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      Reduced COVID-19 severity elicited by weight loss from a medically supervised ketogenic diet in a geographically diverse ambulatory population with type 2 diabetes and obesity

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          Abstract

          Objective

          To investigate factors associated with COVID-19 severity in ambulatory individuals with type 2 diabetes mellitus (T2DM) and obesity treated with a medically supervised ketogenic diet (MSKD).

          Research design and methods

          In this real-world, retrospective, exploratory analysis, multivariate modelling was used to assess clinical factors associated with hospitalisation for COVID-19 in a geographically diverse outpatient population with T2DM treated virtually.

          Results

          Leading up to COVID-19 onset, non-hospitalised patients had higher average ketones (0.64 vs 0.52 mmol/L; p=0.016) and greater weight loss (6.8% vs 4.2%; p=0.009) compared with those hospitalised. Greater weight loss was significantly associated with lower likelihood of hospitalisation (adjusted OR=0.91, p=0.005), controlling for enrolment demographics and medical characteristics.

          Conclusions

          Therapies such as MSKD, which elicit rapid, significant weight loss, may favourably impact COVID-19 hospitalisation rate and severity in individuals with T2DM and obesity.

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          Most cited references20

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          Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

          Jing Yang, Ya Zheng, Xi Gou … (2020)
          Highlights • COVID -19 cases are now confirmed in multiple countries. • Assessed the prevalence of comorbidities in infected patients. • Comorbidities are risk factors for severe compared with non-severe patients. • Help the health sector guide vulnerable populations and assess the risk of deterioration.
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            Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study

            Emma Barron, Chirag Bakhai, Partha Kar … (2020)
            Summary Background Although diabetes has been associated with COVID-19-related mortality, the absolute and relative risks for type 1 and type 2 diabetes are unknown. We assessed the independent effects of diabetes status, by type, on in-hospital death in England in patients with COVID-19 during the period from March 1 to May 11, 2020. Methods We did a whole-population study assessing risks of in-hospital death with COVID-19 between March 1 and May 11, 2020. We included all individuals registered with a general practice in England who were alive on Feb 16, 2020. We used multivariable logistic regression to examine the effect of diabetes status, by type, on in-hospital death with COVID-19, adjusting for demographic factors and cardiovascular comorbidities. Because of the absence of data on total numbers of people infected with COVID-19 during the observation period, we calculated mortality rates for the population as a whole, rather than the population who were infected. Findings Of the 61 414 470 individuals who were alive and registered with a general practice on Feb 16, 2020, 263 830 (0·4%) had a recorded diagnosis of type 1 diabetes, 2 864 670 (4·7%) had a diagnosis of type 2 diabetes, 41 750 (0·1%) had other types of diabetes, and 58 244 220 (94·8%) had no diabetes. 23 698 in-hospital COVID-19-related deaths occurred during the study period. A third occurred in people with diabetes: 7434 (31·4%) in people with type 2 diabetes, 364 (1·5%) in those with type 1 diabetes, and 69 (0·3%) in people with other types of diabetes. Unadjusted mortality rates per 100 000 people over the 72-day period were 27 (95% CI 27–28) for those without diabetes, 138 (124–153) for those with type 1 diabetes, and 260 (254–265) for those with type 2 diabetes. Adjusted for age, sex, deprivation, ethnicity, and geographical region, compared with people without diabetes, the odds ratios (ORs) for in-hospital COVID-19-related death were 3·51 (95% CI 3·16–3·90) in people with type 1 diabetes and 2·03 (1·97–2·09) in people with type 2 diabetes. These effects were attenuated to ORs of 2·86 (2·58–3·18) for type 1 diabetes and 1·80 (1·75–1·86) for type 2 diabetes when also adjusted for previous hospital admissions with coronary heart disease, cerebrovascular disease, or heart failure. Interpretation The results of this nationwide analysis in England show that type 1 and type 2 diabetes were both independently associated with a significant increased odds of in-hospital death with COVID-19. Funding None.
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              Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease

              Yun-Hee Youm, Kim Nguyen, Ryan Grant … (2015)
              Ketone bodies , β-hydroxybutyrate (BHB) and acetoacetate support mammalian survival during states of energy deficit by serving as alternative source of ATP 1 . BHB levels are elevated during starvation, high-intensity exercise or by the low carbohydrate ketogenic diet 2 . Prolonged caloric restriction or fasting reduces inflammation as immune system adapts to low glucose supply and energy metabolism switches towards mitochondrial fatty acid oxidation, ketogenesis and ketolysis 2-6 . However, role of ketones bodies in regulation of innate immune response is unknown. We report that BHB, but neither acetoacetate nor structurally-related short chain fatty acids, butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to several structurally unrelated NLRP3 activators, without impacting NLRC4, AIM2 or non-canonical caspase-11 inflammasome activation. Mechanistically, BHB inhibits NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 were not dependent on chirality or classical starvation regulated mechanisms like AMPK, reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocked NLRP3 inflammasome without undergoing oxidation in TCA cycle, independently of uncoupling protein-2 (UCP2), Sirt2, receptor Gpr109a and inhibition of NLRP3 did not correlate with magnitude of histone acetylation in macrophages. BHB reduced the NLRP3 inflammasome mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases like Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS) and urate crystal induce body cavity inflammation. Taken together, these findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Nutr Prev Health
                Journal ID (iso-abbrev): BMJ Nutr Prev Health
                Journal ID (hwp): bmjnph
                Journal ID (publisher-id): bmjnph
                Title: BMJ Nutrition, Prevention & Health
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2516-5542
                Publication date Collection: December 2022
                Publication date (Electronic): 1 July 2022
                Publication date PMC-release: 1 July 2022
                Volume: 5
                Issue: 2
                Pages: 154-158
                Affiliations
                [1 ] departmentClinical Research , Virta Health , San Francisco, California, USA
                [2 ] departmentDepartment of Medicine , National Jewish Health , Denver, Colorado, USA
                Author notes
                [Correspondence to ] Dr Brittanie M Volk, Virta Health, San Francisco, CA 94105, USA; brittanie@ 123456virtahealth.com
                Article
                Publisher ID: bmjnph-2022-000444
                DOI: 10.1136/bmjnph-2022-000444
                PMC ID: 9813610
                SO-VID: e15ba904-1e58-42e6-80be-21918d42a995
                Copyright statement: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

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                Subject: Original Research
                Subject: 1506
                Subject: 2474
                Custom metadata
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                access-type free

                Keywords: covid-19,nutritional treatment,diabetes mellitus,weight management
                Data availability:
                Keywords: covid-19, nutritional treatment, diabetes mellitus, weight management

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