GLUCOSE INDUCES OSCILLATORY CA2-CELLS( SIGNALING AND INSULIN RELEASE IN HUMAN PANCREATIC BETA)

Mechanisms of pulsatile insulin release in man were explored by studyi ng 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 increase s of capacitance in response to depolarizing pulses suggests that an e nhanced influx of Ca2+ is an effective means of stimulating the secret ory activity of the isolated human beta cell. Activation of muscarinic receptors (1-10 mu mol/l carbachol) and of purinergic P-2 receptors ( 0.01-1 mu mol/l ATP) resulted in repetitive transients followed by sus tained elevation of the cytoplasmic Ca2+ concentration ([Ca2+](i)). Pe riodic mobilisation of intracellular calcium was seen also when inject ing 100 mu mol/l GTP-gamma-S into beta cells hyperpolarized to -70 mV. Individual beta cells responded to glucose and tolbutamide with incre ases 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 alterna tive states of raised [Ca2+](i) at threshold concentrations of the sug ar characteristic for the individual beta cells. The oscillatory chara cteristics of coupled cells were determined collectively rather than b y particular pacemaker cells. In intact pancreatic islets the glucose induction of well-synchronized [Ca2+](i) oscillations had its counterp art in 2-5 min pulses of insulin. Each of these pulses could be resolv ed into regularly occurring short insulin transients. It is concluded that glucose stimulation of insulin release in man is determined by th e number of beta cells entering into a state with Ca2+-induced secreto ry pulses.