An update on the potential role of C-peptide in diabetes and osteoporosis

Purpose: C-peptide secretion is deficient or absent in type 1 diabetes mellitus. It is well accepted that insulin replacement therapy cannot prevent the development of long-term diabetes-related complications, which can often be disabling or even life-threatening. Several cross-sectional investigations have suggested that residual C-peptide production in patients with type 1 diabetes mellitus would help prevent a number of complications. In animal models of diabetes and in patients with type 1 diabetes mellitus, C-peptide replacement improves renal function, skin and skeletal muscle blood flow, nerve conduction, glucose utilization, and other diabetes-related complications. Recent investigations suggest a new beneficial effect of C-peptide, which to date has never been studied. It is known that osteoporosis is the most prevalent short-term complication in type 1 diabetes mellitus. This review will highlight new insights into the pathophysiology and future therapeutic modalities for osteoporosis in individuals with diabetes. Methods: This review provides a concise summary of old and new insights into the role of C-peptide in diabetes-related complications. Results: The data suggest that C-peptide is a bioactive peptide, acting independently of insulin, which binds to a G-protein-coupled membrane binding site in different cell types. By triggering Ca2+-dependent intracellular signaling pathways, both Na+, K+-ATPase and endothelial nitric oxide synthase are activated. C-peptide may act on osteoblast cells by ERK 1/2 pathway activation, modulate collagen biosynthesis and RANKL expression. Furthermore, C-peptide-deficient postmenopausal women, not affected by diabetes, have a lower bone mineral density than those with normal C-peptide levels. Conclusion: Taken together these studies encourage further investigations to elucidate the role of C-peptide in preventing bone loss in type 1 diabetes mellitus and in those individuals with C-peptide deficiency and osteoporosis.