Nutritional Ketosis Research Articles

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements—alternatives to KDs—may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and R-beta-hydroxybutyrate (R-βHB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated R-βHB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

Nutritional Ketosis with Ketogenic Diets or Exogenous Ketones: Features, Convergence, and Divergence

Athletes, clinicians, and practitioners are increasingly interested in the proposed performance and therapeutic benefits of nutritional ketosis (NK). NK is best operationally defined as a nutritionally induced metabolic state resulting in blood β-hydroxybutyrate concentrations of ≥0.5 mM. Most tissues readily metabolize ketone bodies (KBs), and KBs in turn regulate metabolism and signaling in both a systemic and tissue-specific manner. During fasting, starvation, or ketogenic diets, endogenous synthesis of KBs is amplified resulting in a state of NK. Orally administered exogenous ketone supplements rapidly elevate circulating KBs and produce a similar, but far from identical, metabolic state. NK results in a number of convergent features regardless of endogenous or exogenous induction; however, important differences also are observed. The implications of NK across health, disease, and performance is rapidly becoming more evident, thus acknowledging the convergent and divergent features of NK is critical for fully understanding the potential utility of this metabolic state.

65-LB: Regression of Prediabetes following Two Years Treatment with a Continuous Care Intervention Emphasizing Carbohydrate Restriction: A Single-Arm, Prospective, Longitudinal Study

Regression from prediabetes (preD) to normoglycemia (NG) is associated with reduced progression to type 2 diabetes (T2D). Carbohydrate restriction including nutritional ketosis (CR) has emerged as a safe, effective, and sustainable treatment for regression of hyperglycemia in T2D, yet its multi-year effects on preD are unknown. Also, some patients have difficulty initiating and/or sustaining provider-recommended lifestyle changes. Thus, we hypothesized that a remotely delivered continuous care intervention (CCI) emphasizing CR would improve glycemia and weight in patients with preD. In a single-arm, prospective, longitudinal study, we assessed incidence of regression from preD to NG, progression from preD to T2D, and prevalence of metabolic syndrome (MetS) and class II or greater obesity in participants following two years of treatment. Patients with a preD diagnosis enrolled in the study (n=116). Outcomes were assessed among 96 participants (age: 52±10 y; BMI: 39.2±7.1 kg/m2) with preD defined as HbA1c<6.5% with metformin use or HbA1c 5.7-6.4% (inclusive) without glycemic control medication. Retention at two years was 75% (72/96). The crude incidence for first occurrence of regression from preD to NG (HbA1c <5.7% without medication) was 47.6 cases per 100 person-years. Estimated cumulative incidence of NG at two years was 52.3%. One new case of T2D each year was observed, and crude incidence of T2D diagnosis was 1.5 cases per 100 person-years. Estimated cumulative incidence of T2D at two years was 3%. Prevalence of MetS was reduced from 94% to 30% at one and 47% at two years (both P<4.4x10-16). Prevalence of class II or greater obesity was reduced from 67% to 38% at one and 39% at two years (both P<.0013). Among two-year completers, 62.5% achieved ≥7% weight loss. Given these observations, this study demonstrates the potential utility of a CCI emphasizing CR for treatment of preD. Disclosure A. McKenzie: Employee; Self; Virta Health Corp. Stock/Shareholder; Self; Virta Health Corp. S.J. Athinarayanan: Employee; Self; Virta Health Corp. J. McCue: Employee; Self; Virta Health Corp. Stock/Shareholder; Self; Virta Health Corp. R.N. Adams: Employee; Self; Virta Health Corp. J.P. McCarter: Employee; Self; Abbott Laboratories. Stock/Shareholder; Self; Virta Health. J. Volek: Advisory Panel; Self; Atkins Nutritionals, Cook Keto, Virta Health Corp. Stock/Shareholder; Self; PangeaKeto, Virta Health Corp. Other Relationship; Self; Beyond Obesity. Funding Virta Health Corp

Nutritional Ketosis Defined by Diet, Urinary and Capillary Blood Measures

Abstract Objectives Tracking food and beverage intakes daily on a modified Ketogenic diet (MKD) pattern is time consuming, challenging and often, incomplete. The objective of this pre-post test design study was to examine different measures of nutritional ketosis in relation to reported dietary intakes before and during the adoption of the MKD for 8 days. Methods A sample of 19 adult women (mostly nutrition professionals) were instructed on a MKD, monitored foods and beverages consumed daily using the Carb Manager© app (Wombat Apps LLC, WA) and checked urinary ketones (Siemens Labstix Reagent Strips (Malvern, PA, USA)) each morning. On days 0, 7 and 8, participants fasted overnight and provided urine and capillary blood samples for determination of urinary acetoacetate (AoAc) and beta-hydroxybutyrate (BHB) concentrations, respectively. BHB concentrations were determined with device A, Precision Xtra (Alameda, CA, USA) and; device B, KetoMojo (Napa, CA, USA). Nutritional ketosis was defined as blood BHB ≥ 0.5 mmol/L or urinary AoAc ≥ 15 mg/dL. Descriptive statistics and correlations were run using SPSS version 23 (IBM Corp, 2015). Results At baseline, two-day averages of net carbohydrate (nCHO), energy, fiber, protein, and fat were as follows (median, (IQR)): 106 (81, 137); 1470 (1194, 1689); 11.8 (8.0,19.0); 64.2 (47.4, 80.6); and 67 (48, 78). All components except for energy are reported as grams/day. Baseline urinary AoAc concentrations were non-detectable; blood BHB by device A were 0.1 (0.1, 0.2) while device B were 0.1 (0.1, 0.1) mmol/L. Once on the MKD for 7 and 8 days, two-day averages of net carbohydrate (nCHO), energy, fiber, protein, and fat were as follows (median, (IQR)): 27 (25, 30); 1527 (1346, 1638); 18.2 (12.0, 22.2); 64.0 (49.9, 72.2); and 111 (95, 137). Day 8 urinary AoAc levels were 15 (5, 80) mg/dL while blood BHB were 0.6 (0.4, 1.3) with device A and 0.8 (0.3, 1.8) mmol/L with device B. Changes in nCHO intake were correlated with Day 8 BHB values (device A, rho = −0.655, P = 0.004 and device B, rho = −0.652, P = 0.005), and with urinary AoAc (rho = –0.631, P = 0.007). Conclusions All ketone biomarkers reflected changes in nCHO intake. Further study is warranted to confirm these observations and provide estimates of biomarker reliability to determine the most cost-effective method for assessing adherence to the MKD. Funding Sources Departmental.

MON-LB125 Dka From a Ketogenic Diet and Intermittent Fasting or Ketosis-Prone Diabetes?

Background: Ketogenic diets and intermittent fasting (IF) are popularly used for weight loss. Generation of ketone bodies for fuel from fatty acid oxidation underlies both diets, combined or separately. We present a case of a prediabetic patient admitted for DKA after starting a combination keto/IF diet. Clinical Case: A 63-year-old man with hypertension, prediabetes, and alcohol use was admitted from clinic after receiving lab test results consistent with diabetic ketoacidosis (DKA). Two months ago, he had started a keto diet with IF (5 days/week, 18 hour fast/day) and achieved weight loss of 20 pounds. He reported polyuria and polydipsia, which was attributed to the recent initiation of chlorthalidone. Laboratory testing revealed glucose 519 (</= 199 mg/dL), bicarbonate 12 (20-30 mmol/L), creatinine 1.6 (0.5-1.5 mg/dL), anion gap of 23 (6-16 mEq/L), HbA1c 12.2% (4-5.6%), c-peptide 1.37 (0.80-3.85 ng/mL) with glucose 294, GAD65 Ab <5 (<5 IU/mL), IA2 Ab <5.4 (<5.4 U/mL), Insulin Ab <0.4 (<0.4 U/mL), triglyceride 546 (0-199 mg/dL), LDL-d 176 (0-129 mg/dL), cholesterol 310 (0-199 mg/dL) and HDL 39 (>/= 40 mg/dL). Workup for precipitating causes of DKA was negative including normal lactate, lipase and troponin. The patient was managed with an insulin drip and discharged on subcutaneous insulin (Lantus 45 units/day, Aspart 13 units with meals) and metformin. The patient re-introduced carbohydrates into his diet after meeting with the nutritionist. Eight weeks later, the HbA1c decreased to 6.6% and insulin was significantly reduced to Lantus 25 units/day. Sixteen weeks after discharge, the HbA1c further declined to 5.1% and Lantus was reduced to 10 units/day. Beta cell function at that time was preserved as evidenced by c-peptide 1.82 ng/mL. Insulin therapy was discontinued and the patient was closely monitored for urinary ketones and recurrence of hyperglycemia, neither which have developed. Conclusion: This is a unique case of DKA precipitated by a keto/intermittent fasting diet, without the use of SGLT2 inhibitor. Interestingly, previous metabolic studies show that nutritional ketosis typically generates low levels of serum ketones without a clinically significant anion gap metabolic acidosis. With negative beta cell autoantibodies and preserved beta cell function, this presentation is also consistent with ketosis-prone diabetes type 2B. It is possible that nutritional ketosis triggered the onset of KPD, although the mechanism remains unclear particularly since it is known that lipotoxicity is not pathogenic in the development of KPD.

SAT-LB125 Broad Spectrum Effects of a Ketogenic Diet Delivered by Remote Continuous Care on Inflammation and Immune Modulators in Type 2 Diabetes and Prediabetes

Type 2 diabetes (T2D) is associated with, and often preceded by, increased levels of circulating c-reactive protein (CRP) and WBC count that mediate the body’s inflammatory and immune responses (inflammatory mediators [IMs]). This relationship between inflammation and diabetes is complex, as statins have anti-inflammatory properties but paradoxically promote or exacerbate T2D. Recently it has been reported that beta-hydroxybutyrate levels characteristic of nutritional ketosis enhance cellular defenses against oxidative stress and block the assembly of the NLRP3 inflammasome. As part of an ongoing study of the effects of a well-formulated ketogenic diet (WFKD) delivered via a web-based continuous care intervention (CCI) on 262 patients with T2D1 and 116 with prediabetes (PreD), we determined plasma levels of 16 IMs at baseline, 1 yr, and 2 yrs. These same IMs were concurrently monitored in 87 patients with T2D recruited as usual care controls (UC). At baseline, a statin was prescribed for 50% of the T2D/CCI patients, 27% of PreD/CCI patients, and 59% of the T2D/UC patients; at which time statin use was associated with reduced plasma CRP (P=7 x 10-5) compared to non-statin users in the T2D/CCI group only. There were no other significant baseline differences between statin users and non-users for any IMs (WBC, TNFa, IL-1b, IL-6, IL-8, IL-18, IFN-g, E- L-, and P-selectins, EGF, VEGF-A, MCP-1, ICAM-1 and VCAM-1). After 1 yr and 2 yrs of the CCI, mean weight losses in T2D were 12% and 10%, HbA1c reductions were 1.3% and 0.9%, and diabetes medication use was reduced by 51% and 53%, respectively. Linear mixed effects models were used to assess change in IMs over the 2 yrs, facilitating intent-to-treat analyses. Fourteen of the 16 IMs (excluding ICAM-1 and VCAM-1) were reduced compared to baseline in T2D/CCI (P<0.001), with none showing significant increases between yrs 1 and 2. A similar pattern albeit at lower magnitudes was seen in patients with PreD/CCI. Despite lower CRP values at baseline, T2D/CCI patients prescribed a statin experienced further reductions with the WFKD over the 2 years (P=3 x 10-5). In the T2D/UC group, no significant changes in any of the IMs were observed at 1 yr or 2 yrs. These observations suggest that a WFKD delivered via the CCI has broad-spectrum anti-inflammatory and immune modulatory effects in patients with T2D and PreD. Consistent with prior reports, statin use was associated with reduced CRP at baseline in the T2D/CCI group, but this effect was not significant in PreD/CCI and T2D/UC groups. CRP reductions were nonetheless significant in T2D/CCI statin users, suggesting added benefit of the WFKD. We conclude that improvements in IMs induced by a combination of nutritional ketosis and weight loss contribute to the beneficial effects of the CCI in the management of T2D.1. Athinarayanan SJ, et al. Front Endocrinol. 2019. 5;10:348

SUN-LB113 A Continuous Remote Care Intervention Utilizing Carbohydrate Restriction Including Nutritional Ketosis Improves Markers of Metabolic Risk and Reduces Diabetes Medication Use in Patients With Type 2 Diabetes Over 3.5 Years

Novel lifestyle, pharmaceutical, and/or surgical therapies for type 2 diabetes (T2D) are under study to assess lasting impact on metabolic risk. Among them, carbohydrate restriction including nutritional ketosis (CR) has emerged as a safe and effective nutrition therapy for reducing hyperglycemia in patients with T2D1, yet longer term effects are unknown. At the conclusion of a 2-year study assessing a continuous remote care intervention utilizing CR (CCI) among patients who selected this therapy, intervention participants were offered the opportunity to consent to participate in a 3-year extension assessing outcomes at 3.5- and 5-y following initial enrollment. 143 of 169 extension-consented participants provided data at 3.5-y follow up. Among 3.5-y completers, linear mixed effects models were used to assess change over time in diabetes-related outcomes and McNemar’s tests were used to assess for a difference in the proportion of participants meeting certain criteria at baseline compared to follow-up. At enrollment, 3.5-y completers were (mean±SE) 55±1 y of age, 40.8±0.7 kg/m2, and 8±1 y since diagnosis. Following treatment with the CCI for 3.5 y, significant improvements compared to baseline were observed in HbA1c (-0.6±0.1 from 7.4±0.1%; P = 1.9x10-5), weight (-10.9±1.1 from 117.4 kg; P = 6.9x10-17), nonHDL-C (-10±4 from 139±3 mg/dL; P = 0.005), triglycerides (-41±11 from 189±10 mg/dl; P = 2.1x10-4), and HDL-C (+9±1 from 43±1 mg/dl; P = 3.0x10-11); total cholesterol and LDL-C were statistically unchanged. The percentage of participants prescribed diabetes medication decreased from 84.6 to 67.1% (P = 5.0x10-6), while 50.2% of diabetes medications and 71.4% of diabetes medications other than metformin were discontinued. The percentage of participants treated with no pharmaceuticals or monotherapy increased from 52.5 to 81.9% (P = 1.3x10-8). 45.5% (65/143) of participants achieved HbA1c <6.5% with either no medication (34/65, 52%) or only metformin (31/65, 48%) at 3.5 y; 37.8% of participants maintained this status from 1 through 3.5 y of treatment. 22% of participants achieved diabetes remission at 3.5 y, and 17.5% of participants maintained remission status from 2 through 3.5 y of treatment. This demonstrates that clinically meaningful improvements across multiple markers of metabolic risk can be sustained in patients with T2D who selected treatment with this CCI for 3.5 y. Improvements in metabolic risk markers reduced the need for diabetes medication, allowing some patients to achieve and sustain diabetes remission. This ongoing trial will assess 5-y effects.1. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2020; 43(Supplement 1): S48-S65. 2. Athinarayanan SJ, et al. Front Endocrinol. 2019; 10:348.

Low-Carbohydrate Diets in the Management of Obesity and Type 2 Diabetes: A Review from Clinicians Using the Approach in Practice.

Low-carbohydrate diets are increasingly used to help patients with obesity and type 2 diabetes. We sought to provide an overview of the evidence for this treatment approach, considering the epidemiology and pathophysiology of obesity and diabetes in terms of carbohydrate excess. We describe the mechanistic basis for the clinical benefits associated with nutritional ketosis and identify areas of practice where the evidence base could be improved. We summarize the key principles which inform our approach to treating patients with low-carbohydrate diets. The scientific controversy relating to these diets is real but is consistent with the known challenges of any dietary interventions and also the limitations of nutritional epidemiology. Secondly, notwithstanding any controversy, international guidelines now recognize the validity and endorse the use of these diets as a therapeutic nutritional approach, in appropriate patients. Thirdly, we have found that early de-prescription of diabetes medications is essential, in particular insulin, sulphonylureas, and sodium-glucose cotransporter (SGLT2) inhibitors. Fourthly, we encourage patients to eat ad libitum to satiety, rather than calorie counting per se. Furthermore, we monitor cardiovascular risk factors frequently, as with all patients with obesity or diabetes, but we do not necessarily consider an increase in low-density lipoprotein (LDL)-cholesterol as an absolute indication to stop these diets, as this is usually related to large LDL particles, which are not associated with increased cardiovascular risk. In the absence of large randomized controlled trials with cardiovascular and other hard endpoints, adopting a low-carbohydrate diet is a legitimate and potentially effective treatment option for patients with diabetes or obesity.

A Modified MCT-Based Ketogenic Diet Increases Plasma β-Hydroxybutyrate but Has Less Effect on Fatigue and Quality of Life in People with Multiple Sclerosis Compared to a Modified Paleolithic Diet: A Waitlist-Controlled, Randomized Pilot Study

Objective To investigate the feasibility of a modified MCT-based ketogenic diet and its impact on plasma β-hydroxybutyrate and MS outcomes compared to a modified Paleolithic diet and usual diet in people with Multiple Sclerosis (MS). Methods Fifteen individuals with MS were randomized to 3 groups: 1) modified Paleolithic diet (Paleo; n = 6); 2) medium-chain triglyceride (MCT)-based ketogenic diet that included coconut as a fat source (Keto; n = 5); or 3) usual diet (Control; n = 4). Participants had blood drawn every 4 weeks to monitor nutritional ketosis. Participants completed 4-day weighed food records, measures of disability, fatigue, quality of life (QoL), cognitive function, and physical function at baseline and 12-weeks. Results Macronutrient intake significantly shifted toward a ratio indicative of a ketogenic diet in the Keto group at 12 weeks. Similarly, plasma β-hydroxybutyrate indicated nutritional ketosis in the Keto group, whereas neither macronutrient intake nor plasma β-hydroxybutyrate indicated nutritional ketosis in the Paleo and Control groups. The Paleo group had significant within group reductions in fatigue scores and maintained cognitive function scores compared to the Control group. The Keto group had significant reductions in fasting glucose and insulin compared to baseline values; however, no clinical outcomes significantly changed. Conclusions Participants consuming the MCT-based ketogenic diet achieved nutritional ketosis; however, it was not associated with significant clinical improvement in this study whereas the modified Paleolithic diet was associated with significant clinical improvements. Larger randomized controlled trials are needed to determine the safety and efficacy of the modified Paleolithic and MCT-based ketogenic diets on MS.

An overlooked danger of ketogenic diets: Making the case that ketone bodies induce vascular damage by the same mechanisms as glucose.

Intense debate surrounds the use of low-carbohydrate, ketogenic diets for the promotion of weight loss and avoidance of cardiovascular disease. The rationale behind these diets is that they promote fat oxidation and minimize the addition of glucose to proteins in the formation of adducts that trigger inflammation. Although nutritional ketosis is widely assumed to be a safe metabolic condition, proper consideration has not been given to the fact that ketones are reactive toward proteins through the same mechanisms as glucose. Here, the case is made that ketone bodies are more potent than glucose in bringing about the protein modifications to which the harmful effects of glucose have been attributed. It is suggested, therefore, that attempts to minimize such protein modifications through nutritional ketosis are futile and may lead to adverse health outcomes.

Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency.

A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise‐induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long‐Chain acyl‐CoA Dehydrogenase (VLCAD). Five patients (range 17‐45 y; 4 M/1F) patients were included in an investigator‐initiated, randomised, blinded, placebo‐controlled, 2‐way cross‐over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2max). The protocol was repeated after a 1‐week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31P‐MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD‐specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders.Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders.

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson's disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone-glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate-glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

Exogenous Ketones as Therapeutic Signaling Molecules in High-Stress Occupations: Implications for Mitigating Oxidative Stress and Mitochondrial Dysfunction in Future Research.

High-stress occupations (ie, firefighters, military personnel, police officers, etc.) are often plagued by cardiometabolic diseases induced by exposure to chronic stressors. Interrupted sleep cycles, poor dietary patterns, lack of physical activity, and smoke exposure along with simultaneous psychological stressors promote chronic low-grade inflammation and excessive oxidative stress. Collectively, these data suggest that practical interventions which might mitigate the underlying pathologies of these cardiometabolic diseases are warranted. Ketones, specifically R-βHB, modulates intracellular signaling cascades such as the cellular redox ratios of NAD+/NADH, the activity of NAD dependent deacetylases SIRT1 and SIRT3, and promotes a robust mitochondrial environment which favors reductions in oxidative stress and inflammation. To date, the literature examining R-βHB as a signaling metabolite has mostly been performed from endogenous R-βHB production achieved through nutritional ketosis or cell culture and mouse models using exogenous R-βHB. To the authors knowledge, only 1 study has attempted to report on the effects of exogenous ketones and the mitigation of oxidative stress/inflammation. Therefore, the scope of this review is to detail the mechanisms of R-βHB as a signaling metabolite and the role that exogenous ketones might play in mitigating diseases in individuals serving in high-stress occupations.

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

Capillary blood tests may overestimate ketosis: triangulation between three different measures of β-hydroxybutyrate.

The ketone body β-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.

Exogenous Ketone Supplementation and Keto-Adaptation for Endurance Performance: Disentangling the Effects of Two Distinct Metabolic States.

Ketone bodies (KB) provide an alternative energy source and uniquely modulate substrate metabolism during endurance exercise. Nutritional ketosis (blood KBs > 0.5mM) can be achieved within minutes via exogenous ketone supplementation or days-to-weeks via conforming to a very low-carbohydrate, ketogenic diet (KD). In contrast to short-term (< 2weeks) KD ingestion, chronic adherence (> 3weeks) leads to a state of keto-adaptation. However, despite elevating blood KBs to similar concentrations, exogenous ketone supplementation and keto-adaptation are not similar metabolic states as they elicit diverse and distinct effects on substrate availability and metabolism during exercise; meaning that their influence on endurance exercise performance is different. In contrast to contemporary, high(er)-carbohydrate fuelling strategies, inducing nutritional ketosis is rarely ergogenic irrespective of origin and, in fact, can impair endurance performance. Nonetheless, exogenous ketone supplementation and keto-adaptation possess utility for select endurance events and individuals, thus warranting further research into their performance effects and potential strategies for their optimisation. It is critical, however, that future research considers the limitations of measuring blood KB concentrations and their utilisation, and assess the effect of nutritional ketosis on performance using exercise protocols reflective of real-world competition. Furthermore, to reliably assess the effects of keto-adaptation, rigorous dietary-training controls of sufficient duration should be prioritised.

INNV-01. KETOGENIC METABOLIC THERAPY SIGNIFICANTLY IMPROVES RADIOGRAPHIC AND CLINICAL RESPONSE TO SALVAGE TEMAZOLAMIDE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS

Abstract Ketogenic Metabolic Therapy (KMT), by the proposed Warburg effect, has been shown in animal studies to augment responses to chemotherapy in laboratory models of high grade gliomas. Anecdotal responses in human patients have also been reported. We advised patients in our clinic to adhere to a low-carbohydrate, high-fat diet to obtain a state of nutritional ketosis while undergoing temazolamide (TMZ) chemotherapy for recurrent high-grade gliomas. A registered dietitian, specifically trained in KMT was utilized as a consultant for all of these patients. Blood ketone levels were checked frequently to assure ketone levels above 0.5 mmol/L. Nine patients have documented a near-continuous state of ketosis for at least 3 months while on TMZ therapy and have shown significant radiographic resolution of recurrent disease based on serial high resolution MRI surveillance imaging. All of these patients had shown progressive recurrent disease on serial MRI imaging prior to initiation of KMT. 4 of the 9 patients obtained a complete response, while the other 5 experienced a partial response. None of the patients failed to show any improvement in their imaging follow-up while on KMT. Three of the 9 patients also had salvage radiation therapy to some local area of recurrence prior to initiating KMT. There were no adverse effects related to the KMT diet. Most patients stated that they felt an overall improvement in quality of life while on the diet and embraced the diet as a means of feeling more in control of their disease. The diet was well tolerated and not felt to be a hardship or burdensome after an initial learning curve transition period was overcome. Based on these highly positive preliminary results, we suggest that KMT be included in larger prospective randomized trials for up-front and recurrent high-grade glioma trials to augment standard and experimental therapies.

Ketone body supplement label claims: what supplement has been supplemented?

There is a keen interest in performance-enhancing supplementation and the associated benefits, despite reports of incorrect label claims made by manufacturers and the questionable efficacy of the supplements. The use of ketone body supplements as a source of fuel during exercise and sporting performance, in particular, is of interest to sportspeople. By increasing blood ketone body levels, with an accompanying decrease in blood glucose, may indicate a state of nutritional ketosis, whereby the body no longer relies on glucose metabolism but rather the metabolism of ketone bodies. This could be beneficial for long, slow steady-state endurance exercise. There are numerous ketone body supplements on the market manufactured in South Africa and internationally. However, unlike medicines, the sports supplementation industry is poorly regulated. Furthermore, ketone body supplementation with regard to its effects on improving exercise and athletic performance is still unconvincing. Within the ever-changing sports supplementation industry, ketone body supplements are being used despite controversies regarding the accuracy and scientific merit of label claims. The ingredients and their quantities, as well as the performance benefits, need to be objectively validated.

Age and Ketogenic Diet Have Dissociable Effects on Synapse-Related Gene Expression Between Hippocampal Subregions.

As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication. In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.