DXM and DXO increase the electrical activity of whole islets. (A) Representative membrane potential recording of an islet cultured on a microelectrode array. Islets were stimulated with 8 mM glucose and acutely treated with DXM (10 µM upper trace, 100 µM lower trace). (B) Evaluation of all experiments represented in (A). DXM (100 µM) elevates the FOPP considerably more than 10 µM DXM. (C) Same experimental setup as in (A and B) but with DXO instead of DXM. (D) Acute application of DXO (100 µM) elevates the FOPP substantially more than 10 µM DXO. The number in brackets stands for the number of evaluated islets. Islets were isolated from female/male mice as follows: 3/0 (B), 3/0 (D). ***P ≤ 0.001.

DXM increases [Ca²⁺]_c in whole islets. (A) Representative recordings of [Ca²⁺]_c of an islet stimulated with 8 mM glucose alone (upper trace) or together with 100 µM DXM (lower trace). DXM was present 1 hour before and during the experiment as indicated. (B) Summary of all experiments represented in (A). DXM elevates mean Ca²⁺ at 8 mM glucose in islets after 1 hour of preincubation. Basal Ca²⁺ evaluated at the end of each measurement is also elevated in islets preincubated with 100 µM DXM. (C) DXM elevates mean Ca²⁺ at 3 mM glucose in islets after 1 hour of preincubation. (D) Summary of all experiments presented in (C). (E) Representative recordings of [Ca²⁺]_c in islets stimulated with 8 mM glucose with acute application of 100 µM DXM (upper trace) or 100 µM DXO (lower trace). Compounds were added 15 minutes after starting the recording. (F) Summary of all experiments represented in (E). Evaluation of the last 5 minutes of treatment with DXM shows a relevant increase of mean [Ca²⁺]_c. Acute application of 100 µM DXO slightly elevates mean [Ca²⁺]_c of whole islets without an initial drop. The number of evaluated islets (B, D, and F) is given below each data plot. Islets were isolated from female/male mice as follows: 1/2 (B), 1/2 (D), 2/4 (F). **P ≤ 0.01; ***P ≤ 0.001.

In contrast to DXO, DXM reduces Ca²⁺ action potentials in glucose-stimulated β-cells. (A) Representative membrane potential recording of a pancreatic β-cell in the perforated-patch configuration. DXM (100 µM) decreases the frequency of action potentials (8 mM glucose). (B) Summary of all experiments represented in (A). (C) Summary of analogous experiments with 15 mM glucose. A lower concentration of DXM (10 µM) does not affect the number of Ca²⁺ action potentials (APs). (D) Similar experiments as in (A) but with DXO. DXO (100 µM) has no effect on Ca²⁺ action potentials. The number in brackets represents the number of experiments with different cells from three mice. Islet cells were isolated from female/male mice as follows: 2/1 (B), 4/3 (C), 2/1 (D). *P ≤ 0.05; **P ≤ 0.01.

DXM acutely decreases Ca²⁺ peak currents, and both compounds inhibit K_ATP channels of murine β-cells. (A) Representative voltage-clamp recording in the whole-cell configuration shows a decrease of the maximal Ca²⁺ current during administration of DXM (solid, black line) compared with the control condition (solid, gray line). (B) Summary of all experiments represented in (A). DXM (100 µM) reduces the Ca²⁺ current about 25%. (C and F) Representative recordings of K_ATP current measured in the whole-cell configuration. Administration of DXM (C) or DXO (F) directly decreases the K_ATP current. The current was identified as K_ATP current by the specific K_ATP channel inhibitor tolbutamide (Tolb; 100 µM). (D) Dose-response curve for the direct effect of DXM (10, 20, 50, and 100 µM) on K_ATP current. Statistically significant inhibition occurred with 50 and 100 µM. (E) Lack of antagonism of the DXM-induced inhibition by diazoxide (100 µM). (G) Summary of all experiments with 100 µM DXO. The number in brackets indicates the number of experiments with different cells from three mice. Islet cells were isolated from female/male mice as follows: 4/1 (B), 7/3 (D), 0/3 (E), 3/0 (G). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 vs. all other conditions, ^#P ≤ 0.05 vs. control and 20 µM DXM, ^##P ≤ 0.01 vs. control.