Prediction of postprandial blood glucose under intra-patient variability and uncertainty and its use in the design of insulin dosing strategies for type 1 diabetic patients

In this thesis I propose a novel method to estimate the dose and injection-to-meal time for low-risk intensive insulin therapy. This dosage-aid system uses an optimization algorithm to determine the insulin dose and injection-to-meal time that minimizes the risk of postprandial hyper- and hypoglycaemia in type 1 diabetic patients. To this end, the algorithm applies a methodology that quantifies the risk of experiencing different grades of hypo- or hyperglycaemia in the postprandial state induced by insulin therapy according to an individual patient’s parameters. This methodology is based on modal interval analysis (MIA). Applying MIA, the postprandial glucose level is predicted with consideration of intra-patient variability and other sources of uncertainty. A worst-case approach is then used to calculate the risk index. In this way, a safer prediction of possible hyper- and hypoglycaemic episodes induced by the insulin therapy tested can be calculated in terms of these uncertainties.

Caracterització de metabòlits produïts per soques de "Pseudomonas fluorescens" efectives en el control biològic de fongs fitopatògens

El principal objectiu d'aquest treball ha estat estudiar la producció de metabòlits amb activitat antibiòtica per soques de l'espècie Pseudomonas fluorescens de la col·lecció EPS, i també avaluar la seva potencialitat com a agents de biocontrol. Es va disposar també de diverses soques de P. fluorescens, cedides per altres investigadors, que van utilitzar-se com a referència perquè algunes són actives en control biològic i produeixen metabòlits secundaris d'interès en el biocontrol de malalties de plantes. La present memòria s'estructura en cinc capítols, que són, introducció al control biològic, descripció de l'etapa de selecció de soques i cerca dels metabòlits produïts, estudi de la producció d'HCN per la soca EPS288, estudi de la producció de l'antibiòtic 2,4-diacetilfloroglucinol (DAPG), i finalment, el darrer capítol, on s'ha estudiat la producció de DAPG sobre material vegetal i la capacitat de colonitzar arrels per diverses soques d'interès. En l'etapa de prospecció, va demostrar-se que un 37% del total de les soques de la col·lecció EPS produïen HCN, totes de l'espècie P. fluorescens, i un 90% d'aquestes provenien de les arrels de plantes. Es va confirmar la producció dels metabòlits secundaris 2,4-diacetilfloroglucinol, àcid fenazina-1-carboxílic, i pirrolnitrina, per diverses soques de la col·lecció EPS seleccionades mitjançant tècniques moleculars. Així, de la col·lecció EPS, les soques EPS317 i EPS808 produeixen DAPG, la EPS263 àcid fenazina-1-carboxílic i pirrolnitrina i, EPS894, EPS895, EPS945 produeixen àcid fenazina-1-carboxílic. La producció d'HCN es va estudiar més exhaustivament en la soca EPS288, seleccionada per la seva activitat antifúngica i candidata a agent de biocontrol contra Stemphylium vesicarium, causant de la estemfiliosi de la perera, i contra Penicillium expansum, causant de la podridura blava en conservació de fruita a postcollita. Per aquest estudi, es va dissenyar i validar un sistema per recollir l'HCN a partir de cultius en medi líquid. S'ha demostrat que la temperatura d'incubació, la concentració cel·lular de sembra i la composició del medi de cultiu afectaven a la producció d'HCN. Els medis complexos i la glicina n'afavorien la síntesi i la font de carboni no afectava. La soca EPS288 va produir més HCN que P. fluorescens CHA0, soca de referència productora d'HCN i descrita com a activa en processos de biocontrol de fongs fitopatògens. En l'estudi de la producció de DAPG, les soques de la col·lecció EPS i de referència, es van comparar en diversos medis de cultiu estudiant l'efecte de la complexitat i consistència del medi, i l'addició de ferro o de glucosa. Va demostrar-se que la producció de DAPG depèn principalment de la soca i de les característiques del medi de cultiu. La glucosa estimula la producció, mentre que el ferro pràcticament no afecta, i en general, el medi sòlid i complex estimula la producció de DAPG. Tanmateix, aquests efectes varien en alguna de les soques assajades donant lloc a comportaments singulars. En el seguiment del creixement amb un sistema automàtic es va comprovar que la velocitat específica de creixement i la concentració cel·lular assolida al final del cultiu, estaven condicionades per la composició del medi de cultiu. En les proves d'antagonisme vers fitopatògens que foren seleccionats com a indicadors, va observar-se que tant l'antagonisme in vitro com la inhibició d'infeccions sobre material vegetal estaven parcialment relacionades amb la producció dels metabòlits secundaris estudiats. La promoció del creixement de portaempelts per aquestes soques depenia de la soca i de l'hoste, però no es pogué establir una relació causa-efecte amb el metabòlits produïts. També es va comprovar que algunes de les soques podien sobreviure en ferides de pomes i de peres, on produïren DAPG. Mutants resistents a rifampicina de diverses soques de la col·lecció EPS i de referència es van inocular en llavors de pomera i de tomatera que es van sembrar i incubar en condicions controlades. Es va fer el seguiment de la població bacteriana total i resistent a rifampicina present a les arrels durant 72 dies. Totes les soques van colonitzar les arrels de les plantes, mantenint una elevada població durant 37 dies, cap d'elles va estimular el creixement ni mostrar efectes fitotòxics, no afectant tampoc signicativament a la població bacteriana espontània de les arrels. La soca EPS808, una de les seleccionades pel treball, va aconseguir uns nivells de producció de DAPG, una velocitat de creixement i una supervivència relativa a les arrels similar a altres soques de referència descrites com a bons agents de biocontrol. En conseqüència, se la considera una candidata a agent de biocontrol que hauria de ser objecte de futurs estudis d'eficàcia.

Metabolismo del desecho en la determinación social de la salud: economía política y geografía crítica de la basura en el Ecuador 2009-2013

La investigación analiza el metabolismo social capitalista a través del estudio de su quinto proceso, la excreción. En una suerte de relación subsunción-autonomía, partimos de la construcción de una teoría crítica del metabolismo del desecho en la determinación social de la salud que aterriza en un estudio nacional de economía política y geografía crítica de la basura en el Ecuador, y termina con un estudio de caso que devela de qué manera esos procesos macro determinan las condiciones de vida, de salud o su pérdida en comunidades afectadas por sistemas de disposición final de residuos, especialmente recicladores/as informales y sus familias. El primer capítulo propone un abordaje conceptual de ruptura, que toma como marcos disciplinarios la crítica de la economía política, la ecología política, la epidemiología crítica y las teorías del Estado. El segundo capítulo realiza un análisis sociohistórico a nivel nacional, desde los años del neoliberalismo durante los que se gesta la crisis de la basura, hasta los años del gobierno actual en los que la crisis de la basura tiene un boom, con el colapso de muchos de los sistemas de disposición final, especialmente en cabeceras cantonales. El tercer capítulo analiza la determinación social, exposición, vulnerabilidad y perfil epidemiológico de trabajadores informales y sus familias, en el botadero a cielo abierto del cantón Portoviejo en Ecuador. La investigación finaliza evidenciando el peso que representa, en términos económicos para el Estado, mantener el subsidio de la gestión y administración de los residuos sólidos y propone el modelo de “Basura cero”, reparador del metabolismo social.

Effect of dietary supplementation of different oils during the first or second half of pregnancy on the glucose tolerance of the sow

Poor glucose tolerance may be an under-researched contributory factor in the high (10% to 20%) pre-weaning mortality rate observed in pigs. Insulin resistance commences at around week 12 of gestation in the sow, although there are conflicting reports in the literature about the extent to which insulin resistance is modulated by maternal diet. The aim of the study was to determine the effects of supplementing the maternal diet with different dietary oils during either the first half or the second half of gestation on the glucose tolerance of the sow. Sows were offered the control (C: n = 5) diet as pellets or the C diet plus 10% extra energy (h = 16 per group) derived from either. (i) extra pellets; (ii) palm oil; (iii) olive oil; (iv) sunflower oil; or (v) fish oil. Experimental diets were fed during either the first (G1) or second (G2) half of gestation. A glucose tolerance test (GTT) was conducted on day 108 of gestation by administering 0.5g/kg glucose i.v. Blood samples were taken every 5 to 10 min for 90 min post administration. The change in body weight and backfat thickness during gestation was similar but both type and timing of dietary supplementation influenced litter size and weight. With the exception of the sunflower oil group, supplementing the maternal diet in G1 resulted in larger and heavier litters, particularly in mothers offered palm oil. Basal blood glucose concentrations tended to be more elevated in G1 than G2 groups, whilst plasma insulin concentrations were similar Following a GTT, the adjusted area under the curve was greater in G1 compared to G2 sows, despite no differences in glucose clearance. Maternal diet appeared to influence the relationship between glucose curve characteristics following a GTT and litter outcome. In conclusion, the degree of insulin sensitivity can be altered by both the period during which maternal nutritional supplementation is offered and the fatty acid profile of the diet.

Intergenerational effects of birth weight on glucose tolerance and reproductive performance

Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (0)). After they had given birth, the growth and development of the lightest (I) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at similar to 6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at similar to 4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between I and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species.

Microwave activation of the electro-oxidation of glucose in alkaline media

The oxidation of glucose is a complex process usually requiring catalytically active electrode surfaces or enzyme modified electrodes. In this study the effect of high intensity microwave radiation on the oxidation of glucose in alkaline solution at Au, Cu, and Ni electrodes is reported. Calibration experiments with the Fe(CN)(6)(3-/4-) redox system in aqueous 0.1 M NaOH indicate that strong thermal effects occur at both 50 and 500 mu m diameter electrodes with temperatures reaching 380 K. Extreme mass transport effects with mass transport coefficients of k(mt) > 0.01 m s(-1) (or k(mt) > 1.0 cm s(-1)) are observed at 50 mu m diameter electrodes in the presence of microwaves. The electrocatalytic oxidation of glucose at 500 mu m diameter Au, Cu, or Ni electrodes immersed in 0.1 M NaOH and in the presence of microwave radiation is shown to be dominated by kinetic control. The magnitude of glucose oxidation currents at Cu electrodes is shown to depend on the thickness of a pre-formed oxide layer. At 50 mu m diameter Au, Cu, or Ni electrodes microwave enhanced current densities are generally higher, but only at Au electrodes is a significantly increased rate for the electrocatalytic oxidation of glucose to gluconolactone observed. This rate enhancement appears to be independent of temperature but microwave intensity dependent, and therefore non-thermal in nature. Voltammetric currents observed at Ni electrodes in the presence of microwaves show the best correlation with glucose concentration and are therefore analytically most useful.

Effect of prolonged intravenous glucose and essential amino acid infusion on nitrogen balance, muscle protein degradation and ubiquitin-conjugating enzyme gene expression in calves

Background: Intravenous infusions of glucose and amino acids increase both nitrogen balance and muscle accretion. We hypothesised that co-infusion of glucose ( to stimulate insulin) and essential amino acids (EAA) would act additively to improve nitrogen balance by decreasing muscle protein degradation in association with alterations in muscle expression of components of the ubiquitin-proteasome proteolytic pathway. Methods: We examined the effect of a 5 day intravenous infusions of saline, glucose, EAA and glucose + EAA, on urinary nitrogen excretion and muscle protein degradation. We carried out the study in 6 restrained calves since ruminants offer the advantage that muscle protein degradation can be assessed by excretion of 3 methyl-histidine and multiple muscle biopsies can be taken from the same animal. On the final day of infusion blood samples were taken for hormone and metabolite measurement and muscle biopsies for expression of ubiquitin, the 14-kDa E2 ubiquitin conjugating enzyme, and proteasome sub-units C2 and C8. Results: On day 5 of glucose infusion, plasma glucose, insulin and IGF-1 concentrations were increased while urea nitrogen excretion and myofibrillar protein degradation was decreased. Co-infusion of glucose + EAA prevented the loss of urinary nitrogen observed with EAA infusions alone and enhanced the increase in plasma IGF-1 concentration but there was no synergistic effect of glucose + EAA on the decrease in myofibrillar protein degradation. Muscle mRNA expression of the ubiquitin conjugating enzyme, 14-kDa E2 and proteasome sub-unit C2 were significantly decreased, after glucose but not amino acid infusions, and there was no further response to the combined infusions of glucose + EAA. Conclusion: Prolonged glucose infusion decreases myofibrillar protein degradation, prevents the excretion of infused EAA, and acts additively with EAA to increase plasma IGF-1 and improve net nitrogen balance. There was no evidence of synergistic effects between glucose + EAA infusion on muscle protein degradation or expression of components of the ubiquitin-proteasome proteolytic pathway.

Anthraquinone catalysis in the glucose-driven reduction of indigo to leuco-indigo

Anthraquinone immobilised onto the surface of indigo microcrystals enhances the reductive dissolution of indigo to leuco-indigo. Indigo reduction is driven by glucose in aqueous NaOH and a vibrating gold disc electrode is employed to monitor the increasing leuco-indigo concentration with time. Anthraquinone introduces a strong catalytic effect which is explained by invoking a molecular "wedge effect'' during co-intercalation of Na+ and anthraquinone into the layered indigo crystal structure. The glucose-driven indigo reduction, which is in effective in 0.1 M NaOH at 65 degrees C, becomes facile and goes to completion in the presence of anthraquinone catalyst. Electron microscopy of indigo crystals before and after reductive dissolution confirms a delamination mechanism initiated at the edges of the plate-like indigo crystals. Catalysis occurs when the anthraquinone-indigo mixture reaches a molar ratio of 1:400 (at 65 degrees C; corresponding to 3 mu M anthraquinone) with excess of anthraquinone having virtually no effect. A strong temperature effect ( with a composite E-A approximate to 120 kJ mol(-1)) is observed for the reductive dissolution in the presence of anthraquinone. The molar ratio and temperature effects are both consistent with the heterogeneous nature of the anthraquinone catalysis in the aqueous reaction mixture.

Electrochemical determination of plant-derived leuco-indigo after chemical reduction by glucose

Electrochemical determination of redox active dye species is demonstrated in indigo samples contaminated with high levels of organic and inorganic impurities. The use of a hydrodynamic electrode system based on a vibrating probe (250 Hz, 200 mu m lateral amplitude) allows time-independent diffusion controlled signals to be enhanced and reliable concentration data to be obtained under steady state conditions at relatively fast scan rates up to 4 V s-1In this work the indigo content of a complex plant-derived indigo sample (dye content typically 30%) is determined after indigo is reduced by addition of glucose in aqueous 0.2 M NaOH. The soluble leuco-indigo is measured by its oxidation response at a vibrating electrode. The vibrating electrode, which consisted of a laterally vibrating 500 mu m diameter gold disc, is calibrated with Fe(CN)(6) 3-/4- in 0.1 M KCl and employed for indigo determination at 55, 65, and 75 C in 0.2 M NaOH. Determinations of the indigo content of 25 different samples of plant-derived indigo are compared with those obtained by conventional spectrophotometry. This comparison suggests a significant improvement by the electrochemical method, which appears to be less sensitive to impurities.

Electrochemical and sonoelectrochemical monitoring of indigo reduction by glucose

The reduction of indigo (dispersed in water) to leuco-indigo (dissolved in water) is an important industrial process and investigated here for the case of glucose as an environmentally benign reducing agent. In order to quantitatively follow the formation of leuco-indigo two approaches based on (i) rotating disk voltammetry and (ii) sonovoltammetry are developed. Leuco-indigo, once formed in alkaline solution, is readily monitored at a glassy carbon electrode in the mass transport limit employing hydrodynamic voltammetry. The presence of power ultrasound further improves the leuco-indigo determination due to additional agitation and homogenization effects. While inactive at room temperature, glucose readily reduces indigo in alkaline media at 65 degrees C. In the presence of excess glucose, a surface dissolution kinetics limited process is proposed following the rate law d eta(leuco-indigo)/dt = k x c(OH-) x S-indigo where eta(leuco-indigo) is the amount of leuco-indigo formed, k = 4.1 x 10(-9) m s(-1) (at 65 degrees C, assuming spherical particles of I gm diameter) is the heterogeneous dissolution rate constant,c(OH-) is the concentration of hydroxide, and Sindigo is the reactive surface area. The activation energy for this process in aqueous 0.2 M NaOH is E-A = 64 U mol(-1) consistent with a considerable temperature effects. The redox mediator 1,8-dihydroxyanthraquinone is shown to significantly enhance the reaction rate by catalysing the electron transfer between glucose and solid indigo particles. (c) 2006 Elsevier Ltd. All fights reserved.

Polymorphisms in the apolipoprotein L1 gene and their effects on blood lipid and glucose levels in middle age males

Apolipoprotein L1 in plasma is associated with high- density lipoprotein. Novel APOL1 polymorphisms are investigated along with the association of two common haplotypes (Lys166Glu, Ile244Met, Lys271Arg) with circulating lipid and glucose levels. Although the amino acid substitutions occur in the amphipathic alpha helices region involved in lipid binding, these substitutions were found not to independently account for variability in circulating lipid and glucose levels in 149 middle age males.

Microwave activation of the electro-oxidation of glucose in alkaline media

The oxidation of glucose is a complex process usually requiring catalytically active electrode surfaces or enzyme-modified electrodes. In this study the effect of high intensity microwave radiation on the oxidation of glucose in alkaline solution at Au, Cu, and Ni electrodes is reported. Calibration experiments with the Fe(CN)63–/4– redox system in aqueous 0.1 M NaOH indicate that strong thermal effects occur at both 50 and 500 µm diameter electrodes with temperatures reaching 380 K. Extreme mass transport effects with mass transport coefficients of kmt > 0.01 m s–1(or kmt > 1.0 cm s–1) are observed at 50 µm diameter electrodes in the presence of microwaves. The electrocatalytic oxidation of glucose at 500 µm diameter Au, Cu, or Ni electrodes immersed in 0.1 M NaOH and in the presence of microwave radiation is shown to be dominated by kinetic control. The magnitude of glucose oxidation currents at Cu electrodes is shown to depend on the thickness of a pre-formed oxide layer. At 50 µm diameter Au, Cu, or Ni electrodes microwave enhanced current densities are generally higher, but only at Au electrodes is a significantly increased rate for the electrocatalytic oxidation of glucose to gluconolactone observed. This rate enhancement appears to be independent of temperature but microwave intensity dependent, and therefore non-thermal in nature. Voltammetric currents observed at Ni electrodes in the presence of microwaves show the best correlation with glucose concentration and are therefore analytically most useful.

Introduction of vinyl and hydroxymethyl functionalities at C-4 of glucose-derived substrates: synthesis of spirocyclic, bicyclic, and tricyclic nucleosides

Installing hydroxymethyl and hydroxyethyl substitutions at C-4 through vinylation and hydroboration-oxidation reactions of the C-4 bis-hydroxymethyl derivative of D-glucose based substrate, and inserting heteroatoms thereafter permitted formation of N-, O-, or S-heterocycles leading to [4,5]or [5,5]-spirocycles and a bicyclo[3.3.0]octane product. Some of the spirocycles were converted to spironucleosides under Vorbruggen glycosidation reaction conditions. Similarly, the bicyclic product was elaborated to the corresponding bicyclic nucleoside as well as an unexpected tricyclic nucleoside.