New study identifies ‘chain breaking’ of insulin as it passes through the bloodstream as a game changer in understanding and treating diabetes and insulin resistance.
Study: Insulin chain cleavage: an underlying mechanism of insulin resistance? Image credit: Nastasiiaa / Shutterstock
In a recent study published in the journal NPJ Metabolic Health and Diseaseresearchers hypothesize that degradation of endogenously secreted insulin (as opposed to commonly believed defects in insulin receptor signaling) is the mechanism underlying insulin resistance in humans. The hypothesis posits that thiol-mediated “chain scission,” which is dependent on the redox potential of the surrounding plasma, occurs when human insulin (HI) is degraded by redox reactions at concentrations typical of human plasma.
They support their chain cleavage hypothesis with new evidence from both in vitro (human plasma) and in vivo (rats injected with human insulin) and demonstrate that degradation of the A- and B-HI chains results in reduced insulin availability in target cells. thereby directly contributing to the observed insulin resistance. Specifically, the study highlights that chain cleavage rates align with redox potentials typically found in human plasma, supporting the physiological relevance of the findings. These findings challenge current worldviews about the mechanism underlying insulin resistance and provide a new research avenue for future pharmacological interventions against the condition.
Background
Insulin resistance is a chronic and serious medical condition that occurs when the body’s cells do not respond adequately to circulating endogenous insulin. Since insulin is the hormone that controls glucose uptake, insulin resistance often leads to a progressive increase in blood glucose levels, significantly increased risk of prediabetes and type 2 diabetes (T2D), in turn contributing to obesity, cardiovascular diseases (CVDs), the metabolic syndrome and polycystic ovaries. syndrome (PCOS).
In addition, insulin resistance (specifically, spikes in blood glucose levels) causes the pancreas to compensate through increased insulin production and secretion. The persistent inability of cells to respond to this increased secretion triggers a positive feedback loop, ultimately contributing to pancreatic disease or failure. Together, these findings highlight the need for enhanced understanding of the mechanisms underlying insulin resistance, allowing for pharmacological interventions against this condition estimated to affect between 15.5% and 46.5% of all adults.
Unfortunately, despite decades of research, the cascade of events leading to insulin-resistant phenotypes remains poorly understood. Current worldviews recognize the multifactorial nature of insulin resistance, but assume that tissue/target cell defects or insulin receptor signaling deficiencies underlie the observed insulin resistance. Emerging evidence suggests that plasma redox states, influenced by factors such as diet, lifestyle, and exercise, may modulate insulin degradation mechanisms, adding complexity to this model.
About the Study
In the present study, the researchers hypothesize a new mechanism of insulin resistance called “chain scission.” The hypothesis holds that degradation of endogenous insulin during its journey from the pancreas to target cells, not defects in the cells themselves, leads to insulin-resistant phenotypes. This hypothesis highlights the role of redox potentials in the plasma environment in driving the chain scission process. They use in vitro and in vivo experiments to demonstrate the process of chain separation in insulin A and B chains and substantiate their claims with data from the literature.
Study data were obtained from two healthy human volunteers (in vitro experiments) and male Sprague Dawley rats (~350 g, in vivo). Experimental procedures began with the isolation of human insulin (HI) from the blood plasma of human participants. Purified HI was treated with a glutathione redox couple comprising reduced (GSH) and oxidized forms (GSSG), initiating chain cleavage at the HI A-chain. Lower redox potentials were found to accelerate chain cleavage, reinforcing the importance of redox conditions in insulin degradation. The resulting chain A was purified using a reverse-phase high-performance liquid chromatography (RP-HPLC) column.
For in vivo experiments, overnight fasted rats were infused with purified HI at two nmol/kg/min in parallel with continuous monitoring (every 10 min) and adjustments to glucose infusion rates (GIR). Blood samples collected at 10, 20, 30, 60, 120, and 180 min were used to quantify insulin and free A-/B-chain concentrations.
All experimental data were acquired via liquid chromatography-mass spectroscopy (LC-MS) systems (TLX-2 TurboFlow high-performance LC system and Acquity I-Class LC system for plasma stability analysis and HI/B chain quantification, respectively). Nonlinear least squares performed in GraphPad Prism 9.0.1 were used for statistical analyzes of the obtained data.
Study Findings
The study demonstrates that a significant portion of HI undergoes degradation through cleavage of the A and B chains during transit from the pancreas to target cells. While this effect was predicted in previous research, its impact was considered negligible, in contrast to the findings of the current study. The GSH/GSSG (redox) couple was found to play an important role in HI degradation, with lower redox potentials increasing the rate of HI chain cleavage.
The left panel represents the insulin concentration gradient from published data18 in healthy subjects. The middle panel shows how increased chain cleavage will lead to a steeper gradient according to our hypothesis, leading to compensatory insulin secretion, plasma hyperinsulinemia and thus insulin resistance as seen in the right panel.
Notably, the GSH/GSSG redox potentials required for chain cleavage match the normal endogenous levels in human blood plasma, supporting the physiological validity of these findings. In addition, plasma redox states influenced by factors such as diet and exercise may modulate the rate of insulin chain cleavage, potentially altering insulin sensitivity. The current hypothesis is further supported by in vivo experiments, where HI-injected rats mirror in vitro blood plasma observations.
“Based on the plasma levels of chain A in the clamp study and the clearance kinetics of chain A determined in the separate PK experiment, we estimate that the rate of appearance of chain A (ie, the rate of cleavage of the HI chain) in the clamp study corresponds to 0.40 nmol/kg/min or about 20% of the HI infusion rate, clearly demonstrating that chain separation is in vivo relevant degradation mechanism for HI as well.’
conclusions
The present study provides evidence supporting a novel mechanism of insulin resistance, which postulates that degradation of insulin during transport (“chain scission”) is a key determinant of insulin-resistant phenotypes. This alternative hypothesis diverges from current insulin resistance worldviews, the latter of which assume that defects in target tissues or cells prevent normal insulin uptake. In addition, the findings suggest that factors such as diet, exercise, and manipulation of redox status may influence insulin degradation, opening avenues for integrated therapeutic approaches. These findings warrant further investigation and may be the first step in a new class of pharmacological interventions against human insulin resistance and its comorbidities.
