TY - JOUR

T1 - Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway.

AU - Thams, Peter

AU - Anwar, Mohammad R

AU - Capito, Kirsten

N1 - Keywords: Adenosine Triphosphate; Adenylate Cyclase; Animals; Calcium; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diazoxide; Enzyme Activation; Forskolin; Glucose; Insulin; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Isoquinolines; Male; Mice; Ouabain; Potassium; Potassium Channels; Protein Kinase C; Sulfonamides

PY - 2005

Y1 - 2005

N2 - OBJECTIVE: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K(+) (K(+)(ATP)) channel-dependent insulin secretion and in glucose amplification of K(+)(ATP) channel-independent insulin secretion. METHODS: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator, forskolin (10 micromol/l). In the presence of 60 mmol/l K(+) and 250 micromol/l diazoxide, which stimulates maximum Ca(2+) influx independently of K(+)(ATP) channels, H89 (10 micromol/l) inhibited Ca(2+)-evoked insulin secretion, but failed to prevent glucose amplification of K(+)(ATP) channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 micromol/l diazoxide, which cause modest Ca(2+) influx, glucose amplification of K(+)(ATP) channel-independent insulin secretion was observed without concomitant Ca(2+) stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs-Ringer medium was augmented and now inhibited by H89 (10 micromol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca(2+)-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca(2+)-evoked insulin secretion at 60 mmol/l K(+) and 250 micromol/l diazoxide was improved, whereas glucose amplification of K(+)(ATP) channel-independent insulin secretion was unaffected. CONCLUSIONS: Glucose may activate PKA through triggering of the K(+)(ATP) channel-dependent pathway. Glucose amplification of K(+)(ATP) channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.

AB - OBJECTIVE: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K(+) (K(+)(ATP)) channel-dependent insulin secretion and in glucose amplification of K(+)(ATP) channel-independent insulin secretion. METHODS: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator, forskolin (10 micromol/l). In the presence of 60 mmol/l K(+) and 250 micromol/l diazoxide, which stimulates maximum Ca(2+) influx independently of K(+)(ATP) channels, H89 (10 micromol/l) inhibited Ca(2+)-evoked insulin secretion, but failed to prevent glucose amplification of K(+)(ATP) channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 micromol/l diazoxide, which cause modest Ca(2+) influx, glucose amplification of K(+)(ATP) channel-independent insulin secretion was observed without concomitant Ca(2+) stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs-Ringer medium was augmented and now inhibited by H89 (10 micromol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca(2+)-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca(2+)-evoked insulin secretion at 60 mmol/l K(+) and 250 micromol/l diazoxide was improved, whereas glucose amplification of K(+)(ATP) channel-independent insulin secretion was unaffected. CONCLUSIONS: Glucose may activate PKA through triggering of the K(+)(ATP) channel-dependent pathway. Glucose amplification of K(+)(ATP) channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.

U2 - 10.1530/eje.1.01885

DO - 10.1530/eje.1.01885

M3 - Journal article

C2 - 15817925

VL - 152

SP - 671

EP - 677

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

SN - 0804-4643

IS - 4

ER -