Diabetes complications.

C-peptide John Wahren (Stockholm, Sweden) discussed the mechanism of action and biological role of C-peptide. He stated that C-peptide should be considered as an endogenous peptide hormone, playing an important role in the maintenance of vascular homeostasis and exerting physiological effects of importance for the prevention and treatment of type 1 diabetes. C-peptide is stored with insulin in -cell granules, and the two are secreted in equimolecular amounts, although unlike insulin, C-peptide escapes first-pass hepatic clearance and is only cleared by the kidneys, so that circulating concentrations are 10 times higher than those of insulin. Wahren addressed the question of whether there is evidence of a role of C-peptide deficiency in the microvascular diseases associated with diabetes, noting that persons with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) who maintained C-peptide in low but sustained levels showed reduced incidence of long-term complications and had greater ability to avoid hypoglycemia (1). Pancreatic or islet cell transplantation with restoration of endogenous C-peptide leads to amelioration and, in some experimental settings, to reversal of neuropathy and nephropathy. In patients and in animal models, Cpeptide corrects glomerular hyperfiltration at the onset of diabetes, reduces albuminuria, and decreases mesangial matrix expansion. C-peptide also increases sensory and motor nerve conduction velocity (NCV) in the early phase of diabetic neuropathy and ameliorates or reverses diabetes-induced nerve structural changes. C-peptide administration increases blood flow in peripheral nerve, kidney, skeletal muscle, myocardium, and skin; accelerates myocardial repolarization; increases ventricular contraction and relaxation velocities; improves stroke volume; improves erythrocyte deformability; and increases muscle glucose uptake. Wahren commented that there is no effect of C-peptide in healthy persons but only in persons with type 1 diabetes who have C-peptide deficiency. Wahren noted that it has been difficult to demonstrate binding of C-peptide with radioligand-binding techniques. Using fluorescence correlation spectroscopy with rhodamine-labeled C-peptide, it is possible to measure the diffusion time of C-peptide in tiny (0.2-fl) volumes in incubation medium, as compared with such measures in similar volumes present just above cell membranes, renal tubular cells, and many other cell types, which show markedly delayed average diffusion time above the cell membrane, suggesting binding. This phenomenon shows competitive dislocation by unlabeled Cpeptide, but not by insulin, proinsulin, IGF-I, IGF-II, or neuropeptide Y, confirming specificity. Using the technique, renal cells show C-peptide binding in the low nanomolar range, with saturation at 1 nmol/l in the physiologic range, explaining the lack of effect of exogenous C-peptide in persons without type 1 diabetes who possess endogenous Cpeptide. C-peptide increases calcium influx (2), further suggesting its biologic effect. C-peptide increases Na,K ATPase activity of renal tubular cells (3), an effect blocked by pertussis toxin. In vivo, streptozotocin (STZ)-induced diabetes is associated with decreased Na,K ATPase activity, which can be substantially restored with C-peptide administration (4). C-peptide also increases endothelial nitric oxide (NO) synthase (eNOS) activity and, over time, increases eNOS expression (5), suggesting a vasodilatory function. In a study reported at the meeting, Kobayashi et al. (abstract 140) showed that both insulinand C-peptide–stimulated mitogen-activated protein kinase phosphorylation in cultured human aortic smooth muscle cells but that C-peptide decreased protein kinase B phosphorylation and increased translocation of Rho GTPbinding protein to the cell membrane, whereas insulin increased protein kinase B phosphorylation and had no effect on Rho. Sciatic nerve blood flow is decreased with STZ-induced diabetes and partially restored by C-peptide administration (6). In persons with type 1 diabetes, with a stepped C-peptide infusion increasing Cpeptide from 0 to 0.3 and to 1.1 nmol/l, forearm blood flow increases in a dosedependent fashion. C-peptide also may have insulinomimetic effects, acting on the insulin receptor tyrosine kinase (7). Wahren presented a model suggesting that C-peptide increases Ca influx, increasing eNOS and Na,K ATPase, acting via a G-protein–coupled receptor that increases protein kinase C (PKC) activity, and stimulating the ERK 1/2 and p38 mitogen-activated protein kinase pathways. Bo-Lennart Johansson (Stockholm, Sweden) discussed renal findings in humans with diabetes and in experimental diabetes. He reviewed the early findings of nephropathy in type 1 diabetes, with glomerular hyperfiltration, loss of renal functional reserve, renal enlargement, and glomerular hypertrophy with basal membrane thickening and microalbuminuria, as well as late findings of macroalbuminuria and hypertension and gradual loss of renal function. Glycemia and antihypertensive treatment have beneficial effect, but the underlying mechanisms are not fully understood. Lack of C-peptide may be one of the contributing factors, so that replacement might prevent or retard development of diabetic nephropathy in type 1 diabetes. 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