Abnormally decreased NO and augmented CO production in islets of the leptin-deficient ob/ob mouse might contribute to explain hyperinsulinemia and islet survival in leptin-resistant type 2 obese diabetes

作者：Jimenez Feltstrom Javier; Salehi Albert^*; Abaraviciene Sandra Meidute; Henningsson Ragnar; Lundquist Ingmar

来源：Regulatory Peptides, 2011, 170(1-3): 43-51.

DOI：10.1016/j.regpep.2011.04.011

• Insulin secretion
• Islet nitric oxide synthases
• Islet heme oxygenase
• Insulinotropic peptides
• Leptin

The role of the gaseous messengers NO and CO for beta-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in blob islets associated with markedly increased insulin release. Both types of islets displayed iNOS activity appearing after similar to 60 min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon. GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.

• 出版日期2011-10-10