Pulsatility of insulin release – a clinically important phenomenon

The mechanisms and clinical importance of pulsatile insulin release are presented against the background of more than half a century of companionship with the islets of Langerhans. The insulin-secreting β-cells are oscillators with intrinsic variations of cytoplasmic ATP and Ca2+. Within the islets the β-cells are mutually entrained into a common rhythm by gap junctions and diffusible factors (ATP). Synchronization of the different islets in the pancreas is supposed to be due to adjustment of the oscillations to the same phase by neural output of acetylcholine and ATP. Studies of hormone secretion from the perfused pancreas of rats and mice revealed that glucose induces pulses of glucagon anti-synchronous with pulses of insulin and somatostatin. The anti-synchrony may result from a paracrine action of somatostatin on the glucagon-producing α-cells. Purinoceptors have a key function for pulsatile release of islet hormones. It was possible to remove the glucagon and somatostatin pulses with maintenance of those of insulin with an inhibitor of the P2Y1 receptors. Knock-out of the adenosine A1 receptor prolonged the pulses of glucagon and somatostatin without affecting the duration of the insulin pulses. Studies of isolated human islets indicate similar relations between pulses of insulin, glucagon, and somatostatin as found during perfusion of the rodent pancreas. The observation of reversed cycles of insulin and glucagon adds to the understanding how the islets regulate hepatic glucose production. Current protocols for pulsatile intravenous infusion therapy (PIVIT) should be modified to mimic the anti-synchrony between insulin and glucagon normally seen in the portal blood

Emergent global oscillations in heterogeneous excitable media: The example of pancreatic beta cells

Using the standard van der Pol-FitzHugh-Nagumo excitable medium model I demonstrate a novel generic mechanism, diversity, that provokes the emergence of global oscillations from individually quiescent elements in heterogeneous excitable media. This mechanism may be operating in the mammalian pancreas, where excitable beta cells, quiescent when isolated, are found to oscillate when coupled despite the absence of a pacemaker region.Comment: See home page http://lec.ugr.es/~julya

Inhibition of purinoceptors amplifies glucose-stimulated insulin release with removal of its pulsatility

External ATP has been proposed to be an autocrine regulator of glucose-stimulated insulin secretion and responsible for the synchronization of the Ca2+ rhythmicity in the P-cells required for a pulsatile release of insulin from the pancreas. The importance of external ATP for glucose-stimulated insulin release was evaluated in rats with the aid of 2-deoxy-N-methyladenosine3,5-bisphosphate (MRS 2179), an inhibitor of the purinoceptors known to affect the Ca2+ signaling in R-cells. The concentration of cytoplasmic Ca2+ was measured in single P-cells and small aggregates with ratiometric fura-2 technique and the release of insulin recorded from isolated islets and the perfused pancreas. Addition of 1 mu mol/l ATP induced premature cytoplasmic Ca2+ concentration ([Ca2+](i)) oscillations similar to those found in P-cells exposed to 20 mmol/l glucose. In most experiments, the presence of 10 mu mol/l MRS 2179 did not remove the glucose-induced [Ca2+] rhythmicity in single R-cells or the synchronization seen in coupled cells. Nevertheless, the same concentration of MRS 2179 promptly interrupted the pulsatility (frequency 0.22 +/- 0.01/min) of insulin secretion, raising the total amounts released from the pancreas. Prolonged exposure of islets to 1 and 10 mu molA MRS 2179 enhanced insulin secretion at 20 mmol/l glucose 33% (P < 0.05) and 63% (P < 0.01), respectively, without affecting the release at 3 mmol/l glucose. The results support the idea that neural ATP signals entrain the islets into a common rhythm resulting in pulsatile release of insulin and that glucose stimulation of the secretory activity is counteracted by accumulation of inhibitory ATP around the beta-cells

Absence of adenosine A(1) receptors unmasks pulses of insulin release and prolongs those of glucagon and somatostatin.

AIMS: Extracellular ATP modulates pulsatile release of insulin, glucagon and somatostatin by activating P2Y(1) receptors. The present study examines if adenosine via A(1) receptors (A(1)R) interferes with pulsatile islet hormone release. MAIN METHODS: Pancreas was perfused in mice expressing or lacking the A(1) receptor and the hormones measured with radioimmunoassay. Cytoplasmic Ca(2+) was recorded in isolated beta-cells using the fura-2 indicator. KEY FINDINGS: Addition of 10microM adenosine removed the Ca(2+) transients supposed to coordinate the insulin release pulses. This effect of adenosine was counteracted by 100nM of the A(1)R antagonist DPCPX. In situ perfusion of the pancreas indicated two phases of islet hormone release when glucose was raised from 3.3 to 16.7mM. The first phase was characterized by a brief dip followed by a peak, which was more pronounced for insulin and somatostatin than for glucagon. The second phase was markedly affected by knock out of A(1)R. The wild-type A(1)R (+/+) mice, usually lacked statistically verified insulin pulses but generated antisynchronous glucagon and somatostatin pulses with half-widths of 4min. In the A(1)R (-/-) mice time-average release of insulin during the second phase was almost three times higher than in the controls and 30% of the hormone was released as distinct pulses with half-widths of 3min. The absence of the A(1)R receptor resulted in 50% prolongation of the pulse cycles of glucagon and somatostatin and loss of their antisynchronous relationship. SIGNIFICANCE: The A(1)R receptor is important both for the amplitude (insulin) and duration (glucagon and somatostatin) of islet hormone pulses

Carbon monoxide stimulates insulin release and propagates Ca2+ signals between pancreatic beta-cells

A key question for understanding the mechanisms of pulsatile insulin release is how the underlying beta-cell oscillations of the cytoplasmic Ca2+ concentration ([Ca2+](i)) are synchronized within and among the islets in the pancreas. Nitric oxide has been proposed to coordinate the activity of the beta-cells by precipitating transients of [Ca2+](i). Comparing ob/ob mice and lean controls, we have now studied the action of carbon monoxide (CO), another neurotransmitter with stimulatory effects on cGMP production. A strong immunoreactivity for the CO-producing constitutive heme oxygenase (HO-2) was found in ganglionic cells located in the periphery of the islets and in almost all islet endocrine cells. Islets from ob/ob mice had sixfold higher generation of CO ( 1 nmol.min(-1).mg protein(-1)) than the lean controls. This is 100-fold the rate for their constitutive production of NO. Moreover, islets from ob/ob mice showed a threefold increase in HO-2 expression and expressed inducible HO (HO-1). The presence of an excessive islet production of CO in the ob/ob mouse had its counterpart in a pronounced suppression of the glucose-stimulated insulin release from islets exposed to the HO inhibitor Zn-protoporhyrin (10 muM) and in a 16 times higher frequency of [Ca2+](i) transients in their beta-cells. Hemin (0.1 and 1.0 muM), the natural substrate for HO, promoted the appearance of [Ca2+](i) transients, and 10 muM of the HO inhibitors Zn-protoporphyrin and Cr-mesoporphyrin had a suppressive action both on the firing of transients and their synchronization. It is concluded that the increased islet production of CO contributes to the hyperinsulinemia in ob/ob mice. In addition to serving as a positive modulator of glucose-stimulated insulin release, CO acts as a messenger propagating Ca2+ signals with coordinating effects on the beta-cell rhythmicity