Fatty acids may influence insulin dynamics through modulation of albumin-Zn 2+ interactions

Insulin is stored within the pancreas in an inactive Zn -bound hexameric form prior to release. Similarly, clinical insulins contain Zn and form multimeric complexes. Upon release from the pancreas or upon injection, insulin only becomes active once Zn disengages from the complex. In plasma and other extracellular fluids, the majority of Zn is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn . The Zn -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/Zn dynamics. We envisage this novel concept to have important implications for personalized treatments and management of diabetes-related conditions in the future.