This thesis was conducted to investigate risk factors for ketosis development in lactating dairy cattle and evaluate treatments for affected animals. Four main studies were carried out. A systematic review of the ketosis treatment literature was performed to analyze the current body of literature available and provide guidance for treatments to be used in future studies. Secondly, a randomized clinical trial was performed on seventeen commercial dairy farms to determine the effectiveness of a combination butaphosphan cyanocobalamin product, insulin, and propylene glycol for ketosis treatment. A second randomized clinical trial was performed on nine commercial dairy herds to further evaluate the usefulness of a combination butaphosphan cyanocobalamin product and two durations of propylene glycol treatment on ketosis resolution and early lactation milk production. Finally, records from five commercial dairy farms were analyzed to evaluate individual cow risk factors associated with ketosis development. Evaluation of the ketosis treatment literature revealed the lack of well-designed ketosis treatment studies and the need for further investigation to determine an effective treatment regimen. Both treatment trials showed an effect of blood glucose concentrations at the time of enrollment on the efficacy of study treatments that had not been previously described in the literature. Animals that had blood glucose < 2.2 mmol/L at the time of ketosis diagnosis were more likely to cure and produced more milk when treated with insulin, butaphosphan cyanocobalamin, or extended duration of propylene glycol than untreated controls with blood glucose < 2.2 mmol/L. Treatment benefits did not extend to animals with blood glucose > 2.2 mmol/L at the time of enrollment. Older age at first calving, extended days open in the previous lactation, longer dry period, and increased parity increased ketosis risk. Also, animals that were ketotic during a lactation were more likely to become ketotic in the subsequent lactation. The information contained in this thesis helps increase understanding of ketosis risk and proper treatment. The novel interaction of the level of blood glucose and ketosis sheds light on previous inconsistent results on ketosis impacts and will change approaches to understanding and treatment of the condition in the field. / Ontario Ministry of Agriculture and Food, Bayer Animal Health, Vetoquinol, American Association of Bovine Practitioners Research Assistantship

There has been much consideration over whether exogenous ketone bodies have the capacity to enhance exercise performance through altered substrate metabolism. This systematic review aimed to determine the effects of both ketone precursors and monoesters on endurance exercise performance. A systematic search was conducted in PubMed, SPORTDiscus, and CINAHL for randomized controlled trials investigating endurance performance outcomes in response to ingestion of a ketone supplement compared to a nutritive or non-nutritive control in humans. A meta-analysis was performed to determine the standardized mean difference between interventions using a random-effects model. Hedges’ g and 95% confidence intervals (CI) were reported. The search yielded 569 articles, of which 8 were included in this review (80 participants; 77 men, 3 women). When comparing endurance performance amongst all studies, no significant differences were found between ketone and control trials (Hedges g=0.136; 95% CI, -0.195, 0.467; p=0.419). Sub-analyses based on type of endurance tests showed no significant differences in time to exhaustion (Hedges g=-0.002; 95% CI, -0.312, 0.308; p=0.989) or time trial (Hedges g=0.057; 95% CI, -0.282, 0.395; p=0.744) values. Based on these findings, exogenous ketone precursors and monoesters do not significantly improve endurance exercise performance. While all studies reported an increase in blood ketone concentrations after ingestion, ketone monoesters appear to be more effective at raising concentrations than precursors.

As metabolic substrates, ketone bodies provide an alternative to glucose in order to pro- long survival during starvation. A low carbohydrate, high fat diet can be used to promote ketogenesis without fasting, but long-term compliance can be difficult. Dietary ketone bod- ies may be an alternative method to induce ketosis, so the aim of the work in this Thesis was to investigate the metabolism of exogenous ketones. In the first experimental Chap- ter, the effects of ketone ester and salt drinks on blood &beta;-hydroxybutyrate (βHB), glucose, lipids, electrolytes and pH were determined in healthy humans at rest. Blood D-&beta;HB levels were higher following ketone ester drinks, but it was found that total &beta;HB levels with ke- tone salts were similar, as over 50&percnt; of βHB delivered in the salt was the L-isoform, which was only slowly removed from the blood. Circulating glucose and lipid concentrations fell following both ketone drinks. Blood pH fell following ketone ester consumption, but rose following ketone salt drinks, whilst both compounds raised blood sodium and chloride, and lowered potassium. Work in the second Chapter investigated the repeatability of ketone es- ter metabolism with food, successive drinks or continuous nasogastric (NG) infusion. Peak D-&beta;HB levels were repeatable between- and within- subjects at rest but were lower after a meal, although blood acetoacetate, breath acetone and urine &beta;HB were unaffected by feed- ing. &beta;HB kinetic parameters were not altered by existing hyperketonemia from successive ketone ester drinks and total &beta;HB uptake was identical when isovolumetric amounts of ketone ester were continuously infused through a NG tube. The third Chapter explored side-effects of ketone drinks: ketone ester drinks decreased appetite compared to isocaloric dextrose; which may have been linked to effects of &beta;HB on enteroendocrine cells. Fur- thermore, both ester and salt drinks were found to be unpalatable, and to cause a few, mild gastro-intestinal effects that increased with intake. As exogenous ketones could be a per- formance enhancing supplement in sport, the fourth Chapter used a survey to investigate supplement use by endurance athletes. The results demonstrated widespread supplement use, which was highest at the elite level. In the final Chapter, the effect of glycogen lev- els on the oxidation of &beta;HB was determined in isolated perfused rat hearts. Low cardiac glycogen levels decreased &beta;HB oxidation and levels of the intermediates of glycolysis and the Krebs cycle, whilst increasing muscle amino acid levels, suggesting that low glycogen may have impaired anaplerosis. In conclusion, this work extends current understanding of the novel physiological ketosis that occurs following exogenous ketone consumption.

The aim of this study was to evaluate antiketogenic prophylaxis of the veterinary medicine Kexxtone, in breeding of Holstein cows, in the company Agrodam Hořepník, s.r.o. There were then evaluated the parameters of a metabolic state in the herd monitored. Furthermore I evaluated the milk yield, amount of fats, proteins, lactose and somatic cells in the milk during 100 days of lactation and subsequently, the level of pregnancy after the 1st and the 2nd insemination was evaluated. The observation took place from July 2014 to December 2014 in a way that every two months was selected 8 cows and 8 heifers with a similar calving date. After that they were split into two groups i.e. into the experimental group (the kexxtone medicine was used) and into the control one. These cows were bled and milked. Subsequently, those biological samples were sent to a laboratory to be diagnosed. The higher milk yield was found within the experimental group and so as the content of milk constituents, i.e. fats and proteins. A beneficial effect of this antiketogenic medicine on the amount of ketones in blood and milk of animals was also confirmed within the experimental group. There were not found any significant statistical differences in other monitored parameters.

No description available.

No description available.

Chronic wounds represent an under-acknowledged socioeconomic epidemic, affecting 1.8 million new patients per year and costing the US health care system upwards of $25 billion annually. This substantial cost is rapidly growing due to a disproportionate occurrence in the ever-aging population. Key features associated with age-related impairment of wound healing include limited energy and nutrient exchange, unremitting inflammations, increased reactive oxygen species (ROS), and diminished blood flow. Most chronic wound therapies target specific molecular mechanisms; however, there are often multiple mitigating factors that prevent normal wound closure. This is likely one reason most wound therapies are minimally effective. In the standard American diet, carbohydrates are broken down for fuel (glucose). While fasting, starvation, and calorie or carbohydrate restriction, beta-oxidation of stored fats in the liver produces ketone bodies (primarily acetoacetate (AcAc) and β-hydroxybutyrate (βHB) to serve as energy metabolites for extra-hepatic tissues. In addition to enhancing metabolic physiology, ketone bodies have recently been discovered to have signaling properties that are independent of their function as energy metabolites. Here we present the evidence for a novel method of inducing therapeutic ketosis via exogenous ketone supplementation to promote enhanced ischemic wound healing in young and aged Fischer 344 rats. Preliminary mechanistic studies demonstrated that exogenous ketone supplementation enhanced wound healing via increasing proliferation and migration, decreasing lactate production, and decreasing ROS production as well as affecting inflammatory cytokines and growth factors. We conclude that exogenous ketone supplementation will be an effective, cost efficient, low toxicity therapy to promote enhancement of wound healing in an aged population.

Elevated ketone production and utilization results in a host of health benefits. The aim of this study was to assess the rate of ketone production during a prolonged fast and to evaluate how an initial bout of exercise influences this production. Mood and hunger, along with plasma insulin and glucagon, were also assessed. In this crossover study, 20 adult subjects (11 Male, 9 Female) completed two 36-hour fasts, with one protocol requiring the subject to complete an intense treadmill exercise session at the beginning of the fast. Ketone levels were assessed via blood ketone meter and recorded every two hours. Subjective mood and hunger ratings were also recorded every two hours. Venipuncture was performed every 12 hours to assess plasma insulin and glucagon. The mean area under the ketone production curve for the nonexercise intervention was 19.19 ± 2.59 mmol/L and 27.49 ± 2.59 mmol/L for the exercise intervention, resulting in a significant 8.30 mmol/L difference between conditions (95% probability interval was 1.94 to 14.82 mmol/L). The mean time to nutritional ketosis was 21.07 ± 2.95 hours with fasting alone, and 17.5 ± 1.69 hours when combined with exercise (posterior probability = 0.89). There was a significant decrease in insulin over time (F(3,133) = 61.75, p < 0.0001). There was also a significant increase in glucagon over time (F(3,133) = 21.10, p < 0.0001). Hunger and stomach discomfort did not differ between conditions. Anger (F(10,394) = 2.74, p = 0.0028), depression (F(10,394) = 2.91, p = 0.0016), tension (F(10,394) = 2.29, p = 0.0128), vigor (F(10,394) = 11.65, p < 0.0001), and fatigue (F(10,394) = 10.60, p = 0.0001) increased over the course of the fast, but did not differ between conditions. Completing aerobic exercise at the beginning of a 36-hour fast results in significantly more ketone production. The impact of exercise on ketone production comes at little or no impact on hunger, stomach discomfort and negative moods. A difference in time to achieving nutritional ketosis between conditions may exist, but this was not observed in this study.

Purpose: The primary aim of this study was to determine the impact of various fast-interrupting shakes on markers of glycemic control including glucose, β-hydroxybutyrate (BHB), insulin, glucagon, GLP-1, and GIP. Methods: Twenty-seven adults (12 female, 15 male) completed all three conditions of this study. One condition consisted of a 38-hour water-only fast, and the other two conditions were similar but the fasts were interrupted at 24 hours by either a high carbohydrate/low fat (HC/LF) or a low carbohydrate/high fat (LC/HF) shake. Results: The water only fast resulted in 135.3% more BHB compared to the HC/LF condition (t = 7.77, p < 0.0001) and 69.6% more compared to the LC/HF condition (t = 5.12, p < 0.0001). Conversely, the LC/HF condition exhibited a 38.8% higher BHB level than the HC/LF condition (t = 2.70, p = 0.0086). Additionally, the area under the curve (AUC) for glucose was 14.2% higher in the HC/LF condition than in the water condition (t = 6.23, p < 0.0001) and 6.9% higher compared to the LC/HF condition (t = 3.14, p = 0.0024), with the LC/HF condition yielding 7.8% more glucose than the water condition (t = 3.21, p = 0.0020). At the 25-hour mark, insulin and glucose-dependent insulinotropic polypeptide (GIP) were significantly elevated in the HC/LF condition compared to the LC/HF condition (F = 3.84, p = 0.0002 and F = 2.27, p = 0.0244, respectively) and compared to the water condition (F = 7.00, p < 0.0001 and F = 9.96, p < 0.0001, respectively). Furthermore, insulin, glucagon-like peptide-1 (GLP-1), and GIP were increased in the LC/HF condition compared to the water condition at 25 hours (F = 3.19, p = 0.0016, F = 2.43, p = 0.0158, and F = 12.13, p < 0.0001, respectively). Notably, glucagon concentrations at the 25-hour mark decreased in the HC/LF group compared to the LC/HF condition (F = 3.37, p = 0.0009). However, by the 38-hour time point, no statistically significant differences were observed among the conditions for any of the analyzed hormones. Conclusions: While a LC/HF shake does not mimic a fast completely, it does preserve some of the metabolic changes including elevated BHB and glucagon, and decreased glucose and insulin compared to a HC/LF shake.

Le Ketosis-Prone Diabetes (KPD) est un phénotype de diabète intermédiaire entre le diabète de type 1 et le diabète de type 2, fréquemment rencontré chez le sujet d’origine noire africaine. Cette forme de diabète suscite un intérêt certain de par son évolution clinique marquée notamment par la restauration de l’insulinosécrétion initialement altérée. Sobngwi et coll. en 2008 ont établi une association entre le virus HHV8 et le KPD chez des sujets Africains vivant en France. Nulle part ailleurs l’étude n’a été reproduite. L’objectif de cette thèse était de rechercher la potentielle association entre l’infection à HHV8 et le KPD ; puis d’évaluer l’impact de l’infection à HHV8 sur le profil inflammatoire des phénotypes du diabète de type 2. L’étude s’appuie sur une population de patients Africains vivant en Afrique admis consécutivement pour une décompensation hyperglycémique (glycémie à jeun≥2,5g/l) au Centre National d’Obésité de l’Hôpital Central de Yaoundé. Plus spécifiquement, il était question de :• étudier la fréquence du diabète non auto-immun à tendance cétosique (KPD); • étudier l’association entre le virus HHV8 et le KPD;• rechercher si l’infection à HHV8 est associée à un profil inflammatoire pouvant participer aux phénotypes de diabète. Etait inclus dans l’étude tout patient diabétique âgé de plus de 18 ans présentant un diabète aigu avec syndrome cardinal et cétonurie (KPD1), ceux ayant présenté un diabète inaugural aigu avec syndrome cardinal et cétonurie et en rémission depuis plus de trois mois et sans cétonurie à l’inclusion (KPD2), et ceux présentant un diabète de type 2 connu sans cétonurie (DT2). Etait exclu de l’étude tout patient présentant des stigmates d’auto-immunité du diabète de type 1 A, un diabète « MODY », une endocrinopathie, une maladie du pancréas, ou un diabète de type auto-immun. Chez l’ensemble des participants admis, nous avons collecté les données cliniques (le poids, la taille, l’IMC, le rapport tour de taille sur tour de hanche, la pression artérielle, et le pourcentage de graisse) et des prélèvements à jeun ont été effectués (sérum et cellules mononuclées du sang périphérique) pour les analyses biologiques : la glycémie par glucose oxydase, l’HbA1c par HPLC, les paramètres du profil lipidique par des methodes enzymatiques, les concentrations d’insuline et de peptide-C par électrochimiluminescence, les anticorps anti-HHV8 par immunofluorescence, l’ADN viral HHV8 par PCR en temps réel, et les marqueurs de l’inflammation par le Luminex. Les indices HOMA-β et HOMA-IR ont été utilisés pour évaluer l’insulinosécrétion et la sensibilité à l’insuline respectivement. Les marqueurs sérologiques de l’inflammation recherchés étaient : TNF-α, MCP-1, IL-8, MIP-1β, VEGF et MIP-1α... / Ketosis-Prone Diabetes (KPD) is a diabetes phenotype intermediate between type 1 and type 2 diabetes, frequently encountered in populations of African origin. This form of diabetes arouses some interest because of its clinical course marked in particular by restoring the initial impaired insulin secretion. Sobngwi et al. in 2008 established an association between HHV-8 virus and KPD in African population living in France. Nowhere else has the study been replicated. The objective of this thesis was to investigate the potential association between HHV-8 infection and KPD; then evaluate the impact of HHV-8 infection on the inflammatory profile of type 2 diabetes phenotypes. The study is based on African patients living in Africa consecutively admitted for hyperglycemic decompensation (Fasting blood glucose≥2,5g/l) at the National Obesity Centre of the Yaounde Central Hospital. More specifically, the issue was:• study the frequency of non-immune ketosis-prone diabetes (KPD);• investigate the association between HHV8 and KPD;• investigate whether HHV-8 infection is associated with an inflammatory profile that may participate in diabetes phenotypes.Was included in this study all diabetic patients old more than 18 years with acute diabetes with syndrome cardinal and ketonuria (KPD1), those who presented with an acute inaugural cardinal syndrome and diabetes ketonuria and in remission for more than three months and without ketonuria at baseline (KPD2), and those with type 2 diabetes experienced without ketonuria (T2D). Was excluded from the study all patient with stigmata of autoimmunity of type 1 A diabetes, diabetes "MODY", endocrinopathy, pancreatic disease or an autoimmune diabetes.Among all participants admitted, we collected clinical data (weight, height, BMI, waist to hip ratio, blood pressure, and the percentage of fat) and levies fasting were made (serum and peripheral blood mononuclear cells) for biological testing: glyceamia by glucose oxidase, HbA1c by HPLC, lipid profile by enzymatic methods, the insulin and C-peptide concentrations by electrochemiluminescence, anti-HHV8 antibodies by immunofluorescence, HHV8 viral DNA by real-time PCR, and markers of inflammation by Luminex. HOMA-β and HOMA-IR indices were used to assess insulinsecretion and insulinsensitivity respectively. Serological markers of inflammation investigated were : TNF-α, MCP-1, IL-8, MIP-1β, MIP-1α and VEGF...