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

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 personalised treatments and management of diabetes-related conditions in the future.