title: Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation.
abstract: The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that signals for glucose-stimulated insulin secretion and proinsulin biosynthesis diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, and acetoacetate were investigated as candidate stimulus-coupling signals specific for glucose-induced proinsulin biosynthesis in rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed comparable effects on proinsulin biosynthesis and total protein synthesis. Although it is a cofactor, ATP is unlikely to be a metabolic stimulus-coupling signal specific for glucose-induced proinsulin biosynthesis. Neither glutamic acid methyl ester nor acetoacetic acid methyl ester showed a specific effect on glucose-stimulated proinsulin biosynthesis. Interestingly, among Krebs cycle intermediates, only succinic acid monomethyl ester specifically stimulated proinsulin biosynthesis. Malonic acid methyl ester, an inhibitor of succinate dehydrogenase, also specifically increased glucose-induced proinsulin biosynthesis without affecting islet ATP levels or insulin secretion. Glucose caused a 40% increase in islet intracellular succinate levels, but malonic acid methyl ester showed no further effect, probably due to efficient conversion of succinate to succinyl-CoA. In this regard, a GTP-dependent succinyl-CoA synthetase activity was found in cytosolic fractions of pancreatic islets. Thus, succinate and/or succinyl-CoA appear to be preferential metabolic stimulus-coupling factors for glucose-induced proinsulin biosynthesis translation.
authors.affiliation: Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alarcon
authors.forename: Barton
authors.initials: B
authors.lastname: Wicksteed
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Corkey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D002458:Cell Fractionation; D005650:Fumarates / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008293:Malates / Q000378:metabolism; D008297:Male; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011384:Proinsulin / Q000096:biosynthesis / Q000235:genetics*; D014176:Protein Biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013004:Somatostatin / Q000494:pharmacology; D013379:Substrate Specificity; D013386:Succinates / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D005650:Fumarates; D008293:Malates; D013386:Succinates; D013004:Somatostatin; D000255:Adenosine Triphosphate; D011384:Proinsulin; D005947:Glucose; D002118:Calcium