Glucose induces oscillatory Ca2+ signalling and insulin release in human pancreatic beta cells.
Mechanisms of pulsatile insulin release in man were explored by studying the induction of oscillatory Ca2+ signals in individual beta cells and islets isolated from the human pancreas. Evidence was provided for a glucose-induced closure of ATP-regulated K+ channels, resulting in voltage-dependent entry of Ca2+. The observation of step-wise increases of capacitance in response to depolarizing pulses suggests that an enhanced influx of Ca2+ is an effective means of stimulating the secretory activity of the isolated human beta cell. Activation of muscarinic receptors (1-10 mumol/l carbachol) and of purinergic P2 receptors (0.01-1 mumol/l ATP) resulted in repetitive transients followed by sustained elevation of the cytoplasmic Ca2+ concentration ([Ca2+]i). Periodic mobilisation of intracellular calcium was seen also when injecting 100 mumol/l GTP-gamma-S into beta cells hyperpolarized to -70 mV. Individual beta cells responded to glucose and tolbutamide with increases of [Ca2+]i, manifested either as large amplitude oscillations (frequency 0.1-0.5/min) or as a sustained elevation. Glucose regulation was based on sudden transitions between the basal and the two alternative states of raised [Ca2+]i at threshold concentrations of the sugar characteristic for the individual beta cells. The oscillatory characteristics of coupled cells were determined collectively rather than by particular pacemaker cells. In intact pancreatic islets the glucose induction of well-synchronized [Ca2+]i oscillations had its counterpart in 2-5 min pulses of insulin. Each of these pulses could be resolved into regularly occurring short insulin transients. It is concluded that glucose stimulation of insulin release in man is determined by the number of beta cells entering into a state with Ca(2+)-induced secretory pulses.
Hellman
B
B
Department of Medical Cell Biology, University of Uppsala, Sweden.
Gylfe
E
E
Bergsten
P
P
Grapengiesser
E
E
Lund
P E
PE
Berts
A
A
Tengholm
A
A
Pipeleers
D G
DG
Ling
Z
Z
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D001363:Awards and Prizes; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D003920:Diabetes Mellitus / Q000266:history; D005060:Europe; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D049673:History, 20th Century; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects*; D012955:Societies, Medical; D013548:Sweden
D007328:Insulin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000255:Adenosine Triphosphate; D002217:Carbachol; D005934:Glucagon; D005947:Glucose; D002118:Calcium