L’expansion des maladies métaboliques dans les sociétés modernes exige plus d’activités de recherche afin d’augmenter notre compréhension des mécanismes et l’identification de nouvelles cibles d’interventions cliniques. L’obésité, la résistance à l’insuline (RI) et la dyslipidémie, en particulier sont tous des facteurs de risque associés à la pathogenèse du diabète de type 2 (DT2) et des maladies cardiovasculaires. Ainsi, la dyslipidémie postprandiale, notamment la surproduction des lipoprotéines hépatiques et intestinales, contribue d’une façon significative à l’hypertriglycéridémie. Quoique plusieurs études cliniques et fondamentales chez l’homme et les modèles animaux aient mis en évidence les rôles importants joués par le foie et l’intestin dans la dyslipidémie, les mécanismes moléculaires en cause ne sont pas bien élucidés. L’une des voies principales régulant le métabolisme lipidique est la voie de la protéine kinase AMPK. L’épuisement de l’ATP intracellulaire entraîne une activation de l’AMPK qui va œuvrer pour rétablir l’équilibre énergétique en stimulant des voies génératrices d’ATP et en inhibant des voies anaboliques consommatrices d’ATP. Les effets positifs de l’activation de l’AMPK comprennent l’augmentation de la sensibilité à l’insuline dans les tissus périphériques, la réduction de l’hyperglycémie et la réduction de la lipogenèse, d’où son importance dans les interventions cliniques pour la correction des dérangements métaboliques. Il est à souligner que le rôle de l’AMPK dans le foie et l’intestin semble plus complexe et mal compris. Ainsi, la voie de signalisation de l’AMPK n’est pas bien élucidée dans les situations pathologiques telles que le DT2, la RI et l’obésité. Dans le présent projet, notre objectif consiste à caractériser le rôle de cette voie de signalisation dans la lipogenèse hépatique et dans le métabolisme des lipides dans l’intestin chez le Psammomys obesus, un modèle animal d’obésité, de RI et de DT2. À cette fin, 3 groupes d’animaux sont étudiés (i.e. contrôle, RI et DT2). En caractérisant la voie de signalisation de l’AMPK/ACC dans le foie, nous avons constaté une augmentation de l’expression génique des enzymes clés de la lipogenèse (ACC, FAS, SCD-1 et mGPAT) et des facteurs de transcription (ChREBP, SREBP-1) qui modulent leur niveau d’expression. Nos analyses détaillées ont révélé, par la suite, une nette augmentation de l’expression de l’isoforme cytosolique de l’ACC, ACC1 (impliqué dans la lipogenèse de novo) concomitante avec une invariabilité de l’expression de l’isoforme mitochondrial ACC2 (impliqué dans la régulation négative de la β-oxydation). En dépit d’un état adaptatif caractérisé par une expression protéique et une phosphorylation (activation) élevées de l’AMPKα, l’activité de la kinase qui phosphoryle et inhibe l’ACC reste très élevée chez les animaux RI et DT2. Au niveau de l’intestin grêle des animaux RI et DT2, nous avons démontré que l’augmentation de la lipogenèse intestinale est principalement associée avec une diminution de la voie de signalisation de l’AMPK (i.e. expression protéique et phosphorylation/activation réduites des deux isoformes AMPKα1 et AMPKα2). La principale conséquence de la diminution de l’activité AMPK est la réduction de la phosphorylation de l’ACC. Étant donné que le niveau d’expression totale d’ACC reste inchangé, nos résultats suggèrent donc une augmentation de l’activité des deux isoformes ACC1 et ACC2. En parallèle, nous avons observé une réduction de l’expression protéique et génique de la CPT1 [enzyme clé de la β-oxydation des acides gras (AG)]. L’ensemble de ces résultats suggère une inhibition de l’oxydation des AG concomitante avec une stimulation de la lipogenèse de novo. Enfin, nous avons démontré que l’intestin grêle est un organe sensible à l’action de l’insuline et que le développement de la résistance à l’insuline pourrait altérer les deux voies de signalisation (i.e. Akt/GSK3 et p38MAPK) essentielles dans plusieurs processus métaboliques. En conclusion, nos résultats indiquent que l’augmentation de la lipogenèse qui contribue pour une grande partie à la dyslipidémie dans la résistance à l’insuline et le diabète serait due, en partie, à des défauts de signalisation par l’AMPK. Nos observations illustrent donc le rôle crucial du système AMPK au niveau hépatique et intestinal, ce qui valide l’approche thérapeutique consistant à activer l’AMPK pour traiter les maladies métaboliques. / Understanding the cellular mechanisms involved in the development of insulin resistance, and later on the occurrence of type 2 diabetes and its metabolic complications, is a perquisite step toward the identification of new therapeutic targets to fight against the development of these metabolic diseases. In the present studies, we used the gerbil Psammomys obesus, a well-established animal model of obesity, insulin resistance (IR) and type 2 diabetes (T2D), to characterize the hepatic and intestinal signaling abnormalities associated with lipid metabolism disorders during the pathogenesis of IR and T2D. Thus, we are able to demonstrate that the development of these metabolic diseases in Psammomys obesus animals, is accompanied by increased hepatic and intestinal lipogenesis with very high efficiency to form triglycerides rich-lipoproteins. In the liver, we observed an increase in mRNA levels of key lipogenic enzymes (ACC, FAS, SCD-1 and mGPAT) and transcription factors (SREBP-1, ChREBP), which modulate the expression level of lipogenic enzymes. Thereafter, our detailed analysis of the AMPK/ACC signaling pathway revealed a rise in the gene expression of the cytosolic ACC1 isoform of ACC(involved in de novo lipogenesis) concomitant with a constant expression of the mitochondrial ACC2 (negative regulator of β-oxidation). In spite of an adaptive state characterized by higher protein expression and phosphorylation (activation) of AMPKα, the kinase that phosphorylates and inhibits ACC, the activity of the later remains very high in IR and T2D animals. In the small intestine of IR and T2D animals, we demonstrated that the increase in intestinal lipogenesis is mainly associated with a decrease of AMPK signaling pathway (i.e. reduced expression and protein phosphorylation/activation of the two AMPKα1 and AMPKα2 isoforms). The main consequence of the decline in AMPK activity is the reduction of ACC phosphorylation. Given that, the expression levels of ACC remain unchanged; our results thus suggest an increased activity of both ACC isoforms, ACC1 and ACC2. Next, we observed a reduction in protein and gene expression of CPT1 [key enzyme in fatty acid (FA) β-oxidation]. Taken together, these results suggest an inhibition of FA β-oxidation concomitant with a stimulation of de novo lipogenesis. Finally, we demonstrated that the small intestine is an insulin sensitive organ and that the development of IR affects two signaling pathways (i.e. Akt/GSK3 and p38MAPK) essentials for several metabolic processes. In conclusion, our results indicate that increased lipogenesis, in IR and T2D, which exacerbate the dyslipidemia associated with these diseases, might be, at least partially, a result of AMPK signaling defects. In addition, our observations illustrate the crucial role of AMPK/ACC in the liver and intestine and validate AMPK as a potential target to treat the metabolic diseases.

Tyrimo tikslas – nustatyti sergančiųjų 2 tipo diabetu su sveikata susijusios gyvenimo kokybės sąsajas su emocine įtampa ir psichotropinių medžiagų vartojimu. Tyrime iš viso dalyvavo 149 asmenys, sergantys 2 tipo diabetu (57 vyrai ir 92 moterys). 56 tiriamieji buvo iš diabeto klubų (37 – Marijampolės „Diabetikas ABC“ ir 28 – Jonavos „Ramunė“). Taip gavus prof. A. Goštauto leidimą, buvo naudoti 84 tiriamųjų duomenys, paimti iš archyvinių duomenų, surinktų iniciatyvinių tyrimų, atliktų 2009 m. KMU Endorinologijos klinikoje Diabetologijos skyriuje besigydančiais ligoniais sergančiais 2 tipo diabetu, metu. Tiriamieji užpildė Pasaulio sveikatos organizacijos su sveikata susijusios gyvenimo kokybės klausimyną (PSOGK-100). Tyrimo rezultatai parodė, sergantys 2 tipo diabetu vyrai ir moterys, patiriantys daugiau emocinės įtampos, savo su sveikata susijusią gyvenimo kokybę vertina prasčiau, nei patiriantys mažiau emocinės įtampos. Prastesni savo su sveikata susijusios gyvenimo kokybės vertinimai pastebėti ir rūkančių vyrų bei alkoholį vartojančių moterų grupėse. Tuo tarpu rūkančių moterų ir alkoholį vartojančių vyrų grupėse su sveikata susijusios gyvenimo kokybės įvertinimai yra geresni. Taip pat sergantys 2 tipo diabetu vyrai ir moterys, kurie rūko, patiria daugiau emocinės įtampos, nei tie, kurie nerūko ir atvirkščiai. Sergančių 2 tipo diabetu vyrų ir moterų, vartojančių ir nevartojančių alkoholio, tarp patiriamos emocinės įtampos statistiškai patikimų skirtumų nerasta. Sergančių 2... [toliau žr. visą tekstą] / The aim of the study was to assess the relations between health-related quality of life, emotional tension and psychotropic substances consumption in people with type 2 diabetes. The subjects of the study were 149 people with type 2 diabetes (57 men and 92 women), 56 subjects were from diabetes clubs (37 from Marijampolė club „Diabetikas ABC“ and 28 from Jonava club „Ramunė“). Also after receiving permission from prof. A. Goštautas, 84 archival cases, which taken from KMU Endokrinology clinic Department of Diabetology‘s patiens with type 2 diabetes, was used in this study. The subjects completed World Health Organization Quality of Life Questionnaire (WHOQoL-100). The results of the study showed that men and women with type 2 diabetes who reported more emotional tension rated their health-related quality of life poorer than those who reported less emotional tension. Though smoking men and alcohol consuming women rated their health-related quality of life poorer, smoking women and alcohol consuming men rated their health-related quality of life higher. Also smoking men and women with type 2 diabetes reported more emotional tension than non-smokers and vice versa. There were found no relations between emotional tension and alcohol consumption in both men and woman. Men with type 2 diabetes rated their health-related quality of life higher compared with women. Also more men than women were smokers and alcohol consumers. There were found no differences between men and women... [to full text]

The objective of this thesis was to determine the association of leg length (LL), a marker of early childhood conditions, with metabolic abnormalities underlying type 2 diabetes. Utilizing data from a population at-risk for diabetes, the associations of LL with i) insulin resistance (IR) and beta-cell dysfunction and ii) a continuous metabolic syndrome risk score (MetScore) were analyzed. Results showed that shorter LL was associated with IR and beta-cell dysfunction, and that the combination of short legs and large waist (a marker of adult obesogenic conditions) was associated with the greatest IR. Height, a marker of overall childhood conditions, was found to be inversely associated with the MetScore. Therefore, both adverse childhood conditions and early-late life mismatched conditions may increase the risk for diabetes through differing pathways. Improving childhood conditions (i.e. nutritionally or economically) may be an important strategy to prevent diabetes.

The objective of this thesis was to determine the association of leg length (LL), a marker of early childhood conditions, with metabolic abnormalities underlying type 2 diabetes. Utilizing data from a population at-risk for diabetes, the associations of LL with i) insulin resistance (IR) and beta-cell dysfunction and ii) a continuous metabolic syndrome risk score (MetScore) were analyzed. Results showed that shorter LL was associated with IR and beta-cell dysfunction, and that the combination of short legs and large waist (a marker of adult obesogenic conditions) was associated with the greatest IR. Height, a marker of overall childhood conditions, was found to be inversely associated with the MetScore. Therefore, both adverse childhood conditions and early-late life mismatched conditions may increase the risk for diabetes through differing pathways. Improving childhood conditions (i.e. nutritionally or economically) may be an important strategy to prevent diabetes.

Type 2 diabetes is a significant health problem because of its high prevalence and strong association with cardiovascular morbidity and mortality. An increase of type 2 diabetes is predicted due to increasing obesity and sedentary lifestyle habits. The development from latent to diagnostic disease spans many years and during this time it is possible to prevent or postpone type 2 diabetes using lifestyle and pharmacological interventions. The objective of this thesis is to investigate and describe early patterns and risk indicators of type 2 diabetes. The focus is on type 2 diabetes as one component in metabolic syndrome, i.e. the clustering of several cardiovascular risk markers. Two studies based on the Västerbotten Intervention Programme (VIP) provided the data; one case-referent study nested within VIP which includes 237 diabetes cases that were clinically diagnosed 5.4 years after the health survey, each with two referents; and one panel study with 5 consecutive annual cohorts including subjects that participated in VIP between1990 and 1994 and returned to a follow-up after 10 years, a total of 16 492 individuals. Associations between risk markers and type 2 diabetes or metabolic syndrome are evaluated by several statistical techniques. A model of metabolic syndrome is hypothesized. A prediction model for developing type 2 diabetes among middle-aged individuals is proposed, where high risk is defined as having at least two out of three risk criteria (fasting plasma glucose ≥6.1 mmol/L, HbA1c ≥4.7% (Swedish Mono-S standard) and BMI ≥27 in men and BMI ≥30 in women). With positive predictive values of 32% in men and 46% in women, this model performs at least as well as other published prediction models. Information on family history of diabetes does not improve the result and the cumbersome oral glucose tolerance test is not needed. Therefore this model should be feasible for use in routine care. A model of metabolic syndrome with five composite factors, based on 14 variables including markers produced by adipose tissue and b-cells, suggest that obesity with insulin resistance and b-cell decompensation are the core perturbations in the early stages of type 2 diabetes, while inflammation and dyslipidemia could not be shown to be independent early risk indicators. The composite factors do not improve the prediction as compared to the single markers of fasting glucose, BMI and proinsulin and, possibly blood pressure values. Stress (measured as passive or tense working conditions) and weak social support (measured as emotional support), are suggested to be strong risk indicators along with high BMI for type 2 diabetes in women. In men BMI is predictive, but the stress variables are not shown to be associated with future type 2 diabetes. A social gap is indicated by double risk of metabolic syndrome among subjects with low (≤ 9 years at school) compared to high education (≥ 13 years). High consumption of Swedish smokeless tobacco, snuff (>4 cans/week), is independently associated with metabolic syndrome, obesity and hypertriglyceridemia, but not with dysregulation of glucose. To conclude, single markers, that are commonly used in daily practice, are useful and sufficient for identification of subjects that are in the early stages of type 2 diabetes. Obesity with insulin resistance and b-cell decompensation are the core perturbations in early development to T2DM. Lifestyle, socioeconomic and psychosocial markers, in addition to biomarkers, are important determinants of future type 2 diabetes and metabolic syndrome, albeit not similarly among men and women.

The increased prevalence of obesity amongst adolescents is considered a worldwide epidemic. Within the black population of South Africa, obesity is significantly more prevalent amongst black girls than black boys. The high prevalence of obesity amongst children can be attributed to a combination of various lifestyle factors, namely a decrease in physical activity, an increase in television viewing, Westernization and increased food supply. The decrease in physical activity amongst adolescents over the last few decades has led to an increase in the number adolescents diagnosed with type 2 diabetes mellitus. Research has indicated that insulin sensitivity improves with regular physical endurance activity, irrespective of change in bodyweight. Regular physical exercise also lowers the risk of type 2 diabetes mellitus, and prevents the development of coronary heart diseases, hypertension and obesity. The primary goals of this study were two-fold: Firstly, to determine the relationship between BMI, percentage body fat and insulin sensitivity amongst black adolescents, and, secondly, to determine whether there exists a positive correlation between current cardiovascular fitness (V02-maximum),together with everyday physical activity status, and insulin sensitivity amongst black adolescents. One hundred and twenty-four (124) black boys and 148 black girls between the ages of 14 and 17 participated in the study. The BOD-POD was used to calculate percentage body fat, and blood analysis for fasting glucose and insulin were completed. Insulin sensitivity (QUIKI-index) and resistance (HOMA) were also calculated, and habitual physical activity was measured using the "Previous Day Physical Activity Recall" (pDPAR) questionnaire. Physical development was determined with the Tanner questionnaire, cardiovascular fitness (VO2-maximum) was determined using the "Bleep" test and anthropometry (mass, length, skin folds, waist and hip circumference) was measured to determine body composition. The results of this study found a statistically significant negative correlation between skin fold thickness, percentage body fat, BMI and insulin sensitivity in girls. A significant negative correlation between percentage body fat and V02-maximum was found in boys, while their self-reported activity (PDPAR) did not correlate with percentage body fat. Current cardiovascular fitness and habitual physical activity status (PDPAR) showed no significant relationship with insulin sensitivity. Amongst the girls there was however a tendency towards a positive correlation between insulin sensitivity and V02-maximum. / Thesis (M.Sc. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.

Local control of regional blood flow is exerted mainly through the arterioles. An adequate minute-to-minute regulation of blood perfusion of the kidney and the pancreas is obtained by the modulation of arteriolar reactivity, which will influence the organ function. The importance of purinergic signaling in this concept has been addressed, with special emphasis on the role of the adenosine A1 receptor. The effects of adenosine on two specialized vascular beds, namely the renal glomerulus and the pancreatic islets, have been examined. Characteristic for these regional circulations is their very high basal blood flow, but with somewhat different responses to vasoconstrictor and vasodilator stimuli. By adapting a unique microperfusion technique it was possible to separately perfuse isolated single mouse arterioles with attached glomeruli or pancreatic islets ex vivo. Microvascular responses were investigated following different additions to the perfusion fluid to directly examine the degree of dilation or constriction of the arterioles. This has been performed on transgenic animals in this thesis, e.g. A1 receptor knockout mice. Also effects of P2Y receptors on islet arterioles were examined in both normoglycemic and type 2 diabetic rats. Furthermore, interference with adenosine transport in glomerular arterioles were examined.. Our studies demonstrate important, yet complex, effects of adenosine and nucleotide signaling on renal and islet microvascular function, which in turn may influence both cardiovascular and metabolic regulations. They highlight the need for further studies of other purinergic receptors in this context, studies that are at currently being investigated.

Abstract Type 2 diabetes mellitus is a disease that has trebled in incidence over the last 25 years, affecting both adults and increasingly children. The rapid increase of the disease mirrors the gradients of social position and income distribution, and parallels the accelerated environmental changes witnessed with the rise of neoliberal capitalism. This research situates neoliberal capitalism as a collection of political and economic policies that form an ideology suited to protect discrete elite interests. The current ideology has permeated all social aspects of society, including education and healthcare. Therefore, it is argued that the practice of healthcare and the education of healthcare students are shaped by the sociopolitical environment in which they exist. Ten best-selling postsecondary textbooks in pathology, pathophysiology, and disease processes were selected for content analysis to determine if the interpretation of type 2 diabetes in pathophysiology textbooks reflects neoliberal thinking. The data were interpreted within the tradition of critical discourse analysis and theoretically enriched using Foucault’s descriptions of governmentality, biopolitics, and discursive formations. The results indicate that notions consistent with neoliberal capitalism permeate pathology textbooks in the understandings of type 2 diabetes. Consistent with how neoliberal thought embodies and explicates social conditions, type 2 diabetes is described in a way that stresses iii self-responsibility and culpability for falling ill. The texts also impart the importance of biomedical industry interventions for the treatment of the sick and the surveillance of the healthy. Finally, in a way that substantiates the degradation of the environment and retrenchment of social welfare policies, the textbooks fail to make any reference to the ecological factors that contribute to type 2 diabetes, including urbanisation and the propagation of food deserts, environmental toxins, income inequality, the steepening of the social gradient, and the deleterious effects of globalisation on human nutrition.

Abstract Type 2 diabetes mellitus is a disease that has trebled in incidence over the last 25 years, affecting both adults and increasingly children. The rapid increase of the disease mirrors the gradients of social position and income distribution, and parallels the accelerated environmental changes witnessed with the rise of neoliberal capitalism. This research situates neoliberal capitalism as a collection of political and economic policies that form an ideology suited to protect discrete elite interests. The current ideology has permeated all social aspects of society, including education and healthcare. Therefore, it is argued that the practice of healthcare and the education of healthcare students are shaped by the sociopolitical environment in which they exist. Ten best-selling postsecondary textbooks in pathology, pathophysiology, and disease processes were selected for content analysis to determine if the interpretation of type 2 diabetes in pathophysiology textbooks reflects neoliberal thinking. The data were interpreted within the tradition of critical discourse analysis and theoretically enriched using Foucault’s descriptions of governmentality, biopolitics, and discursive formations. The results indicate that notions consistent with neoliberal capitalism permeate pathology textbooks in the understandings of type 2 diabetes. Consistent with how neoliberal thought embodies and explicates social conditions, type 2 diabetes is described in a way that stresses iii self-responsibility and culpability for falling ill. The texts also impart the importance of biomedical industry interventions for the treatment of the sick and the surveillance of the healthy. Finally, in a way that substantiates the degradation of the environment and retrenchment of social welfare policies, the textbooks fail to make any reference to the ecological factors that contribute to type 2 diabetes, including urbanisation and the propagation of food deserts, environmental toxins, income inequality, the steepening of the social gradient, and the deleterious effects of globalisation on human nutrition.