Blood Ketone Levels Research Articles

Effect of ketone monoester supplementation on elite operators' mountaineering training.

Special Operations Forces (SOF) often conduct operations in physiologically stressful environments such as severe heat, cold, or hypoxia, which can induce decreases in a variety of cognitive abilities. Given the promising empirical demonstration of the efficacy of exogenous ketone monoester (KME) supplementation in attenuating cognitive performance decrease during hypoxia at rest in a laboratory setting, we conducted a real-world, field experiment examining KME's efficacy during high-altitude mountaineering, an austere environment in which US SOF have conducted increasing numbers of operations over the past two decades. Specifically, 34 students and cadre at the US Army 10th Special Forces Group Special Operations Advanced Mountaineering School (SOAMS) participated in a randomized, double-blind, placebo (PLA)-controlled crossover trial (KME vs. PLA) over 2days of tactical mountain operations training. The participants ascended from 7,500 ft in altitude (basecamp) to 12,460 ft on 1 day and 13,627 ft the other day (in randomized order), while performing various training activities inducing high physical and cognitive loads over 8-12h, and consumed six doses of KME or PLA 2-3h apart throughout each training day. While KME increased blood ketone levels and decreased glucose levels, there were no clear indications that the elevated ketone level enhanced physical or cognitive performance. KME also produced a greater incidence of heartburn, nausea, and vomiting. In these elite operators, high-altitude mountaineering had a limited impact on cognitive performance, and KME supplementation did not demonstrate any benefit.

Examining capillary ketone testing in hospitalised patients: indications and outcomes.

Elevated blood ketone levels (ketosis) in inpatients with diabetes can herald diabetic ketoacidosis (DKA). However, ketosis can also occur in individuals without diabetes in certain settings. It is unclear what proportion of inpatients with ketosis are in DKA and which patients are at the highest risk of DKA. This study determined that many ketone tests are performed in individuals at low risk of DKA, and a β-hydroxybutyrate <1.0 mmol/L had a low incidence of DKA and less need for escalation in their management.

Attenuation of brown adipocyte whitening in high-fat diet-induced obese rats: Effects of melatonin and β-hydroxybutyrate on Cidea, Fsp27 and MT1 expression.

To investigate the effects of β-hydroxybutyrate (BHB) and melatonin on brown adipose tissue (BAT) plasticity in rats fed a high-fat diet (HFD). We employed a 7-week experimental design for a study on 30 male Sprague-Dawley rats divided into five groups: (1) a control-diet fed group; (2) a high-fat diet (HFD)-fed group; (3) a group that received an HFD and a BHB solution in their drinking water; (4) a group that received an HFD with 10 mg/kg/day melatonin in their drinking water; and (5) a group that received an HFD and were also treated with the combination of BHB and melatonin. Following the treatment period, biochemical indices, gene expression levels of key thermogenic markers (including uncoupling protein 1 [UCP1], PR domain containing 16 [PRDM16], Cidea, fat-specific protein 27 [Fsp27], and metallothionein 1 [MT1]), and stereological assessments of BAT were evaluated. Treatment with BHB and melatonin significantly boosted blood ketone levels, improved lipid profiles, and reduced weight gain from an HFD. It also downregulated genes linked to WAT, namely, Cidea and Fsp27, and upregulated key BAT markers, including UCP1, PRDM16 and peroxisome proliferator-activated receptor-gamma coactivator-1-alpha. Additionally, the co-treatment increased MT1 receptor expression and enhanced the structural density of BAT. The combined oral administration of BHB and melatonin successfully prevented the whitening of BAT in obese rats fed an HFD, indicating its potential as a therapeutic strategy for obesity-related BAT dysfunction. The synergistic effects of this treatment underscore the potential of a combined approach to address BAT dysfunction in obesity.

Effect of Oral Administration of Mytragina Speciosa on Blood Ketone Level and Glomerular Histology in Streptozotocin Induced Diabetic Mice

Effect of Oral Administration of Mytragina Speciosa on Blood Ketone Level and Glomerular Histology in Streptozotocin Induced Diabetic Mice

Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

Euglycemic Ketoacidosis Induced by SGLT2 Inhibitor in Latent Autoimmune Diabetes in Adults: A Case Report

Background: Euglycemic ketoacidosis (EKA) is a medical condition characterized by the presence of ketoacidosis without significant hyperglycemia. It is particularly challenging to diagnose due to normal or near-normal blood glucose levels. SGLT2 inhibitors, used in managing type 2 diabetes mellitus, are known to cause EKA. This risk is increased in patients with latent autoimmune diabetes in adults (LADA), a type of Type 1diabetes presented in adult (Hybrid form of diabetes) Case Report: A 64-year-old male with a history of diabetes mellitus and hypothyroidism presented with shortness of breath, nausea, and dizziness. Despite taking Metformin, Glimepride, Thyroxin, and Empagliflozin, he had poor glycemic control (HbA1c 9%) Physical examination showed generalized vitiligo and tachycardia. Initial laboratory results revealed high anion gap metabolic acidosis with normal blood glucose, consistent with EKA. Extensive diagnostic workup confirmed the presence of LADA and SGLT2 inhibitor induced EKA. Result: The patient was diagnosed with type 1 diabetes mellitus (LADA) and EKA induced by SGLT2 inhibitors. Management included discontinuation of the SGLT2 inhibitor, initiation of insulin therapy, and monitoring of metabolic parameters. Conclusion: Euglycemic ketoacidosis induced by SGLT2 inhibitors in patients with LADA is a serious condition requiring prompt recognition and treatment. Clinicians should be vigilant in monitoring adult patients with diabetes and other autoimmune conditions who are on SGLT2 inhibitors for symptoms of ketoacidosis even when blood glucose levels are normal. Recommendations: Regular monitoring of blood ketone levels in patients on SGLT2 inhibitors. Consideration of alternative glucose-lowering therapies in patients with LADA. Education for patients and healthcare providers on the risks of EKA. Keywords: Euglycemic ketoacidosis, SGLT2 inhibitors, Latent autoimmune diabetes in adults, Diabetes management, Metabolic acidosis.

DIET2TREAT: A randomized, multi-center, phase 2 trial of a ketogenic diet vs standard dietary guidance in combination with standard-of-care treatment for patients with newly diagnosed glioblastoma.

TPS2103 Background: Presented with a dismal prognosis and limited treatment options, many glioblastoma (GBM) patients seek complementary interventions. Of particular interest is a high-fat / low-carbohydrate diet known as the ketogenic diet (KD). Preclinical models and results from early-phase trials suggest potential benefits with KD for patients with GBM receiving standard-of-care (SOC) treatment, but definitive evidence of clinical efficacy is still lacking. Methods: We are conducting a multicenter randomized controlled phase 2 clinical trial of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients will receive SOC chemoradiation. Patients with newly diagnosed GBM age ≥ 18 years with Karnofsky Performance Status ≥ 70 are eligible. Exclusion criteria include inability to wean steroids below 8 mg dexamethasone/day or equivalent, Body Mass Index &lt; 21 kg/m2, or food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD (3:1 ratio between grams of fat to grams of carbohydrates + protein) or SD (based on guidelines from the American Cancer Society and American Institute of Cancer Research) for a study period of 18 weeks, starting the same time as chemoradiation. Post-randomization, all patients receive diet education, followed by in-person or virtual dietitian consultation every 2 weeks at minimum while on study. The primary objective is to assess overall survival for patients on the KD arm vs the SD arm. Secondary endpoints include assessments of progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)), as benefits in any of these domains would be impactful for patients. Patients randomized to the KD arm will be provided a fingerstick monitor (Keto-Mojo) to check blood ketone and glucose levels daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. While the primary analysis for this study is intent-to-treat, we will also perform secondary per protocol and as-treated analyses using food diaries plus glucose and ketone data. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of January 2024, the trial is open for enrollment at Cedars-Sinai Medical Center and will be opening at UCSF, Duke, Pacific Neuroscience Institute, and the Medical College of Wisconsin soon. Ten patients have been randomized so far. This trial is funded by NIH R01CA276919 and a grant from the Foundation for Metabolic Cancer Therapies and is registered as NCT05708352. Clinical trial information: NCT05708352 .

The Influence of Soy Isoflavones and Soy Isoflavones with Inulin on Kidney Morphology, Fatty Acids, and Associated Parameters in Rats with and without Induced Diabetes Type 2.

Diabetes mellitus resulting from hyperglycemia stands as the primary cause of diabetic kidney disease. Emerging evidence suggests that plasma concentrations of soy isoflavones, substances with well-established antidiabetic properties, rise following supplemental inulin administration. The investigation encompassed 36 male Sprague-Dawley (SD) rats segregated into two cohorts: non-diabetic and diabetic, induced with type 2 diabetes (high-fat diet + two intraperitoneal streptozotocin injections). Each cohort was further divided into three subgroups (n = 6): control, isoflavone-treated, and isoflavone plus inulin-treated rats. Tail blood glucose and ketone levels were gauged. Upon termination, blood samples were drawn directly from the heart for urea, creatinine, and HbA1c/HbF analyses. One kidney per rat underwent histological (H-E) and immunohistochemical assessments (anti-AQP1, anti-AQP2, anti-AVPR2, anti-SLC22A2, anti-ACC-alpha, anti-SREBP-1). The remaining kidney underwent fatty acid methyl ester analysis. Results unveiled notable alterations in water intake, body and kidney mass, kidney morphology, fatty acids, AQP2, AVPR2, AcetylCoA, SREBP-1, blood urea, creatinine, and glucose levels in control rats with induced type 2 diabetes. Isoflavone supplementation exhibited favorable effects on plasma urea, plasma urea/creatinine ratio, glycemia, water intake, and kidney mass, morphology, and function in type 2 diabetic rats. Additional inulin supplementation frequently modulated the action of soy isoflavones.

The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischaemic heart failure.

Cardiac energy metabolism is perturbed in ischaemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and β-hydroxybutyrate (β-OHB) (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. Mice with heart failure exhibited a 56% drop in ejection fraction, which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet, no increase in overall cardiac energy production was observed, and instead, there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischaemic heart and a decrease in insulin-stimulated glucose oxidation.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease

BackgroundA ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD).ObjectiveEvaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG).MethodsA one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson’s Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity.ResultsA total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups.ConclusionsAn MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease.Trial RegistrationTrial Registration Number NCT04584346, registration dates were Oct 14, 2020 – Sept 13, 2022.

Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.

Heavy reliance on glucose metabolism and a reduced capacity to use ketone bodies makes glioblastoma (GBM) a promising candidate for ketone-based therapies. Ketogenic diet (KD) is well-known for its promising effects in controlling tumor growth in GBM. Moreover, synthetic ketone ester (KE) has demonstrated to increase blood ketone levels and enhance animal survival in a metastatic VM-M3 murine tumor model. Here, we compared the efficacy of a KE-supplemented Atkins-type diet (ATD-KE) to a classic KD in controlling tumor progression and enhancing survival in a clinically relevant orthotopic patient-derived xenograft GBM model. Our findings demonstrate that ATD-KE preserves body weight (percent change from the baseline; 112±2.99 vs. 116.9±2.52 and 104.8±3.67), decreases blood glucose (80.55±0.86 vs. 118.6±9.51 and 52.35±3.89 mg/dl), and increases ketone bodies in blood (1.15±0.03 mM vs. 0.55±0.04 and 2.66±0.21 mM) and brain tumor tissue (3.35±0.30 mM vs. 2.04±0.3 and 4.25±0.25 mM) comparable to the KD (results presented for ATD-KE vs. standard diet [STD] and KD, respectively). Importantly, the ATD-KE treatment significantly enhanced survival compared to the STD and was indistinguishable from the KD (47 days in STD vs. 56 days in KD and ATD-KE), suggesting that a nutritionally balanced low carbohydrate ATD combined with KE may be as effective as the KD alone in reducing brain tumor progression. Overall, these data support the rationale for clinical testing of KE-supplemented low-carb diet as an adjunct treatment for brain tumor patients.

Personalized nutritional ketosis through a whole‐food low‐carb diet, medium chain triglycerides, and other ketogenic strategies for people with mild cognitive impairment and Alzheimer’s disease

AbstractInsulin resistance with abnormal brain glucose uptake, a brain‐energy gap, and neuroinflammation are common in the aging brain and are exaggerated in people with Alzheimer’s disease (AD) and in some people with MCI (Cunnane Nature Reviews Drug Discovery 2020). Ketones are an alternative fuel for the brain and ketone uptake is normal in brain regions affected by abnormal glucose uptake in AD (Castellano J Alzheim Dis 2015). Ketones are anti‐inflammatory (Kim Frontiers Immunol 2022) and lessen beta amyloid plaques, tau tangles, and anxiety in animal models (Kashiwaya PNAS 2000; Wu FASEB 2020). Increased brain energy from ketones has been demonstrated using PET imaging in clinical trials of MCT oil (Fortier Alz Dementia 2021), ketogenic diet (KD) (Neth Neurobiol Aging 2020), and exercise (Vandenberghe Appl Physiol Nutr Metab 2019). Recent studies report cognitive and/or other clinical improvements in MCI and/or AD with KD (Brandt J Alzheimers Dis 2019), modified Mediterranean KD (Neth Neurobiol Aging 2020), KD with MCT oil (Taylor Alzheimers Dement 2017), KD with coconut oil in keto study diet recipes (Phillips Alz Research &amp; Therapy 2021), MCT oil with habitual diet (Reger Neurobio Ageing 2004; Constantini Nutri Metab 2009; Maynard Neuropsych Disease Treat 2013; Abe J Nutr Sci Vitaminol 2017; Abe J Nutr 2016; Xu et al. Clin Nutr 2020; Fortier Alz &amp; Dementia 2021), and coconut oil with habitual diet (De la Rubia Orti Nutr Hosp 2017). Case reports of people with AD consuming KD, MCTs, and/or ketone ester also report cognitive improvement (Maynard Neuropsych Disease Treat 2013; Newport Alz Dementia 2015; Stoykovich Alz Dementia 2019; Morrill Diab Metab Syndr:Clin Res &amp; Rev 2019). Ketone esters can rapidly and substantially increase blood ketone levels. Given the lack of any FDA‐approved drug that results in meaningful improvement for people with AD, accumulating evidence suggests that adopting a personalized program for people with AD, aiming for mild to moderate ketosis (blood betahydroxybutyrate levels 0.5‐2 mmol/L), could provide a safe and reasonable therapeutic approach to improve cognitive impairment and other symptoms and could offer a strategy to delay or prevent AD in persons at risk.

Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment

Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate—lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague–Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI − 0.6 to 1.2). Plasma glucose levels were reduced by 36% (− 4.5 mmol/L), p < 0.05 (95% CI − 6.7 to − 2.5). Standard base excess was increased from − 3.5 mmol/L (IQR − 4 to − 2) to 0.5 mmol/L (IQR − 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.

Promoting the Anti-Tumor Activity of Radiotherapy on Lung Cancer through a Modified Ketogenic Diet and the AMPK Signaling Pathway

Taking advantage of the characteristics of high metabolic heterogeneity of tumor cells, the modified ketogenic diet (KD) combined with radiotherapy was used to investigate and analyze the radiosensitivity of a lung cancer model from the perspective of energy metabolism. Different concentrations of glucose and βhydroxybutyrate (βHB) were used at the cellular level to simulate the level of ketone bodies. A cell counting kit was used to detect the effect of different concentrations of glucose (2.78mM, 5.56mM, 12.5mM, and 25mM) and βHB (0mM, 5mM, and 10mM) combined with radiotherapy on the proliferation of LLC cells. Flow cytometry was used to detect tumor cell cycle and apoptosis. Immunofluorescence was used to detect the expression of γH2AX, a DNA damage marker, and western blot was used to detect the expression of AMPK and ρ-AMPK. At the animal level, C57BL/6J female mice were used to establish a transplanted tumor model of lung cancer, and fed with different fat ratio diets combined with radiotherapy. The volume, tumor size, blood glucose level, blood ketone level, survival time and safety of the mice were monitored and observed. The LLC cells were treated with different concentrations of glucose and βHB. The results showed that the survival rate of LLC cells decreased significantly with the increase of irradiation dose when the glucose concentration was 5.56mM and 2.78mM; However, the survival rate of cells in low glucose medium added with βHB was significantly lower than that of the control group, and the survival rate of LLC decreased significantly with the extension of culture time after irradiation (p < 0.001). After irradiation, LG (low glucose) group, LG+βHB 5mM group and LG+βHB 10mM group had a significantly higher proportion of G2 phase, and a significantly higher proportion of early and late phase than the control group. γH2AX foci were detected in LG group, LG +βHB 5mM group and LG +βHB 10mM group at 2h and 24h after radiotherapy, which were significantly higher than those in the control group (p < 0.05). The median survival time was 38 days in the PT group, 55 days in the PT+RT group, 41 days in the 45F group, and not reached in the 45F+RT group. HE staining showed no tumor metastasis and toxic side effects in liver and kidney. The expression of ρ-AMPK/AMPK in the combined treatment group was higher than that in the other groups. The expression of ρ-AMPK/AMPK in RT, 45F and combined treatment group was higher than that in PT group. The expression of ρ-AMPK/AMPK in RT group was higher than that in 45F group, and the difference was statistically significant (p < 0.01). Modified ketogenic diet can enhance the anti-tumor effect of radiotherapy in LLC tumor-bearing mice by reducing glucose and increasing the energy supply ratio from fat.

Younger patients and low c-peptide immunoreactivity index but not nutritional states affect fasting blood ketone levels in Japanese with type 1 diabetes after sodium-glucose cotransporter 2 inhibitor administration.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c-peptide immunoreactivity (CPR) index and body composition. In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated. All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = -0.514, p < .001) and the CPR index (r = -0.523, p = .038) after taking SGLT2is. Using a mixed-effects model based on the results before starting the inhibitors, it was noted that both patient-to-patient and age, or patient-to-patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (β = -0.504, p = .003) and a low ratio of basal to bolus insulin (β = -0.420, p = .005). When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given.

Impact of the COVID-19 pandemic on diabetic ketoacidosis management in the pediatric intensive care unit.

Diabetic ketoacidosis (DKA) is a common endocrine emergency in pediatric patients. Early presentation to health facilities, diagnosis, and good management in the pediatric intensive care unit (PICU) are crucial for better outcomes in children with DKA. This was a single-center, retrospective cohort study conducted between February 2015 and January 2022. Patients with DKA were divided into two groups according to pandemic status and diabetes diagnosis. The study enrolled 59 patients, and their mean age was 11±5 years. Forty (68%) had newly diagnosed type 1 diabetes mellitus (T1DM), and 61% received follow-up in the pre-pandemic period. Blood glucose, blood ketone, potassium, phosphorus, and creatinine levels were significantly higher in the new-onset T1DM group compared with the previously diagnosed group (P=0.01, P=0.02, P<0.001, P=0.01, and P=0.08, respectively). In patients with newly diagnosed T1DM, length of PICU stays were longer than in those with previously diagnosed T1DM (28.5±8.9 vs. 17.3±6.7 hours, P<0.001). The pandemic group was compared with pre-pandemic group, there was a statistically significant difference in laboratory parameters of pH, HCO3, and lactate and also Pediatric Risk of Mortality (PRISM) III score. All patients survived, and there were no neurologic sequelae. Patients admitted during the pandemic period were admitted with more severe DKA and had higher PRISM III scores. During the pandemic period, there was an increase in the incidence of DKA in the participating center compared to that before the pandemic.

A transcriptomic study of osteoporosis induced by ketogenic diet in mice

To investigate the molecular mechanism of osteoporosis caused by ketogenic diet (KD) using transcriptomic analysis. Sixteen 8-week-old female C57BL/6J mice were divided into KD group and sham group for feeding with KD and normal diet for 3 months, respectively. Body weight, blood glucose and blood ketone levels of the mice were measured every two weeks. Microstructure of the cancellous bone in the distal femur was observed with Micro-CT. Total RNA was extracted from bone marrow cells for transcriptomic analysis and bioinformatics analysis. RT-qPCR was used to verify the expression levels of the genes with significant differential expression between the groups. KD obviously weakened the microstructure of the cancellous bone in mice. Compared with those in the sham group, the mice in KD group showed 165 differentially expressed genes (94 up-regulated and 71 down-regulated ones), including Acot1, Mpig6b, Gp9, Ppbp, Slc2a9, etc. KEGG pathway enrichment analysis showed obvious enrichment of the Apelin signaling pathway, PI3K- Akt signaling pathway and ECM-receptor interaction signal transduction pathway with greater number of differential genes. RTqPCR results showed that the 5 differential genes screened by transcriptomics were significantly upregulated in KD group, among which Acot1, Mpig6b and Ppbp were upregulated by over two folds (2.49 ± 0.665, 2.58 ± 0.470, and 2.59 ± 0.611, respectively), suggesting their involvement in KD-induced osteoporosis. The differentially expressed genes and enriched pathways identified in the mouse models provide new clues for studying the molecular mechanism and prevention of KD-induced osteoporosis.

878-P: Absolute Amount of Urinary Glucose Excretion, Not the Change, Is the Measure Determinant for the Effects of SGLT2 inhibitors

SGLT2 inhibitors exhibit hypoglycemic effect via increased urinary glucose excretion (UGE) by inhibiting glucose reabsorption in the kidney. Although the effects of SGLT2 inhibitors are theoretically dependent on UGE, clinical trials have shown renoprotective effect even in severely impaired kidney function. Thus, we aimed to investigate the relationship between UGE and various parameters before and after the administration of SGLT2 inhibitors. The patients newly administered SGLT2 inhibitors and measured 24-hour UGE before and after the administration during hospitalization for diabetes education were included. Body weight (BW), blood ketone levels, hematocrit (Ht), eGFR, and 7-point SMBG (DBG) were measured, and the correlations between the parameters before(b-), after (a-) and the change (Δ-) were analyzed by simple linear regression. A total of 32 patients (age 59.3±10.9 years, 19 males) were included (empagliflozin 5, tohogliflozin 6, dapagliflozin 2, canagliflozin 4, luseogliflozin 15). The mean A1C and BW were 8.8±1.2% and 77.7±11.5kg, and mean UGE, average of DBG at baseline were 15.4 ± 27.5g/day and 10.3±2.0mM/L, respectively. As shown in table, ΔDBG showed correlation only with UGE before and after administration but not with ΔUGE. In conclusion, hypoglycemic effect of SGLT2 inhibitors is dependent on absolute amount of UGE but not on ΔUGE after administration. Disclosure Y.Hamamoto: None. Y.Yamada: Speaker's Bureau; Novo Nordisk Pharma Ltd., Teijin Pharma Limited, Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. Y.Seino: Research Support; Terumo Corporation, Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Speaker's Bureau; Merck &amp; Co., Inc., Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd.

271-OR: Capillary Blood Ketone Level and Future Ketoacidosis Risk in Type 1 Diabetes Using Sodium–Glucose Linked Transporter Inhibitors

Adjunctive-to-insulin Sodium-Glucose Linked Transporter inhibitors (SGLTi) improve metabolic control in T1D but cause diabetic ketoacidosis (DKA). We aimed to determine if time-varying ketone levels could predict future DKA. We explored data on 1194 participants randomly assigned to empagliflozin in a T1D trial program (NCT02414958 and NCT02580591). Protocol called for fasted capillary blood ketone levels 2-3 times/week, categorized into maximum, mean, and last values for sequential 1-month ‘index test’ periods during 6-12-month follow-up. Trial-adjudicated DKA/Ketosis was determined in subsequent 1-month ‘outcome’ periods. Area under the Receiver Operator Characteristic curves (AROC) were calculated. Gradient-boosted trees determined if prediction could be improved. Participants had mean age 44.3 years, HbA1c 8.14±0.60 percent, and contributed 3.70±2.97 ketone measurements/week. 617 outcomes (568 ketosis, 49 DKA events) occurred over follow-up. On-treatment ketone levels were higher for index test periods preceding an outcome period with an event compared to those without (for example, maximum ketone was 1.32±1.03 vs 0.80±0.71 mmol/l, respectively, p&amp;lt;0.001). AROC for maximum, mean and last ketone levels were 0.764, 0.755, and 0.682 respectively. Maximum ketone level ≥ 0.9 mmol/l had sensitivity 59%, specificity 84%, likelihood ratio positive 3.65, likelihood ratio negative 0.49, and diagnostic odds ratio 7.39. Inclusion of the other ketone measures (mean or last) or clinical variables did not improve the predictive validity of maximum ketone levels on their own. Routine surveillance of morning capillary ketone levels in T1D patient using SGLTi can predict 1-month risk of DKA/Ketosis and could allow for interventions to mitigate risk. Disclosure P.Bapat: None. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. D.Mumford: None. G.Tomlinson: None. L.Lovblom: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). S.Dhaliwal: None. C.Song: None. D.R.Budhram: None. A.M.K.Bakhsh: None. D.Scarr: None. A.Weisman: None. M.Fralick: None. N.Ivers: Consultant; Novo Nordisk Canada Inc., IQVIA Inc. Funding Diabetes Canada (OG-3-21-5572-BP)

530-P: Capillary Blood Ketone Level and the Prediction of Future Diabetic Ketoacidosis Risk in Type 1 Diabetes

Identification of those at risk of diabetic ketoacidosis (DKA) in T1D is challenging. Rather than during illness while DKA is developing, we aimed to determine if levels of routine point-of-care capillary blood ketones could predict DKA months prior to the event. In exploratory analysis, we examined 484 participants randomly assigned to placebo in an adjunct-to-insulin medication trial program (NCT02414958 and NCT02580591). Participants provided morning fasted capillary blood ketone levels twice per week via electronic logbook, and we calculated the maximum and mean level for each individual during a 2-month baseline period. Outcome was the 6 to 12-month occurrence of trial-adjudicated DKA. Area under the Curve (AUC) for the Receiver Operator Characteristic curves were generated. In sensitivity analysis we applied supervised machine learning methods (gradient-boosted trees). Participants had median age 43 [IQR 33, 54], mean HbA1c 8.2±0.6 percent, and provided 2 [1, 4] ketone measurements per week. Twelve DKA events occurred at median 105 [43, 199] days. Maximum and mean ketone levels were higher at baseline for the 12 cases compared to controls (for example, maximum ketone level 0.8 [0.6, 1.2] compared to 0.3 [0.2, 0.7] mmol/L, p=0.002). Maximum ketone level had AUC of 0.769 (95% CI 0.655-0.883). Maximum ketone ≥0.8 mmol/L had sensitivity 64%, specificity 78%, and likelihood ratios positive and negative of 2.9 and 0.5. Machine learning methods outperformed the single-metric analyses. Results provide proof-of-concept that routine capillary ketone surveillance can identify individuals at high-risk of future DKA. Simple or complex machine learning algorithms could be implemented in ketone meters or in future continuous ketone measurement technology. Disclosure C.Song: None. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. D.Mumford: None. G.Tomlinson: None. L.Lovblom: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). S.Dhaliwal: None. P.Bapat: None. A.M.K.Bakhsh: None. D.R.Budhram: None. D.Scarr: None. A.Weisman: None. M.Fralick: None. N.Ivers: Consultant; Novo Nordisk Canada Inc., IQVIA Inc. Funding Diabetes Canada (OG-3-21-5572-BP)