Serum Ketone Levels Research Articles

Ketogenic diet therapy leads to antiseizure medication reduction in children and adults with drug-resistant epilepsy.

This study aimed to evaluate the safety of reducing or withdrawing anti-seizure medications (ASMs) in a cohort comprising both adults and children with drug-resistant epilepsy (DRE) undergoing ketogenic diet therapy (KDT). We conducted a comprehensive analysis of clinical profiles in adults and children with DRE who had adhered to KDT for at least 6 months. Successful withdrawal or reduction of an ASM was defined as discontinuation or dose reduction without subsequent resumption or increase and without initiation of any new ASM throughout the entire follow-up period. Changes in the ASM load were calculated specifically for adult patients. The study enrolled 56 participants (34 children and 22 adults) with DRE, with 64.3% achieving successful withdrawal of at least one ASM. The probability of ASM withdrawal remained consistent for children (64.7%) versus adults (63.6%), as well as for responders (62.5%) versus non-responders (68.8%), and it was not associated with other clinical factors. Early ASM reduction (including withdrawal) after diet initiation occurred in 15 patients (26.8%), with treatment outcomes comparable to those of the remaining participants. Among the 22 adults, the mean values of ASM load reduced by 24.5%, with a similar magnitude observed for responders (24.2%) versus non-responders (25.1%). In addition, adults tend to have a slower elevation in serum ketone levels compared to children. This study demonstrates the safe achievability of ASM withdrawal through KDT in most patients with DRE, irrespective of age or seizure frequency reduction.

Tirzepatide-Induced Ketoacidosis in Non-Diabetic Patients.

Tirzepatide is a novel glucagon-like peptide 1/glucose-dependent insulinotropic peptide (GLP-1/GIP) receptor agonist. It was recently approved for diabetes control and weight reduction in non-diabetic patients. We report the first case of ketoacidosis after the use of tirzepatide in an obese non-diabetic patient, secondary to the possibility of starvation ketoacidosis and insulin resistance. The dual-acting GLP-1 and GIP receptor agonists, tirzepatide, can induce ketoacidosis in obese non-diabetic patients. The dual-acting GLP-1 and GIP receptor agonists can cause ketoacidosis in obese non-diabetic patients.Ketoacidosis induced by tirzepatide is serious, and physicians should be aware of this complication and be alert to early symptoms, check serum and urine ketone levels, and stop medication.

Incidência de cetose subclínica em vacas leiteiras na região semiárida da Paraíba

Subclinical ketosis (SCK) is one of the main metabolic diseases to occur during the transition period in dairy herds. The aim of this study was to evaluate the localized incidence of SCK in dairy cows in the semi-arid region of the state of Paraíba, Brazil, and to correlate this data with the number of weeks of lactation and the body condition score (BCS). Samples were collected from the coccygeal vein of 257 lactating dairy cows, with a view to determining serum ketone and glucose body levels. Animals that presented serum ketone body levels equal to or greater than 1.2 mmol/dL were considered to have SCK. It was found that 5.45% of the dairy cows presented SCK. The weeks of lactation and the BCS had no influence (P > 0.05) on the levels of serum ketone bodies or glucose of the dairy cows. For serum ketone body levels, 94.55% (243) of the cows remained within the normal limits for metabolites. Most of the cows, 67.70% (174) were within normal serum glucose levels, while 23.35% (60) presented hypoglycaemia, and 8.95% (23) presented hyperglycaemia. The BCS and serum glucose levels are negatively correlated, with a coefficient of -0.1329 (P = 0.0335). No significance was found 0.087 (P = 0.1608) for the correlation between the BCS and serum ketone body levels. The localized incidence of SCK in this study was 5.45% of the total number of cows, with the BCS and number of weeks of lactation having no influence on incidence of the disorder.

Utility of serum ketone levels for assessment of myocardial glucose suppression for 18F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis

Background18F-FDG PET/CT is used to diagnose cardiac sarcoidosis and endocarditis. It requires myocardial glucose utilization (MGU) suppression to avoid false positives, which occur in up to 20% of patients. Serum beta-hydroxybutyrate (BHB) levels may help identify incomplete suppression of MGU. We determined the optimal timing and diagnostic thresholds to identify incomplete suppression of MGU. Methods and resultsWe retrospectively identified 114 patients referred for 18F-FDG PET/CT for endocarditis, wherein myocardial uptake outside of paravalvular regions is not related to pathology and can be confidently ascribed as being due to inadequate suppression of MGU. Patients followed a high-fat, low-carbohydrate diet and received heparin. Serum BHB, insulin, glucose and hemoglobin A1c were measured. Maximum standardized uptake value (SUVmax) of left ventricle (LV) and mean SUV (SUVmean) in LV blood pool (LVBP) was measured. Logistic regression and area under the receiver-operating characteristic analyses were used to quantify the relationship between biomarkers and MGU suppression. A threshold of BHB ≥ 0.35 mmol·L−1 to detect suppression resulted in sensitivity of 88% and specificity of 61%. A threshold of BHB ≥ 0.95 mmol·L−1 resulted in sensitivity of 45% and specificity of 100%. AUC was 0.87. BHB measured ~ 4 hours prior to 18F-FDG injection performed similarly to or better than later timepoints. ConclusionsSerum BHB levels are useful for assessing suppression of MGU and could simplify interpretation of 18F-FDG PET/CT inflammation studies.

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants

Oral ketone supplements may mimic the beneficial effects of endogenous ketones on energy metabolism as β-hydroxybutyrate has been proposed to increase energy expenditure and improve body weight regulation. Therefore, our objective was to compare the effects of a one-day isocaloric ketogenic diet, fasting and supplementation with ketone salts on energy expenditure and appetite perception. Eight healthy young adults (4 women, 4 men, age 24±3 years, BMI 24.3±3.1kg/m2) participated in a randomized cross-over trial with four 24 h-interventions in a whole room indirect calorimeter at a physical activity level of 1.65: (i) total fasting (FAST), (ii) isocaloric ketogenic diet (3.1% energy from carbohydrates (CHO), KETO), (iii) isocaloric control diet (47.4% energy from CHO, ISO), and (iv) ISO supplemented with 38.7g/d ketone salts (exogenous ketones, EXO). Effects on serum ketone levels (15 h-iAUC), energy metabolism (total energy expenditure, TEE; sleeping energy expenditure, SEE; macronutrient oxidation) and subjective appetite were measured. Compared to ISO, ketone levels were considerably higher with FAST and KETO and little higher with EXO (all p>0.05). Total and sleeping energy expenditure did not differ between ISO, FAST and EXO whereas KETO increased TEE (+110±54kcal/d vs. ISO, p<0.05) and SEE (+201±90kcal/d vs. ISO, p<0.05). CHO oxidation was slightly decreased with EXO compared to ISO (-48±27g/d, p<0.05) resulting in a positive CHO balance (p<0.05). No differences between the interventions were found for subjective appetite ratings (all p>0.05). A 24 h-ketogenic diet may contribute to maintain a neutral energy balance by increasing energy expenditure. Exogenous ketones in addition to an isocaloric diet did not improve regulation of energy balance. NCT04490226 https://clinicaltrials.gov/.

Association between Edinburgh Postnatal Depression Scale and Serum Levels of Ketone Bodies and Vitamin D, Thyroid Function, and Iron Metabolism.

Suicide due to postpartum depression is the most common perinatal-related death and is a social concern in Japan. Nutritional deficiencies during pregnancy may contribute to postpartum depression; therefore, we investigated the relationship between postpartum depression and nutritional status during pregnancy and postpartum. We focused specifically on ketone bodies because they are known to protect brain cells. The relationship between the Edinburgh Postnatal Depression Scale (EPDS) scores and the serum levels of ketone bodies and vitamin D, thyroid function, and iron metabolism was examined. Overall, 126 pregnant women were identified for the study, and 99 were eventually included in the analysis. We defined an EPDS score of ≥9 as being positive for postpartum depression, and serum ketone levels were found to be higher in the group with an EPDS score of ≥9 during the second trimester; however, there were no other significant findings. We may be able to predict postpartum depression from a pregnant woman's serum ketone levels in the second trimester. There was a positive correlation between the EPDS scores at 3 days and 1 month postpartum (r = 0.534, p < 0.001). EPDS scores assessed in the early postpartum period may be useful for the timely detection of postpartum depression.

Breath Analysis in Children with Ketogenic Glycogen Storage Diseases

(1) Background: The treatment goal of ketogenic glycogen storage diseases (GSDs) is appropriate control of hypoglycemia and other disturbances such as dyslipidemia. Monitoring and treatment of ketosis are known to improve outcomes. We used breath analysis to identify volatile organic compounds (VOCs) that correlate with serum ketones in order to provide a non-invasive method of monitoring ketosis. (2) Methods: Consecutive children with ketogenic GSDs were recruited from a single center during routine admission to monitor serum glucose and ketone levels. Five breath samples were collected from every patient at the same time of blood draws. SIFT-mass spectrometry was used to analyze breath samples. Univariate linear mixed-effects regression models for 22 known VOCs and either serum ketones or glucose were performed. (3) Results: Our cohort included 20 patients aged 5–15 years with a mean BMI of 20 kg/m2 (72% tile). Most patients had GSD type 0 (35%), while 25% had type IX. VOCs that showed a significant correlation with serum ketone levels included acetone (p &lt; 0.0001), trimethylamine (p &lt; 0.0001), pentane (p = 0.0001), 3-methylhexane (p = 0.0047), and carbon disulfide (p = 0.0499). No correlation was found between serum glucose and any VOC. (4) Conclusions: Breath analysis is a promising noninvasive tool that can be used to predict ketone serum levels in patients with GSD.

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.

Cachexia is a debilitating comorbidity affecting many lung cancer patients. We have previously found that cachectic mice with lung cancer have reduced serum ketone body levels due to low PPARα activity in the liver. Restoring hepatic PPARα activity with fenofibrate increased circulating ketones and delayed muscle and white adipose tissue wasting. We hypothesized that the loss of circulating ketones plays a pathophysiologic role in cachexia and performed two dietary intervention studies to test this hypothesis. In the first study, male and female mice were randomized to consume either a very low carbohydrate, ketogenic diet (KD) or normal chow (NC) after undergoing tumor induction. The KD successfully restored serum ketone levels and decreased blood glucose in cachectic mice but did not improve body weight maintenance or survival. In fact, there was a trend for the KD to worsen survival in male but not in female mice. In the second study, we compounded a ketone ester supplement into the NC diet (KE) and randomized tumor-bearing mice to KE or NC after tumor induction. We confirmed that KE was able to acutely and chronically increase ketone body abundance in the serum compared to NC. However, the restoration of ketones in the circulation was not able to improve body weight maintenance or survival in male or female mice with lung cancer. Finally, we investigated PPARα activity in the liver of mice fed KE and NC and found that animals fed a ketone ester supplement showed a significant increase in mRNA expression of several PPARα targets. These data negate our initial hypothesis and suggest that restoring ketone body availability in the circulation of mice with lung cancer does not alter cachexia development or improve survival, despite increasing hepatic PPARα activity.

Serum Ketone Levels May Correspond with Preoperative Body Weight Loss in Patients Undergoing Elective Surgery: A Single-Center, Prospective, Observational Feasibility Study.

Although nutritional-risk scoring systems allow the determination of the patient’s malnutrition at admission, additional tools might be useful in some clinical scenarios. Previous medical history could be unavailable in unconscious or demented patients. This study aimed to assess the ketone bodies serum levels in patients undergoing elective surgeries and to determine the possible correlation between ketone bodies serum levels and preoperative body weight loss. The study included 21 patients who underwent elective surgery. Hyperketonemia, defined as ketone bodies over 1 mmol/L, was observed in seven (33.3%) patients. Patients with hyperketonemia had significantly higher preoperative percentage body weight loss (p = 0.04) and higher nutritional risk scores prior to surgery (p = 0.04). Serum glucose and the percentage of body weight loss were associated with increased ketone bodies serum levels (Odds Ratios: 0.978 (0.961–0.996, p = 0.019) and 1.222 (1.0–1.492, p = 0.05), respectively). A significant linear correlation was found between the percentage of body weight loss and both ketones bodies (r2 = 0.25, p = 0.02) and albumin serum levels (r2 = 0.19, p = 0.04). Our study’s results might suggest a positive association between preoperative body weight loss and ketone bodies serum levels. The observation between increased ketone bodies serum levels in patients and preoperative body mass loss merits further research.

Abstract 9085: Phenome-Wide Association Study (phewas) Identifies Clinical Factors Associated With Plasma Ketones from Four Large Studies

Background: Ketosis is an adaptive mechanism to the stress imposed by cardiovascular disease, including heart failure (HF), with ketones constituting a more efficient myocardial fuel. Contributing factors to the development of ketosis and its association with adverse events have not been well studied. Methods: We performed a phenome-wide association study (PHeWAS) for serum ketone (beta-hydroxybutyrate [BHB]) levels in four cohorts with a total of 6,508 participants across a broad array of cardiovascular health, including CATHGEN (N=4,374), RELAX (N=161), TECOS (N=995), and EXSCEL(N=978). On cross-sectional analysis, we performed a random effects meta-analysis relating clinical and echocardiographic predictor variables to log transformed BHB using linear regression (with false discovery rate adjusted p-values). The relationship between BHB and HF metrics (HF history, ejection fraction, right ventricular systolic pressure [RSVP]) with markers of insulin resistance was assessed in each cohort. The association between BHB and death or HF hospitalization was assessed using Cox regression. Results: The mean age was 62 years, 36% female, and 75% white. Log BHB was associated with higher heart rate (beta-coefficient 0.009, p=0.001), HF (0.188, p=0.02), ejection fraction &lt; 55% (-0.138, p=0.008), RVSP (0.010, p=0.02), ischemic heart disease (-0.094, p=0.002), and statin use (-0.13, p=0.002). The association between HF phenotypes and BHB was not explained by markers of insulin resistance. Higher BHB levels were associated with increased risk for death and HF hospitalization ( Figure ), driven primarily by death. Conclusions: We identified several novel non-diabetic associations between ketosis and clinical measures in patients with cardiovascular disease. The link between ketosis and HF was independent of insulin resistance. BHB is a powerful predictor of outcomes, particularly death, across a spectrum of cardiovascular disease, including HF.

Study of glucagon response and its association with glycemic control and variability after administration of ipragliflozin as an adjunctive to insulin treatment in patients with type 1 diabetes (Suglat-AID)

Abstract Background: Despite advances in insulin preparation, insulin delivery systems and glucose monitoring, it is extremely difficult to maintain glucose levels within the non-diabetic range in patients with type 1 diabetes (T1D). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently raised the prospect of improving glucometabolic outcomes in an insulin-independent manner. SGLT2 inhibitors adjunctive to insulin treatment have been shown in T1D clinical trials to improve glycemic variability without increasing hypoglycemia. Conversely, some meta-analyses raised valid concerns regarding increased risk of euglycemic ketoacidosis after treatment of SGLT2 inhibitors in T1D. Increased hepatic ketogenesis caused by elevated glucagon secretion in patients receiving SGLT2 inhibitors has been discussed as a potential mechanism for euglycemic ketoacidosis in insulinopenic T1D, but the mechanism has not been fully elucidated. In this study, we investigate 1) whether glucagon secretions are altered by treatment with the SGLT2 inhibitor ipragliflozin as an adjunctive to insulin therapy in T1D patients, and 2) whether the glucagon responses are associated with amelioration/deterioration in glycemic control and serum ketone levels. Methods/design: This is a single-arm, multicenter, open-label, prospective exploratory trial designated Suglat-AID. Eligible participants are absolute-insulin-deficient T1D patients with glycated hemoglobin levels over 7.5%, who are receiving intensive insulin therapy using intermittently scanned continuous glucose monitoring. Thirty patients will be recruited and will take orally administered ipragliflozin as an add-on to insulin therapy. The primary endpoint is the change in glucagon levels during a mixed meal tolerance test between before and 12 weeks after initiation of ipragliflozin. Secondary endpoints include the changes in insulin and glucose levels during mixed meal tolerance test, the change in the patients’ glycemic control, change in the intermittently scanned continuous glucose monitoring-based profile and others. Discussion: To the best of our knowledge, this will be the first study assessing changes in glucagon response to an SGLT2 inhibitor in patients with T1D in a clinical setting. This study may help to clarify the pathophysiological role of glucagon in glycemia and ketogenesis in patients with T1D receiving SGLT2 inhibitors. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (https://umin.ac.jp) on 24 March, 2020 under registration no. UMIN000039635.

Tryptophan, kynurenine pathway, and diabetic ketoacidosis in type 1 diabetes.

Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA’s metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6–12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA’s acute and chronic insults.

Abstract CT142: A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma

Abstract Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &amp;lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease.Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov R. Lawrence, Keren Porper, Yael Shpatz, Luba Plotkin, Ronit Pechthold, Alisa Talianski, Zvi Symon, uri Amit, Zvi Cohen, Hili Gnessin, Yair Anikster, Yael Mardor, Leor Zach. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT142.

Abstract PO-004: A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma

Abstract Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &amp;lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach. A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-004.

DDRE-17. A PHASE I CLINICAL TRIAL OF DOSE-ESCALATED METABOLIC THERAPY COMBINED WITH CONCOMITANT RADIATION THERAPY IN HIGH-GRADE GLIOMA

BACKGROUNDAnimal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We sought to assess the feasibility of combined radiation, KD and metformin in adults with high grade gliomas.METHODSA prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin combined with dietary intervention and 3) high-dose metformin combined with dietary intervention. Clinicaltrials.gov NCT02149459.RESULTSA total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4 / 5 adverse events, and only one grade 3 event (nausea). The median level of ketones during the intervention was 0.5 mM. Ketone levels were associated with dietary factors (high fat, low carbohydrates, MCT intake), use of metformin and low insulin levels. Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease.CONCLUSIONSThe intervention was fairly well tolerated, however only moderate ketones levels were obtained. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a low-carbohydrate diet combined with 850mg metformin twice daily.

Edible dairy formula fortified with coconut oil for neuroprotection against aluminium chloride-induced Alzheimer's disease in rats

• The dairy formula restored learning and memory impairment induced by AlCl 3 in rats. • It can reduce lipid peroxidation in the brain of AlCl 3 -treated rats. • And increase the total antioxidant capacity in the brain of AlCl 3 -treated rats. • A reduction of the matrix metalloproteinase in AlCl 3 -treated rats was observed. • The formula reversed histological alterations in the brain of AlCl 3 -treated rats. This study investigates the potential protective effects of a dairy formula fortified with virgin coconut oil (VCO) against aluminium chloride (AlCl 3 )-induced Alzheimer. Forty-two Wistar rats were allocated into seven groups which received the fortified formula, VCO, the standard drug (rivastigmine), AlCl 3 and a combination of these variants with AlCl 3 . Different chemical, biochemical, behavioral and histopathological and immunohistochemical evaluations were conducted in this study. Results showed that VCO contains 61.0% medium chain triglycerides, 49.8 mg eq./kg total phenolic compounds and its antioxidant activity (DDPH, IC 50 ) was 53.7 µg/ml. Compared to AlCl 3 treated rats, the fortified dairy formula improved the cognitive abilities, increased the serum ketone levels, reduced lipid peroxidation, reduced matrix metalloproteinase (2 and 9) enzyme activity, reversed histological alterations in brain and activate immunohistochemical Nrf2/HO-1 signaling cascade. Overall, the results showed that the developed dairy formula fortified with VCO can induce beneficial effects for cognitive deficits associated with Alzheimer’s disease.

Neuroprotective Effect of Ketone Metabolism on Inhibiting Inflammatory Response by Regulating Macrophage Polarization After Acute Cervical Spinal Cord Injury in Rats.

ObjectiveTo investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats.MethodsSixty-four adult male Sprague–Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury.ResultsThe serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups.ConclusionThe present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.

Methionine- and Choline-Deficient Diet Enhances Adipose Lipolysis and Leptin Release in aP2-Cre Fatp4-Knockout Mice.

Inadequate intake of choline commonly leads to liver diseases. Methionine- and choline-deficient diets (MCDD) induce fatty liver in mice which is partly mediated by triglyceride (TG) lipolysis in white adipose tissues (WATs). Because Fatp4 knockdown has been shown to increase adipocyte lipolysis in vitro, here, the effects of MCDD on WAT lipolysis in aP2-Cre Fatp4-knockout (Fatp4A-/- ) mice are determined. Isolated WATs of Fatp4A-/- mice exposed to MCD medium show an increase in lipolysis, and the strongest effect is noted on glycerol release from subcutaneous fat. Fatp4A-/- mice fed with MCDD for 4 weeks show an increase in serum glycerol, TG, and leptin levels associated with the activation of hormone-sensitive lipase in subcutaneous fat. Chow-fed Fatp4A-/- mice also show an increase in serum leptin and very-low-density lipoproteins as well as liver phosphatidylcholine and sphingomyelin levels. Both chow- and MCDD-fed Fatp4A-/- mice show a decrease in serum ketone and WAT sphingomyelin levels which supports a metabolic shift to TG for subsequent WAT lipolysis CONCLUSIONS: Adipose Fatp4 deficiency leads to TG lipolysis and leptin release, which are exaggerated by MCDD. The data imply hyperlipidemia risk by a low dietary choline intake and gene mutations that increase adipose TG levels.

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.

Ketonuria Is Associated with Changes to the Abundance of Roseburia in the Gut Microbiota of Overweight and Obese Women at 16 Weeks Gestation: A Cross-Sectional Observational Study

The gut microbiome in pregnancy has been associated with various maternal metabolic and hormonal markers involved in glucose metabolism. Maternal ketones are of particular interest due to the rise in popularity of low-carbohydrate diets. We assessed for differences in the composition of the gut microbiota in pregnant women with and without ketonuria at 16 weeks gestation. Fecal samples were obtained from 11 women with fasting ketonuria and 11 matched controls. The samples were analyzed to assess for differences in gut microbiota composition by 16S rRNA sequencing. Supervised hierarchical clustering analysis showed significantly different beta-diversity between women with and without ketonuria, but no difference in the alpha-diversity. Group comparisons and network analysis showed that ketonuria was associated with an increased abundance of the butyrate-producing genus Roseburia. The bacteria that contributed the most to the differences in the composition of the gut microbiota included Roseburia, Methanobrevibacter, Uncl. RF39, and Dialister in women with ketonuria and Eggerthella, Phascolarctobacterium, Butyricimonas, and Uncl. Coriobacteriaceae in women without ketonuria. This study found that the genus Roseburia is more abundant in the gut microbiota of pregnant women with ketonuria. Roseburia is a butyrate producing bacterium and may increase serum ketone levels.