Comparative study of hormonal counterregulation during GCIIS-guided hypoglycemia tests using human proinsulin and...

Counterregulatory effect following administration of biosynthetic human proinsulin (BHPI) and human insulin (BHI) were compared during hypoglycemia standardized by means of a glucose controlled insulin infusion system (GCIIS). A total of 0.148 +/- 0.010 U/kg of BHPI had to be given by the GCIIS in order to obtain a minimal blood glucose (BG) of 26 +/- 2 mg/dl (means +/- SEM) at 43 +/- 2 min. In contrast, 0.083 +/- 0.004 U/kg of BHI were sufficient to produce a minimal BG of 21 +/- 1 mg/dl (n.s.) at 35 +/- 1 min. (P less than 0.005). Moreover, BHPI infusion resulted in prolonged hypoglycemia and delayed blood glucose recovery. On a molar basis, the acute BG lowering effect of BHPI was about 13% that of BHI (BHPI 3.94 +/- 0.27 vs. BHI 0.51 +/- 0.03 nmol/kg). Serum proinsulin after BHPI reached its maximum of 19.4 +/- 2 pmol/ml at 20 min. and still exceeded basal values markedly at the end of the test period at 240 min. Serum insulin peaked at 10 min. (162 +/- 47 microU/ml) and had already returned to basal values (7.5 +/- 1 microU/ml) after 45 min. No severe side effects were observed and there was no need for glucose administration, but clinical symptoms of hypoglycemia were more pronounced after BHPI. Compared to BHI, BHPI produced a higher cortisol peak (252 +/- 16 vs. 168 +/- 10 ng/ml), a more pronounced secretion of ACTH and GH as well as a stronger decline of serum potassium (3.20 +/- 0.06 vs. 3.58 +/- 0.08 mmol/l). Counterregulatory prolactin secretion did not differ significantly. Urinary epinephrine secretion following hypoglycemia after BHPI exceeded that after BHI (10.3 +/- 4.8 vs. 3.0 +/- 0.5 ng/120 min.). Serum lactate increase after BHPI was more prolonged (1.68 +/- 0.24 vs. 0.37 +/- 0.14 mmol/l at 120 min.). BHPI-induced inhibition of lipolysis, as determined by free fatty acid patterns, was delayed and less pronounced. Our results indicate that the observed more distinct glucose counterregulation is due to prolonged hypoglycemia rather than to any specific BHPI action on the hypothalamic-pituitary axis. We regard this as a consequence of the prolonged circulating and biological half-life. A preferential proinsulin action on the liver may play an additional role. Whether this "depot effect" may be beneficial in the treatment of diabetes mellitus remains to be established.