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

Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1055-63. doi: 10.1152/ajpendo.00498.2002.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Body Weight
  • Calcium / metabolism*
  • Carbon Monoxide / metabolism
  • Carbon Monoxide / pharmacology*
  • Cyclic GMP / metabolism
  • Cytoplasm / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Glucose / pharmacology
  • Heme Oxygenase (Decyclizing) / analysis
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Hemin / pharmacology
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nitric Oxide / metabolism
  • Obesity / enzymology
  • Obesity / metabolism
  • Protoporphyrins / pharmacology
  • Signal Transduction / drug effects*


  • Blood Glucose
  • Enzyme Inhibitors
  • Insulin
  • Membrane Proteins
  • Protoporphyrins
  • zinc protoporphyrin
  • Nitric Oxide
  • Hemin
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • heme oxygenase-2
  • Cyclic GMP
  • Glucose
  • Calcium