Fatty acids may influence insulin dynamics through modulation of albumin‐Zn²⁺ interactions

Abstract

Insulin is stored within the pancreas in an inactive Zn2+‐bound hexameric form prior to release. Similarly, clinical insulins contain Zn2+ and form multimeric complexes. Upon release from the pancreas or upon injection, insulin only becomes active once Zn2+ disengages from the complex. In plasma and other extracellular fluids, the majority of Zn2+ is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn2+. The Zn2+‐binding properties of HSA are attenuated by non‐esterified fatty acids (NEFAs) also transported by HSA. Elevated NEFA concentrations are associated with obesity and type 2 diabetes. Here we present the hypothesis that higher NEFA levels in obese and/or diabetic individuals may contribute to insulin resistance and affect therapeutic insulin dose‐response profiles, through modulation of HSA/Zn2+ dynamics. We envisage this novel concept to have important implications for personalized treatments and management of diabetes‐related conditions in the future.

Reactive Cu2+-peptide intermediates revealed by kinetic studies gain relevance by matching time windows in copper metallomics

“…Similar rules will probably apply to other metal ions and other bioligands, paving the way to novel metal ion binding and exchange interactions, to be revealed by future systematic studies. Among many areas of potential interest we would like to suggest the extracellular and intracellular Zn(II) trafficking, for example the mechanism and time course of Zn(II) release from insulin hexamers and its reabsorption by HSA, crucial for maintaining the insulin activity, 45 , 46 , 104 and intracellular delivery of Zn(II) ions to thousands of zinc proteins by a heterogeneous system comprising transporters, chaperones, and small molecules. 105–108 …”

Direct determination of free Zn concentration in samples of biological interest

“…We therefore propose that AGNES measurements, such as those developed here, may not only pave the way to addressing biological questions regarding processes where [Zn 2+ ] in extracellular media plays major roles (e.g. blood clotting [5,40]), but may also offer an independent method to calibrate the response of fluorescent dyes in other biological fluids of interest.…”

“…Amongst essential metals, zinc is perhaps the most versatile, with about 10% of the human proteome estimated to correspond to zinc-requiring proteins [2]. This pervasiveness is also reflected in the manifold biological processes that require the involvement of zinc [3], which include regulation of gene expression and cell cycle progression [4], energy metabolism [5], the immune system [6], host-pathogen interactions [7], hemostasis [8] and neurochemical processes involved in learning and memory [9]. Correspondingly, zinc deficiency or disturbances in zinc metabolism promote a range of disorders, including impairment of cognitive and immune functions, growth retardation, and diabetes [10].…”

“…Indeed, at least some membrane-bound zinc uptake transporters are known to function in an electrodiffusional manner, with transport directly dependent on the gradient in free Zn 2+ [38]. Thus, although in vivo only 0.1% of body zinc resides in blood plasma [39], it turns over about 150 times a day [3] and its total levels and speciation govern not only zinc-dependent processes in this compartment (including hemostasis [40], insulin activity [5], and response to pathogens [41]), but ultimately also affect transfer from plasma to all organs and tissues, and hence whole-body zinc homeostasis [3]. Studying zinc speciation in serum and plasma is therefore a matter of central importance [30].…”

Albumin-mediated extracellular zinc speciation drives cellular zinc uptake

“…2 This illustrates the highly dynamic character of zinc speciation in plasma -not least because several processes occurring within plasma are zinc-mediated, including blood clotting, insulin activation, and immune function. [22][23][24] One particular group of metabolites has a major impact on albuminmediated zinc speciation: free (i.e., non-esterified) fatty acids (FFA). FFA levels in plasma are also highly dynamic, and are Fig.…”