Zn(II) ions co-secreted with insulin suppress inherent amyloidogenic properties of monomeric insulin

Abstract

Insulin, a 51-residue peptide hormone, is an intrinsically amyloidogenic peptide, forming amyloid fibrils in vitro. In the secretory granules, insulin is densely packed together with Zn(II) into crystals of Zn(2)Insulin(6) hexamer, which assures osmotic stability of vesicles and prevents fibrillation of the peptide. However, after release from the pancreatic beta-cells, insulin dissociates into active monomers, which tend to fibrillize not only at acidic, but also at physiological, pH values. The effect of co-secreted Zn(II) ions on the fibrillation of monomeric insulin is unknown, however, it might prevent insulin fibrillation. We showed that Zn(II) inhibits fibrillation of monomeric insulin at physiological pH values by forming a soluble Zn(II)-insulin complex. The inhibitory effect of Zn(II) ions is very strong at pH 7.3 (IC(50)=3.5 microM), whereas at pH 5.5 it progressively weakens, pointing towards participation of the histidine residue(s) in complex formation. The results obtained indicate that Zn(II) ions might suppress fibrillation of insulin at its release sites and in circulation. It is hypothesized that misfolded oligomeric intermediates occurring in the insulin fibrillation pathway, especially in zinc-deficient conditions, might induce autoantibodies against insulin, which leads to beta-cell damage and autoimmune Type 1 diabetes.

New perspectives of zinc coordination environments in proteins

“…In addition to the physiological role of zinc in the formation of insulin crystals, zinc/protein interactions are discussed in β-cell pathophysiology. Zinc inhibits fibrillation of monomeric insulin, which is amyloidogenic, with an IC 50 value of 3.5 μM at pH 7.3 [41]. The human islet amyloid polypeptide is another amyloidogenic β-cell protein.…”

Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis

“…Insulin, is stored as a hexamer containing two Zinc ions in -cells of the pancreas and released into the portal venous system at the time of -cells de-granulation [7]. The Zn(II) ions which are co-secreted with insulin suppress inherent amyloidogenic properties of monomeric insulin [8]. Zalewski, et al showed that high concentrations of glucose and other secretagogues decrease the islet cell labile Zinc and video fluorescence analysis showed Zinc concentrated in the islet cells was related to the synthesis, storage and secretion of insulin [9].…”

Is Serum Zinc Associated with Pancreatic Beta Cell Function and Insulin Sensitivity in Pre-Diabetic and Normal Individuals? Findings from the Hunter Community Study

“…[6]. Zinc is involved in the synthesis, storage, and secretion of monomeric insulin, as well as conversion to a dimeric form for storage and secretion as crystalline insulin [7], [8]. Zinc is essential in insulin action and carbohydrate metabolism [9].…”