Contrasting effects of nateglinide and rosiglitazone on insulin secretion and phospholipase C activation.
When stimulated with 6 mmol/L glucose, a minimal, transient insulin secretory response was observed from perifused rat islets. The inclusion of 5 micromol/L nateglinide significantly amplified release. Elevating glucose to 8 or 10 mmol/L resulted in an increasing insulin secretory response that was again markedly potentiated by the further inclusion of nateglinide. The calcium channel antagonist, nitrendipine, abolished secretion to 8 mmol/L glucose plus nateglinide. Unlike nateglinide, rosiglitazone (5 micromol/L), troglitazone (1 to 10 micromol/L), or darglitazone (10 micromol/L), 3 peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, were without any acute stimulatory effect on insulin release in the simultaneous presence of 6 to 10 mmol/L glucose. Glucose (8 to 10 mmol/L) significantly increased inositol phosphate accumulation. Nateglinide amplified this response. Nitrendipine reduced inositol phosphate (IP) accumulation in response to the combination of 8 mmol/L glucose plus 5 micromol/L nateglinide. Rosiglitazone had no effect on IP accumulation. These results confirm the efficacy of nateglinide as a potent glucose-dependent insulin secretagogue that exerts its stimulatory effect, at least in part, through the activation of phospholipase C (PLC). No acute potentiating effect of rosiglitazone on either insulin secretion or IP accumulation could be detected in isolated rat islets.
Zawalich
Walter S
WS
School of Nursing, Yale University, New Haven, CT 06536-0740, USA.
Tesz
Gregory
G
Zawalich
Kathleen C
KC
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077715:Nateglinide; D010477:Perfusion; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D010738:Type C Phospholipases / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D002839:Chromans; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D007295:Inositol Phosphates; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077715:Nateglinide; D010649:Phenylalanine; C089948:darglitazone; D010738:Type C Phospholipases; D000077288:Troglitazone; D005947:Glucose; D000077191:Wortmannin