Diabetic nephropathy (DN) eventually affects about one third of patients affected by type 1 diabetes mellitus. Among the long-term complications of diabetes, DN retains the highest human, social, and economical costs. DN represents a leading cause of end-stage renal failure and the strongest predictor of premature death and cardiovascular disease in type 1 diabetes [24]. The risk of developing this complication is not linear with time, reaches a peak between 10 and 20 years of diabetes, and then declines, thus suggesting that only a subgroup of patients affected by type 1 diabetes may be susceptible to renal complications [25]. Recent clinical evidences suggest that, despite the continuous improvement of clinical protocols aimed to control glucose metabolism and blood pressure, the risk of developing end-stage renal disease as a consequence of DN has not significantly changed during the last 20 years [26]. Altogether these findings suggest that the cellular/molecular mechanisms leading to the development of DN are probably not yet fully understood and that further studies are needed to identify in advance patients predisposed to develop DN (at stages that precede the appearance of microalbuminuria) and, in parallel, to develop new drugs able to prevent the onset of DN rather than to modulate its progression.

That genetic factors may play a role in the development of DN is suggested by the clustering of this complication in families [27]. Furthermore, arterial blood pressure can be higher in parents of patients affected by type 1 diabetes and proteinuria than in parents of normoalbuminuric patients matched for age and duration of diabetes, suggesting that an inherited predisposition to essential hypertension may be related to the susceptibility to DN in patients affected by type 1 diabetes [28, 29].

This hypothesis was further supported by two independent studies [30, 31] showing an elevated activity of Na–Li countertransport in red blood cells of type 1 diabetic patients with DN. Elevated activity of Na–Li countertransport is presently considered the most consistent intermediate phenotype of essential hypertension [32, 33], and genetic epidemiology studies have suggested that the activity of this membrane transport can be explained by inheritance more than environmental factors, when a major gene and polygenic effects are taken into account [34, 35]. Subsequently, further evidences have confirmed that an increased activity of Na–Li countertransport predicts the development of both essential hypertension [36, 37] and DN [38] and cannot be therefore considered a mere consequence of the development of these human diseases. Studies aimed to identify the genetic component of essential hypertension and DN are presently underway; on this regard the recent demonstration that Na–Li countertransport is actually mediated by the first isoform of Na–H exchange [39], a sodium transport present in virtually all living cells where it is in charge of controlling the rate of proliferation, might potentially lead to the identification of polymorphisms of Na–H exchange associated with the development of essential hypertension and/or DN.

Although the natural history of DN is supposed to invariably end with a global glomerular sclerosis and consequent renal failure [40], recent studies demonstrated that long-lasting pancreas transplantation may reverse the glomerular lesions that characterize DN in man [41].

That long-term normoglycemia might by itself be responsible for the regression of lesions of DN is presently under debate [42]. Although the Diabetes Control and Complications Trial (DCCT) demonstrated that a reduction of the risk of developing microalbuminuria and a slower progression of existing nephropathy were associated to the improved HbA1c levels consequent to intensive insulin treatment, no clinical regression of established DN could be associated to this procedure [1, 43].

A major difference between intensive insulin treatment and pancreas transplantation is that the latter not only normalizes plasmatic insulin levels but also restores the physiologic concentration of C-peptide, the product, along with insulin, of the cleavage of proinsulin [44, 45].

Although for long time considered to have no biologic function, C-peptide is now considered as an active peptide hormone, independent of insulin with a specific G protein-coupled membrane receptor [46, 47]. Recent evidences suggest that C-peptide might have a protective role in the development of diabetic complications [48–50] both in animals and in humans. In line with this hypothesis, we have demonstrated the existence of a decreased C-peptide/creatinine ratio in plasma of type 1 diabetic patients with DN when compared to normoalbuminuric patients of similar age and duration of diabetes [51].

How C-peptide can possibly exert its beneficial effect is presently unknown. In animal models the Na–K pump activity is decreased by hyperglycemia, and C-peptide reverses this dysfunction [48]. Activation of Na–K pump by C-peptide was also demonstrated in man [52], but whether the protection of C-peptide from DN is mediated by this mechanism is still unclear, as the activity of the Na–K pump seems not to be decreased in DN [30].

Altogether a huge number of studies in the field did not allow to solve the problem whether C-peptide actually protects from the development of diabetic complications. The recent finding that preservation of C-peptide secretion has beneficial outcomes in type 1 diabetic patients adds to the ongoing dispute [53]. Clinical studies aimed in verifying the effect of the reintegration of physiologic levels of C-peptide on the development/regression of diabetic complications appear to be mandatory in order to clarify the issue.

The progression of diabetic nephropathy is characterized by a gradual decrease of the number of podocytes (the arborized, postmitotic, and terminally differentiated cells in charge of the selective permeability of glomerular filtration barrier) residing inside the renal glomerulus [54–56]. This phenomenon is paralleled by an increasing loss of these same cells with urine (so-called podocyturia) [57, 58].