Author:
Lundquist Ingmar,Alm Per,Salehi Albert,Henningsson Ragnar,Grapengiesser Eva,Hellman Bo
Abstract
A key question for understanding the mechanisms of pulsatile insulin release is how the underlying β-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 β-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 μM) and in a 16 times higher frequency of [Ca2+]i transients in their β-cells. Hemin (0.1 and 1.0 μM), the natural substrate for HO, promoted the appearance of [Ca2+]i transients, and 10 μM 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 β-cell rhythmicity.
Publisher
American Physiological Society
Subject
Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism
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