Sulfonylurea Stimulation of Insulin Secretion

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FIG. 2.
FIG. 2.

A: Single-channel currents recorded at −60 mV in the absence (top) or presence (bottom) of a saturating concentration of gliclazide (10 μmol/l). B: Kinetic scheme for KATP channel gating in the presence of sulfonylureas. Agents that increase PO usually mediate their effects by increasing the burst duration and reducing the frequency of the interburst closed states (i.e., they reduce k2). The relation between k2, PO, and IC50 was derived as described previously (27). When drug is bound but untransduced, the channel can exist in states OB, C1B, or C2B. The closed states that result following the conformational change permitted by drug binding are given by CT and CT2. O, open state; C1, intraburst closed state; C2, lumped interburst closed states; gray box, burst state. C and D: Relation between channel PO and the fraction of current that remains unblocked in the presence of a saturating concentration of sulfonylurea (L) (C) or IC50 (D). The PO in the presence of sulfonylurea predicted by the kinetic scheme in B is given by Formula where κ2 = k2/k-2; κ = kB/k-B; κTO = kTO/k−TO, and κTC = kTC/k-TC. Equating Pos/PO with I/IO leads to Formula where IC50 = 1/{κ × [1 + λ × (Pmax − PO)]}, Formula where ΔGC2T,CT = GC2T − GCT. For these plots, the values of λ and κ were obtained from the IC50 and L (0.4) measured for gliclazide block of Kir6.2/SUR1 currents (19), assuming a PO of 0.32 (25). IC50 = 50 nmol/l for the high-affinity site and 3 mmol/l for the low-affinity site. E: Relation between the inhibition of the KATP current and drug concentration at various values of PO, calculated using the kinetic scheme given in B and the equations in C and D. The low-affinity block is assumed to be unchanged by alterations in channel PO, as found experimentally (25). The curves are fit to equation 2.

This Article

  1. Diabetes vol. 51 no. suppl 3 S368-S376