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Experimental Diab. Res., 5:25–36, 2004 c Copyright Taylor and Francis Inc. ISSN: 1543-8600 print / 1543-8619 online DOI: 10.1080/15438600490424497 The C-peptide Signaling George Grunberger1 and Anders A. F. Sima2 1Grunberger Diabetes Institute, Bloomfield Hills, Michigan, USA 2Departments of Pathology and Neurology and Morris Hood Jr. Comprehensive Diabetes Center, Wayne State University, Detroit, Michigan, USA of a specific cell-surface peptide receptor, and by the seemingly For years an assumption was made that C-peptide, a satisfactory explanation of C-peptide’s role as a substance al- byproduct of insulin biosynthesis, possessed no apprecia- lowing proper folding of the proinsulin molecule. That view ble physiologic role. As other contributions in this volume has undergone transformation over the past decade as data have amply testify, the time has come to re-evaluate that notion. accumulated showing diverse biological effects after adminis- C-peptide either directly through interaction with its spe- cific cell-surface receptor or indirectly through an interac- tration of C-peptide. These results are described in detail else- tion with a related membrane entity, exerts a unique effect where in this volume. To summarize, in several animal models on several intracellular processes. We review here results of of diabetes and in patients with autoimmune insulin-deficient studies attempting to elucidate such molecular effects of (type 1) diabetes mellitus, C-peptide replacement seems to en- C-peptide in different cell systems and tissues. Lacking a hance skin and skeletal muscle blood flow, to improve renal purified C-peptid