Abstract
AbstractInsulin 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.
Highlights
Insulin is a protein hormone that promotes glucose uptake from the blood into liver, fat, and skeletal muscle cells.[1]
Insulin is produced in pancreatic beta cells, where it is packaged into secretory granules that accumulate in the cytoplasm close to the plasma membrane
It has recently been proposed that serum albumin, the most abundant protein and primary carrier of Zn2+ in plasma and other extracellular fluids, serves this purpose and may control Zn2+ availability in a manner that acts to control insulin pharmacodynamics.[34]
Summary
Insulin is a protein hormone that promotes glucose uptake from the blood into liver, fat, and skeletal muscle cells.[1]. Exocytotic insulin release is regulated by a complex of three SNARE proteins (SNAP25, syntaxin and synaptobrevin; [11]), which promote plasma and vesicle membrane fusion to form an ∼1.5 nm ion channellike fusion pore This pore connects the secretory granules with the extracellular space, enabling release of vesicular content.[12,13] Insulin secretion is mediated through expansion of the lipidic fusion pore to up to 12 nm.[14] Structures of T6 and R6 insulin hexamers reveal these complexes to be ∼5 nm in diameter, transportable through the fully open lipidic fusion pore. Rapid- and short-acting insulin helps reduce blood glucose levels before mealtimes, while intermediate or long-acting insulin serve the body’s general needs, with effects often lasting for a day, or even longer.[15] Most clinical insulins are administered in hexameric forms in formulations that contain zinc. It binds to serum albumin via the fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect.[23]
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