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 microM) and in a 16 times higher frequency of [Ca2+]i transients in their beta-cells. Hemin (0.1 and 1.0 microM), the natural substrate for HO, promoted the appearance of [Ca2+]i transients, and 10 microM 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.
Lundquist
Ingmar
I
Department of Pharmacology, Institute of Physiological Sciences, University of Lund, BMC F13, S-221 84 Lund, Sweden. ingmar.lundquist@farm.lu.se
Alm
Per
P
Salehi
Albert
A
Henningsson
Ragnar
R
Grapengiesser
Eva
E
Hellman
Bo
B
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002118:Calcium / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D008565:Membrane Proteins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D009569:Nitric Oxide; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2; D006152:Cyclic GMP; D005947:Glucose; D002118:Calcium