Atualmente, a obesidade é considerada uma epidemia mundial. Está associada a um estado de inflamação crônica e ativação do estresse do retículo endoplasmático (ERE), relacionados à patogênese de diversas doenças como diabetes mellitus tipo 2, doenças cardiovasculares, câncer, hipertensão, dentre outras. Nesse contexto, são necessários estudos para encontrar alternativas que melhorem o processo inflamatório. Vários estudos em humanos e animais já demostraram as propriedades anti-inflamatórias do ácido graxo ômega-3. O objetivo do nosso trabalho foi avaliar os efeitos da suplementação do ácido alfa-linolênico (ALA) no metabolismo e no estresse do retículo endoplasmático em obesos grau III. Foi conduzido um estudo prospectivo, randomizado, placebo-controlado, duplo-cego. No total, 52 pacientes foram randomizados para a suplementação com 3g/dia de ALA ou placebo, sendo 27 indivíduos do grupo ômega-3/ALA e 25 do grupo controle. Foi avaliado perfil lipídico, glicídico e inflamatório antes e após suplementação. O tecido adiposo visceral (TAV) foi coletado durante cirurgia bariátrica após suplementação. O perfil de ácidos graxos incorporados no TAV foi avaliado por cromatografia gasosa. Os genes foram avaliados através de PCR em tempo real. Não houve alteração nos níveis séricos de IL-6 (p=0,2201), TNF-? (0.7703) e PCR (p=0,57) após suplementação com ômega-3/ALA, porém observamos diminuição nos níveis séricos de Leptina (p=0.0154) e IP-10 (p=0.0410), citocinas inflamatórias, e aumento na IL-4 (p=0,0211), citocina anti-inflamatória. Foi observado incorporação significativa do ALA (p=0,0002), EPA (p<0,0001) e DHA (p=0,0005) no TAV. Avaliação molecular evidenciou um aumento da expressão gênica do XBP1 (p=0,0013), sXBP1 (p<0,0001), EIF2-? (p=0,0063) e da chaperona CCT4 (p=0,0001) e diminuição na expressão gênica da leptina (p=0,0410). Podemos concluir que o ALA pode modular o ERE através da via da IRE1/XBP, levando ao aumento das chaperonas (CCT4), o que pode demonstrar um potencial terapêutico do ALA em pacientes obesos. / Currently, obesity is considered a worldwide epidemic. It is associated with chronic inflammation and stress activation of the endoplasmic reticulum (ERE), related to the pathogenesis of various diseases such as type 2 diabetes mellitus, cardiovascular diseases, cancer, hypertension, among others. In this context, studies are needed to find alternatives that improve the inflammatory process. Several studies in humans and animals have already demonstrated the anti-inflammatory properties of omega-3 fatty acid. The objective of our study was to evaluate the effects of alpha-linolenic acid (ALA) supplementation on the metabolism and stress of the endoplasmic reticulum in obese patients. A prospective, randomized, placebo-controlled, double-blind study was conducted. In total, 52 patients were randomized to supplementation with 3 g / day of ALA or placebo, 27 individuals from the omega-3 / ALA group and 25 from the control group. Lipid, glycidic and inflammatory profile were evaluated before and after supplementation. Visceral adipose tissue (TAV) was collected during bariatric surgery after supplementation. The fatty acid profile incorporated in the TAV was evaluated by gas chromatography. Genes were evaluated by real-time PCR. There was no change in serum levels of IL-6 (p = 0.2201), TNF-? (0.7703) and CRP (p = 0.57) after supplementation with ALA, but we observed a decrease in serum Leptin levels (P = 0.0154) and IP-10 (p = 0.0410), inflammatory cytokines, and increase in IL-4 (p = 0.0211), anti-inflammatory cytokine. Significant incorporation of ALA (p = 0.0002), EPA (p <0.0001) and DHA (p = 0.0005) into the TAV was observed. Molecular evaluation showed an increase in the gene expression of XBP1 (p = 0.0013), sXBP1 (p <0.0001), EIF2-? (p = 0.0063), GADD34 (p=0,0117) and CCT4 chaperone (p = 0.0001), decrease in the gene expression of leptin (p = 0.0410) and ATF-6 (p=0,0305) and a tendency to decrease the gene expression of CHOP. We can conclude that ALA can modulate ERE through the IRE1 / XBP, PERK and ATF-6 pathways, leading to increased chaperones (CCT4), which may demonstrate a therapeutic potential of ALA in obese patients.

Atualmente, a obesidade é considerada uma epidemia mundial. Está associada a um estado de inflamação crônica e ativação do estresse do retículo endoplasmático (ERE), relacionados à patogênese de diversas doenças como diabetes mellitus tipo 2, doenças cardiovasculares, câncer, hipertensão, dentre outras. Nesse contexto, são necessários estudos para encontrar alternativas que melhorem o processo inflamatório. Vários estudos em humanos e animais já demostraram as propriedades anti-inflamatórias do ácido graxo ômega-3. O objetivo do nosso trabalho foi avaliar os efeitos da suplementação do ácido alfa-linolênico (ALA) no metabolismo e no estresse do retículo endoplasmático em obesos grau III. Foi conduzido um estudo prospectivo, randomizado, placebo-controlado, duplo-cego. No total, 52 pacientes foram randomizados para a suplementação com 3g/dia de ALA ou placebo, sendo 27 indivíduos do grupo ômega-3/ALA e 25 do grupo controle. Foi avaliado perfil lipídico, glicídico e inflamatório antes e após suplementação. O tecido adiposo visceral (TAV) foi coletado durante cirurgia bariátrica após suplementação. O perfil de ácidos graxos incorporados no TAV foi avaliado por cromatografia gasosa. Os genes foram avaliados através de PCR em tempo real. Não houve alteração nos níveis séricos de IL-6 (p=0,2201), TNF-? (0.7703) e PCR (p=0,57) após suplementação com ômega-3/ALA, porém observamos diminuição nos níveis séricos de Leptina (p=0.0154) e IP-10 (p=0.0410), citocinas inflamatórias, e aumento na IL-4 (p=0,0211), citocina anti-inflamatória. Foi observado incorporação significativa do ALA (p=0,0002), EPA (p<0,0001) e DHA (p=0,0005) no TAV. Avaliação molecular evidenciou um aumento da expressão gênica do XBP1 (p=0,0013), sXBP1 (p<0,0001), EIF2-? (p=0,0063) e da chaperona CCT4 (p=0,0001) e diminuição na expressão gênica da leptina (p=0,0410). Podemos concluir que o ALA pode modular o ERE através da via da IRE1/XBP, levando ao aumento das chaperonas (CCT4), o que pode demonstrar um potencial terapêutico do ALA em pacientes obesos. / Currently, obesity is considered a worldwide epidemic. It is associated with chronic inflammation and stress activation of the endoplasmic reticulum (ERE), related to the pathogenesis of various diseases such as type 2 diabetes mellitus, cardiovascular diseases, cancer, hypertension, among others. In this context, studies are needed to find alternatives that improve the inflammatory process. Several studies in humans and animals have already demonstrated the anti-inflammatory properties of omega-3 fatty acid. The objective of our study was to evaluate the effects of alpha-linolenic acid (ALA) supplementation on the metabolism and stress of the endoplasmic reticulum in obese patients. A prospective, randomized, placebo-controlled, double-blind study was conducted. In total, 52 patients were randomized to supplementation with 3 g / day of ALA or placebo, 27 individuals from the omega-3 / ALA group and 25 from the control group. Lipid, glycidic and inflammatory profile were evaluated before and after supplementation. Visceral adipose tissue (TAV) was collected during bariatric surgery after supplementation. The fatty acid profile incorporated in the TAV was evaluated by gas chromatography. Genes were evaluated by real-time PCR. There was no change in serum levels of IL-6 (p = 0.2201), TNF-? (0.7703) and CRP (p = 0.57) after supplementation with ALA, but we observed a decrease in serum Leptin levels (P = 0.0154) and IP-10 (p = 0.0410), inflammatory cytokines, and increase in IL-4 (p = 0.0211), anti-inflammatory cytokine. Significant incorporation of ALA (p = 0.0002), EPA (p <0.0001) and DHA (p = 0.0005) into the TAV was observed. Molecular evaluation showed an increase in the gene expression of XBP1 (p = 0.0013), sXBP1 (p <0.0001), EIF2-? (p = 0.0063), GADD34 (p=0,0117) and CCT4 chaperone (p = 0.0001), decrease in the gene expression of leptin (p = 0.0410) and ATF-6 (p=0,0305) and a tendency to decrease the gene expression of CHOP. We can conclude that ALA can modulate ERE through the IRE1 / XBP, PERK and ATF-6 pathways, leading to increased chaperones (CCT4), which may demonstrate a therapeutic potential of ALA in obese patients.

<p>The presence of protein amyloid in pancreas and its association to diabetes was first described 100 years ago in 1901, but was not identified as Islet Amyloid Polypeptide (IAPP) until 1986. The aim of the present work was to determine the role of the beta cell hormone, IAPP, in normal pancreatic islet physiology and during early disturbances of islet function.</p><p>Intra-islet peptides, i.e. chromogranin peptides and an extra-islet peptide, i.e. leptin, were studied to identify possible endogenous regulators of IAPP and insulin secretion. Chromogranin-B, but not chromogranin-A or pancreastatin, had the ability to inhibit islet IAPP and insulin release, suggesting that chromogranin-B may serve as an autocrine regulator of IAPP and insulin secretion. </p><p>Leptin had a more potent effect on IAPP secretion than on insulin secretion, which was dissociated from effects on islet glucose metabolism. Glucose oxidation rates were increased at physiological leptin concentrations, whereas higher leptin concentrations showed an inhibitory effect and chronically high leptin concentrations had no effect.</p><p>Female NOD mice were studied to investigate the release of IAPP in the progression to type 1 diabetes. The release of IAPP was lower than that of insulin from immune cell infiltrated islets, indicating preferential insulin release during the early course of the disease. </p><p>IAPP is expressed at an early embryonic stage. The effect of IAPP on cell proliferation in neonatal rat islets was studied in the search for a physiological role of IAPP. IAPP concentrations of (1-1000) nM stimulated neonatal islet cell proliferation mostly in beta cells and to a lesser extent in alpha cells. IAPP did not have any marked effect on the islet cell death frequency. These data indicate a role for IAPP as a potential regulator of beta cell proliferation in neonatal pancreatic islet.</p><p>It is concluded that IAPP may be involved in regulation of pancreatic beta cell function both in fetal and adult life.</p>

<p>Ormarsdóttir, S. 2001. Osteoporosis in Chronic Liver Disease. Acta Universitatis Upsaliensis. <i>Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine</i> 1037. 60 pp. Uppsala. ISBN 91-554-5021-0. </p><p>Osteoporosis is a well-known and frequently reported complication of chronic liver disease (CLD) with a high fracture rate contributing to significant morbidity after liver transplantation. The pathogenesis is unknown and controversy exists about many risk factors for osteoporosis in CLD. </p><p>In the present thesis, bone mineral density (BMD) was found to be significantly lower at the lumbar spine (<i>p</i><0.01) in a cohort of patients with CLD compared with age- and gender -matched individuals. Osteoporosis was found in 30% of the patients and 15% of the controls, respectively. Low body mass index (BMI), corticosteroid treatment, prothrombin time, age and female gender were independent risk factors for osteoporosis in the patients. </p><p>In a follow-up study, 43 of 72 patients were available for a second BMD measurement 25 months (median) after the first. Bone loss at the femoral neck was 1.5 ± 2.4% in females and 2.9 ± 2.0% in males with a significant decrease in BMD Z-score over time (<i>p</i>=0.005 and <i>p</i>=0.02 for females and males, respectively), indicating increased bone loss at this site. Hyperbilirubinaemia and low circulating levels of 25-hydroxy vitamin D₃ predicted increased bone loss at the femoral neck. These findings suggest that cortical bone, in addition to trabecular bone, may be affected in CLD and bilirubin and vitamin D₃ may be involved in the pathophysiology of osteoporosis in CLD. </p><p>In order to elucidate the suggested role of insulin-like growth factors (IGFs) and leptin in the pathophysiology of osteoporosis in CLD, we studied the relationship between these factors and BMD. Levels of IGFs were extremely low (<i>p</i><0.0001 compared with the controls) and related to liver function but no correlation was found between the IGFs and BMD. Serum leptin adjusted for BMI correlated negatively with BMD in female patients (<i>p</i>=0.003 and <i>p</i>=0.04 at the lumbar spine and the femoral neck, respectively) and in male patients at the femoral neck (<i>p</i>=0.04). Thus, the IGFs appear not to be involved in the pathophysiology of osteoporosis in CLD but a role of circulating leptin is possible. </p>

<p>The high prevalence of diabetes mellitus among the Sudanese population is linked to obesity, poor glycaemic control and a high rate of complications. This study investigated 1/ Leptin hormone and its correlations with different biochemical characteristics in Sudanese diabetic subjects, 2/ The impact of glycaemic control on pregnancy outcome in pregnancies with diabetes, 3/ The glycaemic response to Sudanese traditional carbohydrate foods, 4/ The influence of glucose self-monitoring on the glycaemic control among this population, 5/ The health related quality of life in Sudanese subjects with diabetes-related lower limb amputation. </p><p>Leptin was significantly lower in diabetic subjects compared with controls of same BMI in both females (P =0.0001) and males (P =0.019). In diabetic subjects, serum leptin correlated positively with the homeostatic assessment (HOMA) of both beta-cell function (P =0.018) and insulin resistance (P =.038). In controls, leptin correlated only with insulin resistance. Pregnancy complications were higher among diabetic compared with control women (P<0.0001) and varied with the type of diabetes. Infants of diabetic mothers had a higher incidence of neonatal complications than those of non-diabetic women (P<0.0001). In six Sudanese traditional carbohydrate meals over all differences in incremental AUCs were significant for both plasma glucose (P = 0.0092) and insulin (P = 0.0001). Millet porridge and wheat pancakes displayed significantly lower post-prandial glucose and insulin responses, whereas maize porridge induced a higher post-prandial glucose and insulin response. In type 2 diabetic subjects SMBG or SMUG was not related to glycaemic control. In type 1 diabetic subjects, SMBG was significantly associated with better glycaemic control, as assessed by HbA1c (P=0.02) and blood glucose at clinic visits (P=<0.0001), similar associations were found for SMUG respectively. Neither glycaemic control nor glucose self-monitoring was associated with education level. Diabetic subjects with LLA had significantly poorer HRQL compared to a reference diabetic group (P=<0.0001). Duration of diabetes and amputation had negative impact on HRQL in subjects with LLA (P=<0.0001) respectively. Diabetic subjects with LLA had decreased sense of coherence and high presence of symptoms. Improving health services at the primary level is important to reduce the complications and burden of disease in the Sudanese population.</p>

The presence of protein amyloid in pancreas and its association to diabetes was first described 100 years ago in 1901, but was not identified as Islet Amyloid Polypeptide (IAPP) until 1986. The aim of the present work was to determine the role of the beta cell hormone, IAPP, in normal pancreatic islet physiology and during early disturbances of islet function. Intra-islet peptides, i.e. chromogranin peptides and an extra-islet peptide, i.e. leptin, were studied to identify possible endogenous regulators of IAPP and insulin secretion. Chromogranin-B, but not chromogranin-A or pancreastatin, had the ability to inhibit islet IAPP and insulin release, suggesting that chromogranin-B may serve as an autocrine regulator of IAPP and insulin secretion. Leptin had a more potent effect on IAPP secretion than on insulin secretion, which was dissociated from effects on islet glucose metabolism. Glucose oxidation rates were increased at physiological leptin concentrations, whereas higher leptin concentrations showed an inhibitory effect and chronically high leptin concentrations had no effect. Female NOD mice were studied to investigate the release of IAPP in the progression to type 1 diabetes. The release of IAPP was lower than that of insulin from immune cell infiltrated islets, indicating preferential insulin release during the early course of the disease. IAPP is expressed at an early embryonic stage. The effect of IAPP on cell proliferation in neonatal rat islets was studied in the search for a physiological role of IAPP. IAPP concentrations of (1-1000) nM stimulated neonatal islet cell proliferation mostly in beta cells and to a lesser extent in alpha cells. IAPP did not have any marked effect on the islet cell death frequency. These data indicate a role for IAPP as a potential regulator of beta cell proliferation in neonatal pancreatic islet. It is concluded that IAPP may be involved in regulation of pancreatic beta cell function both in fetal and adult life.

Ormarsdóttir, S. 2001. Osteoporosis in Chronic Liver Disease. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1037. 60 pp. Uppsala. ISBN 91-554-5021-0. Osteoporosis is a well-known and frequently reported complication of chronic liver disease (CLD) with a high fracture rate contributing to significant morbidity after liver transplantation. The pathogenesis is unknown and controversy exists about many risk factors for osteoporosis in CLD. In the present thesis, bone mineral density (BMD) was found to be significantly lower at the lumbar spine (p&lt;0.01) in a cohort of patients with CLD compared with age- and gender -matched individuals. Osteoporosis was found in 30% of the patients and 15% of the controls, respectively. Low body mass index (BMI), corticosteroid treatment, prothrombin time, age and female gender were independent risk factors for osteoporosis in the patients. In a follow-up study, 43 of 72 patients were available for a second BMD measurement 25 months (median) after the first. Bone loss at the femoral neck was 1.5 ± 2.4% in females and 2.9 ± 2.0% in males with a significant decrease in BMD Z-score over time (p=0.005 and p=0.02 for females and males, respectively), indicating increased bone loss at this site. Hyperbilirubinaemia and low circulating levels of 25-hydroxy vitamin D3 predicted increased bone loss at the femoral neck. These findings suggest that cortical bone, in addition to trabecular bone, may be affected in CLD and bilirubin and vitamin D3 may be involved in the pathophysiology of osteoporosis in CLD. In order to elucidate the suggested role of insulin-like growth factors (IGFs) and leptin in the pathophysiology of osteoporosis in CLD, we studied the relationship between these factors and BMD. Levels of IGFs were extremely low (p&lt;0.0001 compared with the controls) and related to liver function but no correlation was found between the IGFs and BMD. Serum leptin adjusted for BMI correlated negatively with BMD in female patients (p=0.003 and p=0.04 at the lumbar spine and the femoral neck, respectively) and in male patients at the femoral neck (p=0.04). Thus, the IGFs appear not to be involved in the pathophysiology of osteoporosis in CLD but a role of circulating leptin is possible.

The high prevalence of diabetes mellitus among the Sudanese population is linked to obesity, poor glycaemic control and a high rate of complications. This study investigated 1/ Leptin hormone and its correlations with different biochemical characteristics in Sudanese diabetic subjects, 2/ The impact of glycaemic control on pregnancy outcome in pregnancies with diabetes, 3/ The glycaemic response to Sudanese traditional carbohydrate foods, 4/ The influence of glucose self-monitoring on the glycaemic control among this population, 5/ The health related quality of life in Sudanese subjects with diabetes-related lower limb amputation. Leptin was significantly lower in diabetic subjects compared with controls of same BMI in both females (P =0.0001) and males (P =0.019). In diabetic subjects, serum leptin correlated positively with the homeostatic assessment (HOMA) of both beta-cell function (P =0.018) and insulin resistance (P =.038). In controls, leptin correlated only with insulin resistance. Pregnancy complications were higher among diabetic compared with control women (P&lt;0.0001) and varied with the type of diabetes. Infants of diabetic mothers had a higher incidence of neonatal complications than those of non-diabetic women (P&lt;0.0001). In six Sudanese traditional carbohydrate meals over all differences in incremental AUCs were significant for both plasma glucose (P = 0.0092) and insulin (P = 0.0001). Millet porridge and wheat pancakes displayed significantly lower post-prandial glucose and insulin responses, whereas maize porridge induced a higher post-prandial glucose and insulin response. In type 2 diabetic subjects SMBG or SMUG was not related to glycaemic control. In type 1 diabetic subjects, SMBG was significantly associated with better glycaemic control, as assessed by HbA1c (P=0.02) and blood glucose at clinic visits (P=&lt;0.0001), similar associations were found for SMUG respectively. Neither glycaemic control nor glucose self-monitoring was associated with education level. Diabetic subjects with LLA had significantly poorer HRQL compared to a reference diabetic group (P=&lt;0.0001). Duration of diabetes and amputation had negative impact on HRQL in subjects with LLA (P=&lt;0.0001) respectively. Diabetic subjects with LLA had decreased sense of coherence and high presence of symptoms. Improving health services at the primary level is important to reduce the complications and burden of disease in the Sudanese population.

Tesis por compendio de publicaciones / La gran preocupación que existe actualmente alrededor del peso corporal, está colaborando a la proliferación de innumerables dietas de adelgazamiento entre las personas “no satisfechas con su peso”. En este sentido hemos estudiado la obesidad desde un punto de vista cronobiológico, para poder dilucidar la importancia que tiene la alteración circadiana de ciertos ritmos biológicos en la ganancia de peso o la no pérdida del mismo. El acúmulo de grasa corporal y el grado de lipogénesis en el tejido adiposo podría ser diferente a distintas horas del día, ingiriendo las mismas calorías. A su vez uno de los aspectos más interesantes, es poder conseguir una caracterización cronobiológica de cada individuo, establecer mejoras en las terapias de comportamiento alimentario, introducir nuevos índices que permitan detectar pacientes de riesgo y poder establecer pautas alimentarias y hábitos de vida individualizados que ayuden a estos pacientes a alcanzar la meta de peso propuesta. / The great controversy now there about body weight, is collaborating with the proliferation of countless diets among people "not satisfied with their weight." In this sense, we have studied obesity from a chronobiological viewpoint, to elucidate the importance of the alteration of circadian biological rhythms in weight gain or no loss. The accumulation of body fat and the degree of lipogenesis in adipose tissue may be different n accordance with the time of day, even eating the same calories. In turn one of the most interesting aspect, is to be able to characterize the individual chronobiology of each patient, establish improved therapies feeding behavior, introducing new indices to detect patients at risk and to establish dietary patterns and lifestyle habits that help these patients to achieve the proposed weight goal.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal