Effect of C-Peptide on Glucose Metabolism in Patients With Type 1 Diabetes

In recent years, various biological activities of C-peptide have been confirmed, e.g., its ability to improve skin capillary blood flow in the feet, increase microvascular blood flow and oxygen uptake in the exercising forearm, decrease urinary albumin excretion, and improve nerve function in patients with type 1 diabetes (1,2). Furthermore, C-peptide stimulates glucose transport in human muscle strips of nondiabetic and diabetic subjects (3). Using a sequential insulin clamp technique, Li et al. (4) demonstrated that C-peptide in physiological concentrations stimulates body glucose utilization in diabetic rats. In a recent investigation by Grunberger et al. (5), C-peptide was shown to activate insulin receptor tyrosine kinase, insulin receptor substrate-1, tyrosine phosphorylation, phosphatidylinositol 3-kinase, mitogen-activated protein kinase phosphorylation, p90 Rsk (90-kDa ribosomal 56 protein kinase), and glycogen synthase kinase-3 phosphorylation. In addition, C-peptide mimics the effect of insulin, such as glycogen synthesis and amino acid uptake in rat muscle cells. However, in clinical studies involving C-peptide treatment for 1 or 3 months in type 1 diabetic patients, no clear-cut effect on blood glucose concentrations could be observed (2). In summary, it remains to be elucidated whether C-peptide has a clinically relevant metabolic effect in humans.

We studied the glucodynamic effects of intravenous C-peptide infusion during a euglycemic glucose clamp in patients with type 1 diabetes. A total of 10 patients (6 men and 4 women, aged 25–45 years, duration of diabetes 15 ± 10 years) with baseline C-peptide levels <0.1 mmol/l were included in this double blind, placebocontrolled, two-way crossover study. The patients arrived at the institute on the evening before the study. After admission, the patients were connected to a Biostator (Life Science Instruments, Elkhardt, IN) and remained fasting overnight. The blood glucose was stabilized at a target blood glucose level of 5.5 mmol/l by means of variable low-dose intravenous insulin infusion. Two hours before the start of the experimental procedure (C-peptide or placebo infusion), the insulin infusion was fixed at a constant rate of 0.2 mU · kg^–1 · min^–1. This infusion remained constant until the end of the experiments. The patients received C-peptide (98% purity; Clinalfa AG, Läufelfingen, Switzerland) intravenously in two different concentrations, 2 pmol · kg^–1 · min^–1 for 90 min and 8 pmol · kg^–1 · min^–1 for another 90 min. For placebo infusion, the patients received d-mannitol (Clinalfa AG) in an equal amount. Areas under the curve for glucose infusion rates were calculated for the infusion time of C-peptide or placebo.

The amount of insulin infused overnight was identical on both study arms. Also, not-significant differences were observed with respect to the time course of the insulin infusion and the insulin levels established. C-peptide infusion resulted in an increase of serum C-peptide levels during the low infusion period from 0 to 0.58 ± 0.20 nmol/l (means ± SD) and to 2.3 ± 0.67 nmol/l during the high infusion period (P < 0.01, respectively). In comparison with the metabolic effect observed during placebo infusion, the glucose infusion necessary to keep blood glucose constant was lower during the low C-peptide infusion period (26 [6–745] vs. 69 [33–132] mg · kg^–1 · min^–1; P < 0.05) (median [interquartile range]) and tended to be lower during the high infusion period (29 [10–104] vs. 88 [63–120] mg · kg^–1 · min^–1; P = 0.07). Total glucose consumption during the whole infusion period (180 min) was lower during C-peptide infusion compared with placebo infusion (48 [18–162] vs. 151 [51–287] mg · kg^–1 · min^–1; P < 0.05). Serum insulin levels were comparable during placebo and C-peptide infusion periods (13 ± 8 vs. 12 ± 8 μU/ml; NS).

In contrast to the results obtained with isolated human muscle strips and in streptozotocin-induced diabetic rats, our study could not demonstrate an activation of glucose metabolism during short-term C-peptide supplementation in patients with type 1 diabetes. In this context, it is interesting that Grunberger et al. (5) found that the maximal insulinomimetic effects of C-peptide on rat muscle cells could be reached in a low concentration range (0.3–3 nmol/l) and that higher doses of C-peptide blunted the stimulatory responses. The authors speculated that low C-peptide and insulin concentrations might be helpful for fuel storage and that high postprandial C-peptide concentrations could blunt the peripheral insulin effects. Since, in our study, postprandial C-peptide levels had been reached already within the low infusion range, it might be possible that the C-peptide levels reached in our human experiment reflect a postprandial state and that they were in a range in which insulin effects on glucose metabolism are sufficiently inhibited. Further studies are necessary to evaluate whether there are dose-dependent differences in the effect of C-peptide on glucose metabolism in patients with type 1 diabetes in a low concentration range.