The effects of hyperbaric oxygen therapy on insulin resistance—an approach to physiology

Background: Diabetes mellitus (DM) is a severe, chronic and complex metabolic disease that leads to multiple dysfunctions, including micro and macrovascular complications, which are a major cause of morbidity and mortality. Type 2 DM (T2D) is highly preventable, and the stages that precede it are the ideal target for therapeutic intervention. Hyperbaric oxygen therapy (HBOT) is an established medical treatment for several clinical conditions. Because DM is one of the most prevalent comorbidities in patients under HBOT, it has allowed the observation and inference of some of its effects on DM, suggesting clinical benefit in different spectrums of the disease. Our main aim was to gather the existing evidence on the impact of HBOT on insulin resistance, as this is the best predictor for the development of T2D.

Materials and methods: The scoping review was the methodology chosen to include all available data. Exclusion criteria consisted of articles that did not mention the effects of HBOT on insulin resistance, described only the use of normobaric oxygen, or had no available translation to English, Spanish, or Portuguese. In addition, all data discussing any effects on insulin, insulin resistance, or insulin sensitivity were included.

Results: Two hundred and thirty studies were found, and 17 were eligible. The HBOT appears to improve fasting glycaemia and decrease insulin resistance in patients with DM, with effects appearing after 1 treatment session. Additionally, it reduces levels of proinflammatory cytokines that contribute to insulin resistance. The duration of this sensitisation effect remains unknown, as do the contributing molecular factors.

Conclusion: HBOT seems to improve glycaemic levels and insulin sensitivity, thus presenting a potential treatment approach to treat insulin resistance and its consequences. However, translation into clinical practice remains contingent on robust, yet unavailable, randomized clinical trials.

Introduction

Diabetes mellitus (DM) is the most common severe metabolic disease in humans, with hyperglycemia as its main characteristic. Globally, it is the 8ᵗʰ leading cause of death, directly causing approximately 1.5 million deaths per year (1). By itself, hyperglycemia is responsible for an additional 2.2 million deaths (1), as it increases cardiovascular risk and also negatively contributes to other comorbidities.

Hyperglycemia results from an autoimmune process that selectively destroys pancreatic β-cells in type 1 DM (T1D). On the other hand, type 2 DM (T2D) is highly preventable and is preceded by a prediabetes phase, with a therapeutic window where intervention can cause the regression of disease mechanisms.

Several risk factors for T2D are well described, including insulin resistance. This is the best predictor of T2D development (2), and pertains to the relative impairment of insulin action in target tissues (e.g., liver, muscle, and adipose tissue). Insulin resistance disrupts glucose absorption in peripheral tissues and its hepatic synthesis (3). This phenomenon is frequently encountered in individuals before they develop T2D and seems to be associated with an increased prevalence of arterial hypertension, obesity, and dyslipidaemia. Insulin resistance is also a diagnostic criteria for metabolic syndrome (4).

Since T2D has shown a frightening tendency toward an increase in its prevalence, it is becoming increasingly important to focus on prevention and study the mechanisms of reversal and delay of the disease.

Hyperbaric oxygen therapy (HBOT) has seen a massive evolution in medical practice since the 20th century (5). Its physiological effects result from the increase in dissolved oxygen content.

Although T2D is not a formal indication for HBOT (6), this therapy is a valuable asset in the treatment of one of its consequences: diabetic foot ulcers (type 2 indication, level B evidence) (6).

The increasing number of diverse clinical conditions (decompression sickness, central retinal artery occlusion, sudden hearing loss, diabetic and atherogenic ulcers, late radiation-induced lesions, etc.) in which it has been used allowed us to understand that HBOT can affect human physiology far beyond what was initially expected.

The present manuscript discusses the most recent evidence on the effects of hyperbaric oxygenation on insulin resistance.

Materials and methods

The scoping review, which followed the PRISMA criteria (7), was the methodology of choice to include all available data on HBOT’s effects on insulin resistance.

Queries were run on PubMed, Google Scholar, Cochrane Library and LILACS, employing <<“hyperbaric oxygenation” [MeSH] AND “insulin” [MeSH]>>. Exclusion criteria consisted of 1. articles that did not mention the effects of HBOT on insulin; 2. articles that described only normobaric oxygen use or exposure to hyperbaric air, not hyperbaric oxygenation therapy; 3. articles with no available translation to English, Portuguese or Spanish. All papers discussing any effect of HBOT on insulin, insulin resistance, or insulin sensitivity were included.

The database search was completed by the 9th of December 2024.

Results

In the primary identification phase (e.g., article searching), 249 results were obtained (Figure 1). In the screening phase, duplicates, articles with no available translations for the aforementioned languages, and those that did not fit the objectives of this review were excluded.

Figure 1

Figure 1. Adaptation of the PRISMA 2020 flow diagram for new systematic reviews (7).

Ultimately, of the 44 articles independently assessed for eligibility by two authors (e.g., entirely read and analyzed), 17 were deemed eligible, excluding articles with no available manuscripts and those that did not meet the previously mentioned goals.

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HBOT) refers to the administration of pure oxygen (100%) for a brief period at a pressure higher than 1.4 ATA (absolute pressure). Its most frequent medical applications occur between 2.0 and 2.5 ATA, from 60 to 120 min (8). By using pressures higher than those found at sea level (1 ATA), the treatment sessions must occur in a hyperbaric chamber - a hermetically closed device where such pressures are obtained. The main goal of HBOT is to increase oxygen availability in different tissues.

Two fundamental commandments of physics are essential to understanding HBOT’s physiological effects: Dalton’s and Henry’s laws. Dalton’s law postulates that each gas exerts pressure in a gaseous mixture according to its proportion in the total volume. From this, it is inferred that oxygen constitutes approximately 21% of atmospheric gas and has a partial pressure of 160 mmHg. On the other hand, Henry’s law states that the concentration of a gas in a fluid will be given by pressure and its solubility coefficient. Therefore, the pressure exerted on a fluid by a dissolved gas differs from the pressure the same gas exerts on the gaseous phase. By applying the principle above, we know that, at T = 37 °C, carbon dioxide is 20 times more soluble than the oxygen molecule. 3,5 therefore, Dalton’s law allows us to know the partial pressure of each gas in a mixture, while Henry’s law allows us to assess the quantity of gas dissolved in a liquid.

Additionally, when addressing undersea and hyperbaric medicine, it is important to consider Boyle-Mariotte’s law, which states that a perfect gas at a constant temperature has an inversely proportional volume to its absolute pressure. This principle is extremely important as it can be used to steer recompression (e.g., for decompression sickness). Still, it also explains one of the main and most frequent adverse effects of HBOT (e.g., barotrauma).

In a physiological state, the human respiratory rate at rest ranges from 12 to 15 cycles per minute, with 6 to 8 liters of air inhaled per cycle. Given the percentages of gasses in the atmospheric mixture, we breathe approximately 250 mL of oxygen and 200 mL of carbon dioxide per minute. The passage of oxygen from the alveoli to the capillary occurs through facilitated diffusion and results from alveolar and ventilated oxygen pressure variation. As the variation in alveolar pressure of oxygen (104 mmHg) is constant, the only arm of this equation that can be modeled is the ventilatory rate. Thus, oxygen consumption can increase (up to 20-fold during strenuous physical activity) with no compromising diffusion, increasing capillary recruitment, vasodilation, and alveolar dilation.

After reaching arterial blood, 97% of our oxygen is transported by hemoglobin, and only 3% is dissolved in plasma, the latter referred to as “free oxygen.” Typically, 100 mL of blood carries 5 mL of oxygen to the peripheral tissues, where the partial pressure of oxygen is maintained at constant intervals. Even in strenuous physical activity, as this process causes a decrease in interstitial oxygen pressure, only 3 times as much oxygen can be transferred to tissues in the average person. Furthermore, when analyzing the sigmoidal shape of the hemoglobin-oxygen dissociation curve, it is evident that the affinity of hemoglobin for oxygen increases as the partial pressure of oxygen increases. In other words, the more oxygen molecules hemoglobin is bound to, the higher its affinity toward them.

Given the physical and physiological principles presented so far, it becomes evident that the physiological mechanisms from which HBOT’s effects arise do not target hemoglobin-bound oxygen but its fraction dissolved in plasma. Although the exact mechanism is yet to be clarified, it is known that under hyperbaric conditions, the partial pressure of oxygen in the plasma is 10 times higher (60 mL of oxygen per 1 L of plasma), satisfying the metabolic needs of the organism (9). This oxygen is more rapidly consumed in the different tissues, as it is not bound to hemoglobin. Jain (5), presents an interesting adaptation of the hemoglobin-oxygen dissociation curve, which shows that as pressure increases from normobaric (1 ATA) to different hyperbaric (1.5–3 ATA) environments, there are no changes in the quantity of oxygen bound to hemoglobin. Still, there is a linear increase in the partial pressure of oxygen.

Adverse effects of hyperbaric oxygen therapy

Although the previously mentioned principles justify the benefits of HBOT, they also explain its most common adverse effects, which mainly include barotrauma and oxygen toxicity (5).

Boyle’s Law fundamentally defines the pathophysiology of barotrauma. It occurs when the pressure of an air-filled area cannot equalize with the ambient pressure. This pressure-related injury is frequent in phases with more significant pressure variations (e.g., descent and ascent phases) and occurs in entirely or partially non-collapsible cavities (10). Thus, the main affected sites include the middle ear, sinuses, lungs, intestines, teeth, eyes, and pathological spaces.

On the other hand, oxygen toxicity is believed to occur due to the body’s inability to eliminate excess oxygen free radicals. This complication impacts all tissues somewhat- the greater the inspired amount of oxygen, the earlier the manifestations appear. Seizures are a late sign of oxygen toxicity in the central nervous system (5, 7, 11). However, the frequency of these complications is significantly reduced when appropriate therapeutic protocols are applied. These should prioritize patient education (e.g., correctly performing Valsalva maneuvres during descent), judicious patient selection, and inclusion of proper air intervals (e.g., when the patient can stop inhaling hyperbaric oxygen inside the chamber) (5, 8, 10, 11).

Physiology of insulin

Insulin is one of four hormones secreted by pancreatic β-cells. Discovered only in 1921, it regulates the metabolism of lipids, proteins, and carbohydrates in three primary target tissues: liver, muscle, and adipose tissue. Encoded by a single gene, the latter is transcribed and processed into pre-proinsulin, which is further cleaved into proinsulin. After removing the C peptide, an insulin molecule is formed. As this process occurs within the rough endoplasmic reticulum, this hormone is contained within a secretory granule, where it will associate itself with zinc. When glucose is stimulated, the β-cell releases a vesicle with insulin, proinsulin, and C peptide into the portal circulation.

Glucose is, therefore, the primary stimulus for insulin secretion. Its blood concentration (glycaemia) may vary in response to food intake or fasting, but healthy individuals do not have large fluctuations. Although to a lesser magnitude, β-cells also respond to galactose and mannose, which means that any of these three monosaccharides can induce insulin secretion. Nevertheless, glucose is the most potent secretagogue of insulin. Simply put, it enters the β-cell through GLUT2, where it undergoes glycolysis, increasing ATP concentration. This causes potassium channels to close and the cell membrane to depolarise, activating voltage-dependent calcium channels. With high calcium permeability, there is an influx of free calcium and an increase in its intracellular concentration, ultimately leading to insulin release.

It is relevant to consider the rich innervation of the islet of Langerhans by both divisions of the autonomic nervous system. This implies that β-adrenergic stimulation, where the vagus nerve releases acetylcholine, functions as an agonist of insulin secretion. On the other hand, in alpha-adrenergic stimulation, where the celiac nerves release noradrenaline, insulin secretion is inhibited. By increasing alpha-adrenergic activity, physical exercise constitutes an essential inhibitor of insulin secretion. Instead, food intake triggers multiple pathways that are ultimately stimulatory. In addition to this glucose-stimulating effect, there are enteric factors capable of increasing the β-cell’s response glucose per os, known as incretins: glucagon-like intestinal peptide 1 (GLP-1), cholecystokinin, and gastric inhibitory polypeptide (GIP).

After reaching the portal blood, during its first passage through the liver, 60% of the insulin is removed (3). Thus, insulinemia is not a reliable marker of the quantity of insulin secretion. In each target tissue, insulin will bind to its receptor (a tyrosine-kinase receptor) and propagate its signal through tyrosine phosphorylation. In the liver, it regulates key processes of energy metabolism. It affects glycogen metabolism, as increased insulinemia decreases the degradation and consumption of glycogen but promotes glycogenesis (formation of glycogen from plasma glucose). Here, insulin also promotes glycolysis and inhibits gluconeogenesis by promoting glucose metabolism. Regarding lipidic metabolism, this hormone stimulates lipogenesis, promotes lipid storage, and inhibits fatty acid oxidation. Moreover, insulin stimulates protein synthesis and inhibits protein degradation in the liver.

The remaining 40% that reach peripheral tissues will act on the muscle and adipose tissue. In these tissues, there is a different glucose transporter - GLUT4. In muscle, insulin stimulates GLUT4 (increasing the speed of glucose transport to the sarcoplasm) and enhances gluconeogenesis and glycolysis. Additionally, it also stimulates protein synthesis. In adipose tissue, insulin stimulates glucose absorption by recruiting more GLUT4 to the cell membrane and promoting glycolysis. In contrast to the liver and muscle, insulin promotes the use of glucose in synthesizing triglycerides and lipidic storage.

Pathophysiology of insulin resistance

Insulin resistance occurs when this hormone fails to exert its effects at full capacity. The number of insulin receptors in each cell depends on new receptor synthesis, endocytosis and recycling, and endocytosis and degradation. A delicate balance between these three factors can maintain homeostasis, where despite the high number of receptors on the cell surface, there is a low recruitment rate.

However, cells chronically exposed to hyperinsulinemia are downregulated, experiencing a gradual decrease in insulin receptors and, consequently, a reduction in insulin sensitivity, even with its maximum effect (which occurs when, in a healthy individual, only 5% of the receptors are occupied) preserved (3). A practical example of this pathological phenomenon is observed in the adipocytes of patients with T2D, with fewer receptors per adipocyte area than healthy controls. In these cells, insulin resistance occurs, requiring a much higher concentration, even with a large fraction of occupied receptors (3). But, insulin resistance is a complex phenomenon that results from the sum of several malfunctions. Furthermore, it also includes impaired downstream receptor signaling, decreased insulin receptor activity, decreased PI3K activity, and possibly other steps that include recruitment of GLUT4 to the target cell plasma membrane (3, 12–16).

Insulin sensitisation is a much-desired effect of current therapies, whether behavioral (e.g., dietary changes and physical exercise) or pharmacological. As insulin and physical activity synergise by enhancing the recruitment of GLUT4 and increasing glucose oxidation, insulin sensitisation is a fundamental part of the therapeutic regimen of patients with DM.

Effects of hyperbaric oxygen therapy on insulin resistance

While there is evidence in the literature that HBOT improves fasting glycaemia, declining it by 36% (16), and diminishing insulin resistance in diabetic patients, the mechanisms that account for the insulin-sensitizing effect of hyperbaric oxygenation still lack clarification. Vera-Cruz et al. interestingly postulate that hyperoxia’s acute blockage of carotid bodies might explain this effect, as these chemoreceptors are potent glucose and insulin sensors (17). Thus, as they can impact insulin sensitivity, their functional inhibition might account for the glucose tolerance observed in T2D patients exposed to HBOT.

Zhang et al. (18), inducing T2D in mice using streptozotocin and a high-fat diet, found that diabetic mice exposed to HBOT significantly decreased insulin resistance compared to non-exposed ones. Nevertheless, despite diabetic mice showing worse baseline pancreatic β-cell function, exposure to HBOT increased the cells’ area and volume, showing no differences, though no therapeutic effects were seen. Hyperbaric oxygenation seemed to decrease pancreatic β-cell apoptosis, which the authors hypothesized may contribute to its insulin-sensitisation effect.

In 2022, Sarabhai et al. again demonstrated that HBOT enhanced insulin sensitivity across all body tissues and reduced fasting blood glucose. The authors also described a discernible improvement in mitochondrial function, accompanied by stimulating reactive oxygen species (ROS) production and antioxidative defense in skeletal muscle and white adipose tissue (19).

In 2021, Kahraman et al. (20), proposed that the insulin sensitisation effect of HBOT was due to changes in the expression of resistin, PAI-I, and adiponectin. These adipokines are intrinsically associated with insulin sensitivity: high levels of resistin and PAI-I are associated with insulin resistance, while high levels of adiponectin are associated with insulin sensitivity. After submitting mice to hyperbaric oxygenation at 2,5 ATA for 20 consecutive days, they encountered a 7-fold increase in adiponectin mRNA compared to the other adipokines, raising the hypothesis that the effect of adiponectin is dominant over the others.

In another study, Wilkinson et al. (21), proved that HBOT’s insulin-sensitizing effect only occurs when using hyperbaric oxygen and not in hyperbaric air. Thus, the high partial oxygen pressures needed for this effect are only obtainable in an HBOT setting. Merely1 session of HBOT is enough to significantly increase peripheral insulin sensitivity, which persists for at least 30 min after exiting the hyperbaric chamber (21, 22). This effect is not exclusive to diabetic patients (22).

Moreover, when trying to evaluate the combination of stem cell therapy with hyperbaric oxygenation therapy, Xu et al. (21), discovered that HBOT also lowers the level of pro-inflammatory cytokines, such as TNF-alpha and IL-6. These are key factors for inflammation initiation and maintenance and are upregulated in T2D individuals, thus contributing to insulin resistance. Nevertheless, the impact of HBOT will depend on the severity of insulin resistance (23).

Hyperbaric oxygenation also seems to significantly reduce glycaemia and HbA1C, with increased C-peptide secretion. It decreases the dose of oral hypoglycaemic drugs and insulin, translating to improving metabolic control and β-cell function (24–29). When studying the effect of HBOT with autologous bone marrow stem cell transplantation, Wang et al. (28), concluded that this dose-decreasing effect was mainly seen in patients with shorter duration of disease and/or on lower doses of hypoglycaemic drugs. Additionally, pancreatic β-cell function only seems to improve transiently. Nevertheless, in a randomized controlled trial, when evaluating the combination of autologous bone marrow mononuclear cell infusion and HBOT, Wu et al. (30), observed that these results were not verified in the group exposed to HBOT alone (Table 1).

Table 1

Table 1. Summary of the case series or clinical trials described in the literature regarding the effects of hyperbaric oxygen therapy on glucose metabolism.

Discussion

Despite HBOT having been used therapeutically for more than a century, many of its effects are still unknown and poorly studied. T2D is the perfect paradigm of a disease that is sufficiently common for patients undergoing HBOT to have, but little is known regarding this therapy’s effects. This review shows that HBOT can improve fasting glycaemia, diminish insulin resistance and lower the levels of pro-inflammatory cytokines. With these effects appearing as early as the first treatment session, there is a need to explore this subject further.

Although there has been a gradual gathering of evidence that supports more significant investment in the study of HBOT as a complementary treatment modality for T2D, there continue to be several gaps that need more precise elucidation. In addition to clarifying the exact molecular mechanisms involved in sensitisation effects, evidence from randomized, double-blind, and placebo-controlled clinical trials should be privileged to guide clinical practice.

Further research should also try to understand and clarify inconsistent results between different studies (26). A shared aspect of the various available results is the inability to determine the duration of this sensitizing effect. Additionally, experiments have not yet ascertained which effects are transient and chronic, and with T2D being a chronic condition, efforts must be made to optimize these therapeutic effects for long periods. The ability to clarify this issue and determine specific timings of action and duration will considerably contribute to HBOT’s inclusion in T2D and metabolic syndrome therapy, as well as in the prevention of insulin resistance in patients with other major risk factors.

A specific aspect deserving special attention is the transversal lack of inclusion of women in human studies. This situation merits investment in future research, as it is essential to ascertain whether the observed benefits of HBOT are maintained in females, especially considering the endocrinological particularities that distinguish and might influence results between both sexes (22). Thus, sex-specific analyses are recommended. Additionally, any implications for clinical practice should ultimately be derived from robust randomized clinical trials, which are currently lacking in this area.

This review is subject to inherent limitations, most notably the substantial heterogeneity of the included studies, spanning preclinical and clinical designs, human and animal models, and varying experimental protocols. Additionally, no formal risk of bias assessment was performed. These methodological concessions were intentional, aiming to collate the entirety of available evidence in this field, thereby facilitating the identification of knowledge gaps and guiding future research directions.

Regarding the importance of including HBOT in the therapeutic regimen of patients with T2D, the current availability of other effective, less time-consuming and more low-cost treatment options is recognized. Nevertheless, none of these therapies has been shown to reverse insulin resistance – this remains a therapeutic target for which no effective intervention is currently available. Additionally, HBOT is associated with known adverse effects, which are outlined in this review. However, with current protocols and safety measures, such events have become infrequent.

Furthermore, because of its many therapeutic indications, HBOT has the potential ability to treat multiple diseases at once, decreasing the need/dosage for medications with more serious side effects. The ideal future of research in this field should investigate whether early intervention with HBOT in patients with insulin resistance has the power to reverse this condition in the long term and prevent its complications - something that the available pharmacological therapy cannot yet guarantee.

Conclusion

The HBOT seems to improve glycaemia levels and insulin sensitivity, thus making it a weapon worth investigating in the fight against insulin resistance and its consequences (e.g., metabolic syndrome and T2D). Current literature presents enough evidence to support further and firmer investigation in this field, even with current optimized medical treatment. However, translation into clinical practice remains contingent on robust, yet unavailable, randomized clinical trials.

Author contributions

MS-A: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Supervision, Visualization, Writing – original draft, Writing – review & editing. DAC: Resources, Supervision, Validation, Visualization, Writing – review & editing. IG-A: Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing. JN: Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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