Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: Diabetes, Obesity and Metabolism
To understand better the control of insulin secretion (IS) by human β-cells and identify similarities and differences with rodent models.Dynamic IS was measured in perifused human islets treated with pharmacological agents of known modes of action.Glucokinase activation (Ro28-1675) lowered the glucose threshold for stimulation of IS to 1 mmol/l (G1), augmented the response to G3-G5 but not to G8-G15 whereas tolbutamide remained active in G20, which indicates that not all KATP -channels were closed by high glucose. An almost two-fold greater response to G15 than to supramaximal tolbutamide in G3 or to KCl+diazoxide in G15 versus G3 quantified the contribution of metabolic amplification to IS. Both disruption (latrunculin-B) and stabilization (jasplakinolide) of microfilaments augmented IS without affecting metabolic amplification. Tolbutamide-induced IS was consistently greater in G10 than G3, with a threshold at 1 and maximum at 10 µmol/l tolbutamide in G10, versus 10 and 25 µmol/l in G3. Sulfonylurea effects were thus clearly glucose-dependent. IS was also increased by inhibiting K-channels other than KATP -channels: Kv or BK channels (tetraethylammonium), TASK-1 channels (ML-365) and SK4 channels (TRAM-34). Opening KATP -channels with diazoxide inhibited glucose-induced IS with IC50 of 9.6 and 24 µmol/l at G7 and G15. Blockade of L-type Ca-channels (nimodipine) abolished IS whereas a blocker of T-type Ca-channels (NNC-55-0396) was ineffective at specific concentrations. Blockade of Na-channels (tetrodotoxin) did not affect glucose-induced IS.In addition to sharing a KATP -channel-dependent triggering pathway and a metabolic amplifying pathway, human and rodent β-cells show more similarities than differences in the control of IS.