Plasma membrane depolarization as a determinant of the first phase of insulin secretion.
The role of plasma membrane depolarization as a determinant of the initial phase of insulin secretion was investigated. NMRI mouse islets and beta-cells were used to measure the kinetics of insulin secretion, ATP and ADP content, membrane potential, and cytosolic free Ca(2+) concentration ([Ca(2+)](i)). The depolarization of metabolically intact beta-cells by KCl corresponded closely to the theoretical values. In contrast to physiological (glucose) or pharmacological (tolbutamide) ATP-sensitive K(+) (K(ATP)) channel block, KCl depolarization did not induce action potential spiking. The depolarization by 15 mM K(+) (21 mV) corresponded to the plateau depolarization by 50 or 500 microM tolbutamide; that by 40 mM K(+) (41 mV) corresponded to the action potential peaks. Nifedipine and diazoxide abolished action potentials but not KCl depolarization, suggesting that the depolarizing strength of 15, but not 40 mM K(+) corresponds to that of K(ATP) channel closure. K(+) (40 mM) induced a massive secretory response in the presence of 5 mM glucose, whereas 15 mM K(+), like 50 microM tolbutamide, was only slightly effective, even though a marked increase in [Ca(2+)](i) was produced. Raising glucose from 5 to 10 mM in the continued presence of 15 mM K(+) resulted in a strongly enhanced biphasic response. The depolarization pattern of this combination could be mimicked by combining basal glucose with 15 mM K(+) and 50 microM tolbutamide; however, the secretory response to these nonnutrients was much weaker. In conclusion, the initial secretory response to nutrient secretagogues is largely influenced by signaling mechanisms that do not involve depolarization.
Hatlapatka
K
K
Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Braunschweig, Germany.
Willenborg
M
M
Rustenbeck
I
I
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D054086:KATP Channels / Q000037:antagonists & inhibitors; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D011189:Potassium Chloride / Q000494:pharmacology; D013997:Time Factors; D014044:Tolbutamide / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D000244:Adenosine Diphosphate; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005947:Glucose