Zn2+ chelation by serum albumin improves hexameric Zn2+-insulin dissociation into monomers after exocytosis

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Abstract
β-cells release hexameric Zn2+-insulin into the extracellular space, but monomeric Zn2+-free insulin appears to be the only biologically active form. The mechanisms implicated in dissociation of the hexamer remain unclear, but they seem to be Zn2+ concentration-dependent. In this study, we investigate the influence of albumin binding to Zn2+ on Zn2+-insulin dissociation into Zn2+-free insulin and its physiological, methodological and therapeutic relevance. Glucose and K+-induced insulin release were analyzed in isolated mouse islets by static incubation and perifusion experiments in the presence and absence of albumin and Zn2+ chelators. Insulin tolerance tests were performed in rats using different insulin solutions with and without Zn2+ and/or albumin. Albumin-free buffer does not alter quantification by RIA of Zn2+-free insulin but strongly affects RIA measurements of Zn2+-insulin. In contrast, accurate determination of Zn2+-insulin was obtained only when bovine serum albumin or Zn2+ chelators were present in the assay buffer solution. Albumin and Zn2+ chelators do not modify insulin release but do affect insulin determination. Preincubation with albumin or Zn2+ chelators promotes the conversion of “slow” Zn2+-insulin into “fast” insulin. Consequently, insulin diffusion from large islets is ameliorated in the presence of Zn2+ chelators. These observations support the notion that the Zn2+-binding properties of albumin improve the dissociation of Zn2+-insulin into subunits after exocytosis, which may be useful in insulin determination, insulin pharmacokinetic assays and islet transplantation.
Funding Information
  • Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CB07/08/0006)
  • Instituto de Salud Carlos III (PI14/010015)
  • Instituto de Salud Carlos III (RD/0012/0028)
  • Junta de Andalucía (PAI-BIO311)
  • Junta de Andalucía (PAI-CTS576)
  • Instituto de Salud Carlos III (RD16/0011/0009)
  • Instituto de Salud Carlos III (PI16/00259)

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