Premature Insulin Secretion as a Primary Mechanism of Functional Insulin Resistance: A Conformational Energy Hypothesis

We propose a mechanistic hypothesis in which functional insulin resistance arises, at least in part, from the chronic secretion of conformationally immature insulin molecules. Under conditions of sustained hyperglycaemia, pancreatic beta cells are compelled to release insulin before the oxidative folding process in the endoplasmic reticulum is complete. The resulting molecules, while structurally similar to mature insulin, lack the conformational strain energy stored in correctly formed disulfide bonds. This strain energy, we argue, is not merely structural but functional: it is the mechanical energy that drives the conformational change in the insulin receptor upon ligand binding, thereby activating the intracellular tyrosine kinase cascade. Immature molecules bind receptors but fail to execute this mechanical work, producing a state of apparent resistance that is not due to receptor downregulation or post-receptor signalling defects, but to energetically deficient ligands. This hypothesis is mechanistically coherent, consistent with the known elevated proinsulin:insulin ratio in type 2 diabetes, and generates several testable, falsifiable predictions.