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

doi:10.1007/s00125-022-05797-0

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

Diabetologia. 2023 Jan;66(1):57-69. doi: 10.1007/s00125-022-05797-0. Epub 2022 Sep 30.

Authors

Theresia Sarabhai^{1

2

3}, Lucia Mastrototaro^{2

3}, Sabine Kahl^{2

3}, Gidon J Bönhof^{1

2

3}, Marc Jonuscheit^{2

3}, Pavel Bobrov^{3

4}, Hisayuki Katsuyama^{2

3}, Rainer Guthoff⁵, Martin Wolkersdorfer⁶, Christian Herder^{1

2

3}, Sven G Meuth⁷, Sven Dreyer⁸, Michael Roden^{9

10

11}

Affiliations

¹ Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
² Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany.
³ German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany.
⁴ Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany.
⁵ Department of Ophthalmology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁶ Department of Production, Hospital Pharmacy, Landesapotheke Salzburg, Salzburg, Austria.
⁷ Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁸ Clinic for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁹ Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. michael.roden@ddz.de.
¹⁰ Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany. michael.roden@ddz.de.
¹¹ German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany. michael.roden@ddz.de.

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, HbA_1c 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.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Diabetes Mellitus, Type 2* / therapy
Glucose
Humans
Hyperbaric Oxygenation*
Insulin Resistance*
Male
Middle Aged
Oxygen
Serine
Young Adult

Substances

Oxygen
Glucose
Serine

Associated data

ClinicalTrials.gov/NCT04219215