Differential acute and long term actions of succinic acid monomethyl ester exposure on insulin-secreting BRIN-BD11 cells.
Esters of succinic acid are potent insulin secretagogues, and have been proposed as novel antidiabetic agents for type 2 diabetes. This study examines the effects of acute and chronic exposure to succinic acid monomethyl ester (SAM) on insulin secretion, glucose metabolism and pancreatic beta cell function using the BRIN-BD11 cell line. SAM stimulated insulin release in a dose-dependent manner at both non-stimulatory (1.1 mM) and stimulatory (16.7 mM) glucose. The depolarizing actions of arginine also stimulated a significant increase in SAM-induced insulin release but 2-ketoisocaproic acid (KIC) inhibited SAM induced insulin secretion indicating a possible competition between the preferential oxidative metabolism of these two agents. Prolonged (18 hour) exposure to SAM revealed decreases in the insulin-secretory responses to glucose, KIC, glyceraldehyde and alanine. Furthermore, SAM diminished the effects of non-metabolized secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of BRIN-BD11 cells to oxidise glucose was unaffected by SAM culture, glucose utilization was substantially reduced. Collectively, these data suggest that while SAM may enhance the secretory potential of non-metabolized secretagogues, it may also serve as a preferential metabolic fuel in preference to other important physiological nutrients and compromise pancreatic beta cell function following prolonged exposure.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002208:Caproates / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology; D007700:Kinetics; D013386:Succinates / Q000494:pharmacology*
D000596:Amino Acids; D002208:Caproates; D007328:Insulin; D007651:Keto Acids; D013386:Succinates; C013082:alpha-ketoisocaproic acid; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine; C041105:monomethyl succinate