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

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

doi:10.1007/s00125-022-05797-0

Cited by 11 publications

(15 citation statements)

References 41 publications

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“…Hepatic H2O2 emission was assessed fluorimetrically by using Amplex Red in isolated mitochondria [14]. Thiobarbituric acid reactive substances (TBARS) were assessed fluorometrically in liver samples (BioTek, Bad Friedrichshall, Germany) [21,27]. Catalase activity was measured colorimetrically in liver tissue lysates (Cayman Chemical Company, Ann Arbor, Michigan, United States).…”

Section: Methodsmentioning

confidence: 99%

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in obesity-related fatty liver disease

Sarabhai

Kahl

Gancheva

et al. 2023

Preprint

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Background Obesity and type 2 diabetes feature higher prevalence of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). In obesity-related insulin resistance, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in progressive NAFL/NASH remains uncertain. Methods This cross-sectional study compared individuals with class III obesity (n=8/group) and with NAFL (OBE NAFL, NAFLD activity score: 2.3±0.4), NASH (OBE NASH, 5.3±0.3, p<0.05 vs. both other groups) or without fatty liver (control, OBE CON; 0.4±0.1). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry and biomarkers of mitochondrial quality control by protein expression. Results Mitochondrial oxidative capacity was 31% higher in OBE NAFL, but 25% lower in OBE NASH (both p<0.05 vs. OBE CON). Conversely, OBE NASH showed ~1.5fold lower mitochondrial number, but ~1.2-1.5fold higher mitochondrial diameter and area (p<0.001 vs. both other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE NASH (p<0.05 vs. OBE NAFL). Selected biomarkers (p62, p-PARKIN/PARKIN, p-DRP-1) were lower in OBE NAFL (p<0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion and fission biomarkers and with oxidative capacity, but positively with H2O2. Conclusion Humans with NAFL exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity. In NASH, oxidative stress likely mediates the progressive decline of mitochondrial turnover along with impaired mitochondrial ultrastructure and respiration. Thus, mitochondrial quality control is key for hepatic energy metabolism and may have potential for targeting obesity-related NASH.

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Section: Methodsmentioning

confidence: 99%

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in obesity-related fatty liver disease

Sarabhai

Kahl

Gancheva

et al. 2023

Preprint

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“…There was no association between these disturbances and the amount of insulin administered suggesting that the degree of insulin resistance varied between patients and even within individual patients. There was no evidence that higher doses of insulin (up to 10U/kg/h) were associated with more adverse effects that low doses [56] A rapid and marked increase in mitochondrial function and ATP production also resulted from another example of increased fuel availability in the form of 2 hours of hyperbaric oxygen in type 2 diabetic subjects [57].…”

Section: High Dose Insulinmentioning

confidence: 99%

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Bradley¹

2023

Preprint

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Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

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“…Meanwhile, Lecoultre [ 247 ] et al found that exposure to moderate hypoxic (15 ± 0.5% O 2 , ~2400 m altitude) for 10 consecutive nights in obese men (a within-group comparison without controls) increased insulin sensitivity. Some studies also found that for type 2 diabetes patients, peripheral insulin sensitivity increased during hyperbaric oxygen treatment (HBOT), and this increase was maintained for 30 min after HBOT [ 248 , 249 , 250 ].…”

Section: Application Of Hypoxic Exercise In Treatment Of Metabolic Di...mentioning

confidence: 99%

Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities

Wang

Sun

et al. 2022

Cells

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The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies indicated endogenous hyperoxia as the opposite trend. Endogenous hypoxic aggravates dysfunction in adipose tissue and stimulates secretion of inflammatory molecules, which contribute to obesity. In contrast, hypoxic exposure combined with training effectively generate exogenous hypoxic to reduce body weight and downregulate metabolic risks. The (patho)physiological effects in adipose tissue are distinct from those of endogenous hypoxic. We critically assess the latest advances on the molecular mediators of endogenous hypoxic that regulate the dysfunction in adipose tissue. Subsequently we propose potential therapeutic targets in adipose tissues and the small molecules that may reverse the detrimental effect of local endogenous hypoxic. More importantly, we discuss alterations of metabolic pathways in adipose tissue and the metabolic benefits brought by hypoxic exercise. In terms of therapeutic intervention, numerous approaches have been developed to treat obesity, nevertheless durability and safety remain the major concern. Thus, a combination of the therapies that suppress endogenous hypoxic with exercise plans that augment exogenous hypoxic may accelerate the development of more effective and durable medications to treat obesity and comorbidities.

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

Cited by 11 publications

References 41 publications

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in obesity-related fatty liver disease

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in obesity-related fatty liver disease

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities

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