bims-kimdis 2023-10-15 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–10–15
twenty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Exogenous Ketone Supplementation and Ketogenic Diets for Exercise: Considering the Effect on Skeletal Muscle Metabolism.
Ketogenic effects of medium chain triglycerides containing formula and its correlation to breath acetone in healthy volunteers: a randomized, double-blinded, placebo-controlled, single dose-response study.
Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.
Role of insulin resistance and leptin in the effect of intermittent feeding with a high-protein ketogenic diet on body composition in rats.
Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.
Hepatic safety profile of pancreatic cancer‑bearing mice fed a ketogenic diet in combination with gemcitabine.
Pilot study of a ketogenic diet in bipolar disorder.
Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilisation.
GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction-Reply.
Propofol for Anesthesia in Pediatric Patients With Epilepsy on the Ketogenic Diet: A Single-Center Experience.
The effectiveness of blood glucose and blood ketone measurement in identifying significant acidosis in diabetic ketoacidosis patients.
Effects of Intermittent Energy Restriction Compared to Those of Continuous Energy Restriction on Body Composition and Cardiometabolic Risk Markers - A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Adults.
Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.
Effects of Hyperthermia and Acidosis on Mitochondrial Production of Reactive Oxygen Species.
Intermittent fasting in health and disease.
ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency.
Autophagy protects mitochondrial health in heart failure.
Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.
Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.
Intense interval exercise induces greater changes in post-exercise metabolism compared to submaximal exercise in middle-aged adults.
Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.
Changes in 24-h energy expenditure, substrate oxidation, and body composition following resistance exercise and a high protein diet via whey protein supplementation in healthy older men.
Key Exercise Concepts in the Rehabilitation from Severe Burns.
Triglycerides and Cognition: Are All Lipids the Same?
Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Nutrients. 2023 Sep 30. pii: 4228. [Epub ahead of print]15(19):

Exogenous Ketone Supplementation and Ketogenic Diets for Exercise: Considering the Effect on Skeletal Muscle Metabolism.

Hannah Khouri, John R Ussher, Céline Aguer.

  In recent years, ketogenic diets and ketone supplements have increased in popularity, particularly as a mechanism to improve exercise performance by modifying energetics. Since the skeletal muscle is a major metabolic and locomotory organ, it is important to take it into consideration when considering the effect of a dietary intervention, and the impact of physical activity on the body. The goal of this review is to summarize what is currently known and what still needs to be investigated concerning the relationship between ketone body metabolism and exercise, specifically in the skeletal muscle. Overall, it is clear that increased exposure to ketone bodies in combination with exercise can modify skeletal muscle metabolism, but whether this effect is beneficial or detrimental remains unclear and needs to be further interrogated before ketogenic diets or exogenous ketone supplementation can be recommended.

Keywords:  exercise; exercise performance; ketogenic diet; ketone bodies; ketone supplements; metabolism; skeletal muscle

DOI:  https://doi.org/10.3390/nu15194228
Front Nutr. 2023 ;10 1224740

Ketogenic effects of medium chain triglycerides containing formula and its correlation to breath acetone in healthy volunteers: a randomized, double-blinded, placebo-controlled, single dose-response study.

Kentaro Nakamura, Keisuke Hagihara, Naoko Nagai, Ryuichiro Egashira, Mariko Takeuchi, Mai Nakano, Hitomi Saito, Misaki Moriguchi, Satoko Tonari, Hisako Fujii, Akimitsu Miyake, Yusuke Omae, Kinya Ashida.

  The efficacy of low-carbohydrate, high-fat diets, such as ketogenic diets, for cancer patients is of research interest. We previously demonstrated the efficacy of the ketogenic diet in a case study in which medium-chain triglycerides (MCTs) or MCT-containing formula (ketogenic formula) was used as a supplement to increase blood ketone bodies. However, little is known about the amounts needed to induce ketogenic effects and about the usefulness of monitoring of breath acetone. To investigate the pharmacokinetics of MCTs and their metabolites, blood ketone bodies and breath acetone, 24 healthy subjects received one of four single oral doses of the ketogenic formula (equivalent to 0, 10, 20, and 30 g of MCTs) under fasting conditions. Total blood ketone bodies, β-hydroxybutyrate, octanoic acid, and decanoic acid were increased in a dose-dependent manner. The ketogenic effect was considered to depend on octanoic and decanoic acids, because a positive correlation was observed between them. A strong positive correlation was also observed between total serum ketone bodies and breath acetone at each time points. Therefore, monitoring breath acetone levels seems a less invasive method to predict blood concentrations of ketone bodies during ketogenic diet therapy. Clinical trial registration:https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000032634, UMIN-CTR UMIN000032634.

Keywords:  breath acetone; dose response; ketogenic diet; medium chain triglycerides; single dose study

DOI:  https://doi.org/10.3389/fnut.2023.1224740
medRxiv. 2023 Sep 26. pii: 2023.09.25.23296090. [Epub ahead of print]

Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.

Xinyi Li, Anthony J Young, Lais S Pereira-Rufino, Zhenhao Shi, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Timothy Pond, Mark Elliott, Ravinder Reddy, Robert K Doot, Jan-Willem van der Veen, Henry R Kranzler, Ravi Prakash Reddy Nanga, Jacob G Dubroff, Corinde E Wiers.

Introduction: Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. Individuals with alcohol use disorder (AUD) show elevated brain acetate metabolism at the expense of glucose, a shift in energy utilization that persists beyond acute intoxication. We recently reported that nutritional ketosis and administration of ketone bodies as an alternative energy source to glucose reduce alcohol withdrawal severity and alcohol craving in AUD. However, the regional effects of nutritional ketosis on brain ketone (beta-hydroxybutyrate [BHB]) and glucose metabolism have not been studied in AUD.
Methods: Five participants with AUD underwent two magnetic resonance imaging (MRI) sessions and 4 participants with AUD underwent two positron emission tomography (PET) sessions with 18 F-fluorodeoxyglucose. All participants completed one session without KE intervention and one session during which they consumed 395 mg/kg (R) -3-hydroxybutyl (R) -3-hydroxybutyrate Ketone Ester (KE) intervention (TdeltaS Global Inc.) before the scan. The order of the sessions was randomized. For the PET cohort, blood glucose and ketone levels were assessed and voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) were computed at each session. For the MRI cohort, brain anterior cingulate BHB levels were assessed using magnetic resonance spectroscopy.
Results: A single dose of KE elevated blood BHB and anterior cingulate BHB levels compared to baseline. Moreover, blood glucose levels were lower with KE than baseline, and whole-brain CMRglc decreased by 17%. The largest KE-induced CMRglc reductions were in the frontal, occipital, cortex, and anterior cingulate cortices.
Conclusion: These findings provide preliminary evidence that KE administration elevates ketone and reduces brain glucose metabolism in humans, consistent with a shift from glucose to ketones as a brain energy source. Average reductions in CMRglc of 17% are similar to global average reductions documented with administration of 0.25-0.5 g/kg of alcohol. Documenting the clinical and neurometabolic effects of nutritional ketosis will yield fundamental knowledge as to its potential beneficial effects as a treatment for AUD and its underlying neural mechanisms.

DOI: https://doi.org/10.1101/2023.09.25.23296090
Nutrition. 2023 Sep 07. pii: S0899-9007(23)00241-1. [Epub ahead of print]117 112213

Role of insulin resistance and leptin in the effect of intermittent feeding with a high-protein ketogenic diet on body composition in rats.

Gul Eyikudamaci, Hasan Ege, Nihal Ensen, Nermin Yelmen.

   OBJECTIVES: The prevalence of obesity and overweight in children has been increasing rapidly worldwide and threatens society with various chronic diseases that these children are born with. High-protein ketogenic diets and intermittent nutrition are thought to be protective against obesity and metabolic syndrome MetS. However, the exact effects and results, insulin resistance, and the role of leptin in the functioning mechanism of these diets have not been fully elucidated. The aim of this study was to investigate the roles of insulin resistance and leptin hormone on the effects of body composition with a high-protein ketogenic diet and intermittent nutrition combination.
METHODS: Thirty-two young non-obese rats were randomly divided into four equal groups. Both the standard diet and the high-protein ketogenic diet were given ad libitum and intermittently to the rats for 6 wk. The body weight and fat mass of the rats were measured at the end of the experiment. The fasting glucose, leptin, insulin, high- and low-density lipoprotein, and triacylglycerols were measured with the blood samples.
RESULTS: The lowest body weight was observed in the intermittent and high-protein ketogenic diet group, followed by the free high-protein ketogenic diet and standard intermittent diet group, respectively. Also, the lowest body fat mass was observed in the intermittent and high-protein ketogenic diet group, followed by the standard intermittent diet group. Although there was no change in leptin, insulin, high- and low-density lipoprotein, and triacylglycerol levels in any group, the lowest blood glucose rate was observed in the intermittent and high-protein ketogenic diet group.
CONCLUSION: The results of the present study revealed that an intermittent high-protein ketogenic diet is more effective than others in weight loss without disrupting biochemical health parameters, and the applied diets do not prevent growth and development.

Keywords:  High-protein diet; Insulin resistance; Intermittent feeding; Ketogenic diet; Leptin

DOI:  https://doi.org/10.1016/j.nut.2023.112213
Metab Brain Dis. 2023 Oct 12.

Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Yu- Cai Ye, Shi-Fan Chai, Xin-Ru Li, Mei-Na Wu, Hong-Yan Cai, Zhao-Jun Wang.

  Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Keywords:  Alzheimer’s disease; Brain energy rescue; Brain glucose metabolism; Intermittent fasting; Ketone body

DOI:  https://doi.org/10.1007/s11011-023-01288-2
Oncol Lett. 2023 Nov;26(5): 479

Hepatic safety profile of pancreatic cancer‑bearing mice fed a ketogenic diet in combination with gemcitabine.

Natalia E Cortez, Cecilia Rodriguez Lanzi, Payam Vahmani, Karen Matsukuma, Gerardo G Mackenzie.

  Ketogenic diets (KDs) are actively being evaluated for their potential anticancer effects. Although KDs are generally considered safe, their safety profile when combined with chemotherapy remains unknown. It is known that a KD enhances the anticancer effect of gemcitabine (2',2'-difluoro-2'-deoxycytidine) in LSL-KrasLSL-G12D/+Trp53R172H/+Pdx-1-Cre (KPC) tumor-bearing mice. In the present study, whether a KD in combination with gemcitabine affected the liver safety profile in KPC mice was evaluated. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; % kcal: 20% fat, 65% carbohydrate, 15% protein) + gemcitabine [control plus gemcitabine group (CG)] or a KD (% kcal: 84% fat, 15% protein, 1% carbohydrate) + gemcitabine [ketogenic plus gemcitabine group (KG)] for two months. After two months of treatment, no significant differences in body weight were observed between CGs and KGs. Moreover, the KD did not significantly alter the serum protein expression levels of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. In addition, the KD did not alter markers of liver-lipid accumulation as well as serum cholesterol and triglyceride levels, compared with the CG-treated group. Upon histologic examination, steatosis was rare, with no notable differences between treatment groups. When examining liver fatty acid composition, KD treatment significantly increased the content of saturated fatty acids and significantly decreased levels of cis-monounsaturated fatty acids compared with the CG. Finally, the KD did not affect liver markers of inflammation and oxidative stress, nor the protein expression levels of enzymes involved in ketone bodies, such as 3-hydroxy-3-methylglutaryl-CoA lyase and hidroximetilglutaril-CoA sintasa, and glucose metabolism, such as hexokinase 2, pyruvate dehydrogenase and phosphofructokinase. In summary, a KD in combination with gemcitabine appears to be safe, with no apparent hepatotoxicity and these data support the further evaluation of a KD as an adjuvant dietary treatment for pancreatic cancer.

Keywords:  KPC mice; gemcitabine; ketogenic diet; liver steatosis; liver toxicity; pancreatic cancer

DOI:  https://doi.org/10.3892/ol.2023.14067
BJPsych Open. 2023 Oct 10. 9(6): e176

Pilot study of a ketogenic diet in bipolar disorder.

Nicole Needham, Iain H Campbell, Helen Grossi, Ivana Kamenska, Benjamin P Rigby, Sharon A Simpson, Emma McIntosh, Pankaj Bahuguna, Ben Meadowcroft, Frances Creasy, Maja Mitchell-Grigorjeva, John Norrie, Gerard Thompson, Melissa C Gibbs, Ailsa McLellan, Cheryl Fisher, Tessa Moses, Karl Burgess, Rachel Brown, Michael J Thrippleton, Harry Campbell, Daniel J Smith.

   BACKGROUND: Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date.
AIMS: To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder.
METHOD: Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198.
RESULTS: Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6-8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication).
CONCLUSIONS: The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Keywords:  Bipolar type I or II disorders; clinical outcomes measures; metabolic psychiatry; neurophysiology; other imaging

DOI:  https://doi.org/10.1192/bjo.2023.568
Cardiovasc Res. 2023 Oct 11. pii: cvad157. [Epub ahead of print]

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilisation.

Dylan Chase, Thomas R Eykyn, Michael J Shattock, Yu Jin Chung.

AIM: Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 (SGLT2) and an effective treatment for type-2 diabetes, has been shown to have cardioprotective effects, independent of improved glycaemic control. Several non-canonical mechanisms have been proposed to explain these cardiac effects, including increasing circulating ketone supply to the heart. This study aims to test whether EMPA directly alters cardiac ketone metabolism independent of supply.
METHODS AND RESULTS: The direct effects of EMPA on cardiac function and metabolomics were investigated in Langendorff rat heart perfused in buffer containing 5 mM glucose, 4 mM β-hydroxybutyrate (βHb) and 0.4 mM intralipid, subject to low flow ischaemia/reperfusion. Cardiac energetics were monitored in situ using 31P NMR spectroscopy. Steady-state 13C-labelling was performed by switching 12C substrates for 13C1 glucose or 13C4 βHb, and 13C incorporation into metabolites determined using 2D 1H-13C HSQC NMR spectroscopy. EMPA treatment improved left ventricular developed pressure during ischaemia and reperfusion compared to vehicle-treated hearts. In EMPA-treated hearts, total ATP and PCr levels, and Gibbs free energy for ATP hydrolysis were significantly higher during ischaemia and reperfusion. EMPA treatment did not alter the incorporation of 13C from glucose into glycolytic products lactate or alanine neither during ischaemia nor reperfusion. In ischaemia, EMPA led to a decrease in 13C1 glucose incorporation and a concurrent increase in 13C4 βHb incorporation into TCA intermediates succinate, citrate, and glutamate. During reperfusion, the concentration of metabolites originating from 13C1 glucose was similar to vehicle but those originating from 13C4 βHb remained elevated in EMPA treated hearts.
CONCLUSIONS: Our findings indicate that EMPA causes a switch in metabolism away from glucose oxidation towards increased ketone utilisation in the rat heart, thereby improving function and energetics both during ischaemia and recovery during reperfusion. This preference of ketone utilisation over glucose was observed under conditions of constant supply of substrate, suggesting that EMPA acts directly by modulating cardiac substrate preference, independent of substrate availability. The mechanisms underlying our findings are currently unknown, warranting further study.
TRANSLATIONAL PERSPECTIVE: Heart failure remains a huge clinical burden. Clinical trials of SGLT2 inhibitors in patients with diabetes and heart failure have reported significant cardio-protection from EMPA treatment that appears independent of improved glycaemic control. The direct cardiac effect of EMPA in modulating ketone metabolism observed in this study raises the potential for EMPA to be used as a therapy for heart failure in both diabetic and non-diabetic patients alike.

DOI: https://doi.org/10.1093/cvr/cvad157
JCI Insight. 2023 Oct 10. pii: e171772. [Epub ahead of print]

GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.

George R Marcotte, Matthew J Miller, Hawley E Kunz, Zachary C Ryan, Matthew D Strub, Patrick M Vanderboom, Carrie J Heppelmann, Sarah Chau, Zachary D Von Ruff, Sean P Kilroe, Andrew T McKeen, Jason M Dierdorff, Jennifer I Stern, Karl A Nath, Chad E Grueter, Vitor A Lira, Andrew R Judge, Blake B Rasmussen, K Sreekumaran Nair, Ian R Lanza, Scott M Ebert, Christopher M Adams.

  Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

Keywords:  Metabolism; Mitochondria; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.171772
JAMA Cardiol. 2023 Oct 11.

Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction-Reply.

Anthony J A Molina, Erich Gnaiger, Dalane W Kitzman.

DOI: https://doi.org/10.1001/jamacardio.2023.3577
Pediatr Neurol. 2023 Aug 25. pii: S0887-8994(23)00289-8. [Epub ahead of print]149 63-68

Propofol for Anesthesia in Pediatric Patients With Epilepsy on the Ketogenic Diet: A Single-Center Experience.

Paul H Bui, Maureen Handoko, Gloria Diaz-Medina, Ann S Ng, Akshat Katyayan.

   BACKGROUND: Propofol use is contraindicated in patients on ketogenic diet (KD) due to higher risk of propofol infusion syndrome (PIS). This study is intended to provide a descriptive analysis of our experience with propofol bolus and short infusions for anesthetic care in patients on the KD and to evaluate if any signs of PIS were observed.
METHODS: All patients on the KD who underwent anesthesia with propofol between 2012 and 2022 were reviewed. Anesthetic encounters and charts were studied for type of surgical procedure; signs of PIS, including new cardiac arrhythmias, acidosis, or rhabdomyolysis in the periprocedural period; hypoglycemia; unplanned admissions within 24 hours of the procedure; if procedure was unexpectedly aborted; and increased seizure frequency within one week.
RESULTS: We identified 65 patients, aged from one to 20 years who underwent 165 anesthetic encounters with propofol, of which 123 were boluses and 42 were infusions. In bolus dosing, the average dose was 2.8 mg/kg (0.7 to 12.8 ± 1.8 mg/kg). Of these, four encounters developed acidosis, one developed rhabdomyolysis, and one developed increased seizures. With infusions, the average infusion rate was 9 mg/kg/hour, with mean infusion duration of 83 minutes (10 to 352 ± 75 minutes). Of these, one developed acidosis and one increased seizures. No cases of PIS were identified. None of the adverse effects were attributed to propofol.
CONCLUSIONS: Boluses and brief infusions of propofol for anesthetic use in patients on the KD did not cause PIS in our cohort.

Keywords:  Epilepsy; Ketogenic diet; Propofol; Propofol infusion syndrome

DOI:  https://doi.org/10.1016/j.pediatrneurol.2023.08.031
Diabetol Metab Syndr. 2023 Oct 13. 15(1): 198

The effectiveness of blood glucose and blood ketone measurement in identifying significant acidosis in diabetic ketoacidosis patients.

Eric S Kilpatrick, Alexandra E Butler, Sawsan Saeed, Naji Alamuddin, Stephen L Atkin, David B Sacks.

   BACKGROUND: Patients with diabetic ketoacidosis (DKA), a potentially fatal complication of type 1 diabetes, have hyperglycemia, ketonemia and metabolic acidosis. Blood glucose and blood ketone results are often used to triage patients with suspected DKA. This study aimed to establish how effective blood glucose and blood ketone (beta-hydroxybutyrate, BOHB) measurements are in identifying patients with significant acidosis and sought to validate existing diagnostic BOHB thresholds.
METHODS: Initial Emergency Department results on 161 presumptive DKA episodes in 95 patients (42 F, 53 M, age range 14-89 years) containing a complete dataset of D (glucose), K (BOHB) and A (Bicarbonate [HCO3] and pH) results.
RESULTS: Blood glucose correlated poorly with BOHB (r = 0.28 p = 0.0003), pH (r= -0.25, p = 0.002) and HCO3 (r= -0.17, p = 0.04). BOHB, though better, was still limited in predicting pH (r = -0.44, p < 0.0001) and HCO3 (r = -0.49, p < 0.0001). A HCO3 of 18mmol/L equated to a BOHB concentration of 4.3mmol/L, whilst a HCO3 of 15mmol/L equated to a BOHB of 4.7mmol/L. Of the 133 of 161 events with HCO3 < 18mmol/L, 22 were not hyperglycemic (> 13.9mmol/L, n = 8), ketonemic (≤ 3mmol/L, n = 9) or either (n = 5).
CONCLUSIONS: The commonly employed BOHB diagnostic cutoff of 3mmol/L could not be verified. Since acid-base status was poorly predicted by both glucose and BOHB, this highlights that, regardless of their results, pH and/or HCO3 should also be tested in any patient suspected of DKA.

Keywords:  Acid-base status; Bicarbonate; Diabetic ketoacidosis; Ketones; beta-hydroxybutyrate; pH

DOI:  https://doi.org/10.1186/s13098-023-01176-w
Adv Nutr. 2023 Oct 10. pii: S2161-8313(23)01391-1. [Epub ahead of print]

Effects of Intermittent Energy Restriction Compared to Those of Continuous Energy Restriction on Body Composition and Cardiometabolic Risk Markers - A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Adults.

Maite M Schroor, Peter J Joris, Jogchum Plat, Ronald P Mensink.

  The interest in intermittent energy restriction (IER) diets as weight loss approach is increasing. Different IER protocols exist, including time-restricted eating (TRE), alternate-day fasting (ADF), and the 5:2 diet. This meta-analysis compared the effects of these IER diets to continuous energy restriction (CER) on anthropometrics and cardiometabolic risk markers in healthy adults. Twenty-eight trials were identified that studied TRE (k=7), ADF (k=10), or the 5:2 diet (k=11) for 2 to 52 weeks. Energy intakes between intervention groups within a study were comparable (17 trials), lower in IER (5 trials) or not reported (6 trials). Weighted mean differences (WMD) were calculated using fixed- or random-effects models. Changes in body weight (WMD: -0.42 kg; 95% CI: -0.96 to 0.13; p=0.132) and fat mass (WMD: -0.31 kg; 95% CI: -0.98 to 0.36; p=0.362) were comparable when results of the three IER diets were combined and compared to those of CER. All IER diets combined reduced fat free mass (WMD: -0.20 kg; 95% CI: -0.39 to -0.01; p=0.044) and waist circumference (WMD: -0.91 cm; 95% CI: -1.76 to -0.06; p=0.036) more than CER. Effects on body mass index (BMI), glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), serum lipids and lipoproteins, and blood pressure did not differ. Further, TRE reduced body weight, fat mass, and fat mass more than CER, while ADF improved HOMA-IR more. BMI reduced less in the 5:2 diet compared to CER. In conclusion, the three IER diets combined did not lead to superior improvements in anthropometrics and cardiometabolic risk markers compared to CER diets. Slightly greater reductions were however observed in fat free mass and waist circumference. To what extent differences in energy intakes between groups within studies may have influenced these outcomes should be addressed in future studies. This meta-analysis was registered at PROSPERO as CRD42022350008.

Keywords:  5:2 diet; Healthy adults; alternate-day fasting; daily calorie restriction; intermittent fasting; meal timing; time-restricted eating

DOI:  https://doi.org/10.1016/j.advnut.2023.10.003
Int J Mol Sci. 2023 Sep 22. pii: 14460. [Epub ahead of print]24(19):

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.

Pamela R Westmark, Aaron K Gholston, Timothy J Swietlik, Rama K Maganti, Cara J Westmark.

  Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep-wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep-wake patterns in adult wild type and Fmr1KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1KO mice exhibited sleep-wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest-activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states.

Keywords:  Fmr1KO; electroencephalography (EEG); fragile X syndrome; ketogenic diet; sleep

DOI:  https://doi.org/10.3390/ijms241914460
Am J Physiol Regul Integr Comp Physiol. 2023 Oct 09.

Effects of Hyperthermia and Acidosis on Mitochondrial Production of Reactive Oxygen Species.

Michael S Davis, Warwick M Bayly, Cristina M Hansen, Montana R Barrett, Cara A Blake.

  Exercise is associated with the development of oxidative stress, but the specific source and mechanism of production of pro-oxidant chemicals during exercise has not been confirmed. We used equine skeletal muscle mitochondria to test the hypothesis that hyperthermia and acidosis affect mitochondrial oxygen consumption and production of reactive oxygen species (ROS). Skeletal muscle biopsies were obtained at rest, after an acute episode of fatiguing exercise, and after a 9-week conditioning program to increase aerobic fitness. Mitochondrial oxygen consumption and ROS production were measured simultaneously using high-resolution respirometry. Both hyperthermia and acidosis increased non-phosphorylating (LEAK) respiration (5.8X and 3.0X, respectively, p<0.001) and decreased efficiency of oxidative phosphorylation. The combined effects of hyperthermia and acidosis resulted in large decreases in phosphorylating respiration, further decreasing oxidative phosphorylation efficiency from 97% to 86% (p<0.01). Increased aerobic fitness reduced the effects of acidosis on LEAK respiration. Hyperthermia increased, and acidosis decreased ROS production (2X and 0.23X, respectively, p<0.001). There was no effect of acute exercise, but an aerobic conditioning program was associated with increased ROS production during both non-phosphorylating and phosphorylating respiration. Hyperthermia increased the ratio of ROS production to O2 consumption during phosphorylating respiration, suggesting that high temperature impaired transfer of energy through the electron transfer system despite relatively low mitochondrial membrane potential. These data support the role of skeletal muscle mitochondria in the development of exercise-induced oxidative stress, particularly during forms of exercise that result in prolonged hyperthermia without acidosis.

Keywords:  Oxidative stress; high-resolution respirometry; horse; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00177.2023
Arch Physiol Biochem. 2023 Oct 13. 1-13

Intermittent fasting in health and disease.

Anubhav Mishra, Devika Sobha, Dimple Patel, Padmanaban S Suresh.

   CONTEXT: Intermittent fasting, a new-age dietary concept derived from an age-old tradition, involves repetitive cycles of fasting/calorie restriction and eating.
OBJECTIVE: We aim to take a deep dive into the biological responses to intermittent fasting, delineate the disease-modifying and cognitive effects of intermittent fasting, and also shed light on the possible side effects.
METHODS: Numerous in vitro and in vivo studies were reviewed, followed by an in-depth analysis, and compilation of their implications in health and disease.
RESULTS: Intermittent fasting improves the body's stress tolerance, which is further amplified with exercise. It impacts various pathological conditions like cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases.
CONCLUSION: During dietary restriction, the human body experiences a metabolic switch due to the depletion of liver glycogen, which promotes a shift towards utilising fatty acids and ketones in the system, thereby significantly impacting adiposity, ageing and the immune response to various diseases.

Keywords:  Intermittent fasting; ageing; calorie restriction; metabolism; obesity

DOI:  https://doi.org/10.1080/13813455.2023.2268301
Mol Metab. 2023 Oct 05. pii: S2212-8778(23)00148-5. [Epub ahead of print] 101814

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency.

Hui Xia, Charlotte Scholtes, Catherine R Dufour, Christina Guluzian, Vincent Giguère.

   OBJECTIVE: Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance.
METHODS: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism.
RESULTS: Genetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis.
CONCLUSION: Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity.

Keywords:  Diabetes; Endurance exercise; Fuel metabolism; Lactate; Mitochondrial oxidative metabolism; Muscle function; Muscle wasting; Myofibers; Nuclear receptor

DOI:  https://doi.org/10.1016/j.molmet.2023.101814
Heart Fail Rev. 2023 Oct 12.

Autophagy protects mitochondrial health in heart failure.

Yating Tang, Wenlong Xu, Yu Liu, Jiajun Zhou, Kai Cui, Yanmei Chen.

  The progression of heart failure is reported to be strongly associated with homeostatic imbalance, such as mitochondrial dysfunction and abnormal autophagy, in the cardiomyocytes. Mitochondrial dysfunction triggers autophagic and cardiac dysfunction. In turn, abnormal autophagy impairs mitochondrial function and leads to apoptosis or autophagic cell death under certain circumstances. These events often occur concomitantly, forming a vicious cycle that exacerbates heart failure. However, the role of the crosstalk between mitochondrial dysfunction and abnormal autophagy in the development of heart failure remains obscure and the underlying mechanisms are mainly elusive. The potential role of the link between mitochondrial dysfunction and abnormal autophagy in heart failure progression has recently garnered attention. This review summarized recent advances of the interactions between mitochondria and autophagy during the development of heart failure.

Keywords:  Autophagy; Heart failure; Mitochondria health; Mitochondria-targeted therapeutics; Mitochondrial quality control

DOI:  https://doi.org/10.1007/s10741-023-10354-x
Ageing Res Rev. 2023 Oct 11. pii: S1568-1637(23)00246-5. [Epub ahead of print] 102087

Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.

Dandan Jia, Zhenjun Tian, Ru Wang.

  The benefits of regular physical activity are related to delaying and reversing the onset of ageing and age-related disorders, including cardiomyopathy, neurodegenerative diseases, cancer, obesity, diabetes, and fatty liver diseases. However, the molecular mechanisms of the benefits of exercise or physical activity on ageing and age-related disorders remain poorly understood. Mitochondrial dysfunction is implicated in the pathogenesis of ageing and age-related metabolic diseases. Mitochondrial health is an important mediator of cellular function. Therefore, exercise alleviates metabolic diseases in individuals with advancing ageing and age-related diseases by the remarkable promotion of mitochondrial biogenesis and function. Exerkines are identified as signaling moieties released in response to exercise. Exerkines released by exercise have potential roles in improving mitochondrial dysfunction in response to age-related disorders. This review comprehensive summarizes the benefits of exercise in metabolic diseases, linking mitochondrial dysfunction to the onset of age-related diseases. Using relevant examples utilizing this approach, the possibility of designing therapeutic interventions based on these molecular mechanisms is addressed.

Keywords:  age-related diseases; ageing; exerkines; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.arr.2023.102087
Front Immunol. 2023 ;14 1219422

Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.

Hoyul Lee, Jae-Han Jeon, Eun Soo Kim.

  Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.

Keywords:  IBD - inflammatory bowel disease; T cell; immunometabolism; inflammation; mitochondria; treatment

DOI:  https://doi.org/10.3389/fimmu.2023.1219422
Eur J Appl Physiol. 2023 Oct 11.

Intense interval exercise induces greater changes in post-exercise metabolism compared to submaximal exercise in middle-aged adults.

Seth F McCarthy, Claudia Jarosz, Emily J Ferguson, Kenji A Kenno, Tom J Hazell.

   INTRODUCTION: High-intensity interval training (HIIT) and sprint interval training (SIT) consistently elevate post-exercise metabolism compared to moderate-intensity continuous training (MICT) in young adults (18-25 years), however few studies have investigated this in middle-aged adults.
PURPOSE: To assess the effect of exercise intensity on post-exercise metabolism following submaximal, near-maximal, and supramaximal exercise protocols in middle-aged adults.
METHODS: 12 participants (8 females; age: 44 ± 10 years; [Formula: see text]O2max: 35.73 ± 9.97 mL·kg-1 min-1) had their oxygen consumption ([Formula: see text]O2) measured during and for 2 h following 4 experimental sessions: (1) no-exercise control (CTRL); (2) MICT exercise (30 min at 65% [Formula: see text]O2max); (3) HIIT exercise (10 × 1 min at 90% maximum heart rate with 1 min rest); and (4) modified-SIT exercise (8 × 15 s "all-out" efforts with 2 min rest). Between session differences for [Formula: see text]O2 and fat oxidation were compared.
RESULTS: O2 consumed post-exercise was elevated during the 1st h and 2nd h following HIIT (15.9 ± 2.6, 14.7 ± 2.3 L; P < 0.036, d > 0.98) and modified-SIT exercise (16.9 ± 3.3, 15.30 ± 3.4 L; P < 0.041, d > 0.96) compared to CTRL (13.3 ± 1.9, 12.0 ± 2.5 L) while modified-SIT was also elevated vs HIIT in the 1st h (P < 0.041, d > 0.96). Total post-exercise O2 consumption was elevated following all exercise sessions (MICT: 27.7 ± 4.1, HIIT: 30.6 ± 4.8, SIT: 32.2 ± 6.6 L; P < 0.027, d > 1.03) compared to CTRL (24.9 ± 4.1 L). Modified-SIT exercise increased fat oxidation (0.103 ± 0.019 g min-1) compared to all sessions post-exercise (CTRL: 0.059 ± 0.025, MICT: 0.075 ± 0.022, HIIT: 0.081 ± 0.021 g·min-1; P < 0.007, d > 1.30) and HIIT exercise increased compared to CTRL (P = 0.046, d = 0.87).
CONCLUSION: Exercise intensity has an important effect on post-exercise metabolism in middle-aged adults.

Keywords:  Excess post-exercise oxygen consumption; Fat oxidation; High-intensity interval training; Moderate-intensity continuous training; Sprint interval training

DOI:  https://doi.org/10.1007/s00421-023-05334-w
Geriatr Gerontol Int. 2023 Oct 13.

Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.

Hiroshi Kondoh, Masahiro Kameda.

  Aging shows biologically complex features with high individual variability, which reflects the exposure to several stimuli and the adaptation to them. Among them, metabolic changes are well observed as consequences or possible causes of aging. Calorie restriction extends organismal life span in experimental models. Several metabolites; for example, resveratrol or nicotinamide mononucleotide, are reported to mimic calorie restriction effects in vivo. Metabolomic research would be useful to evaluate metabolites as biomarkers in aging-relevant events and to identify metabolic regulation of aging. We recently developed the metabolomic approach for whole blood analysis, which functions as strong tool for this purpose. We review the update findings in aging-relevant metabolites detected by this method. Geriatr Gerontol Int 2023; ••: ••-••.

Keywords:  aging; frailty; metabolites

DOI:  https://doi.org/10.1111/ggi.14684
Physiol Rep. 2022 Jun;10(11): e15268

Changes in 24-h energy expenditure, substrate oxidation, and body composition following resistance exercise and a high protein diet via whey protein supplementation in healthy older men.

Corbin Griffen, Derek Renshaw, Michael Duncan, Martin O Weickert, John Hattersley.

   PURPOSE: To investigate changes in 24-h energy expenditure (EE), substrate oxidation, and body composition following resistance exercise (RE) and a high protein diet via whey protein supplementation (alone and combined) in healthy older men.
METHODS: In a pooled groups analysis, 33 healthy older men [(mean ± SE) age: 67 ± 1 years; BMI: 25.4 ± 0.4 kg/m2] were randomized to either RE (2×/week; n = 17) or non-exercise (n = 16) and either a high protein diet via whey protein supplementation (PRO, 2 × 25 g whey protein isolate/d; n = 17) or control (CON, 2 × 23.75 g maltodextrin/d; n = 16). An exploratory sub-analysis was also conducted between RE+CON (n = 8) and RE+PRO (n = 9). At baseline and 12 weeks, participants resided in respiration chambers for measurement of 24-h EE and substrate oxidation and wore an accelerometer for 7 days for estimation of free-living EE.
RESULTS: Resistance exercise resulted in greater increases in fat-free mass (1.0 ± 0.3 kg), resting metabolic rate [(RMR) 36 ± 14 kcal/d], sedentary EE (60 ± 33 kcal/d), and sleeping metabolic rate [(SMR) 45 ± 7 kcal/d] compared to non-exercise (p < 0.05); however, RE decreased activity energy expenditure in free-living (-90 ± 25 kcal/d; p = 0.049) and non-exercise activity inside the respiration chamber (-1.9 ± 1.1%; p = 0.049). PRO decreased fat mass [(FM) -0.5 ± 0.3 kg], increased overnight protein oxidation (30 ± 6 g/d), and decreased 24-h protein balance (-20 ± 4 g/d) greater than CON (p < 0.05). RE+PRO decreased FM (-1.0 ± 0.5 kg) greater than RE+CON (p = 0.04).
CONCLUSION: Resistance exercise significantly increased RMR, SMR, and sedentary EE in healthy older men, but not total EE. PRO alone and combined with RE decreased FM and aided body weight maintenance. This study was registered at clinicaltrials.gov as NCT03299972.

Keywords:  aging; body composition; energy expenditure; protein; resistance exercise; substrate oxidation

DOI:  https://doi.org/10.14814/phy2.15268
Phys Med Rehabil Clin N Am. 2023 Nov;pii: S1047-9651(23)00035-9. [Epub ahead of print]34(4): 811-824

Key Exercise Concepts in the Rehabilitation from Severe Burns.

Eric Rivas, Josh Foster, Craig G Crandall, Celeste C Finnerty, Oscar E Suman-Vejas.

  This article presents information on the benefits of exercise in counteracting the detrimental effects of bed rest, and/or severe burns. Exercise is key for maintaining physical function, lean body mass, metabolic recovery, and psychosocial health after major burn injuries. The details of an exercise training program conducted in severely burned persons are presented, as well as information on the importance of proper regulation of body temperature during exercise or physical activity. The sections on exercise and thermoregulation are followed by a section on the role of exercise in scarring and contractures. Finally, gaps in the current knowledge of exercise, thermoregulation, and contractures are presented.

Keywords:  Aerobic; Burns; Contracture; Exercise; Heat; Resistance; Scar; Thermoregulation

DOI:  https://doi.org/10.1016/j.pmr.2023.05.003
Neurology. 2023 Oct 12. pii: 10.1212/WNL.0000000000208001. [Epub ahead of print]

Triglycerides and Cognition: Are All Lipids the Same?

Nikolaos Scarmeas, Babak Hooshmand.

DOI: https://doi.org/10.1212/WNL.0000000000208001
Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12

Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.

  Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.

Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes

DOI:  https://doi.org/10.7554/eLife.88084