Blood Ketone Bodies Research Articles

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway

Excessive intake of fructose increases lipogenesis in the liver, leading to hepatic lipid accumulation and development of fatty liver disease. Metabolic alterations in the liver due to fructose intake have been reported in many studies, but the effect of fructose administration on hepatic gluconeogenesis is not fully understood. The aim of this study was to evaluate the acute effects of fructose administration on fasting-induced hepatic gluconeogenesis. C57BL/6J mice were administered fructose solution after 14 h of fasting and plasma insulin, glucose, free fatty acids, and ketone bodies were analysed. We also measured phosphorylated AKT and forkhead box O (FoxO) 1 protein levels and gene expression related to gluconeogenesis in the liver. Furthermore, we measured glucose production from pyruvate after fructose administration. Glucose-administered mice were used as controls. Fructose administration enhanced phosphorylation of AKT in the liver, without increase of blood insulin levels. Blood free fatty acids and ketone bodies concentrations were as high as those in the fasting group after fructose administration, suggesting that insulin-induced inhibition of lipolysis did not occur in mice administered with fructose. Fructose also enhanced phosphorylation of FoxO1 and suppressed gluconeogenic gene expression, glucose-6-phosphatase activity, and glucose production from pyruvate. The present study suggests that acute fructose administration suppresses fasting-induced hepatic gluconeogenesis in an insulin-independent manner.

Cardiac metabolic modulation upon low-carbohydrate low-protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13 C pyruvate, butyrate and acetoacetate probes.

To investigate the effects of long-term low-carbohydrate low-protein ketogenic diet (KD) on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats. Diabetic GK rats were fed with KD for 62 weeks. Cardiac function and metabolism were assessed using magnetic resonance imaging and 13 C magnetic resonance spectroscopy (13 C-MRS), at rest and under dobutamine stress. 13 C-MRS was performed following injection of hyperpolarized [3-13 C]acetoacetate, [1-13 C]butyrate or [1-13 C]pyruvate to assess ketone body, short-chain fatty acid or glucose utilization, respectively. Protein expression and cardiomyocyte structure were determined via Western blotting and histology, respectively. KD lowered blood glucose, triglyceride and insulin levels while increasing blood ketone body levels. In KD-fed diabetic rats, myocardial ketone body and glucose oxidation were lower than in chow-fed diabetic rats, while myocardial glycolysis and short-chain fatty acid oxidation were unaltered. Dobutamine stress revealed an increased cardiac preload and reduced cardiac compliance in KD-fed diabetic rats. Dobutamine-induced stimulation of myocardial glycolysis was more enhanced in KD-fed diabetic rats than in chow-fed diabetic rats, which was potentially facilitated via an upregulation in basal expression of proteins involved in glucose transport and glycolysis in the hearts of KD-fed rats. The metabolic profile induced by KD was accompanied by cardiac hypertrophy, a trend for increased myocardial lipid and collagen content, and an increased marker of oxidative stress. KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity.

Two-Week Exclusive Supplementation of Modified Ketogenic Nutrition Drink Reserves Lean Body Mass and Improves Blood Lipid Profile in Obese Adults: A Randomized Clinical Trial.

The ketogenic diet has long been recommended in patients with neurological disorders, and its protective effects on the cardiovascular system are of growing research interest. This study aimed to investigate the effects of two-week of low-calorie ketogenic nutrition drinks in obese adults. Subjects were randomized to consume drinks either a ketone-to-non-ketone ratio of 4:1 (KD 4:1), a drink partially complemented with protein at 1.7:1 (KD 1.7:1), or a balanced nutrition drink (BD). Changes in body weight, body composition, blood lipid profile, and blood ketone bodies were investigated. Blood ketone bodies were induced and maintained in the group that consumed both 4:1 and 1.7:1 ketogenic drinks (p < 0.001). Body weight and body fat mass significantly declined in all groups between 0 and 1 week and between 1 and 2 weeks (p < 0.05), while skeletal muscle mass remained unchanged only in the KD 1.7:1 group (p > 0.05). The blood lipid profile improved, appetite was reduced, and fullness was maintained in the two ketogenic drink groups. This study indicates the possibility for the development of obesity treatments based on ketogenic nutrition drinks even with a moderate ketogenic ratio of 1.7:1, as well as adjuvant therapies based on ketosis induction and maintenance for the treatment of other diseases and health conditions.

Clinical effects of one year of chemotherapy with a modified medium-chain triglyceride ketogenic diet on the recurrence of stage IV colon cancer.

e15709Background: Because many cancer cells display increased levels of glucose transporters that conduct glucose uptake and cancer cells use up to ten times more glucose than normal cells, glucide restrictions may be an effective nutritional therapy for patients with cancer. We introduced and examined effectiveness of modified medium-chain triglyceride (MCT) ketogenic diets with added MCT oil to suppress abdominal symptoms, as a severe carbohydrate intake restriction diet for patients with colon cancer. Methods: We administered chemotherapy in combination with the modified MCT ketogenic diet at a ratio of 1.4:1 for one year in 10 patients with stage IV recurrent colon cancer who experienced exacerbations under standard therapy (chemotherapy, best supportive care). Weight, albumin levels, presence of total blood ketone bodies, Response Evaluation Criteria in Solid Tumors (RECIST) classifications, and Quality of Life (QOL) evaluations were compared between patients in ketogenic diet group and 14 patients i...

A Ketogenic Formula Prevents Tumor Progression and Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

Low-carbohydrate, high-fat diets (ketogenic diets) might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF) is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR), tumor-bearing (TB), and ketogenic formula (KF) groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

Sensing Technologies for Detection of Acetone in Human Breath for Diabetes Diagnosis and Monitoring.

The review describes the technologies used in the field of breath analysis to diagnose and monitor diabetes mellitus. Currently the diagnosis and monitoring of blood glucose and ketone bodies that are used in clinical studies involve the use of blood tests. This method entails pricking fingers for a drop of blood and placing a drop on a sensitive area of a strip which is pre-inserted into an electronic reading instrument. Furthermore, it is painful, invasive and expensive, and can be unsafe if proper handling is not undertaken. Human breath analysis offers a non-invasive and rapid method for detecting various volatile organic compounds thatare indicators for different diseases. In patients with diabetes mellitus, the body produces excess amounts of ketones such as acetoacetate, beta-hydroxybutyrate and acetone. Acetone is exhaled during respiration. The production of acetone is a result of the body metabolising fats instead of glucose to produce energy. There are various techniques that are used to analyse exhaled breath including Gas Chromatography Mass Spectrometry (GC–MS), Proton Transfer Reaction Mass Spectrometry (PTR–MS), Selected Ion Flow Tube-Mass Spectrometry (SIFT–MS), laser photoacoustic spectrometry and so on. All these techniques are not portable, therefore this review places emphasis on how nanotechnology, through semiconductor sensing nanomaterials, has the potential to help individuals living with diabetes mellitus monitor their disease with cheap and portable devices.

Feasibility of skin acetone analysis in patients with cardiovascular diseases.

Breath acetone is reported to be a noninvasive biomarker for heart failure. However, the measurement of this metabolite requires expertize and is not standardized yet. Acetone is also released from the skin; thus, measuring acetone as a skin gas may be easier than breath analysis. We analyzed skin acetone collected from 41 hospitalized patients with cardiovascular diseases. Passive samplers were used to measure skin acetone emission. Passive sampler was softly fixed on the surface of forearm skin for 10 hour at night. Skin acetone emission ranged from 0.00 to 2.70 ng/cm2/h, and was significantly correlated with blood ketone bodies (r = 0.377, p = 0.017). This is the first study to analyze skin gas in patients with cardiovascular diseases. Skin acetone emission was found to reflect blood ketone bodies. It is feasible to measure skin acetone emission for reflecting blood ketone bodies in patients with cardiovascular diseases.

Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?

The ketogenic diet’s (KD) anticonvulsant effects have been well-documented for nearly a century, including in randomized controlled trials. Some patients become seizure-free and some remain so after diet cessation. Many recent studies have explored its expanded therapeutic potential in diverse neurological disorders, yet no mechanism(s) of action have been established. The diet’s high fat, low carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose and improve mitochondrial function and biogenesis. Cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. Based on differential NAD+ utilization during glucose- vs. ketone body-based acetyl-CoA generation for entry into the tricarboxylic cycle, we propose that a KD will increase the NAD+/NADH ratio. When rats were fed ad libitum KD, significant increases in hippocampal NAD+/NADH ratio and blood ketone bodies were detected already at 2 days and remained elevated at 3 weeks, indicating an early and persistent metabolic shift. Based on diverse published literature and these initial data we suggest that increased NAD during ketolytic metabolism may be a primary mechanism behind the beneficial effects of this metabolic therapy in a variety of brain disorders and in promoting health and longevity.

Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep ) or liver-specific overexpression of Ppp1r3b The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3bΔhep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.

High Resolution Ketone Measuring Method using Enzyme Reactions and Electrical Chemical Analysis

Diabetes Mellitus (DM) is caused by the pancreas insufficient produce of insulin or the body cells not responding properly to the blood insulin, which leads to disorder of carbohydrate metabolism. When the body has deficient insulin, tissues cannot take glucose in from blood stream. As an alternative metabolic pathway, burning fatty acids produces ketones (β-hydroxybutyric acid: 3-HB) into bloodstream as well as create energy. Too much concentration of blood ketone body is called ketoacidosis, and it can cause serious disturbance of consciousness, or result in death at the worst case. Therefore it is important to measure blood ketone body concentration and control it. Standard method of measuring blood ketone is venous blood test. Therefore, there is many problems such as 1) difficulty of periodic measurement, 2) risks of infection, 3) pain of injection, 4) waiting time for a measurement result. In this study, we developed a novel enzymatic reactor and H2O2 electrode aiming at the application to measure urine/sweat ketone body non-invasively. To evaluate properties of trial product sensors, we prepared test flow circuit which consisted of continuous flow pump, manual injector, and incubator (30/37°C). Within phosphate buffer solution, different concentration (0.5-113.83 [mM]) of ketone body which mixed in 1.0mL/min of continuous flow path could be detected with high accuracy.

Diet-Induced Ketosis Protects Against Focal Cerebral Ischemia in Mouse.

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5' AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphorylated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2±0.6 vs 7.8±2.2 mm3, mean±SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.

Cerebral Ketone Body Oxidation Is Facilitated by a High Fat Diet Enriched with Advanced Glycation End Products in Normal and Diabetic Rats

Diabetes mellitus (DM) causes important modifications in the availability and use of different energy substrates in various organs and tissues. Similarly, dietary manipulations such as high fat diets also affect systemic energy metabolism. However, how the brain adapts to these situations remains unclear. To investigate these issues, control and alloxan-induced type I diabetic rats were fed either a standard or a high fat diet enriched with advanced glycation end products (AGEs) (HAGE diet). The HAGE diet increased their levels of blood ketone bodies, and this effect was exacerbated by DM induction. To determine the effects of diet and/or DM induction on key cerebral bioenergetic parameters, both ketone bodies (β-hydroxybutyric acid) and lactate oxidation were measured. In parallel, the expression of Monocarboxylate Transporter 1 (MCT1) and 2 (MCT2) isoforms in hippocampal and cortical slices from rats submitted to these diets was assessed. Ketone body oxidation increased while lactate oxidation decreased in hippocampal and cortical slices in both control and diabetic rats fed a HAGE diet. In parallel, the expression of both MCT1 and MCT2 increased only in the cerebral cortex in diabetic rats fed a HAGE diet. These results suggest a shift in the preferential cerebral energy substrate utilization in favor of ketone bodies in animals fed a HAGE diet, an effect that, in DM animals, is accompanied by the enhanced expression of the related transporters.

Prevalence of ketosis, ketonuria, and ketoacidosis during liberal glycemic control in critically ill patients with diabetes: an observational study.

BackgroundIt is uncertain whether liberal glucose control in critically ill diabetic patients leads to increased ketone production and ketoacidosis. Therefore, we aimed to assess the prevalence of ketosis, ketonuria and ketoacidosis in critically ill diabetic patients treated in accordance with a liberal glycemic control protocol.MethodsWe performed a prospective observational cohort study of 60 critically ill diabetic patients with blood and/or urine ketone bodies tested in ICU. All patients were treated according to a liberal glucose protocol targeting a blood glucose level (BGL) between 10 and 14 mmol/l in a single tertiary intensive care unit in Australia. We measured quantitative bedside blood 3-beta-hydroxybutyrate (β-OHB) and semi-quantitative urine ketones on ICU admission and daily during ICU stay, for a maximum of 10 consecutive days.ResultsMedian blood β-OHB level on admission was 0.3 (0.1, 0.8) mmol/l. Ketoacidosis was rare (3 %), but some level of ketosis (β-OHB ≥0.6 mmol/l) was found in 38 patients (63 %) early during their ICU stay. However, there was no significant difference in prevalence or severity of ketonemia and ketonuria among patients with BGL above (permissive hyperglycemia) or below 10 mmol/l. On multivariable linear regression analysis there was no association between blood ketone levels and BGL, HbA1c, lactate levels, hematocrit, catecholamine infusion or APACHE III score. In contrast, blood ketone levels tended to be higher after cardiopulmonary bypass surgery (P = 0.06).ConclusionsLiberal glycemic control in critically ill diabetic patients does not appear to be associated with a high prevalence of ketoacidosis or ketonemia. Moreover, ketosis is typically present on admission and resolves rapidly. Finally, cardiopulmonary bypass surgery may be an important trigger of ketone body production.Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12615000216516; trial registration date 5 March 2015).Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1462-7) contains supplementary material, which is available to authorized users.

Postmortem biochemistry in suspected starvation-induced ketoacidosis

Significantly increased blood ketone body levels can be occasionally observed in the forensic setting in situations other than exposure to cold, diabetic or alcoholic ketoacidosis. Though infrequent, these cases do occur and deserve thorough evaluation in order to establish appropriate differential diagnoses and quantify the role that hyperketonemia may play in the death process. Starvation ketoacidosis is a rare cause of metabolic acidosis and is a phenomenon that occurs normally during fasting, as the body switches from carbohydrate to lipid energy sources. The levels of ketonemia in starvation ketoacidosis is usually mild in comparison to those seen in diabetic or alcoholic ketoacidosis. In the clinical setting, several cases of starvation-induced ketoacidosis mainly associated with gastric banding, pregnancy, malnutrition and low-carbohydrate diets have been reported. However, starvation ketosis causing severe metabolic acidosis has been rarely described in the medical literature. In the realm of forensic pathology, starvation-induced hyperketonemia has been rarely described. In this paper we present the postmortem biochemical results observed in situations of suspected starvation-induced hyperketonemia that underwent medico-legal examination. In all these cases, the diagnosis of starvation induced-hyperketonemia and the subsequent ketoacidosis was established per exclusionem based on all postmortem investigation findings. A review of the literature pertaining to the clinical diagnosis of starvation ketoacidosis is also provided.

Early Shifts of Brain Metabolism By Caloric Restriction Preserve White Matter Integrity and Long‐term Memory in Aging Mice

Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with either control or 40% CR diet. In addition, we determined the animals’ memory and learning ability with behavioral assessments. Blood glucose, blood ketone bodies, and body weight were also measured. We found distinct patterns between normal aging and CR aging on brain functions - normal aging showed reductions in brain glucose metabolism, white matter integrity, and long-term memory, resembling human brain aging. CR aging, in contrast, displayed an early shift from glucose to ketone bodies metabolism, which was associated with preservations of brain energy production, white matter integrity, and long-term memory in aging mice. Among all the mice, we found a positive correlation between blood glucose level and body weight, but an inverse association between blood glucose level and lifespan. Our findings suggest that CR could slow down brain aging, in part due to the early shift of energy metabolism caused by lower caloric intake, and we were able to identify the age-dependent effects of CR non-invasively using neuroimaging. These results provide a rationale for CR-induced sustenance of brain health with extended longevity.

Diabetic Ketoacidosis With Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes.

To assess the incidence of serious adverse events (AEs) of diabetic ketoacidosis (DKA) with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as an add-on to insulin in adults with type 1 diabetes. In this 18-week, randomized, double-blind, phase 2 study, patients (N = 351; HbA1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion received canagliflozin 100 or 300 mg or placebo once daily. The incidence of ketone-related AEs, defined as any event from a prespecified list of preferred terms (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, urine ketone body present), including serious AEs of DKA, was assessed based on AE reports. At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE. Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin. Mitigation strategies are needed for use in future clinical trials to reduce the risk of DKA with canagliflozin treatment in patients with type 1 diabetes.

A field trial on the effects of pure sodium propionate and a combination with herbal extracts on short term development of subclinical ketosis

While glucogenic substances in ketosis prevention are commonly used, there is a lack of clinical studies about the effectiveness of ketosis therapy in particular by means of sodium propionate and herbal extracts. Fresh cows between 5 and 50 days in milk of 25 Swiss and German dairy farms were tested weekly for ketone bodies in blood. From 283 cows, 121 (42.8%) exceeded the threshold of 1.0mmol/l blood-β-hydroxybutyrate (BBHB). Thereof 84 cows were randomly assigned to three treatments on each farm. Treatment SP-H was composed of sodium propionate (120g per application) and an aqueous extract of seven herbs (13.5g drug equivalent per application), treatment SP comprised pure sodium propionate (120g per application) and treatment PL was a placebo. All preparations were fluid (in total 350ml per application) and were supplemented with organic molasses (2%) and water. Applications were given orally twice a day shortly after milking for a period of four days. During an observation period of two weeks, milk yield and milk parameters (acetone, protein, urea), body condition score and BBHB were recorded. All three treatment groups had similar initial conditions, except for a non-significantly lower ketone body concentration in blood and milk in group PL.The results indicated a reduction of ketone bodies in all three treatment groups. Mean values in group SP never differed significantly from those of group PL regarding the observed parameters. During the first week of observation milk-acetone (MAC) concentration was reduced in all treatment groups: mean values in group SP-H were on the lowest level and differed significantly from those in group SP (p=0.035) and PL (p<0.001). The second week of observation did not reveal any significant difference between the assessed parameters. The largest reduction in BBHB concentration after two weeks showed group SP-H with a difference by trend to group SP (p=0.06), but not to group PL. There were no significant differences between the groups concerning the other recorded parameters. Compared to placebo or pure sodium propionate a combination of sodium propionate with herbal extracts seemed to have slight advantages in a four days therapy of subclinical ketotic fresh cows.

Both thyroid hormone levels and resting metabolic rate decrease in African striped mice when food availability decreases.

In response to variation in food availability and ambient temperature (Ta), many animals show seasonal adaptations in their physiology. Laboratory studies showed that thyroid hormones are involved in the regulation of metabolism, and their regulatory function is especially important when the energy balance of an individual is compromised. However, little is known about the relationship between thyroid hormones and metabolism in free-living animals and animals inhabiting seasonal environments. Here, we studied seasonal changes in triiodothyronine (T3) levels, resting metabolic rate (RMR) and two physiological markers of energy balance (blood glucose and ketone bodies) in 61 free-living African striped mice (Rhabdomys pumilio) that live in an semi-arid environment with food shortage during the dry season. We predicted a positive relationship between T3 levels and RMR. Further, we predicted higher T3 levels, blood glucose levels and RMR, but lower ketone body concentrations, during the moist season when food availability is high compared with summer when food availability is low. RMR and T3 levels were negatively related in the moist season but not in the dry season. Both RMR and T3 levels were higher in the moist than in the dry season, and T3 levels increased with increasing food availability. In the dry season, blood glucose levels were lower but ketone body concentrations were higher, indicating a change in substrate use. Seasonal adjustments in RMR and T3 levels permit a reduction of energy expenditure when food is scarce, and reflect an adaptive response to reduced food availability in the dry season.

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure.

We hypothesized that exhaled acetone concentration (EAC), reflecting altered blood ketone body metabolism and increased acetone exhaust because of pulmonary congestion in heart failure (HF), would correlate with hemodynamic parameters in patients with non-ischemic chronic HF. We prospectively enrolled 102 non-ischemic HF patients with New York Heart Association (NYHA) class I-III. Exhaled breath was collected after an overnight fast. Echocardiography and cardiac catheterization were performed in all patients. We also enrolled 17 control patients without HF. EAC in the HF patients was significantly higher than that in the control patients (median EAC; 0.53 vs. 0.38 ppm, P=0.012). EAC positively correlated with blood total ketone bodies (r=0.454, P<0.001), NYHA class (r=0.489, P<0.001), and plasma B-type natriuretic peptide (r=0.316, P=0.001). Right heart catheterization revealed that EAC significantly correlated with pulmonary capillary wedge pressure (PCWP, r=0.377, P<0.001). Receiver-operating characteristic analysis revealed that EAC >1.05 ppm was associated with PCWP ≥18 mmHg (area under the curve [AUC] 0.726, sensitivity 50%, specificity 89%). EAC was shown to be a comparable diagnostic biomarker for HF to BNP (AUC 0.760, sensitivity 80%, specificity 70%). EAC may be a novel noninvasive biomarker that correlates hemodynamic severity in non-ischemic chronic HF. (Circ J 2016; 80: 1178-1186).

A Case of Nivolumab-Induced Fulminant Type 1 Diabetes with Steroids and Glucagon-Like Peptide 1 Administration during the Early Onset

Background: Nivolumab is a humanized IgG4 anti-programmed cell death protein-1 (PD-1) antibody. In recent years, type 1 diabetes associated with anti-PD-1 immunotherapy has been reported. Case report: We report a 62-year-old woman with primary choroidal melanoma who developed fulminant type 1 diabetes after anti-PD-1 immunotherapy (nivolumab). She had elevated levels of blood glucose and total blood ketone body. Her hemoglobin A1c level was at the upper limit of normal, and she had decreased endogenous insulin secretion. Anti-glutamic acid decarboxylase and anti-islet antigen 2 antibody tests were negative. Endogenous insulin was still being secreted at the time of diagnosis; therefore, we administered steroids and glucagon-like peptide-1 (GLP-1). However, insulin secretion did not recover. Approximately 10 months after onset, her diabetes was under control with intensive insulin therapy and voglibose treatment. Discussion: The mechanism of diabetes caused by nivolumab is unclear, but it may involve the excessive autoimmune response associated with PD-1 inhibition. GLP-1 has a protective effect on the pancreas by promoting differentiation and proliferation of pancreatic β cells and suppressing pancreatic β cell apoptosis. We attempted to treat with steroids and GLP-1 before depletion of endogenous insulin to suppress the hyperimmunization and protect the pancreatic β cells. Insulin secretion did not recover. However, no reports have described using these therapies to treat diabetes associated with immune checkpoint inhibitors during early onset to date. We consider this case is the meaningful report as a negative data.