Insulin resistacne and hyperinsulinemia are important risk factors for development of type 2 diabetes mellitus and hypertension. Recently, accumulating evidence has shown that endothelial dysfunction, increases in peripheral vessel resistnce and overactivation of the sympathetic neruvous system contribute to the development of insulin resistance-associated hypertension. The signigicance of cardiovascular regulatory center in the brain stem in pathophysiology of the insulin resistance-induced hypertension, however, has not been explored. Previously studies have proved that increases in superoxide anion (O2£»−) production in peripheral tissue and suppression of nitric oxide (NO) expression in the endothial cell are involved in insulin resistance and hypertension. The nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) are involved in neural regulation of blood pressure by serving respectively as the primary baroreceptor afferent terminal sites and the location of sympathetic premotor neurons for cardiovascular regulation in the brain stem. Clinically, the peroxisome proliferator-activated receptor (PPAR) agonist is commonly prescribed for the treatment of type 2 diabetes mellitus by activate PPAR£^ to enhance peripheral tissue insulin sensitizing ability, to maintain blood glucose homeostasis. Intriguingly, both animal and human studies revealed that PPAR£^ agonist also possesses blood pressure lowering effect, although the underlying mechanism is not clear. We therefore investigated in the present study the role of NO and O2£»− in the NTS and RVLM in the pathophysiology of the high fructose diet-induced insulin resistacne and hypertension, and to evaluate the potential central antihypertensive effect of PPAR£^ agonist in rats subjected to high fructose diet. The normotensive male Wistar Kyoto rats (WKY) were divided into 4 groups, including 3 experimental group that received 60% high fructose diet for 8 weeks and one control group that received regular chow diet for the same period of time. Within the 3 experimental groups, two of them received oral administration of rosiglitazone or pioglitazone (10 mg/kg/day) at the last two weeks (from week 6 to week 8) and the third group received saline ingestion. Systemic blood pressure was measured by tail vein sphygmomanometer very week and venous blood was drawn every other week to measure blood sugar and insulin level. At the end of the experiment, oral glucose tolerance test (OGTT) was tested and O2£»− and NO production in the NTS and RVLM were quantified. In adult male WKY rats I found that high fructose diet induced insulin resistance, hypertriglycemia and hypertension. Oral administration of rosiglitazone or pioglitazone significantly blunted the hypertension, hypertriglyceridemia, and ameliorated insulin resistance induced by high fructose diet. The high fructose diet also increased tissue level of O2£»− in the NTS and RVLM. PPAR£^ agonist treatment for two weeks did not affect the induced oxidative stress in these two nuclei. NO production was also increased in the NTS and RVLM after high fructose diet for 6 weeks. Oral treatment of rosiglitazone or pioglitazone significantly attenuated NO production after high fructose diet. At the molecular level, protein expressions of the NADPH oxdase subunits (p40phox, p47phox and gp91phox) and superoxide dismutase (cupper/zinc SOD, mitochondrial SOD, extracellular SOD) were not altered in the NTS or RVLM after high fructose diet alone or in addition with rosiglitazone or pioglitazone treatment. In the RVLM, there was a significant increase in neuronal NO synthase (nNOS) expression with concomitant decrease in inducible NOS (iNOS) expression. Oral treatment of PPAR£^ agonist for two weeks significantly suppressed the induced nNOS upregulation and attenuated the induced downregulation of iNOS expression in the RVLM. Together these results suggest that overproduction of O2£»− and NO in the NTS and RVLM may related to the development of insulin resistance-associated hypertension. Oral treatment of PPAR£^ agonist, including rosiglitazone and pioglitazone, may provide antihypertensive protection by superssing the induced-nNOS expression and increasing the induced-iNOS expression in the RVLM.

Thesis (Ph.D.)--East Carolina University, 2008. / Presented to the faculty of the Department of Exercise and Sport Science. Advisor: G. Lynis Dohm. Title from PDF t.p. (viewed Apr. 23, 2010). Includes bibliographical references.

The literature comparing macronutrient metabolism in healthy and diabetic subjects is abundant; however, little data exists on how non-diabetic subjects with insulin resistance handle macronutrient. We did two studies to investigate the postprandial responses to macronutrient in healthy, hyperinsulinemic and type 2 diabetic (T2DM) subjects. In the first study, twenty-five healthy, non-diabetic subjects [9 with fasting serum insulin (FSI) <40pmol/L; 8 with 40 ≤ FSI < 70pmol/L; and 8 with FSI ≥ 70 pmol/L] were fed eleven test meals (50g oral glucose with 0-30g doses of canola oil or whey protein) after an overnight fast. There were no significant FSI × fat (p=0.19) or FSI × protein (p=0.08) interaction effects on glucose response, suggesting that the effects of fat or protein on glycemia were independent of FSI of the subjects. In addition, the changes in relative glucose response per gram of fat (r = -0.05, p = 0.82) or protein (r = 0.08, p = 0.70) were not related to FSI of the subjects. In the second study, Healthy (FSI < 40pmol/L), Hyperinsulinemic (FSI ≥ 40pmol/L), and T2DM were fed five foods with 50g available carbohydrate. Among the subject-groups, the Glycemic Index (GI) values were not significantly different for each food, and the mean (±SEM) GI values of all foods were not significantly different (p>0.05). However, the mean (±SEM) Insulinemic Index of the foods was higher in T2DM (100±7, n=10) than those of Healthy (78±5, n=9) and Hyperinsulinemic subjects (70±5, n=12) (p=0.05). The Insulinemic Index was inversely associated with insulin sensitivity (r=-0.66, p<0.0001), positively related to fasting- and postprandial-glucose (both r=0.68, p<0.0001) and hepatic insulin extraction (r=0.62, p=0.0002). The oral-glucose data were pooled from the two studies to investigate whether there was any relationship between GLP-1 and insulin sensitivity, β-cell function and hepatic insulin extraction. No significant correlation was observed (p>0.05). The results suggest that the glucose-lowering effect of fat and protein is not affected by insulin sensitivity. GI is independent of the metabolic status of the subjects; however, unlike GI, Insulinemic Index is influenced by the metabolic status of the subjects, and thus may have limited clinical utility.

The purpose of this study was to determine if, after adjusting for the contribution of exercise dose, exercise intensity was associated with the improvement of insulin sensitivity. Abdominally obese, sedentary men (n = 16, [mean±SD] age: 45.0±7.5 yr; waist circumference: 108.6±5.3 cm) and women (n = 18, [mean±SD] age: 42.3±6.2 yr; waist circumference: 100.1±8.2 cm) performed daily, supervised exercise for 3 and 4 months, respectively. Exercising at a self selected exercise intensity, men were required to expend expended 700 kcal per session and women 500 kcal per session. Exercise intensity and dose were determined using heart rate and oxygen consumption data obtained from repeated graded exercise tests. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. Insulin sensitivity improved in both men and women (change score: men = 7.2±5.4 mg/kgskm/min, women = 5.8±7.1 mg/kgskm/min) (p < 0.05). Exercise intensity was associated with the improvements in insulin sensitivity in men (unstandardized regression coefficient (β) = 0.43, p = 0.02). Adjusting for exercise dose, the change in abdominal adipose tissue (AT), or the change visceral AT did not alter this association (p < 0.05). Exercise intensity was not associated with the improvement of insulin sensitivity in women (β = - 0.11, p = 0.7). Adjusting for exercise dose, the change in abdominal or visceral AT did not change the association in women (p > 0.05). Our findings suggest that exercise intensity is independently associated with the improvement of insulin sensitivity in abdominally obese men but not women. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2011-06-13 19:56:40.465

The literature comparing macronutrient metabolism in healthy and diabetic subjects is abundant; however, little data exists on how non-diabetic subjects with insulin resistance handle macronutrient. We did two studies to investigate the postprandial responses to macronutrient in healthy, hyperinsulinemic and type 2 diabetic (T2DM) subjects. In the first study, twenty-five healthy, non-diabetic subjects [9 with fasting serum insulin (FSI) <40pmol/L; 8 with 40 ≤ FSI < 70pmol/L; and 8 with FSI ≥ 70 pmol/L] were fed eleven test meals (50g oral glucose with 0-30g doses of canola oil or whey protein) after an overnight fast. There were no significant FSI × fat (p=0.19) or FSI × protein (p=0.08) interaction effects on glucose response, suggesting that the effects of fat or protein on glycemia were independent of FSI of the subjects. In addition, the changes in relative glucose response per gram of fat (r = -0.05, p = 0.82) or protein (r = 0.08, p = 0.70) were not related to FSI of the subjects. In the second study, Healthy (FSI < 40pmol/L), Hyperinsulinemic (FSI ≥ 40pmol/L), and T2DM were fed five foods with 50g available carbohydrate. Among the subject-groups, the Glycemic Index (GI) values were not significantly different for each food, and the mean (±SEM) GI values of all foods were not significantly different (p>0.05). However, the mean (±SEM) Insulinemic Index of the foods was higher in T2DM (100±7, n=10) than those of Healthy (78±5, n=9) and Hyperinsulinemic subjects (70±5, n=12) (p=0.05). The Insulinemic Index was inversely associated with insulin sensitivity (r=-0.66, p<0.0001), positively related to fasting- and postprandial-glucose (both r=0.68, p<0.0001) and hepatic insulin extraction (r=0.62, p=0.0002). The oral-glucose data were pooled from the two studies to investigate whether there was any relationship between GLP-1 and insulin sensitivity, β-cell function and hepatic insulin extraction. No significant correlation was observed (p>0.05). The results suggest that the glucose-lowering effect of fat and protein is not affected by insulin sensitivity. GI is independent of the metabolic status of the subjects; however, unlike GI, Insulinemic Index is influenced by the metabolic status of the subjects, and thus may have limited clinical utility.

Obesity is a condition in which fat accumulation in adipose tissue is in excess to an extent that health may be impaired. Insulin resistance is integral to the pathophysiology of obesity-related metabolic complications. Central adiposity and skeletal muscle mass and function determine insulin sensitivity and metabolic risk. A high visceral fat-to-skeletal muscle mass-ratio contributes to an unfavourable metabolic profile. Epidemiological and experimental studies suggest that high dietary saturated fat intake is deleterious while polyunsaturated fatty acids (PUFAs), in particular n-3 PUFAs of marine origin, may be advantageous to metabolic health. The aim was to determine the effect of subcutaneous (SC) and visceral (IAB) fat, and long-chain saturated, n-3 and n-6 PUFAs, and the interactions between them, on insulin sensitivity and the pathways regulating energy metabolism in skeletal muscle. Thereby an adipose tissue-conditioned media-skeletal muscle myotube co-culture system was developed. Adipose tissue-conditioned medium (CM) was generated from SC and IAB fat biopsy of obese humans. Viability of the tissue explants was confirmed by the measurement of lactate dehydrogenase activity in the CM and nuclear DNA fragmentation of tissue explants. The concentrations of cytokines (leptin, adiponectin, interleukin (IL)-1β, IL 6, IL-8, tumor necrosis factor-α, resistin and plasminogen activator inhibitor-1) and long-chain fatty acids were determined in CM. CM from IAB but not SC fat reduced insulin-stimulated glucose uptake. The effect of IAB fat was predominantly mediated by IL-6 via the activation of a nuclear factor kappa B/mammalian target of rapamycin complex 1 (NFκB/mTORC1)-dependent pathway. Palmitic acid (PA; 16:0) reduced insulin-stimulated glucose uptake, an effect mediated by intramuscular accumulation of ceramide and the activation of NFκB and mTORC1. The effects of fatty acids were similar in the presence of CM from either fat depot, where the effect of PA was partially reversed by docosahexaenoic acid (DHA; 22:6n-3) and completely by linoleic acid (LA; 18:2n-6). The effect of each fatty acid in the presence or absence of CM from each fat depot on mRNA expression of key genes regulating muscle energy metabolism was determined. Protein phosphorylation of adenosine monophosphate-activated protein kinase (AMPK)-α and acetyl-coenzyme A carboxylase (ACC)-β were also determined. PA increased SCD1 mRNA. DHA and LA increased AMPKα2 mRNA and AMPKα and ACCβ protein phosphorylation. Microarray analysis was used to determine the global gene expression changes in PAand DHA-treated L6 myotubes. DHA down-regulated lipogenic genes and upregulated genes which were involved in β-oxidation and mitochondrial function. When compared to PA, DHA down-regulated genes which were involved in lipid synthesis, endoplasmic reticulum metabolism and mitogen-activated protein kinase activity. Taken together, pro-inflammatory cytokines from IAB fat and PA induced insulin resistance in skeletal muscle and both were at least partly mediated by a NFκB/mTORC1-dependent pathway. In contrast, DHA and LA may improve insulin sensitivity by diverting fatty acids towards oxidation and subsequently reducing substrate availability for the formation of lipid metabolites including ceramide. A reduction in PA intake and substitution (rather than addition) of DHA and LA, together with a reduction in overall energy intake and increase in physical activity, is optimal for metabolic health. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1523054 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Jeanne H Freeland-Graves. Vita. Includes bibliographical references. Available also from UMI Company.

Ageing and obesogenic diets are two prominent problems in the developed world, as both lead to an increase in body mass and insulin resistance, which can then result in further pathophysiologies, such as type 2 diabetes, cancer and cardiovascular disease. Protein tyrosine phosphatase 1B (PTP1B) contributes to development of body weight gain and insulin resistance through negatively regulating leptin and insulin signalling, respectively. Liver-specific ptp1b deletion from birth improves insulin sensitivity, lipid metabolism and decreases endoplasmic reticulum (ER) stress. However, as a therapy in humans, PTP1B inhibition would target pre-diabetic and diabetic adults; therefore, we investigated the effects of liver-specific inhibition of PTP1B in adult, insulin resistant, obese mice. Restricting the amount of the essential amino acid, methionine, five-fold in the diet, decreases body weight, adiposity and improves insulin sensitivity in young mice. In order to delineate if this would be a feasible treatment in adulthood, we administered the diet to 12-month-old mice with age-induced obesity and insulin resistance and compared its effects to those in 2-month-old mice. As hepatic ptp1b deletion and methionine restriction (MR) both improve hepatic insulin signalling, we investigated if the combined treatment could have additive effects compared to MR alone on whole-body glucose homeostasis. To examine if the effects of MR are methionine-specific or if they would occur with restriction of other EAAs, we compared leucine restriction (LR) to MR in adult mice. Overall, hepatic PTP1B inhibition in adult mice reversed high-fat diet (HFD) -induced glucose intolerance, hepatic lipid accumulation and ER stress. MR administered to 12-month-old adult mice reversed the metabolic effects of ageing back to levels measured in healthy, young, 2-month-old mice. The combination of MR and hepatic ptp1b deletion from birth had no further beneficial effect in male mice, but possibly an additional effect in female mice. MR produced stronger beneficial metabolic effects than LR in mice, suggesting methionine-specific mechanisms may play a role.

Type 2 diabetes mellitus results from a combination of insulin resistance and impaired insulin secretion. The aim of this study is to investigate the effect of endogenous and exogenous cannabinoids on insulin resistant cell lines, viz skeletal muscle (C2C12) and fat (3T3-L1), and to investigate the effects of these cannabinoids on insulin secretion in pancreatic β-cells (INS 1). Insulin resistance was induced in the cells using 20 ng/mL TNF-α (3T3-L1) and 100 nM insulin (C2C12). Insulin resistant cells were exposed to cannabinoids for 48 hours after which glucose uptake, RT-PCR and Western blot analysis was performed. Additionally, adipokine assays were performed on the 3T3-L1 cells. The insulin resistant 3T3-L1 and C2C12 cells had reduced glucose uptake, decreased IRS-1 and Glut-4 expression indicative of an insulin resistant state. The extract and THC significantly enhanced glucose uptake, IRS-1 and Glut-4 in 3T3-L1 and C2C12 cells. The extract and THC thus have the potential to be an insulin sensitizing agent. Interleukin-6 was significantly decreased by THC. INS 1 cells, cultured under normoglycemic conditions, were exposed to cannabinoids for 48 hours after which glucose-stimulated insulin secretion, radioimmunoassay, oxygen consumption, RT-PCR and Western blot analysis was performed. Insulin stimulatory index was not significantly affected after cannabinoid exposure, except by THC. The cannabinoids decreased insulin content, in a concentration dependent manner, but the inhibition mechanism remains elusive. The cannabinoid Treated cells showed insulin gene expression levels similar to the control, while only THC proved effective in significantly stimulating Glut-2 gene expression. Oxygen consumption studies showed levels lower than the control cells. Most of the cannabinoids inhibited insulin secretion under normoglycemia except THC, while the cannabinoids exhibited the potential to improve insulin resistant adipocyte and myocytes response to glucose and gene regulation.