Renal effects of C-peptide in experimental type-1 diabetes mellitus

Sammanfattning: The incidence and prevalence of diabetic nephropathy are increasing continuously, mainly due to the increase in type-2 diabetes. In contrast, the risk of diabetic nephropathy for the individual patient has decreased considerably in recent decades due to improved glycemic control, successful treatment of hypertension and hyperlipidemia and the use of renin angiotensin system inhibitors, which have protective effects beyond those on blood pressure. However, optimal glycemic control and normal blood pressure offer only incomplete protection from diabetic nephropathy. Thus, other factors are likely to be involved. In type-1 diabetes, one such factor may be proinsulin C-peptide. C-peptide has been thought to lack metabolic effects but in the past decade several studies have shown that C-peptide itself can be beneficial in preventing diabetic complications. The aims of the studies in this thesis have been to further evaluate the functional and morphological effects of C-peptide in the kidneys in experimental diabetes. Furthermore, the aim was to compare the C-peptide effects with those of an angiotensin concerting enzyme inhibitor (ACEI) and to evaluate the effects of combined C-peptide and ACEI treatment. Studies were performed in streptozotocin diabetic Sprague-Dawley and Wistar rats and the results demonstrate that C-peptide prevents or reduces diabetes-induced glomerular hyperfiltration by 17-42% (p<0.01) and urinary albumin excretion and urinary albumin/creatinine ratio. Furthermore, C-peptide reduces glomerular and renal hypertrophy by 19-32% (p<0.01), glomerular mesangial matrix fraction by 37% (p<0.001), glomerular expression of type-IV collagen by 42% (p<0.001) and prevents diabetes-induced overexpression of receptors for advanced glycation end products (RAGE). In addition, C-peptide and captopril are equally effective in preventing glomerular hyperfiltration, albuminuria and glomerular RAGE expression, besides having additive effects in lowering glomerular type-IV collagen by 90% (p<0.001) and glomerular filtration fraction (p<0.05). C-peptide does not affect renal blood flow significantly more than placebo. In conclusion, in experimental type-1 diabetes, C-peptide beneficially affects risk factors or manifestations of diabetic nephropathy such as glomerular hyperfiltration, albuminuria, glomerular hypertrophy, mesangial matrix expansion and glomerular expression of type-IV collagen and RAGE. There may also be potentially beneficial effects from combining Cpeptide and an ACEI in preventing this complication in type-1 diabetes.