Insulin degradation discovered as a new driver of resistance

Insulin degradation discovered as a new driver of resistance

New study identifies insulin “chain scission” during transport through the bloodstream as a game-changer for understanding and treating diabetes and insulin resistance.

In a study recently published in the journalNPJ Metabolic Health and DiseaseResearchers believe that degradation of endogenously secreted insulin (as opposed to the commonly assumed insulin receptor signaling defects) is the mechanism underlying insulin resistance in humans. The hypothesis is that thiol-mediated “chain scission,” which is dependent on the redox potential of the plasma environment, occurs when human insulin (HI) is degraded by redox reactions at concentrations typical of human plasma.

They support their chain scission hypothesis with new evidence both in vitro (human plasma) and in vivo (rats infused with human insulin), showing that degradation of A and B-HI chains results in reduced insulin availability in target cells. This directly contributes to the observed insulin resistance. In particular, the study highlights that the chain division rates are consistent with the redox potentials typically found in human plasma, supporting the physiological relevance of the results. These results challenge current worldviews about the mechanism of insulin resistance and provide a new research approach for future pharmacological interventions against the disease.

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Diet and Lifestyle Implications: The study shows how dietary intake, particularly sulfur amino acids, can influence plasma redox potentials and potentially modulate insulin degradation and insulin resistance.

Insulin resistance is a chronic and serious condition that occurs when the body's cells do not respond adequately to circulating endogenous insulin. Since insulin is the hormone that controls glucose absorption, insulin resistance often leads to progressive increases in blood sugar levels, a significantly increased risk of prediabetes and type 2 diabetes (T2D), which in turn leads to obesity, cardiovascular diseases (CVDs), metabolic syndrome and polycystic ovary syndrome (PCOS).

Additionally, insulin resistance (specifically an increase in blood sugar levels) forces the pancreas to compensate by increasing insulin production and secretion. The persistent inability of cells to respond to this increased secretion triggers a positive feedback loop that ultimately leads to pancreatic disease or failure. Taken together, these results highlight the need for a better understanding of the mechanisms that control insulin resistance to enable pharmacological interventions against this condition, which is 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 target tissue/cellular defects or insulin receptor signaling inadequacies determine the observed insulin resistance. New evidence suggests that plasma redox states, influenced by factors such as diet, lifestyle and exercise, can modulate the mechanisms of insulin degradation, making this model more complex.

About the study

Exercise and insulin sensitivity: Acute exercise increases insulin sensitivity by increasing redox potential, suggesting a link between physical activity and reduced insulin chain cleavage.

In the present study, researchers suspect a novel mechanism of insulin resistance called “chain scission.” The hypothesis proposes that degradation of endogenous insulin as it travels from the pancreas to target cells, rather than 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 chain division process across A and B insulin chains and support 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). The experimental procedures began with the isolation of human insulin (HI) from the blood plasma of the human participants. Purified HI was treated with a glutathione redox couple comprising reduced (GSH) and oxidized forms (GSSG), triggering chain scission in the HI-A chain. Lower redox potentials were found to accelerate chain scission, reinforcing the importance of redox conditions for insulin degradation. The resulting A chain was purified using a reversed-phase high-performance liquid chromatography (RP-HPLC) column.

For in vivo experiments, rats fasted overnight received an infusion of purified HI at a rate of two nmol/kg/min with constant monitoring (every 10 minutes) and adjustments in glucose infusion rates (GIR). Blood samples collected at 10, 20, 30, 60, 120, and 180 minutes 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). For statistical analyzes of the obtained data, nonlinear least squares performed in GraphPad Prism 9.0.1 were used.

Study results

The study shows that a significant portion of the HI is broken down by splitting the A and B chains during transport from the pancreas to the target cells. Although this phenomenon was predicted in previous research, its effects were thought to be negligible in contrast to current study results. The GSH/GSSG (redox) couple was found to play a significant role in HI degradation, with lower redox potentials increasing the rate of HI chain scission.

The left panel represents the insulin concentration gradient from published data 18 in healthy individuals. The middle panel illustrates how increased chain scission leads to a larger gradient, according to our hypothesis, leading to compensatory insulin secretion, plasma hyperinsulinemia and therefore insulin resistance, as shown in the right panel.

Notably, the GSH/GSSG redox potentials required for chain scission correspond to normal endogenous levels in human blood plasma, supporting the physiological validity of these results. In addition, plasma redox states, influenced by factors such as diet and exercise, can modulate the rate of insulin chain cleavage and potentially alter insulin sensitivity. The current hypothesis is further supported by in vivo experiments in which HI-infused rats mirrored in vitro blood plasma observations.

“Based on the plasma A chain levels in the clamp study and on the A chain clearance kinetics determined in the separate PK experiment, we estimate that the A chain appearance rate (i.e., the rate of HI chain cleavage) in the clamp study is equivalent to 0.40 nmol/kg/min or approximately 20% of the HI infusion rate, clearly demonstrating that the Chain scission is also a relevant degradation mechanism for HI in vivo.”

Conclusions

The present study provides evidence for a novel mechanism of insulin resistance that proposes that insulin degradation during transport (“chain scission”) is an underlying determinant of insulin-resistant phenotypes. This alternative hypothesis differs from current world views on insulin resistance, the latter of which assume that defects in target tissues or cells prevent normal insulin uptake. Additionally, the results suggest that factors such as diet, exercise, and redox state manipulation may influence insulin breakdown, opening opportunities for integrative treatment approaches. These results merit further research and may represent the first step in a new class of pharmacological interventions against human insulin resistance and its comorbidities.

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