Hyperbaric oxygen rapidly improves tissue-specific insulin sensitivity and mitochondrial capacity in humans with type 2 diabetes: a randomised placebo-controlled crossover trial

Theresia Sarabhai, Lucia Mastrototaro, Sabine Kahl, Gidon J Bönhof, Marc Jonuscheit, Pavel Bobrov, Hisayuki Katsuyama, Rainer Guthoff, Martin Wolkersdorfer, Christian Herder, Sven G Meuth, Sven Dreyer, Michael Roden, Theresia Sarabhai, Lucia Mastrototaro, Sabine Kahl, Gidon J Bönhof, Marc Jonuscheit, Pavel Bobrov, Hisayuki Katsuyama, Rainer Guthoff, Martin Wolkersdorfer, Christian Herder, Sven G Meuth, Sven Dreyer, Michael Roden

Abstract

Aims/hypothesis: Hyperbaric oxygen (HBO) therapy may improve hyperglycaemia in humans with type 2 diabetes, but underlying mechanisms are unclear. Our objective was to examine the glucometabolic effects of HBO on whole-body glucose disposal in humans with type 2 diabetes.

Methods: In a randomised placebo-controlled crossover trial located at the German Diabetes Center, 12 male individuals with type 2 diabetes (age 18-75 years, BMI <35 kg/m2, HbA1c 42-75 mmol/mol [6-9%]), randomly allocated by one person, underwent 2-h HBO, once with 100% (240 kPa; HBO) and once with 21% oxygen (240 kPa; control, CON). Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps with D-[6,6-2H2]glucose, hepatic and skeletal muscle energy metabolism were assessed by 1H/31P-magnetic resonance spectroscopy, while high-resolution respirometry measured skeletal muscle and white adipose tissue (WAT) mitochondrial capacity. All participants and people assessing the outcomes were blinded.

Results: HBO decreased fasting blood glucose by 19% and increased whole-body, hepatic and WAT insulin sensitivity about one-third (p<0.05 vs CON). Upon HBO, hepatic γ-ATP concentrations doubled, mitochondrial respiratory control doubled in skeletal muscle and tripled in WAT (p<0.05 vs CON). HBO increased myocellular insulin-stimulated serine-473/threonine-308 phosphorylation of Akt but decreased basal inhibitory serine-1101 phosphorylation of IRS-1 and endoplasmic reticulum stress (p<0.05 vs CON).

Conclusions/interpretation: HBO-mediated improvement of insulin sensitivity likely results from decreased endoplasmic reticulum stress and increased mitochondrial capacity, possibly leading to low-dose reactive oxygen species-mediated mitohormesis in humans with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT04219215 FUNDING: German Federal Ministry of Health, German Federal Ministry of Education and Research, North-Rhine Westfalia Ministry of Culture and Science, European-Regional-Development-Fund, German-Research-Foundation (DFG), Schmutzler Stiftung.

Keywords: Antioxidative defence; ER stress; Hyperbaric oxygen therapy; Insulin resistance; Mitohormesis.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. Participants with type 2 diabetes (n=12) randomly underwent two 2 h sessions in a hyperbaric chamber once with application of 100% O2 (at 240 kPa; HBO) and once with ambient air as control (21% O2; 240 kPa; CON) from −2.5 h to −0.5 h (intervention period) spaced by an interval of 3 weeks. Skeletal muscle and adipose tissue biopsies were taken at time points −23 h (basal period), +0.5 h (pre-clamp period) and +2.5 h (only skeletal muscle) during a hyperinsulinaemic–euglycaemic clamp test (clamp period), performed from +2 h to +5 h. In vivo 1H/31P-MRS was used to directly quantify hepatic and muscle lipid and energy metabolism
Fig. 2
Fig. 2
Time course of circulating metabolites and hormones in humans with type 2 diabetes before and after HBO or CON treatment. Concentrations (means ± SEM) of fasting blood glucose (a), plasma insulin (b), plasma NEFA (c) and plasma triacylglycerol (d) in humans with type 2 diabetes (n=12, except for plasma triacylglycerol n=10) after two 2 h sessions in a hyperbaric chamber with either 100% O2 (HBO) or 21% O2 ambient air (CON) from −2.5 h to −0.5 h (intervention period). *p<0.05 vs CON for iAUC calculated for pre-clamp and clamp periods combined using the trapezoidal rule corrected for the respective AUC; †p<0.05 for HBO vs CON at time point +120 min, applying the crossover test
Fig. 3
Fig. 3
Whole-body and tissue-specific glucose and lipid metabolism after HBO or CON treatment in humans with type 2 diabetes. (a–d) Pre-clamp period (0 h to +2 h) Rd (a), GOX (b), insulin-adjusted EGP (EGP × insulin; c) and adipose tissue insulin resistance from circulating NEFA (plasma NEFA × insulin; d). (e–h) Clamp period (+2 h to +5 h) insulin-stimulated Rd (e), GOX (f), per cent EGP suppression (g) and per cent NEFA suppression (h). Data are presented as means ± SEM (n=12) for humans with type 2 diabetes after two 2 h sessions in a hyperbaric chamber with either 100% O2 (HBO) or 21% O2 ambient air (CON) from −2.5 h to −0.5 h (intervention period). *p<0.05 and **p<0.01 vs CON (crossover test)
Fig. 4
Fig. 4
Variables of tissue-specific energy metabolism and antioxidative capacity after HBO or CON treatment in humans with type 2 diabetes. Difference (Δ) between pre-clamp and basal periods for hepatic ATP concentration (a), hepatic ATP/Pi concentration (b), IHL concentration (c), skeletal muscle maximal mitochondrial respiration with electron input through CI + CII combined (d) and skeletal muscle maximum mitochondrial production of H2O2 (e), as well as the ratio of reduced/oxidised glutathione (GSH/GSSG) (f), WAT maximal mitochondrial respiration with electron input through CI + CII combined (g), WAT maximum mitochondrial production of H2O2 (h) and GSH/GSSG level (i). Data are presented as means ± SEM for humans with type 2 diabetes (n=10, except for hepatic ATP/Pi and IHL concentration n=12) after two 2 h sessions in a hyperbaric chamber with either 100% O2 (HBO) or 21% O2 ambient air (CON) from −2.5 h to −0.5 h (intervention period). *p<0.05 vs CON (crossover test)
Fig. 5
Fig. 5
Myocellular ER stress and insulin signalling after HBO or CON in humans with type 2 diabetes. (a–f) Difference (Δ) between pre-clamp and basal periods for eIF2α (a), serine-51 phosphorylation of eIF2α (p-eIF2α-S51; b) and p-eIF2α-S51/eIF2α ratio (c), as well as IRS-1 (d), serine-1101 phosphorylation of IRS-1 (p-IRS-1-S1101; e) and Δp-IRS-1-S1101/IRS-1 ratio (f). (g–i) Difference (Δ) between clamp and basal periods for Akt (g), serine-473 phosphorylation of Akt per Akt (p-Akt-S473/Akt; h) and threonine-308 phosphorylation of Akt per Akt (p-Akt-T308/Akt; i). Data are presented as means ± SEM for humans with type 2 diabetes (n=10) after two 2 h sessions in a hyperbaric chamber with either 100% O2 (HBO) or 21% O2 ambient air (CON) from −2.5 h to −0.5 h (intervention period). *p<0.05 vs CON (crossover test). AU, arbitrary unit

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