The C peptide of proinsulin has since its discovery been considered to be without biological effect of its own [1]. In recent years it has been reported, however, that C peptide increases muscle blood flow, glucose and oxygen uptake of the exercising forearm, decreases urinary albumin excretion and improves autonomic nerve function in patients with Type I (insulin-dependent) diabetes mellitus [2±6]. Moreover, C peptide has been shown to stimulate Na + ,K + -ATPase activity in renal tubular cells [7] and to activate the nitric oxide (NO) synthase of endothelial cells [8]. The rat has two proinsulins and thus two C peptides that differ with regard to two amino acids in the middle segment of the molecule [9]. Rat C peptide I and II are equipotent in their ability to stimulate Na + ,K + -ATPase [7]. Studies on isolated muscle strips from Type I diabetic patients and healthy subjects have confirmed the effect of C peptide on glucose transport in vivo and indicated that the stimulation occurs through pathways that do not include the insulin receptor [10]. C peptide does not, however, stimulate muscle glycogen synthesis in isolated mouse muscle [11]. Recent data show that glucose transport in rat muscle and adipose tissue can be Diabetologia (1999)
AbstractAims. To study the effects of physiological concentrations of rat proinsulin C peptide I and II, respectively, on whole body glucose utilization in streptozotocin diabetic and healthy rats. Methods. A sequential insulin clamp procedure was used (insulin infusion rates 3.0 and 30.0 mU × kg ±1 × min ±1 ) in awake animals. C-peptide infusion rates were 0.05 and 0.5 nmol × kg ±1 × min ±1 . Blood glucose was clamped at 7.7 ± 0.3 mmol/l in the diabetic rats and at 3.9 ± 0.1 mmol/l in the healthy rats. Results. In diabetic rats infused at lower rates of C peptide and insulin, glucose utilization increased by 79±90 % (p < 0.001) compared with diabetic animals infused with saline and insulin. Increasing the rate of C-peptide infusion tenfold did not elicit a statistically significant further increase in glucose utilization. C peptide I and II exerted similar effects. The metabolic clearance rate for glucose in the diabetic animals infused with C peptide was not different from that of the healthy rats. During high-dose insulin infusion (30.0 mU´kg ±1´m in ±1 ) glucose utilization increased considerably and no statistically significant C-peptide effects were observed. About 85 % of the increase in glucose utilization induced by C peptide could be blocked by treatment with N-monomethyl-l-arginine. Conclusions/interpretation. Physiological concentrations of homologous C peptide stimulate whole body glucose utilization in diabetic but not in healthy rats. C peptide I and II elicit similar effects. The influence of C peptide on glucose utilization may be mediated by nitric oxide. [Diabetologia (1999) 42: 958±964]