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

Departments of ¹Pharmacology and ²Pathology, Institute of Physiological Sciences, University of Lund, S-221 84 Lund, Sweden; and ³Department of Medical Cell Biology, University of Uppsala, S-75123 Uppsala, Sweden

Submitted 14 November 2002 ; accepted in final form 20 June 2003

A key question for understanding the mechanisms of pulsatile insulin release is how the underlying -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 -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 -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 -cell rhythmicity.

calcium ion; carbon monoxide

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