Molecular basis for the insulinomimetic effects of C-peptide

• Published in: Diabetologia 2001-10, Vol.44 (10), p.1247-1257
• Main Authors: GRUNBERGER, G, QIANG, X, LI, Z, MATHEWS, S. T, SBRISSA, D, SHISHEVA, A, SIMA, A. A. F
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Amino Acids - metabolism; Animals; Biological and medical sciences; C-Peptide - pharmacology; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Line; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation - drug effects; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glycogen - biosynthesis; Glycogen Synthase Kinase 3; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Medical sciences; Mice; Mitogen-Activated Protein Kinases - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Pertussis Toxin; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Receptor, Insulin - metabolism; Ribosomal Protein S6 Kinases - metabolism; Signal Transduction; Virulence Factors, Bordetella - pharmacology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s001250100632

C-peptide, released by the beta-cells of pancreatic islets, elicits salutary responses in Type I (insulin-dependent) diabetes mellitus but the molecular mechanisms behind these effects are not known. We assessed whether synthetic rat C-peptide stimulates insulin-like cellular effects in a classic insulin target tissue. To clarify the molecular mechanisms involved in several insulinomimetic actions, we investigated the effect of C-peptide on the insulin signalling pathway in rat skeletal muscle cells. We used L6 myoblasts and myocytes to measure the effects of C-peptide or insulin or both on glycogen synthesis and amino acid uptake. We also studied the effects of C-peptide on insulin receptor autophosphorylation, its tyrosine kinase activity, phosphorylation of IRS-1, PI 3-kinase, Akt, p90Rsk, MAPK, and GSK3 in these cells. In L6 cells, physiological concentrations of C-peptide (0.3-3 nmol/l) significantly activated insulin receptor tyrosine kinase, IRS-1 tyrosine phosphorylation, PI 3-kinase activity, MAPK phosphorylation, p90Rsk, and GSK3 phosphorylation. A scrambled C-peptide sequence - the control - showed no effects. Wortmannin blocked C-peptide-induced glycogen synthesis while pertussis toxin had no effect. Only submaximal insulin concentrations (up to 10 nmol/l) combined with submaximal C-peptide concentrations led to additive effects. C-peptide added to the maximal insulin dose (100 nmol/l) did not increase the effect of insulin alone. We thus conclude that the same signalling elements are used by both ligands. However, the lack of Akt activation by C-peptide and the bell-shaped dose response induced by C-peptide indicate that C-peptide has some effects by another distinct mechanism. We speculate that C-peptide could modulate the metabolic effects of insulin by enhancing them at low hormone concentrations and dampening them at high hormone concentrations.