An inositol phosphate glycan derived from a Trypanosoma brucei glycosyl-phosphatidylinositol mimics some of the metabolic actions of insulin.
Some of the acute actions of insulin may be mediated by an enzyme-modulating inositol phosphate glycan, produced by the insulin-sensitive hydrolysis of glycosyl-phosphatidylinositol (GPI) that is structurally similar to a membrane protein anchor. An inositol glycan fragment from the structurally characterized Trypanosoma brucei variant surface glycoprotein GPI anchor is evaluated for insulin-mimetic antilipolytic activity. The fragment specifically and dose-dependently inhibits isoproterenol-stimulated lipolysis. Like the effect of insulin, glycan-induced antilipolysis is blocked by the low Km cAMP phosphodiesterase inhibitor imazodan (CI-914) and the serine/threonine phosphatase inhibitor, okadaic acid, suggesting that the activation of both cAMP phosphodiesterase and serine/threonine protein phosphatases are necessary. Moreover, this fragment causes a specific and dose-dependent inhibition of both microsomal glucose-6-phosphatase (EC 3.1.3.9) and cytosolic fructose-1,6-bisphosphatase (EC 3.1.3.11) activity. Additionally, direct addition of the glycan to hepatocytes caused marked inhibition of glucose production from pyruvate. These results suggest that the direct modification of the activities of these two gluconeogenic enzymes by an inositol glycan may play a role in the inhibition of glucose output by insulin and provide the first evidence for the insulin-mimetic properties of a chemically characterized inositol glycan.
Misek
D E
DE
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109.
Saltiel
A R
AR
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002241:Carbohydrates / Q000494:pharmacology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D006017:Glycolipids / Q000737:chemistry* / Q000494:pharmacology; D017261:Glycosylphosphatidylinositols; D007295:Inositol Phosphates / Q000302:isolation & purification* / Q000494:pharmacology*; D007700:Kinetics; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D010716:Phosphatidylinositols / Q000737:chemistry* / Q000494:pharmacology; D011134:Polysaccharides / Q000302:isolation & purification* / Q000494:pharmacology*; D011402:Pronase; D051381:Rats; D011919:Rats, Inbred Strains; D014346:Trypanosoma brucei brucei / Q000737:chemistry*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000737:chemistry* / Q000302:isolation & purification
D002241:Carbohydrates; D006017:Glycolipids; D017261:Glycosylphosphatidylinositols; D007295:Inositol Phosphates; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D011134:Polysaccharides; D014643:Variant Surface Glycoproteins, Trypanosoma; C028039:inositol phosphate glycan; D006597:Fructose-Bisphosphatase; D005952:Glucose-6-Phosphatase; D011402:Pronase