Le tryptophane, un acide aminé essentiel, est soit utilisé pour la synthèse protéique et la synthèse de sérotonine, soit dégradé en plusieurs métabolites appelés collectivement les kynurénines. L’expression et l’activité des enzymes de la voie des kynurénines sont stimulées par l’inflammation. La synthèse des kynurénines est donc susceptible d’être augmentée chez les individus obèses. En effet, l’obésité est caractérisée par une inflammation chronique à bas bruit du tissu adipeux, reflétée par l’augmentation de facteurs inflammatoires circulants qui contribuent à l’apparition de l’insulinorésistance et du diabète de type 2. Plusieurs métabolites de la voie des kynurénines pourraient être des facteurs de risque pour le développement de l’insulinorésistance. La chirurgie bariatrique est actuellement le traitement le plus efficace pour l’obésité sévère, elle permet une perte de poids significative ainsi qu’une diminution des facteurs inflammatoires circulantes et une amélioration de l’insulinorésistance et du diabète. Il a été démontré que l’expression d’IDO1, la première enzyme de la voie des kynurénines, est plus élevée dans le tissu adipeux des individus obèses. Le ratio kynurénine sur tryptophane, qui reflète l’activité D’IDO1, est également augmenté chez les individus obèses.Notre objectif a été de caractériser l’expression des enzymes de la voie des kynurénines dans le tissu adipeux et d’évaluer les concentrations des kynurénines dans les sérums de patientes obèses pour rechercher si certains de ces facteurs pouvaient être reliés à l’apparition du diabète. Ces études ont été réalisées dans une cohorte de femmes obèses normoglycémiques et diabétiques. Puis dans un second temps nous avons étudié les conséquences de la perte de poids induite par la chirurgie bariatrique sur les concentrations circulantes des kynurénines et évalué si les variations des concentrations des kynurénines pourraient expliquer en partie l’amélioration du diabète observée après la chirurgie.Dans cette étude, nous avons montré que plusieurs enzymes de la voie sont plus exprimées dans le tissu adipeux des individus obèses que des minces. L’augmentation de l’expression des enzymes dans le tissu adipeux des individus obèses provient d’une part de la présence de macrophages pro-inflammatoires dans le tissu adipeux et également de la réponse des adipocytes aux stimuli pro-inflammatoires. En parallèle, nous avons montré que les concentrations circulantes des kynurénines et le ratio kynurénine sur tryptophane augmentent avec l’IMC et qu’ils diminuent un an après la chirurgie bariatrique. Dans notre étude, comme attendu, la chirurgie bariatrique est associée à une amélioration voire à une rémission du diabète. Nous avons montré également que le maintien des concentrations d’acide kynurénique et d’acide quinolinique sont associés respectivement à la rémission du diabète et à l’amélioration des traits cliniques qui définissent le diabète. La diminution des concentrations en acide xanthurénique après la chirurgie est associée au contraire à une amélioration des traits cliniques qui définissent le diabète. / Tryptophan, an essential amino acid, is either used in protein synthesis or metabolized via the serotonin or the kynurenine pathway. The kynurenine pathway is the main route of tryptophan degradation and generates several metabolites collectively called “kynurenines”. The expression of kynurenine pathway enzymes is induced by inflammatory mediators. Consequently kynurenine synthesis could be induced in individuals with obesity. In fact, obesity is characterized by a chronic low grade inflammation of the adipose tissue reflected by increased serum levels of inflammatory factors which are known to contribute to the development of obesity-induced insulino-resistance. Some metabolites of the kynurenine pathway have been proposed to be risk factors for the development of insulin resistance. Bariatric surgery is currently the most effective treatment for severe obesity and results in a significant weight loss, a decreased level of inflammatory factors and an amelioration of glucose homeostasis. The first enzyme of the kynurenine pathway, IDO1, is known to be more expressed in the adipose tissue of individuals with obesity compared to lean individuals. The kynurenine over tryptophan ratio reflects the activity of IDO1 and is also increased in individuals with obesity.Our objective was to characterize the expression of the kynurenine pathway enzymes in the adipose tissue of women with severe obesity and to evaluate serum levels of the kynurenine pathway metabolites to determine whether these factors could be associated with the appearance of diabetes. This study was performed in women with severe obesity with or without type 2 diabetes. Then we investigated the consequences of weight loss induced by bariatric surgery on levels of circulating kynurenines in order to evaluate whether these variations could explain the improvement in glucose control and type 2 diabetes remission after one year follow-up.In this study, we have shown that several kynurenine pathway enzymes were more expressed in the adipose tissue of women with obesity compared to lean controls. This increase is due to the presence of pro-inflammatory macrophages in the adipose tissue and also comes from the adipocyte response to inflammatory stimuli. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. As expected, bariatric surgery is associated with the improvement and even the remission of type 2 diabetes. We have shown that higher levels of kynurenic acid and quinolinic acid one year after the surgery are associated respectively with type 2 diabetes remission and better glucose homeostasis and that lower levels of xanthurenic acid are associated with better glucose homeostasis.

nÃo hà / A diabetes à considerada um fator de risco significativo para a ocorrÃncia de doenÃas periodontais. Entretanto, à necessÃrio que estudos a respeito deste assunto seja realizado em diferentes populaÃÃes, com diferentes caracterÃsticas. O objetivo deste estudo transversal foi avaliar os parÃmetros clÃnicos periodontais de diabÃticos do tipo 2 com diferentes padrÃes de controle glicÃmico. Foram selecionados portadores desta doenÃa, de ambos os gÃneros, residentes na sede do municÃpio de Sobral - CearÃ. Estes deveriam ser nÃo-fumantes, com idade igual ou superior a 40 anos, possuir pelo menos 6 dentes na arcada dentÃria e fazer uso de medicaÃÃo hipoglicemiante. Os indivÃduos foram submetidos ao exame clÃnico periodontal: Ãndice de placa visÃvel (IP), sangramento gengival (IG), sangramento à sondagem (SS), profundidade de sondagem (PS) e recessÃo gengival (RG), realizado por um examinador previamente calibrado. Os indivÃduos foram divididos em trÃs grupos de acordo os nÃveis de hemoglobina glicada â Hb1Ac (Controlados - C: Hb1Ac ≤ 7%, n=103; Descontrolados - D: 7,1% ≤ Hb1Ac ≤ 9%, n= 60; Elevado Descontrole = E: Hb1Ac ≥ 9,1%, n=22). NÃo foram observadas diferenÃas significantes em relaÃÃo Ãs mÃdias de idade em anos, mÃdia de dentes presentes, IP, IG e SS. Verificou-se diferenÃa significante entre os grupos para as mÃdias de Hb1Ac e tempo de diagnÃstico da doenÃa. NÃo foi verificada associaÃÃo estatisticamente significante entre elevados nÃveis glicÃmicos e a maior presenÃa de dentes e de sÃtios periodontais com PS ≥ 6 mm. Entretanto quando foram analisados apenas os indivÃduos que apresentaram 20 ou mais dentes isso foi observado. Assim, pÃde-se concluir que o pobre controle glicÃmico dos diabÃticos do tipo 2, foi associado a maior presenÃa de periodontite apenas nos indivÃduos com elevado nÃmero de dentes. / Diabetes is a significant risk factor for the occurrence of periodontal diseases. Studying the relationship of both diseases in different populations with heterogeneous characteristics are still necessary to better understand them. The aim of this cross-sectional study was to evaluate the clinical periodontal parameters of type 2 diabetes patients with different levels of glycemic control. There were selected type 2 diabetics residing in the urban area of Sobral, Ceara. They must be non-smokers, aging 40 years or more and presenting at least and 6 teeth in their mouth. All had to be using any medication to control the glycemic level. Subjects were assigned to three groups based on their respective glycated hemoglobin levels - Hb1Ac (Control - C: Hb1Ac ≤ 7%, n=103; Moderate control - M: 7,1% ≤ Hb1Ac ≤ 9%, n= 60; Poor control = P: Hb1Ac ≥ 9,1%, n=22). The following clinical data were obtained from all patients: Plaque Index (PI), Gingival Index (GI), bleeding on probing (BOP), probing depth (PD) and gingival recession (GR). The mean age, number of teeth, PI, GI and BOP did not show any significance between groups. But this was observed for Hb1Ac mean levels and time of diabetes diagnosis. The presence of at least one periodontal site with PD ≥ 6 mm was considered for the diagnosis of periodontitis. There was no association between the increase of the glycemic level and the presence of periodontitis. However, data from patients presenting at least 20 teeth showed a significant association between periodontal diseases and higher glycemic levels. It can be concluded that the poor glycemic control was associated to the presence of periodontitis only in subjects with high number of teeth.

Prevalence of diabetes, especially type 2 diabetes mellitus (T2DM) is increasing worldwide. Millions of people are already affected by T2DM and estimates predict over half a billion people will likely be suffering from the disease by 2030. T2DM is associated with an increased risk of developing cardiovascular disease. Cardiovascular dysfunction is the leading cause of mortality among type 2 diabetics. Treatment for T2DM has changed over time. Though it was once known as insulin independent, a large portion of type 2 diabetics are now treated with insulin injections. However, type 2 diabetics treated with insulin are more likely to suffer from heart complications. Due to this, we sought to determine the specific effect of insulin and insulin-induced ceramide accrual on heart mitochondrial bioenergetics. To do so we used both in vitro and in vivo models. H9c2 cardiomyocytes and adult male mice were treated with insulin with or without the ceramide biosynthesis inhibitor myriocin. Mitochondrial bioenergetics were determined in permeabilized cardiomyocytes and myocardium. In this study we demonstrate that insulin induced ceramide accrual in both isolated cardiomyocytes and whole murine myocardium. We further found that insulin treatment is sufficient to disrupt mitochondrial respiration in both models. Inhibition of the ceramide accrual rescued mitochondrial respiration, indicating that ceramide is necessary for the insulin-induced alterations in heart mitochondrial respiration. These results suggest that insulin has a role in the development of heart complications associated with T2DM due to cardiomyocyte mitochondrial disruption. They also implicate ceramide as a possible mediator in the development of insulin-related heart disorders.

The prevalence of both Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing worldwide, and the trends are unfortunately expected to continue. AD has recently been tied with mitochondrial dysfunction and insulin resistance, creating a mechanistic tie between AD and T2DM. Unfortunately, insulin resistance is often increased with aging and therefore, all individuals are at risk of brain mitochondrial dysfunction. Without proper mitochondrial function, the brain will degenerate, causing impaired cognitive function and reduced quality of life. The purpose of this study is two-fold: first, to understand the role of ceramides in insulin-induced brain mitochondrial dysfunction, and; second, to understand how ketones can restore brain mitochondrial function in aged brains. To evaluate the role of insulin resistance and ceramides in brain mitochondrial function, we induced hyperinsulinemia in ApoE4 mice. In addition to insulin, one group received myriocin injections to inhibit ceramide biosynthesis. We observed significant increases in brain ceramides in the insulin-treated group, which correlated with disrupted brain mitochondrial function. However, the group receiving myriocin alone, and, importantly, myriocin with insulin, had normal lipid profiles and normal mitochondrial bioenergetics. Altogether, these findings support the hypothesis of the key role of ceramides in insulin resistance-induced mitochondrial dysfunction within the brain. Next, young adult (5 months old) and old (28 months old) rats were assigned to either standard chow diets or very-low-carbohydrate, high-fat, ketogenic diets for 4 weeks. Following the treatment period, we analyzed brain mitochondrial function and oxidative stress. We found that the old rats fed the ketogenic diet had improved mitochondrial function in comparison to the old rats consuming standard rodent chow. In addition, the old rats fed a standard diet had significantly higher levels of oxidative stress than the aged rats on the very-low-carbohydrate, high-fat diet. These findings revealed that ketones can protect brain mitochondrial function in aging. Collectively, these results suggest that insulin resistance has a role in the development of brain mitochondrial dysfunction due to ceramide accumulation, while ketones can help mitigate some of the negative consequences of aging, perhaps some due to insulin resistance, on brain mitochondrial function.

American Indian and Alaska Native adults are 2.6 times more likely to have adult onset diabetes resulting from higher weight at birth. Pregnant women, providers, and Indian Health Service administrators may benefit from timely information during pregnancy to intervene and prevent Type 2 diabetes. The purpose of this study was to examine the role of birth weight in the development of Type 2 diabetes among Southeast Alaska (SEA) Natives. Guided by the socioecological model, this study examined the extent to which birth weight and gestational age predict the incidence of Type 2 diabetes. The study used a quantitative research design with retrospective analysis of 540 Native children born in SEA whose data were abstracted from birth journals and electronic medical records at ages 43-53. A t test indicated a significant positive correlation between gestational birth weight and incidence of Type 2 diabetes (t(285) = 13.91, p < .001). Birth weight for gestational age was associated with frequency of Type 2 diabetes, where small for gestational age (SGA) had the lowest risk (1.42%), average for gestational age (AGA) at medium risk (8.76%), and large for gestational age (LGA) had the highest risk at 32.25% (x^2(12) = 63.29, p < .0005). Findings indicate that adult Type 2 diabetes among the SEA Native population is due to excess intrauterine fetal weight gain. The positive social change implications include preventing Type 2 diabetes in SEA Natives by controlling weight gain during pregnancy; the findings also suggest using diagnostic risk profiles for those who are LGA at birth for the management of diabetes and prevention of obesity and chronic disease.

A research report from the Centers for Disease Control and Prevention (CDC) indicated that more than 50% of people with diabetes mellitus (DM) in the United States (U.S.) also have arthritis. The diabetes population is disproportionately affected by arthritis, but there has been limited and inconsistent research to confirm the association between type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA). The current study aimed to identify an association between T2DM and RA for noninstitutionalized U.S. adults between 1999 and 2012 using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database (n =31,488 ). A quantitative, cross-sectional investigation was conducted to determine if patients with T2DM had an increased prevalence of RA. The current study also sought to identify characteristics that could affect the association between both groups and the prevalence of cardiovascular disease (CVD) in this population. Prevalence and adjusted odds ratios (OR) using logistic regression were calculated. The results show evidence of a strong association between T2DM and concomitant RA. Prevalence of RA was significantly higher in participants with T2DM compare to those without T2DM. Important factors in this association were gender, ethnicity, education, disability, and work functioning. The prevalence of CVD and adjusted OR of association were doubled in participants with T2DM and RA when compared to participants who had just one of the conditions; the OR of association was quadrupled when compared to those without this comorbidity. This study may provide patients and health care providers with a better understanding of the need for management of both conditions in a interdisciplinary manner

The relationship between physicians' perceptions of Mexican American patients at risk for Type 2 diabetes and the subsequent care they provide was studied. Primary care providers responded to questionnaires about their health promotion practices. A 2x2 analysis of variance was used to identify differences in reported treatment of patients that accounted for both ethnicity and risk. Results indicated Hispanic patients received less time with their providers than Caucasian patients regardless of risk for Type 2 diabetes. Both groups received about the same reported care in terms of information gathered for diagnosis, diagnosis made, and treatment regimen prescribed. Data also suggested that providers' scores for treatment regimen and information gathered were disappointingly low, which may not only account for the lack of statistically significant findings, but may reflect a larger issue within the medical care field.

Emerging evidence suggests that an important mechanism for the negative feedback control of insulin signalling involves the inhibition of tyrosine phosphorylation of IRS-1 by its prior serine/threonine (ser/thr) phosphorylation. IRS-1 ser/thr phosphorylation has been linked to the dissociation of IRS-1 from the insulin receptor and PI3K, and its degradation via a proteasome-dependent pathway. Studies in animal models have shown that increases in plasma free fatty acids (FFAs) are associated with reduced IRS-1-signalling, and so it has been postulated that elevated FFA cause insulin resistance by activating pathways that negatively regulate insulin action, including hyper-phosphorylation of ser/thr residues in IRS-1. We have shown that in the case of linoleate-induced insulin resistance in L6 rat skeletal muscle cells, the inhibition of IRS-1-dependent signalling arises via effects on both the phosphorylation status and degradation of IRS-1, which are mediated, in part, by IKKb. In addition, the reduction of IRS-1 mRNA levels allude to transcriptional effects of linoleate treatment that also contribute to the observed reduction in the total levels of this protein. PtdOH, particularly dilinoleoyl PtdOH, was found to be significantly increased in linoleate treated L6 cells, and sufficient to induce at least some of the effects on insulin-signalling that are observed upon linoleate treatment. It is unlikely, however, that IKKb and PtdOH are components of the same inhibitory pathway, since inhibiting IKKb activity did not alleviate the effects of PtdOH on IRS-1 tyrosine (tyr) phosphorylation. Moreover, although an integral component of the mechanism by which linoleate induces insulin-resistance in L6 cells, it appears that restoring IRS-1 function in linoleate treated cells is not sufficient to reverse insulin resistance. Hence, we hypothesise that linoleate induces multiple inhibitory pathways in L6 cells, with at last two of these involving IKKb- and PtdOH-dependent inhibition of IRS-1 signalling, which act in parallel to reduce glucose disposal and cause insulin resistance in this model.

Patients with type 2 diabetes have reduced gene expression of Heat Shock Protein (HSP) 72 which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signalling proteins such as c-jun amino terminal kinase (JNK) can induce insulin resistance but HSP72 can block the induction of these molecules in vitro. Whether up-regulation of HSP72 can protect against insulin resistance is not known. In experiments reported in this thesis we show that HSP72 protects against insulin resistance and blocks the activation of JNK in vivo. We first show that mice that underwent weekly heat shock therapy to increase intramuscular HSP72 protein expression were protected from high fat diet (HFD)-induced hyperinsulinemia, hyperglycemia and glucose intolerance, factors associated with reduced JNK phosphorylation. To determine whether the elevation in intramuscular HSP72 expressio n and protection from insulin resistance are causally linked, we studied muscle specific HSP72 overexpression mice (HSP72+/+). Compared with wild-type mice, HSP72+/+ mice were protected from hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance when placed on a HFD, factors associated with a complete inhibition of HFD-induced JNK phosphorylation in skeletal muscle. Finally, we show that HSP72+/+ mice display greater mitochondrial enzyme activity in the liver, adipose tissue and skeletal muscle, corresponding to reduced plasma free fatty acid levels, white adipose tissue mass and alterations in circulating adipokines. These data identify HSP72 as being pivotal in protecting against obesity-induced insulin resistance possibly by blocking JNK and/or by up-regulation of mitochondrial oxidative capacity.

Purpose: To examine the effectiveness of a community-based intensive multifactorial clinical intervention for patients with Type 2 diabetes, to evaluate the feasibility of achieving clinical targets for glycemic control in a community setting, and to identify factors that are predictive of glycemic control in this cohort (age, gender, disease duration, continuity of care, pharmacologic treatment, diabetes self-care and smoking status). Methods: Participants with Type 2 diabetes referred to the Diabetes Clinic following dissemination of the 2003 Clinical Practice Guidelines of Canadian Diabetes Association and who attended a minimum of two physician visits within a twelve month period were deemed eligible for participation. 70 patients were included in this retrospective study. Baseline and twelve month values for the following biomedical outcomes were collected via chart audit: BMI, hemoglobin A1c, blood pressure (systolic, diastolic) and lipid profile (HDL, LDL, triglycerides, total cholesterol, TC:HDL ratio). Data for identification of predictive factors for glycemic control were also retrieved by chart audit. Results: The results of the paired t-test yielded a significant improvement in hemoglobin A1c (p<0.05), systolic blood pressure (p<0.01), HDL-cholesterol (p<0.05), LDL-cholesterol (p<0.01), total cholesterol (p<0.05) and total cholesterol:HDL ratio (p<0.05) over twelve months. No significant difference in BMI, diastolic blood pressure or triglycerides was reported over twelve months. Over half the sample (52.9%) achieved clinical targets for glycemic control (hemoglobin A1c <7.0%) at twelve months. Logistic regression analysis identified disease duration (O.R. = 0.90, 95% CI Exp(B) = 0.079 - 0.773, p = 0.01) and continuity of care (O.R. = 0.25, 95% CI Exp(B) = 0.831 - 0.969, p = 0.02) as significant predictors of glycemic control at twelve months. Conclusions: These findings demonstrate the effectiveness of this community-based intensive multifactorial clinical intervention for patients with Type 2 diabetes and show that the implementation of CPGs related to glycemic control is feasible in a community-based setting. Additionally, patients in this cohort with increased disease duration and increased continuity of care were less likely to achieve clinical targets for glycemic control following a twelve month intensive multifactorial clinical intervention for Type 2 diabetes. In summary, health professionals should strive to implement similar intensive multifactorial interventions in community practice in order to decrease the likelihood of diabetes-related complications and improve the patients quality of life.