Insulin feedback actions: complex effects involving isoforms of islet nitric oxide synthase.

Research output: Contribution to journalArticle

Standard

Insulin feedback actions: complex effects involving isoforms of islet nitric oxide synthase. / Jimenez, Javier; Lundquist, Ingmar; Obermüller, Stefanie; Salehi, S Albert.

In: Regulatory Peptides, Vol. 122, No. 2, 2004, p. 109-118.

Research output: Contribution to journalArticle

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - Insulin feedback actions: complex effects involving isoforms of islet nitric oxide synthase.

AU - Jimenez, Javier

AU - Lundquist, Ingmar

AU - Obermüller, Stefanie

AU - Salehi, S Albert

PY - 2004

Y1 - 2004

N2 - The present study examined the effects of exogenous insulin on C-peptide release in relation to islet activities of neural constitutive nitric oxide synthase (ncNOS) and inducible NOS (iNOS). The dose–response curves for glucose-stimulated insulin and C-peptide release from isolated islets were practically identical: 0.05–0.1 nmol/l insulin stimulated, 1–100 nmol/l had no effect, whereas concentrations ≥250 nmol/l (“high insulin”), inhibited C-peptide release. Both the stimulatory and inhibitory effects were abolished by the phosphatidylinositol 3′-kinase inhibitor wortmannin. Addition of a NOS inhibitor partially reversed the inhibitory action of high insulin, but had no effect on the stimulatory action of low insulin (0.1 nmol/l). Moreover, high insulin markedly increased islet ncNOS activity and induced a strong iNOS activity. As shown biochemically and with confocal microscopy, the stimulatory action of high insulin on NOS activities and the associated inhibition of C-peptide release were reversed by raising cyclic AMP through addition of either glucagon-like peptide 1 (GLP-1) or dibutyryl cyclic AMP (Bt2cAMP) to the incubated islets. We conclude that the positive feedback mechanisms of action of insulin are independent of islet NOS activities and remain unclear. The negative feedback action of insulin, however, can be explained by its ability to stimulate both islet ncNOS activity and the expression and activity of iNOS. The effects on iNOS are most likely transduced through phosphatidylinositol 3′-kinase and are counteracted by raising islet cyclic AMP levels.

AB - The present study examined the effects of exogenous insulin on C-peptide release in relation to islet activities of neural constitutive nitric oxide synthase (ncNOS) and inducible NOS (iNOS). The dose–response curves for glucose-stimulated insulin and C-peptide release from isolated islets were practically identical: 0.05–0.1 nmol/l insulin stimulated, 1–100 nmol/l had no effect, whereas concentrations ≥250 nmol/l (“high insulin”), inhibited C-peptide release. Both the stimulatory and inhibitory effects were abolished by the phosphatidylinositol 3′-kinase inhibitor wortmannin. Addition of a NOS inhibitor partially reversed the inhibitory action of high insulin, but had no effect on the stimulatory action of low insulin (0.1 nmol/l). Moreover, high insulin markedly increased islet ncNOS activity and induced a strong iNOS activity. As shown biochemically and with confocal microscopy, the stimulatory action of high insulin on NOS activities and the associated inhibition of C-peptide release were reversed by raising cyclic AMP through addition of either glucagon-like peptide 1 (GLP-1) or dibutyryl cyclic AMP (Bt2cAMP) to the incubated islets. We conclude that the positive feedback mechanisms of action of insulin are independent of islet NOS activities and remain unclear. The negative feedback action of insulin, however, can be explained by its ability to stimulate both islet ncNOS activity and the expression and activity of iNOS. The effects on iNOS are most likely transduced through phosphatidylinositol 3′-kinase and are counteracted by raising islet cyclic AMP levels.

KW - Isoforms of islet nitric oxide synthase

KW - Isolated islets

KW - Insulin feedback

KW - GLP-1

KW - Cyclic AMP

U2 - 10.1016/j.regpep.2004.06.004

DO - 10.1016/j.regpep.2004.06.004

M3 - Article

VL - 122

SP - 109

EP - 118

JO - Regulatory Peptides

T2 - Regulatory Peptides

JF - Regulatory Peptides

SN - 1873-1686

IS - 2

ER -