺]_c.

In conclusion, different HIV protease inhibitors surprisingly reveal distinct effects on insulin secretion. Ritonavir inhibits insulin secretion by lowering [Ca²⁺]_c but this effect is evidently independent of the opening of K_ATP channels or the closure of voltage-dependent Ca²⁺ channels, which are commonly considered to play a key role in stimulus-secretion coupling.