The Metabolic Effects of Biosynthetic Human Proinsulin in Individuals with Type I Diabetes*

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Abstract
To assess the significance of deficiency of circulating proinsulin in patients with type I diabetes mellitus, we studied the metabolic effects of biosynthetic human proinsulin in 24 patients.After withdrawing insulin, an infusion of proinsulin to physiological plasma levels did not prevent elevations of plasma glucose or β-hydroxybutyrate. During steady state infusions of insulin and proinsulin, 13.7 times the steady state plasma level of proinsulin compared to insulin was required to maintain euglycemia. This finding indicates that proinsulin is approximately 7.3% as biologically active as insulin on a molar basis in maintaining glucose control. The MCRs of insulin and proinsulin during these steady state infusions were 12.5 ± 2.2 (±SEM) and 2.62 ± 0.33 ml/kg-min, respectively. After maintaining euglycemia overnightwith an infusion of insulin or proinsulin and then acutely stopping these infusions, the rise in plasma glucose after proinsulin was delayed significantly compared to insulin, consistent with proinsulin's slower clearance. Further studies are necessary to determine whether biosynthetic human proinsulin has a specific role in the treatment of diabetes.