Proinsulin human

Summary

Human biosynthetic proinsulin is a recombinant precursor of insulin that has been investigated as a therapeutic for diabetes. It binds the insulin receptor with lower potency than insulin, exhibits a longer circulating half‑life, and shows a modest hepatospecific effect. Early clinical studies explored intravenous and subcutaneous dosing, including basal infusion in type I diabetes and twice‑daily administration in type II diabetes, to assess glucose control and metabolic effects.

Mechanism of Action

Proinsulin retains the three‑domain structure of insulin but its C‑peptide remains attached, resulting in weaker activation of the insulin receptor (≈8–12 % of insulin potency). The intact molecule has a slower clearance, prolonging its plasma half‑life, and appears to act preferentially on hepatic glucose production, producing a modestly hepatospecific response. Its antilipolytic activity is relatively stronger, influencing triglyceride metabolism and HDL2 levels.

What the Research Shows

Human proinsulin has been studied in healthy volunteers (IV dosing) where it produced a delayed but more prolonged hypoglycaemic nadir and stronger antilipolysis than insulin. In type I diabetics, basal subcutaneous infusion of proinsulin via CSII improved mean glucose, variability and M‑value compared with basal insulin, without changing bolus requirements. In type II diabetes, short‑term trials showed similar fasting glucose and hepatic glucose output to NPH insulin, but a marked reduction in plasma triglycerides and an increase in HDL2‑cholesterol. A review of preclinical and clinical data noted marginal hepatospecificity and lower intra‑subject variability, yet multicentre trials failed to demonstrate unique efficacy and reported six myocardial infarctions (two fatal) in long‑term proinsulin users, leading to suspension of further trials.

Reported Benefits

Clinical observations suggest proinsulin’s longer half‑life yields a more sustained glucose‑lowering effect, allowing better basal control in type I diabetes. Its weaker peripheral potency may reduce the risk of severe hypoglycaemia. In type II diabetes, proinsulin has been associated with reductions in plasma triglycerides and increases in HDL2‑cholesterol, indicating a potentially favourable impact on cardiovascular risk markers.

Limitations of the Evidence

Proinsulin is only about 10 % as active as insulin for glucose disposal, requiring higher doses for equivalent effect. Trials have not consistently shown superior glycaemic outcomes versus established insulins. The safety signal of myocardial infarctions in long‑term studies, combined with the lack of clear efficacy advantage, led to cessation of clinical development. Evidence remains limited to short‑term, small‑scale studies.

Safety Considerations

Proinsulin produces a stronger antilipolytic response, which may affect lipid metabolism. While immunogenicity appears low, cardiovascular safety is a concern: multicentre studies reported several myocardial infarctions, including deaths, in patients receiving proinsulin for ≥1 year. No severe hypoglycaemia was noted at equipotent doses, but the delayed glucose nadir warrants careful monitoring. Overall, safety data are insufficient to support routine clinical use.

How It Is Administered

Research protocols have employed intravenous bolus dosing and subcutaneous injection, including basal infusion via insulin pumps (CSII). Formulations used were biosynthetic human proinsulin without added retardation agents. Dosing strategies varied from unit‑equivalent IV administration to split subcutaneous doses administered twice daily.

Routes of Administration

Goals & Uses

• Study insulin biosynthesisResearchHigh
• Investigational hypoglycemic agentTherapeutics / MetabolicLow
• Research tool for insulin biosynthesisBasic ResearchHigh
• Insulinoma diagnosisDiagnostics / OncologyHigh
• Develop insulin analoguesDrug DevelopmentModerate
• Biomarker of beta-cell functionDiagnostics / EndocrinologyHigh

Contraindications

• Insulin hypersensitivityImmunologicHigh
• HypoglycemiaMetabolicHigh

Adverse Effects

• HypoglycemiaMetabolicUncommonAbnormally low blood glucose
• Injection site reactionsLocalUncommon
• Immunogenicity / antibody formationImmunologicUnknown

Drug Interactions

• SulfonylureasModerateMay increase risk of low blood sugar
• Insulin and insulin analoguesModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Renal impairmentOrgan ImpairmentRelative
• Pediatric populationsAgeRelative

Regulatory Status

• European UnionUnapprovedNot approved by EMA. Used as a laboratory diagnostic marker and research tool only.
• United StatesUnapprovedAvailable only as a research chemical.
• United KingdomUnapprovedNot approved by MHRA for therapeutic use. Diagnostic assays for serum proinsulin are available through NHS laboratories.

Not approved for therapeutic use; available as a research grade peptide.

Evidence & Sources

• Biosynthetic human proinsulin, a new therapeutic compound for diabetics? A comparative study of biosynthetic human proinsulin with biosynthetic human insulin
  Journal ArticleModerateRosak C, et al.1988-01-01T00:00:00.000000Z
• Proinsulin as a possible therapeutic agent
  Journal ArticleModerateHadjidakis DJ, Raptis SA1992-01-01T00:00:00.000000Z
• Substitution of basal delivery of insulin by proinsulin in type I diabetic patients under CSII
  Journal ArticleModerateKerner W, et al.1988-01-01T00:00:00.000000Z
• Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience
  Journal ArticleModerateGalloway JA, et al.1992-01-01T00:00:00.000000Z
• Metabolic effects of biosynthetic human proinsulin in type 2 diabetes mellitus
  Journal ArticleModerateKlauser R, et al.1989-01-01T00:00:00.000000Z
• Effects of biosynthetic human proinsulin on plasma lipids in type 2 diabetes mellitus
  Journal ArticleModerateDrexel H, et al.1988-01-01T00:00:00.000000Z

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