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Phosphoinositolglycan-Peptides from Yeast Potently Induce Metabolic Insulin Actions in Isolated Rat Adipocytes, Cardiomyocytes, and Diaphragms

Hoechst AG, Hoechst Marion Roussel (G.M., S.W., A.C.), Research Site Frankfurt, D-65926 Frankfurt am Main, Germany; and Laboratory of Molecular Cardiology (A.K., J.E.), Diabetes Research Institute, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany

Address all correspondence and requests for reprints to: Dr. Günter Müller, Hoechst AG, Hoechst-Marion-Roussel, Research Site Frankfurt, DG Metabolic Diseases, Building H825, D-65926 Frankfurt a.m., Germany.

Polar headgroups of free glycosyl-phosphatidylinositol (GPI) lipids or protein-bound GPI membrane anchors have been shown to exhibit insulin-mimetic activity in different cell types. However, elucidation of the molecular mode of action of these phospho-inositolglycan (PIG) molecules has been hampered by 1) lack of knowledge of their exact structure; 2) variable action profiles; and 3) rather modest effects. In the present study, these problems were circumvented by preparation of PIG-peptides (PIG-P) in sufficient quantity by sequential proteolytic (V8 protease) and lipolytic (phosphatidylinositol-specific phospholipase C) cleavage of the GPI-anchored plasma membrane pro-tein, Gce1p, from the yeast Saccharomyces cerevisiae. The structure of the resulting PIG-P, NH₂-Tyr-Cys-Asn-ethanolamine-PO₄-6(Man1–2)Man1–2Man1–6Man1–4GlcNH₂1–6myo-inositol-1,2-cyclicPO₄, was revealed by amino acid analysis and Dionex exchange chromatography of fragments generated enzymatically or chemically from the neutral glycan core and is in accordance with the known consensus structures of yeast GPI anchors. PIG-P stimulated glucose transport and lipogenesis in normal, desensitized and receptor-depleted isolated rat adipocytes, increased glycerol-3-phosphate acyltransferase activity and translocation of the glucose transporter isoform 4, and inhibited isoproterenol-induced lipolysis and protein kinase A activation in adipocytes. Furthermore, PIG-P was found to stimulate glucose transport in isolated rat cardiomyocytes and glycogenesis and glycogen synthase in isolated rat diaphragms. The concentration-dependent effects of the PIG-P reached 70–90% of the maximal insulin activity with EC₅₀-values of 0.5–5 µM. Chemical or enzymic cleavages within the glycan or peptide portion of the PIG-P led to decrease or loss of activity. The data demonstrate that PIG-P exhibits a potent insulin-mimetic activity which covers a broad spectrum of metabolic insulin actions on glucose transport and metabolism.

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