A retrospective analysis of the incidence, outcome and factors associated with the occurrence of euglycemic ketoacidosis in diabetic patients on sodium glucose co-transporter - 2 inhibitors undergoing cardiac surgery.

Introduction: SGLT2i is a new class of drugs used for type 2 diabetes. SGLT2i are known to cause EuKA in the perioperative period. Euglycemic ketoacidosis (EuKA) can cause life-threatening metabolic acidosis in the perioperative setting. Though the event rate of SGLT2i associated diabetic ketoacidosis in nonoperative setting is low, incidence among peri-operative patients can be very high and remains unknown. Aim: The aim of this study was to find the incidence, analyze outcome, and establish correlation between risk factors and EuKA in cardiac surgical patients on SGLT2i. Materials and Methods: This is a retrospective study analyzing 24 cardiac surgical patients who were on SGLT2i for type 2 diabetes mellitus. Data collection included age, sex, BMI, preoperative HbA1C, albumin, creatinine, type of SGLT2i and timing of stopping before surgery, insulin administration in the immediate pre-operative period; use of CPB, GI infusion and inotropes in the intraoperative period; blood ketone, duration of ventilation, hydration status and length of postoperative stay in postoperative period. Patients were diagnosed to have EuKA if any one of the serially measured postoperative ketone values was more than 0.6 mmol/L (ketone positive). The collected data were used to find an association between the risk factors and the occurrence of EuKA. Results: Of the 24 patients, 17 patients developed EuKA. (70.8.%). 10 of the 17 EuKA in our study required preoperative Insulin for diabetic control whereas none in the ketone negative patients required insulin. This was statistically significant (P = 0.019). Association of other factors to EuKA were not statistically significant. Conclusion: Though the event rate of SGLT2i associated Diabetic ketoacidosis in nonoperative setting is low, (17), the occurrence of EUKA in cardiac surgical patients on SGLT2i in our study was 70.8% (17 out of 24 patients). Patients who require insulin in addition to other oral hypoglycemic drugs for immediate preoperative glycemic control are at risk for the development of SGLT2 inhibitor-induced EuKA postoperatively. Missing the diagnosis of EuKA is fatal in these patients. We couldn't make a diagnosis in our first patient whom we lost. Since it was diagnosed in all our study patients by measuring serial ketone values, there was no mortality and insignificant morbidity. Cessation of SGLT2i before surgery, expectant watch for blood ketones, and treatment with GI infusion reduce morbidity and mortality in cardiac surgical patients.

Pharmacokinetic and metabolic profiling studies of osmundacetone in rats by UPLC-MS/MS and UPLC-QE-Orbitrap-HRMS.

Osmundacetone is a potential medicinal substance existing in ferns and has excellent antioxidant effects. This research aims to obtain the pharmacokinetic data for and metabolite products of osmundacetone. An UPLC-MS/MS quantitative method was established for the measurement of osmundacetonein in rat plasma over a linear range of 6.72-860.00 ng/ml. The signal to noise ratio of the lower limit of quantification was 60:1, the precision was <9.74% and the method had good selectivity and stability. The established method was successfully applied to the pharmacokinetic study of osmundacetone for the first time. Osmundacetone reached a peak at 0.25 h with a maximum value of 3283.33 µg/L. The apparent volume of distribution not multiplied by the bioavailability was 127.96 L/kg, and the half-life of osmundacetone was 5.20 h. At the same time, an UPLC-QE-Orbitrap-HRMS method was established to identify metabolites in plasma, urine and feces for the first time. A total of 30 metabolites were identified and the metabolic profile of osmundacetone was defined. In general, we have established a mass spectrometry quantitative method for osmundacetone for the first time and characterized its metabolic characteristics in rats.

Dietary-Induced Ketogenesis: Adults Are Not Children.

There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

The Combination of Cigarette Smoking and Alcohol Consumption Synergistically Increases Reactive Carbonyl Species in Human Male Plasma.

Cigarette smoking and alcohol consumption are major risk factors for lifestyle-related diseases. Although it has been reported that the combination of these habits worsens risks, the underlying mechanism remains elusive. Reactive carbonyl species (RCS) cause chemical modifications of biological molecules, leading to alterations in cellular signaling pathways, and total RCS levels have been used as a lipid peroxidation marker linked to lifestyle-related diseases. In this study, at least 41 types of RCS were identified in the lipophilic fraction of plasma samples from 40 subjects using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Higher levels of 10 alkanals, 5 trans-2-alkenals, 1 cis-4-alkenal, and 3 alkadienals were detected in the smoking/drinking group (N = 10) as compared to those with either habit (N = 10 each) or without both habits (N = 10) in the analysis of covariances adjusted for age and BMI. The levels of 3 alkanals, 1 trans-2-alkenal, 1 alkadienal, and 1 4-hydroxy-2-alkenal in the smoking/drinking group were significantly higher than those in the no-smoking/drinking and no-smoking/no-drinking groups. These results strongly indicate that the combination of cigarette smoking and alcohol drinking synergistically increases the level and variety of RCS in the circulating blood, and may further jeopardize cellular function.

Ketogenic diet with medium-chain triglycerides restores skeletal muscle function and pathology in a rat model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium-chain triglycerides (MCT-KD) could alter genetically mutated DMD in model rats. We found that the MCT-KD significantly increased muscle strength and fiber diameter in these rats. The MCT-KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT-KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT-KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT-KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT-KD-induced improvement of DMD.

Correlation between ketones and mental fatigue in high fat-induced obese and non-obese rats.

Obesity, often caused by a diet high in calories and low physical activity, may induce physical fatigue, as experienced via decreased locomotor activity and mental fatigue such as impaired cognition. This study aims to evaluate glucose and ketone levels secondary to high-fat diet (HFD) exposure and signs of physical and mental fatigue. Fifty-four 7-week-old male Sprague Dawley rats (Rattus norvegicus) were assigned to either an HFD (n = 28) or a standard diet (SD; n = 26) for a 6-week period during which body weight, blood glucose, and ketones were measured twice per week. An open field (OF) paradigm was used to measure locomotor activity, while novel object recognition (NOR) test was used as an indicator of cognition. Animals in the HFD group weighed more than SD rats (8.4 g; p < 0.05) starting at Day 11, blood glucose levels were higher in the HFD group versus SD rats (3.9 mg/dl; p < 0.05) beginning in Week 5, and ketones were lower for the HFD versus the SD group throughout the study (0.34 mmol/L on average; p < 0.05). Although there was no significant difference in locomotor activity between the HFD and SD groups (p = 0.12), regardless of diet, higher ketone levels were associated with increased NOR time and ratio between the familiar and novel objects (p < 0.01). Thus, this study provides evidence that an increased level of ketones is associated with greater cognitive performance and a lesser probability of experiencing mental fatigue.

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases.

Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., ß-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, ß-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.

An Intermittent Fasting Mimicking Nutrition Bar Extends Physiologic Ketosis in Time Restricted Eating: A Randomized, Controlled, Parallel-Arm Study.

There has been increasing interest in time-restricted eating to attain intermittent fasting's metabolic benefits. However, a more extended daily fast poses many challenges. This study was designed to evaluate the effects of a 200-calorie fasting-mimicking diet (FMD) energy bar formulated to prolong ketogenesis and mitigate fasting-associated side effects. A randomized, controlled study was conducted comparing the impact of consuming an FMD bar vs. continued water fast, after a 15-h overnight fast. Subjects in the FMD group showed a 3-h postprandial beta-hydroxybutyrate (BHB) level and 4-h postprandial BHB area under the curve (AUC0-4) that were non-inferior to those who continued with the water fast (p = 0.891 and p = 0.377, respectively). The postprandial glucose AUC0-4 in the FMD group was non-inferior to that in the water fast group (p = 0.899). A breakfast group served as a control, which confirmed that the instrument used in home glucose and ketone monitoring functioned as expected. The results indicate that FMD bar consumption does not interfere with the physiological ketogenesis associated with overnight fasting and could be used to facilitate the practice of time-restricted eating or intermittent fasting.

Intermittent fasting promotes anxiolytic-like effects unrelated to synaptic mitochondrial function and BDNF support.

Anxiety disorders are linked to mitochondrial dysfunction and decreased neurotrophic support. Since anxiolytic drugs target mitochondria, non-pharmacological approaches to improve mitochondrial metabolism such as intermittent fasting (IF) may cause parallel behavioral benefits against anxiety disorders. Here, we investigated whether a chronic IF regimen could induce anxiolytic-like effects concomitantly to modulation in mitochondrial bioenergetics and trophic signaling in mice brain. A total of 44 Male C57BL/6 J mice (180 days old) were assigned to two dietary regimens: a normal, ad libitum diet (AL group) and an alternate-day fasting (IF group), where animals underwent 10 cycles of 24 h food restriction followed by 24 h ad libitum access. Animals underwent the open field test, dark/light box and elevated plus maze tasks. Isolated nerve terminals were obtained from mice brain and used for mitochondrial respirometry, hydrogen peroxide production and assessment of membrane potential dynamics, calcium handling and western blotting. We showed that IF significantly alters total daily food intake and food consumption patterns but not body weight. There were no differences in the exploratory and locomotory parameters. Remarkably, animals from IF showed decreased anxiety-like behavior. Mitochondrial metabolic responses in different coupling states and parameters linked with H2O2 production, Ca2+ buffering and electric gradient were not different between groups. Finally, no alterations in molecular indicators of apoptotic death (Bax/Bcl-2 ratio) and neuroplasticity (proBDNF/BDNF and synaptophysin were observed). In conclusion, IF exerts anxiolytic-like effect not associated with modulation in synaptic neuronergetics or expression of neurotrophic proteins. These results highlight a potential benefit of intermittent fasting as a nutritional intervention in anxiety-related disorders.

The effect of ketogenic diets on neurogenesis and apoptosis in the dentate gyrus of the male rat hippocampus.

Ketogenic diets (KD) have become popular diet to lose weight. However, the effect of such diets on brain function has not yet been clarified. Thus, we aimed to study the effects of KD on the neurogenesis and apoptosis in the dentate gyrus by assessing the expression of Ki-67 and Caspase-3. Rats (n = 24) were divided into four groups: control (normal diet), ketogenic diet (KD), time-restricted diet (TRD), and the combination of high-fat and time-restricted diet (CD) groups. The expression of Ki-67 in the TRD and CD groups was higher compared to others (P < 0.05), whereas no such difference was observed in the KD group. The number of Capase-3-positive cells decreased significantly in the TRD group (P < 0.05), but such decrease was not observed in the CD group. These results indicate that, although KD could be effective in reducing the body weight, possible adverse effect in the brain cannot be ignored.

A 2 Week Cross-over Intervention with a Low Carbohydrate, High Fat Diet Compared to a High Carbohydrate Diet Attenuates Exercise-Induced Cortisol Response, but Not the Reduction of Exercise Capacity, in Recreational Athletes.

Low carbohydrate, high fat (LCHF) diets are followed by athletes, but questions remain regarding effects of LCHF on metabolic adaptation, exercise-induced stress, immune function and their time-course. In this cross-over study, 14 recreational male athletes (32.9 ± 8.2 years, VO2max 57.3 ± 5.8 mL/kg/min) followed a two week LCHF diet (<10 En% carbohydrates (CHO), ~75En% Fat) and a two week HC diet (>50 En% CHO), in random order, with a wash-out period of >2 weeks in between. After 2 days and 2 weeks on either diet, participants performed cycle ergometry for 90 min at 60%Wmax. Blood samples for analysis of cortisol, free fatty acids (FFA), glucose and ketones, and saliva samples for immunoglobin A (s-IgA) were collected at different time points before and after exercise. The LCHF diet resulted in higher FFA, higher ketones and lower glucose levels compared to the HC diet (p < 0.05). Exercise-induced cortisol response was higher after 2 days on the LCHF diet (822 ± 215 nmol/L) compared to 2 weeks on the LCHF diet (669 ± 243 nmol/L, p = 0.004) and compared to both test days following the HC diet (609 ± 208 and 555 ± 173 nmol/L, both p < 0.001). Workload was lower, and perceived exertion higher, on the LCHF diet compared to the HC diet on both occasions. A drop in s-IgA following exercise was not seen after 2 days on the LCHF diet, in contrast to the HC diet. In conclusion, the LCHF diet resulted in reduced workload with metabolic effects and a pronounced exercise-induced cortisol response after 2 days. Although indications of adaptation were seen after 2 weeks on the LCHF diet, work output was still lower.

Reliability and diagnostic performance of a new blood ketone and glucose meter in humans.

BACKGROUND: Accurate and reliable monitoring of blood ketone and glucose levels is useful for athletes adhering to a ketogenic diet who want to verify that they are in a state of ketosis and, therefore, accruing performance adaptations. However, the cost of devices and testing materials may prohibit their use. More affordable field testing systems are available, but their accuracy and reliability remain in question. The objectives of this study were to evaluate the agreement between a previously validated ketone and glucose meter (Meter 1 - Precision Xtra) and a more affordable meter that has not been validated (Meter 2 - Keto-Mojo), and also to assess the diagnostic performance of Meter 2 for identifying nutritional ketosis. METHODS: Thirteen participants (7 females and 6 males; 21.6 ± 3.0 years old) visited the laboratory three times in this randomized, double-blind cross-over design study. Ketone and glucose levels were measured with Meter 1 and Meter 2 twice before and twice after ingestion of a racemic ketone, natural ketone, or maltodextrin supplement. Intraclass correlation coefficient (ICC) estimates and their 95% confidence intervals were calculated to evaluate interrater reliability for Meter 1 and Meter 2. Bland-Altman plots were constructed to visually assess the agreement between devices. Area under the ROC curve analysis was performed to evaluate the diagnostic ability of Meter 2 to detect nutritional ketosis at a threshold ketone level of 0.5 mM as identified by Meter 1. RESULTS: Reliability between the meters was excellent for measuring ketones (ICC = .968; .942-.981) and good for measuring glucose (ICC = .809; .642-.893), though the Bland-Altman plot revealed substantial differences in agreement for measuring glucose. Area under the ROC curve (Area = 0.913; 0.828-0.998) was excellent for diagnosing nutritional ketosis. CONCLUSIONS: Both Meter 1 and Meter 2 displayed excellent agreement between each other for ketone measurement. Meter 2 also displayed an excellent level of accuracy for diagnosing nutritional ketosis at a threshold value of 0.5 mM, making it an effective and affordable alternative to more expensive testing devices.

Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil.

Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer's disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. PARTICIPANTS: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer's Disease were assessed. INTERVENTION: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. MEASUREMENTS: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. RESULTS: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). CONCLUSION: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

The Effect of Blood Ketone Concentration and Exercise Intensity on Exogenous Ketone Oxidation Rates in Athletes.

INTRODUCTION: Exogenous ketones potentially provide an alternative, energetically advantageous fuel to power exercising skeletal muscle. However, there is limited evidence regarding their relative contribution to energy expenditure during exercise. Furthermore, the effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates is unknown. METHODS: Six athletes completed cycling ergometer exercise on three occasions within a single-blind, random-order controlled, crossover design study. Exercise duration was 60 min, consisting of 20-min intervals at 25%, 50%, and 75% maximal power output (WMax). Participants consumed (i) bitter flavored water (control), (ii) a low-dose ß-hydroxybutyrate (ßHB) ketone monoester (KME; 252 mg·kg BW-1, "low ketosis"), or (iii) a high-dose ßHB KME (752 mg·kg BW-1, "high ketosis"). The KME contained a 13C isotope label, allowing for the determination of whole-body exogenous ßHB oxidation rates through sampled respiratory gases. RESULTS: Despite an approximate doubling of blood ßHB concentrations between low- and high-ketosis conditions (~2 mM vs ~4.4 mM), exogenous ßHB oxidation rates were similar at rest and throughout exercise. The contribution of exogenous ßHB oxidation to energy expenditure peaked during the 25% WMax exercise intensity but was relatively low (4.46% ± 2.71%). Delta efficiency during cycling exercise was significantly greater in the low-ketosis (25.9% ± 2.1%) versus control condition (24.1% ± 1.9%; P = 0.027). CONCLUSIONS: Regardless of exercise intensity, exogenous ßHB oxidation contributes minimally to energy expenditure and is not increased by elevating circulating concentrations greater than ~2 mM. Despite low exogenous ßHB oxidation rates, exercise efficiency was significantly improved when blood ßHB concentration was raised to ~2 mM.

A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.

INTRODUCTION: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

Exogenous Ketosis Impairs 30-min Time-Trial Performance Independent of Bicarbonate Supplementation.

PURPOSE: We recently demonstrated that coingestion of NaHCO3 to counteract ketoacidosis resulting from oral ketone ester (KE) intake improves mean power output during a 15-min time trial (TT) at the end of a 3-h cycling race by ~5%. This ergogenic effect occurred at a time when blood ketone levels were low, as ketosis was only induced during the initial ~2 h of the race. Therefore, in the current study, we investigated whether performance also increases if blood ketone levels are increased in the absence of ketoacidosis during high-intensity exercise. METHODS: In a double-blind crossover design, 14 well-trained male cyclists completed a 30-min TT (TT30') followed by an all-out sprint at 175% of lactate threshold (SPRINT). Subjects were randomized to receive (i) 50 g KE, (ii) 180 mg·kg-1 body weight NaHCO3 (BIC), (iii) KE + BIC, or (iv) a control drink (CON). RESULTS: KE ingestion increased blood d-ß-hydroxybutyrate to ~3-4 mM during the TT30' and SPRINT (P < 0.001 vs CON). In KE, blood pH and bicarbonate concomitantly dropped, causing 0.05 units lower pH and 2.6 mM lower bicarbonate in KE compared with CON during the TT30' and SPRINT (P < 0.001 vs CON). BIC coingestion resulted in 0.9 mM higher blood d-ß-hydroxybutyrate (P < 0.001 vs KE) and completely counteracted ketoacidosis during exercise (P > 0.05 vs CON). Mean power output during TT30' was similar between CON and BIC at 281 W, but was 1.5% lower in the KE conditions (main effect of KE: P = 0.03). Time to exhaustion in the SPRINT was ~64 s in CON and KE and increased by ~8% in the BIC conditions (main effect of BIC: P < 0.01). DISCUSSION: Neutralization of acid-base disturbance by BIC coingestion is insufficient to counteract the slightly negative effect of KE intake during high-intensity exercise.

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes.

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 µmol/day (IQR 17-138), and ß-hydroxybutyrate by 59 µmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

The effect of meloxicam on neonatal dairy calves: Immunoglobulin G uptake and preweaning performance.

Objectives of this study were to determine effects of meloxicam administered in 2 forms on IgG uptake, growth, and health of preweaned calves. Sixteen Holstein bulls and 14 heifers with a body weight (BW) of 44.3 ± 5.24 kg were blocked by birth date in a randomized complete block design. Calves were removed from the dam before suckling, weighed, and randomly assigned to 1 of 3 treatments: (1) colostrum replacer (CR) at 0 h with no meloxicam (control; CON), (2) 1 mg/kg of BW of meloxicam in pill form before CR (PL), or (3) 1 mg/kg of BW of meloxicam mixed in solution with CR (SL). Calves were fed 675 g of dry matter of CR, providing a volume of 3 L and 180 g of IgG. Blood samples were collected at 0 h to analyze initial IgG and ketone concentrations, and at 6, 12, 18, and 24 h to analyze IgG uptake. At 24 h, calves were fed 432 g of dry matter of 24% crude protein milk replacer (MR) split in 2 feedings, and free choice starter and water until 42 d. Weekly blood samples were analyzed for glucose, plasma urea nitrogen, and ketone concentrations. Time of consumption of MR, BW, length, hip and withers height, and heart girth were recorded weekly. All calves achieved adequate transfer of immunity. Meloxicam did not affect apparent efficiency of absorption, serum total protein, or IgG uptake at 6, 18, and 24 h; however, meloxicam-treated calves had lesser IgG concentrations at 12 h (24.40 and 22.59 g/L for PL and SL, respectively) compared with CON (28.47 g/L). Meloxicam treatment did not affect BW. Calves that received PL tended to gain length at a faster rate (0.24 cm/d) than those that received SL (0.19 cm/d). Meloxicam treatment did not affect MR intake, time of consumption of MR, total dry matter intake, or feed efficiency. Meloxicam-treated calves tended to consume more starter (560.4 and 515.4 g/d for PL and SL, respectively) than those that received CON (452.6 g/d). Ketone levels tended to be greater in meloxicam-treated calves (0.15 and 0.17 mmol/L for PL and SL, respectively), suggesting improved rumen development compared with those that received CON (0.12 mmol/L). Meloxicam treatment did not affect plasma urea nitrogen . Glucose concentrations of calves that received PL (73.2 mg/dL) were less than those that received SL (83.3 mg/dL). Results of this study suggest that meloxicam given at 0 h offers positive effects on starter intake, and possibly rumen development, of preweaned dairy calves. Treatment PL, as compared with SL, offered positive results for rumen development, indicated by lower blood glucose levels.

The correlation between breath acetone and blood betahydroxybutyrate in individuals with type 1 diabetes.

Ketone testing is an important element of the self-management of illness in type 1 diabetes. The aim of the present study was to see if a breath test for acetone could be used to predict quantitatively the levels of the ketone betahydroxybutyrate in the blood of those with type 1 diabetes, and thus be used as an alternative to capillary testing for ketones. Simultaneous capillary ketones and breath acetone were measured in 72 individuals with type 1 diabetes attending a diabetes clinic and on 9 individuals admitted to hospital with diabetic ketoacidosis. Capillary blood measurements ranged from 0.1 mmol l-1 (the lower limit of the ketone monitor) to over 7 mmol l-1, with breath acetone varying between 0.25 and 474 parts per million by volume. The two variables were found to be correlated and allowed modelling to be carried out which separated breath acetone levels into three categories corresponding to normal, elevated and 'at risk' levels of blood ketones. The results on this limited set of participants suggest that a breath acetone test could be a simple, non-invasive substitute for capillary ketone measurement in type 1 diabetes.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.