Activation of the Unfolded Protein Response (UPR) following stress in the Endoplasmic Reticulum (ER) is an important mechanism by which obesity results in insulin resistance and type II diabetes. We uncovered a role for the adaptor protein Nck in modulating the UPR. In this study, we report that obese Nck1-/- mice, which show lower levels of UPR in liver and adipose tissue, present improved insulin signalling in these tissues. We established that the effect of Nck1 is cell autonomous by showing that HepG2 cells treated with Nck1 siRNA have reduced ER stress-induced UPR and Insulin Receptor Substrate-1 (IRS-1) serine phosphorylation. In these cells, we observed that the IRS-1 levels and activation of signalling components downstream of the insulin receptor were increased. This correlates with enhanced cell survival to stress and insulin stimulated glycogen synthesis. Overall, we demonstrated that Nck1 participates in ER-stress-induced insulin resistance and regulation of IRS-1-dependent signalling.

Intramyocellular lipid (IMCL), an ectopic fat depot found within skeletal muscle fibers, is highly associated with obesity and strongly correlated with insulin resistance. IMCL accumulation in sedentary individuals may contribute to insulin resistance by interfering with insulin signaling in skeletal muscle, leading to inadequate glucose uptake by the cell. Lipid peroxidation is also associated with both obesity and insulin resistance, and with IMCL, but a relationship has yet to be established among all of these variables. The purpose of this project is to study for the first time the relationships among lipid peroxidation, IMCL content, and glucose uptake in skeletal muscle. Nine insulin-sensitive adults (IS), 13 insulin-resistant adults (IR), 10 diabetic (DB) and 8 subjects pre- and post- 12-week intervention with insulin-sensitizing thiazolinedione (TZD) were assessed for soleus IMCL with nuclear magnetic resonance, insulin sensitivity by both hyperinsulinemic-euglycemic clamp (GDR) and homeostasis model assessment index (HOMA1), and anthropometrics, including body mass index (BMI), percent fat by DEXA scan, and waist circumference. Vastus lateralis biopsies of all subjects were homogenized and analyzed by immunoblotting for post-translational protein modifications occurring from lipid-peroxidation (HNE). GDR and HOMA were significantly different among IS, IR, and DB groups, as expected, as were waist circumference and BMI. IMCL was significantly higher in DB than in IS and IR. HNE was also higher in DB than in IS, although it did not differ from IR. HNE was significantly correlated to GDR, HOMA1, and BMI, but not to IMCL, WAIST, or percent fat measures. IMCL showed a strong, negative correlation with GDR and was the primary, independent predictor of GDR in stepwise multiple regression. HNE was the primary, independent predictor of HOMA in stepwise multiple regression. Paired t-tests revealed improvements in insulin sensitivity measures after 12 weeks of TZD intervention, but no significant differences were observed in IMCL or HNE after intervention. These data show that skeletal muscle HNE and IMCL are both determinants of insulin resistance in obese, sedentary adults. HNE and IMCL are not related and therefore impact insulin resistance independently. These results reveal, for the first time, a negative relationship between skeletal muscle HNE and insulin sensitivity in sedentary individuals and underscore the importance of lipid peroxidation in insulin resistance.

No description available.

Whole yellow pea flour (WPF) and fractionated yellow pea flour (FPF) are novel functional food ingredients that vary in nutritional composition. Consequently, the health benefits of WPF and FPF remain undefined. The purpose of this research was to identify the effects of WPF and FPF on risk factors and morbidities associated with cardiovascular disease, diabetes and obesity as well as the gastrointestinal microbiome. Using USDA recommended dosages of WPF and FPF, clinical endpoints and the colonic microbiome were investigated using a human clinical trial engaging a cross-over design and a diet and energy controlled paradigm. Humans were also utilized to investigate post-prandial glycemic responses and sensory characteristics of novel functional foods formulated with WPF. Finally, Golden Syrian hamsters were used to assess the impact of high doses of WPF and FPF on clinical endpoints and caecal microbial abundance. Results reveal that USDA recommended dosages of WPF and FPF in humans decreased (p<0.05) fasting insulin and estimates of insulin resistance compared to white wheat flour (WF). Android-to-gynoid fat ratios in women were lower (p=0.027) in the WPF group compared to the WF group. FPF decreased (p<0.05) post-prandial energy expenditure alongside a tendency (p<0.075) to reduce carbohydrate oxidation. Novel biscotti and banana bread formulated with WPF induced low post-prandial glycemic responses which were similar to boiled whole yellow peas and significantly lower (p<0.05) than white bread. Sensory analysis of novel WPF biscotti and banana bread demonstrated that WPF-based food products are palatable and acceptable for human consumption. Hamsters consuming diets containing 10% WPF and FPF induced similar reductions (p<0.05) in fasting insulin levels compared to controls. However, animals consuming WPF increased (p<0.05) oxygen consumption while FPF decreased (p<0.05) fasting glucose levels. In addition, terminal restriction fragment length polymorphism analysis revealed that WPF and FPF induced distinct shifts in caecal microbial populations within the phyla Firmicutes. Finally, pyrosequencing analysis of human fecal microbiota demonstrated that FPF and WPF induced shifts in bacterial genera, primarily within Bacteroidetes and Firmicutes. In conclusion, whole and fractionated yellow pea flours are functional food ingredients and can be utilized to manage risk factors for lifestyle-related diseases in humans.

Parmi l’ensemble des désordres métaboliques retrouvés en insuffisance rénale chronique (IRC), la résistance à l’insuline demeure l’un des plus importantes à considérer en raison des risques de morbidité et de mortalité qu’elle engendre via les complications cardiovasculaires. Peu d’études ont considéré la modulation de transporteurs de glucose comme mécanisme sous-jacent à l’apparition et à la progression de la résistance à l’insuline en IRC. Nous avons exploré cette hypothèse en étudiant l’expression de transporteurs de glucose issus d’organes impliqués dans son homéostasie (muscles, tissus adipeux, foie et reins) via l’utilisation d’un modèle animal d’IRC (néphrectomie 5/6e). La sensibilité à l’insuline a été déterminée par un test de tolérance au glucose (GTT), où les résultats reflètent une intolérance au glucose et une hyperinsulinémie, et par les études de transport au niveau musculaire qui témoignent d’une diminution du métabolisme du glucose en IRC (~31%; p<0,05). La diminution significative du GLUT4 dans les tissus périphériques (~40%; p<0,001) peut être à l’origine de la résistance à l’insuline en IRC. De plus, l’augmentation de l’expression protéique de la majorité des transporteurs de glucose (SGLT1, SGLT2, GLUT1; p<0,05) au niveau rénal en IRC engendre une plus grande réabsorption de glucose dont l’hyperglycémie subséquente favorise une diminution du GLUT4 exacerbant ainsi la résistance à l’insuline. L’élévation des niveaux protéiques de GLUT1 et GLUT2 au niveau hépatique témoigne d’un défaut homéostatique du glucose en IRC. Les résultats jusqu’ici démontrent que la modulation de l’expression des transporteurs de glucose peut être à l’origine de la résistance à l’insuline en IRC. L’impact de la parathyroïdectomie (PTX) sur l’expression du GLUT4 a été étudié étant donné que la PTX pourrait corriger l’intolérance au glucose en IRC. Nos résultats démontrent une amélioration de l’intolérance au glucose pouvant être attribuable à la moins grande réduction de l’expression protéique du GLUT4 dans les tissus périphériques et ce malgré la présence d’IRC. L’excès de PTH, secondaire à l’hyperparathyroïdie, pourrait alors être à l’origine de la résistance à l’insuline en IRC en affectant l’expression du GLUT4. L’IRC partage de nombreuses similitudes avec le prédiabète quant aux défaillances du métabolisme du glucose tout comme l’hyperinsulinémie et l’intolérance au glucose. Aucune étude n’a tenté d’évaluer si l’IRC pouvait ultimement mener au diabète. Nos résultats ont par ailleurs démontré que l’induction d’une IRC sur un modèle animal prédisposé (rats Zucker) engendrait une accentuation de leur intolérance au glucose tel que constaté par les plus hautes glycémies atteintes lors du GTT. De plus, certains d’entre eux avaient des glycémies à jeun dont les valeurs surpassent les 25 mmol/L. Il est alors possible que l’IRC puisse mener au diabète via l’évolution de la résistance à l’insuline par l’aggravation de l’intolérance au glucose. / Of all metabolic disorders found in chronic renal failure (CRF), insulin resistance remains one of the most important to consider because of the risk of morbidity and mortality it causes via cardiovascular complications. Few studies have considered the modulation of glucose transporters as the mechanism underlying the emergence and progression of insulin resistance in CRF. We explored this hypothesis by studying the expression of glucose transporters from organs involved in its homeostasis (muscle , fat , liver and kidneys) through the use of an animal model reflecting CRF (5/6th nephrectomy). The insulin sensitivity was determined by a glucose tolerance test (GTT), where the results reflect glucose intolerance and hyperinsulinemia , and transport studies in muscle show a decrease in glucose uptake in CRF ratss (~31% , p<0.05). The significant decrease in GLUT4 in peripheral tissues (~40%, p<0.001) may be the cause of insulin resistance in CRF. Furthermore, increased protein expression of the majority of glucose transporters (SGLT1, SGLT2, GLUT1, p<0.05) within the kidney in CRF causes greater glucose reabsorption in which consequential hyperglycemia promotes a decrease in GLUT4 thus exacerbating insulin resistance. Elevated protein levels of GLUT1 and GLUT2 in the liver reflects an impaired glucose homeostasis in CRF. The results show that the modulation of the expression of glucose transporters may be responsible for insulin resistance in CRF. The impact of parathyroidectomy (PTX) on the expression of GLUT4 was studied since PTX is known to correct glucose intolerance in CRF. Our results show an improvement in glucose intolerance which may be due to less reduction of GLUT4 protein expression in peripheral tissues despite the presence of CRF. The excess of PTH, linked to secondary hyperparathyroidism, could be held responsible to the presence of insulin resistance in CRF by affectant GLUT4 expression. CRF shares many similarities with prediabetes in regards to impaired glucose metabolism such as hyperinsulinemia and glucose intolerance. No studies have attempted to assess whether CRF could lead to diabetes. Our results demonstrated that the induction of CRF in a predisposed animal model (Zucker rats) provoked greater glucose intolerance as evidenced by the highest blood glucose levels reached in the GTT. In addition, some of them had fasting blood glucose levels whose values exceeded 25 mmol/L. It is therefore possible that CRF can lead to diabetes through the evolution of insulin resistance by the worsening of glucose intolerance.

Whole yellow pea flour (WPF) and fractionated yellow pea flour (FPF) are novel functional food ingredients that vary in nutritional composition. Consequently, the health benefits of WPF and FPF remain undefined. The purpose of this research was to identify the effects of WPF and FPF on risk factors and morbidities associated with cardiovascular disease, diabetes and obesity as well as the gastrointestinal microbiome. Using USDA recommended dosages of WPF and FPF, clinical endpoints and the colonic microbiome were investigated using a human clinical trial engaging a cross-over design and a diet and energy controlled paradigm. Humans were also utilized to investigate post-prandial glycemic responses and sensory characteristics of novel functional foods formulated with WPF. Finally, Golden Syrian hamsters were used to assess the impact of high doses of WPF and FPF on clinical endpoints and caecal microbial abundance. Results reveal that USDA recommended dosages of WPF and FPF in humans decreased (p<0.05) fasting insulin and estimates of insulin resistance compared to white wheat flour (WF). Android-to-gynoid fat ratios in women were lower (p=0.027) in the WPF group compared to the WF group. FPF decreased (p<0.05) post-prandial energy expenditure alongside a tendency (p<0.075) to reduce carbohydrate oxidation. Novel biscotti and banana bread formulated with WPF induced low post-prandial glycemic responses which were similar to boiled whole yellow peas and significantly lower (p<0.05) than white bread. Sensory analysis of novel WPF biscotti and banana bread demonstrated that WPF-based food products are palatable and acceptable for human consumption. Hamsters consuming diets containing 10% WPF and FPF induced similar reductions (p<0.05) in fasting insulin levels compared to controls. However, animals consuming WPF increased (p<0.05) oxygen consumption while FPF decreased (p<0.05) fasting glucose levels. In addition, terminal restriction fragment length polymorphism analysis revealed that WPF and FPF induced distinct shifts in caecal microbial populations within the phyla Firmicutes. Finally, pyrosequencing analysis of human fecal microbiota demonstrated that FPF and WPF induced shifts in bacterial genera, primarily within Bacteroidetes and Firmicutes. In conclusion, whole and fractionated yellow pea flours are functional food ingredients and can be utilized to manage risk factors for lifestyle-related diseases in humans.

Objective: To explore the association of insulin resistance (IR) with direct measures of physical activity (PA). Research methods and procedures: A school-based, cross-sectional study was conducted in two remote British Columbia coastal First Nations villages. 74 healthy boys and girls (mean = 11.8yrs ± 2.2; range = 8.8-18.5yrs) volunteered to participate. PA was measured with the ActiGraph accelerometer. IR was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Body mass index standardized for age and sex (zBMI) and waist circumference were used to assess total and central adiposity. Results: From the 39 participants with complete data sets, moderate to vigorous intensity physical activity (MVPA) was inversely related to HOMA-IR (r = -.45, p<0.01) while total and central adiposity were directly related (r= .44, p<.01 and r=.35, p<.05, respectively). Discussion: These data provide evidence of the important role of PA, particularly MVPA, in improving IR and potentially preventing type 2 diabetes in First Nations youth.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.