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Type 2 diabetes (T2D) is a major public health issue worldwide and it currently affects nearly 26 million people in the United States. It is estimated that one third of Americans will have diabetes by 2050. T2D is a result of chronic insulin resistance and loss of beta-cell mass and function. Both in experimental animals and people, obesity is a leading pathogenic factor for developing insulin resistance, which is always associated with the impairment in energy metabolism, causing increased intracellular fat content in skeletal muscle, liver, fat, as well as pancreatic islets. Constant insulin resistance will progress to T2D when beta-cells are unable to secret adequate amount of insulin to compensate for decreased insulin sensitivity. In the present study, I investigated whether sulforaphane, a natural compound derived from cruciferous vegetables, can prevent high-fat (HF) diet-induced obesity and diabetes in C57BL/6 mice. Dietary intake of sulforaphane (250 mg/kg diet) prevented hyperglycemia and increased insulin sensitivity in HF diet-induced obese mice. Mice treated with sulforaphane had significant lower serum insulin levels (1.93±0.11 μg/dl) as compared to those without treatment (3.09±0.27 μg/dl, P<0.05). In second study, administration of sulforaphane (40 mg/kg body weight daily via gavage) in obese mice enhanced body weight loss and improved insulin sensitivity. Moreover, sulforaphane increased pyruvate oxidation by 28.85% (P<0.05) and enhanced fatty acid oxidation efficiency by 2.2 fold (P<0.05) in primary human muscle cells. These results suggest that sulforaphane may be a naturally occurring insulin-sensitizing agent that is capable of preventing T2D. / Master of Science

Insulin resistance is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Intrahepatic triglyceride (IHTG), the primary feature of NAFLD, strongly predicts insulin resistance in the liver and peripheral (skeletal muscle and adipose) tissues. Hepatokines (e.g. fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), follistatin, selenoprotein P, and fetuin-A) are liver-derived proteins with capacity to exert endocrine effects and may potentially modulate the link between IHTG and peripheral insulin sensitivity/glycaemic control. Exercise is integral to the management of NAFLD and T2DM, with evidence suggesting that high-intensity exercise may provide the greatest benefits. Chapter 4 of this thesis demonstrates that, in individuals without chronic metabolic disease, plasma concentrations of FGF21 and LECT2 are higher, and follistatin lower, in individuals with overweight or obesity compared with normal weight individuals. Furthermore, FGF21 and follistatin are transiently elevated for up to 6 h after acute aerobic exercise (60 min at 60% V̇O2 peak). The response of follistatin to acute moderate-intensity exercise is also present in individuals with impaired glucose regulation (Chapter 5), but the response of FGF21 is abolished. A single bout of low-volume high-intensity interval training has no effect on FGF21, follistatin or fetuin-A in individuals with dysglycaemia (Chapter 5). Chapter 6 demonstrates that six weeks of sprint interval training (SIT) is feasible for men with NAFLD and reduces IHTG despite no change in body weight. Peripheral insulin sensitivity tends to increase after SIT but hepatic insulin sensitivity and circulating hepatokines remain unchanged. Through meta-analyses, Chapter 7 confirms that exercise training reduces IHTG, even in the absence of weight loss. However, the magnitude of this effect is greater when weight loss occurs and benefits increase proportionally. Exercise training improves basal hepatic insulin sensitivity, but evidence in this area is currently limited (Chapter 7). Collectively, the studies in this thesis demonstrate that some hepatokines may be sensitive to acute and chronic changes in energy metabolism. However, further evidence is required before definitive statements can be made. Exercise training, including SIT, has the potential to reduce IHTG in men with NAFLD, even in the absence of weight loss. However, the greatest benefits on IHTG will likely be elicited when exercise training is performed in combination with dietary energy restriction to elicit sustained reduction in body weight.

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京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第19629号 / 医科博第67号 / 新制||医科||5(附属図書館) / 32665 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 椛島 健治, 教授 岩井 一宏, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Resveratrol (RSV) is a natural compound that improves mitochondrial function and metabolic health in animal models. Thus far, RSV’s effects on metabolic outcomes in humans are controversial, and RSV’s acute mechanism has not yet been confirmed in vivo. This study aimed to evaluate the effect of an acute dose of RSV on insulin sensitivity and fatty acid oxidation, and to determine RSV’s mechanism of action in human skeletal muscle and adipose tissue. Overweight males (n=8; BMI, 30.5±3.6; VO2peak, 34.0±7.3 ml/kg) reported to the lab on 2 occasions and were provided a breakfast supplemented with 0.3g of RSV or a placebo pill. Experiments were performed in random order using a double blind crossover design. Gas exchange measures, blood samples, and skeletal muscle and adipose tissue biopsies were obtained before and 2 hours after the supplement meal. RSV acutely improved insulin sensitivity, but had no effect on fatty acid oxidation. Additionally, RSV supplementation had no effect on the intracellular signaling of key proteins proposed to mediate its effects in skeletal muscle and adipose tissue. Taken together, these results suggest a single dose of RSV can acutely enhance insulin sensitivity, but its mechanism of action is not conserved across species, and its intracellular signaling pathway is different in humans than previously thought. Due to its insulin sensitizing effect, RSV retains its clinical value, but further research is required to determine its most useful application for human metabolic health. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2013-06-06 13:30:03.522

Aging is associated with increased insulin resistance, a condition in which the tissue response to insulin-stimulated glucose uptake is reduced. Insulin resistance is a strong predictor of disease and mortality. Aging is also associated with a decline in physical activity, lower cardiorespiratory fitness (ability to deliver oxygen to active muscles during exercise), and increase in abdominal fat. Both low cardiorespiratory fitness (CRF) and excess abdominal fat are associated with reduced insulin sensitivity in older adults. Improvements in CRF and abdominal obesity through exercise training may be responsible for improvement in insulin sensitivity. Several investigations have reported that changes in CRF and abdominal obesity through exercise are associated with changes in insulin sensitivity. To our knowledge, no prior study has assessed whether change in CRF or abdominal fat alone explains the association between exercise and improvement in insulin sensitivity in older adults. Our findings suggest that improvement in CRF may not explain the exercise-induced change in insulin sensitivity. The improvement in insulin sensitivity from exercise is explained through a decrease abdominal fat that also occurs with exercise. Additionally, improvements in waist circumference, a surrogate measure for abdominal obesity, and body mass index together explained a large portion of exercise-induced change in insulin sensitivity compared to either variable alone. Our findings suggest that exercise combined with a healthy diet will improve insulin resistance, a risk factor for development of type 2 diabetes and cardiovascular disease in older adults. Our findings suggest that the reduction in abdominal obesity is the conduit by which exercise improves insulin sensitivity in older adults. Although CRF is not related to exercise-induced change in insulin sensitivity, change in CRF from exercise has been reported to decrease risk for other health conditions, such as hypertension and all-cause mortality. Our findings suggest that clinicians should measure both waist circumference and body mass index when evaluating the effectiveness of a lifestyle-based treatment strategy for improving insulin resistance and its associated health outcomes in older adults. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2013-09-27 14:53:00.796

5α-reductases (5αRs) catalyse reduction of 4-pregnene steroids, most notably the androgen testosterone to its more potent metabolite dihydrotestosterone (DHT). Well-characterised isozymes of 5αR are designated 5αR1 and 5αR2. Inhibitors of 5αR, finasteride (a 5αR2 inhibitor) and dutasteride (a dual 5αR1 and 5αR2 inhibitor), are utilised in conditions where a reduction in androgen action is desired, including benign prostatic hyperplasia. Although 5αR2 is predominantly expressed in reproductive tissues, both isozymes, but particularly 5αR1, are expressed in metabolic tissues including liver and adipose and both metabolise glucocorticoids as well as androgens; therefore inhibition of 5αR may have consequences for metabolic health. This thesis addresses the hypotheses that 5αR1 inhibition with dutasteride decreases insulin sensitivity and causes dysregulation of the HPA axis in humans. Metabolism and the HPA axis were studied in men prior to and following 3 months of dutasteride (0.5 mg daily; n=16), finasteride (5 mg daily; n=16) or control (tamsulosin MR; 0.4 mg daily; n=14). Glucose disposal during hyperinsulinaemia was the primary endpoint, measured during a hyperinsulinaemic euglycaemic clamp, with d2-glucose and d5-glycerol tracers. Peripheral insulin sensitivity for both glucose uptake and NEFA suppression decreased with dutasteride versus both finasteride and control, while hepatic insulin sensitivity was preserved. Body fat increased with dutasteride, though was not accompanied by changes in metabolic or inflammatory gene transcript abundance in subcutaneous adipose biopsies, nor any differences in abdominal adipose depots on post-treatment MRI. Subtle dysregulation of the HPA axis was evident with both 5αR inhibitors, though to a greater degree with dutasteride and changes were largely compensated for. In support of this study, this thesis also describes the development, validation and application of two novel liquid chromatography tandem mass spectrometry assays; establishing compliance by measuring serum drug levels, and demonstrating effects of 5αR inhibitors on androgen metabolism and adrenal steroidogenesis by measurement of testosterone, DHT and androstenedione. In conclusion, 5αR1 inhibition with dutasteride, but not finasteride, induces peripheral insulin resistance and increases body fat. Findings presented may have important implications for patients prescribed dutasteride for benign prostatic hyperplasia.