C-Peptide: the missing link in diabetic nephropathy?

Abstract

Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-beta1 and TNFalpha signaling. Several of C-peptide's reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this review, we critically summarize the current state of knowledge regarding C-peptide's renal effects, and discuss possible mechanisms of its beneficial effects in diabetic nephropathy.

Figure 1. The Starling equation

The equaltion includes the effect of hydrostatic and oncotic forces on the movement of fluid across capillary membranes. The equation above is modified for approximating GFR, but can be applied to all capillary flow.

Figure 2. C-peptide-induced constriction of isolated renal afferent arteriole from a diabetic mouse

A: the arteriole at baseline. B: the arteriole after 15 minutes of C-peptide perfusion. C: the arteriole after 30 minutes of C-peptide perfusion.

Figure 3. Constriction of afferent arterioles

C-peptide induces dose-dependent constriction of afferent arterioles in diabetic mice. No effect was seen for scrambled C-peptide or vehicle. Via normalization of hyperfiltration, this may be one of the mechanisms in the renoprotective action of C-peptide. Modified from [24].

Figure 4. Urinary albumin excretion

Geometric means of urinary albumin excretion in type 1 diabetic patients given C-peptide plus insulin (filled columns) or placebo plus insulin (open columns) for 3 months. Asterisks indicate significant differences from the baseline period. Modified from [4].