Interactions between lithium, inositol and mono-oleoylglycerol in the regulation of insulin secretion from isolated perifused rat islets.
In response to stimulation by 20 mM-glucose, 15 mM-4-methyl-2-oxopentanoate or 10 mM-glyceraldehyde, isolated perifused rat islets respond with brisk biphasic insulin-secretory responses. The inclusion of 10 mM-LiCl significantly decreased second-phase insulin release in response to all agonists. Inositol, at a concentration (10 mM) which has no effect on secretion in the presence of 2.75 mM-glucose, restored significantly glucose-, 4-methyl-2-oxopentanoate- or glyceraldehyde-induced second-phase release from Li+-treated islets. The addition of the diacylglycerol kinase inhibitor mono-oleoylglycerol, at a concentration (25 microM) which has no stimulatory effect on insulin secretion in the presence of 2.75 mM-glucose, significantly amplified both the first- and second-phase insulin responses to 20 mM-glucose. This amplifying effect of mono-oleoylglycerol was readily reversible and dependent on Ca2+ influx into the beta-cell. Li+ decreased the amplified insulin response to 20 mM-glucose plus mono-oleoylglycerol. Inositol restored release under this condition. These findings suggest that Li+ inhibits release by sequestering inositol into biosynthetically ineffective inositol phosphates. By limiting phosphoinositide resynthesis, the continued hydrolysis of phosphoinositides is diminished. Our results with mono-oleoylglycerol suggest further that diacylglycerol content may play a critically important role in the regulation of both the first and second phases of insulin secretion.
Zawalich
W S
WS
Yale University School of Nursing, New Haven, CT 06536-9740.
Zawalich
K C
KC
Rasmussen
H
H
D000818:Animals; D002469:Cell Separation; D002712:Chlorides / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D007294:Inositol / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D018021:Lithium Chloride; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D002712:Chlorides; D005989:Glycerides; D007328:Insulin; D007294:Inositol; D008094:Lithium; C005953:monoolein; D018021:Lithium Chloride