Therapeutic potential of C-peptide on diabetic nephropathy

A number of experimental studies and clinical trials have attempted to identify whether C-peptide has any renoprotective effects. The short-term effects of C-peptide on renal function have been examined in STZ-induced diabetic rats (Sjoquistet al., 1998). Continuous infusion of human C-peptide for 1 h diminished glomerular hyperfiltration and proteinuria, and improved renal functional reserve, whereas scrambled C-peptide had no effect. Similar results have been reported and C-peptide also ameliorated glomerular hyperfiltration to a similar extent as that caused by the angiotensin converting enzyme (ACE) inhibitor, captopril (Samnegardet al., 2004). However, the effect of C-peptide on blood flow was less than that mediated by captopril and no additive effects of these two agents were seen. The effects of longer C-peptide administration on renal function and morphology have also been studied. IV infusion of C-peptide for 14 days at physiological concentrations prevented the development of glomerular hyperfiltration, glomerular hypertrophy and albuminuria, and preserved the existing renal functional reserve in STZ-induced diabetic rats (Samnegard et al., 2001). Furthermore, glomerular volume expansion induced by diabetes in rats was partially alleviated by C-peptide (Samnegard et al., 2001). Indeed, glomerular volume in treated rats exceeded that of the control by no more than 23% compared with a 63 % increase in untreated diabetes rats. Moreover, C-peptide caused a dose-dependent lowering of GFR by 40 % and urinary albumin excretion by 50 % in STZ-induced diabetes rats (Huang et al., 2002). In that study, healthy control rats were unresponsive to C-peptide. At a later time point, treatment of STZ-induced diabetes rats with C-peptide for 4 weeks elicited improvements in renal function by preventing glomerular hypertrophy and mesangial matrix expansion (Samnegard et al., 2005). Similar findings were reported in STZ-induced diabetic mice treated with C-peptide for 7 days. These mice had decreased microalbuminuria and reduced glomerular expression of transforming growth factor-b (TGF-b), a profibrotic cytokine, and type IV collagen (Maezawa et al., 2006). In microdissection and microperfusion studies of glomeruli from rats and mice with induced diabetes, C-peptide constricted afferent glomerular arterioles and dilated efferent glomerular arterioles, providing a potential mechanism by which it was able to reduce glomerular hyperfiltration (Nordquist et al., 2008a; Nordquist et al., 2009). Urinary sodium loss was also reduced in STZ-induced diabetic rats treated with C-peptide for 4 weeks at physiological concentrations, in addition to other improvements in renal function (Rebsomen et al., 2006).