C-Peptide: From Biosynthetic Byproduct to Potential Therapeutic Agent for Diabetic Complications

I. Introduction to C-Peptide

A. Historical Context and Evolving Understanding

C-peptide, or connecting peptide, was first identified as the segment linking the A- and B-chains within the proinsulin molecule.[1] For many years following its discovery, it was largely considered a biologically inert byproduct of insulin biosynthesis, with its primary clinical utility being a marker for endogenous insulin production and pancreatic β-cell function.[3] This perception stemmed from early studies that failed to demonstrate direct insulin-like effects on glucose metabolism.[4] The measurement of C-peptide levels became, and remains, a valuable tool in distinguishing between type 1 and type 2 diabetes mellitus (T1DM and T2DM), assessing residual β-cell function in insulin-treated patients, and evaluating states of hypoglycemia.[3]

However, over the past few decades, a paradigm shift has occurred. A growing body of evidence from preclinical and clinical studies has revealed that C-peptide is, in fact, a biologically active peptide hormone with its own specific cellular targets and physiological effects.[4] This revised understanding was partly fueled by observations that T1DM patients who retained some level of endogenous C-peptide production experienced a lower incidence and severity of chronic microvascular complications, such as neuropathy, nephropathy, and retinopathy, compared to those with no detectable C-peptide.[4] This suggested a protective role for the peptide, independent of insulin's glycemic control. The historical undervaluation of C-peptide's intrinsic bioactivity likely delayed concerted research into its therapeutic potential for these debilitating diabetic complications. The initial focus on insulin as the sole active product of proinsulin processing, coupled with C-peptide's lack of direct glucose-lowering effects, contributed