Pharmacological approach to understanding the control of insulin secretion in human islets.
(2017) Diabetes, obesity & metabolism — Vol. 19, n° 8, p. 1061-1070 (2017)
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- Aims: To understand better the control of insulin secretion by human β cells and to identify similarities to and differences from rodent models. Methods: Dynamic insulin secretion was measured in perifused human islets treated with pharmacological agents of known modes of action. Results: Glucokinase activation (Ro28-1675) lowered the glucose threshold for stimulation of insulin secretion 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 concentrations. An almost 2-fold greater response to G15 than to supramaximal tolbutamide in G3 or to KCl+diazoxide in G15 vs G3 quantified the contribution of metabolic amplification to insulin secretion. Both disruption (latrunculin-B) and stabilization (jasplakinolide) of microfilaments augmented insulin secretion without affecting metabolic amplification. Tolbutamide-induced insulin secretion was consistently greater in G10 than G3, with a threshold at 1 and maximum at 10 μmol/L tolbutamide in G10, vs 10 and 25 μmol/L in G3. Sulphonylurea effects were thus clearly glucose-dependent. Insulin secretion 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 insulin secretion with half maximum inhibitory concentrations of 9.6 and 24 μmol/L at G7 and G15. Blockade of L-type Ca channels (nimodipine) abolished insulin secretion, 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 insulin secretion. Conclusions: In addition to sharing a KATP channel-dependent triggering pathway and a metabolic amplifying pathway, human and rodent β cells were found to display more similarities than differences in the control of insulin secretion.
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Henquin, J.-C., Dufrane, D., Gmyr, V., Kerr-Conte, J., & Nenquin, M. (2017). Pharmacological approach to understanding the control of insulin secretion in human islets. Diabetes, obesity & metabolism, 19(8), 1061-1070. https://doi.org/10.1111/dom.12887 (Original work published 2017)